Glossary of terms

• A-1 was a US Army aircraft used in Vietnam for CAS is:
  • Close Air Support by the Air Force of ground troops.  CAS aircraft: US A-1, A-10 , Cheyenne helicopter, Stuka; target tanks, bridges etc. to limit the operations of the enemy ground forces and enable movement by friendly forces. 
    
  • Complex Adaptive System is an emergent, complex system which leverages evolution to iteratively plan and execute activites by agents. 
    
  . 
  
• A-10 Warthog CAS is:
  • Close Air Support by the Air Force of ground troops.  CAS aircraft: US A-1, A-10 , Cheyenne helicopter, Stuka; target tanks, bridges etc. to limit the operations of the enemy ground forces and enable movement by friendly forces. 
    
  • Complex Adaptive System is an emergent, complex system which leverages evolution to iteratively plan and execute activites by agents. 
    
  aircraft.  It was promoted and developed by Pierre Sprey was a McNamara Whiz Kid, who, according to Robert Coram, entered Yale at fifteen graduating with a double major in French literature and mechanical engineering, then studied statistics and operational research at Cornell before running the statistical consulting shop at Grumman Aviation, before working for McNamara under Alain Enthoven.  Sprey became an expert on the history of warfare and tactical aviation.  He developed a report on interdiction bombing which asserted it would not deter Soviet forces from invading Western Europe and that the US Air Force should focus on CAS and providing tactical air cover.  He was asked to manage the program to develop the A-10, where he leveraged John Boyd's E-M theory and data.  Sprey was a vocal critic of the Pentagon's expensive, complex procurement process, and especially the computer model based vulnerability testing of tanks and armored vehicles, since the models weren't validated by field testing.  He helped Jim Burton to develop a live-fire test program to provide the validation. 
  who ensured it matched the requirements of Vietnam war US is the United States of America.   CAS pilots and reflected the observations of top German Stuka pilot Hans Rudel. 
  
• A1C test is a blood test that assesses a person's average level of blood glucose over a 3 month period.  Because glucose attaches to hemoglobin the 3 month lifetime of red blood cells can be used as a buffer of blood glucose. 
  
• ABA is the:
  
• American Bankers Association.  
• American Board of Anesthesiology. 
• Abacavir is a nucleoside reverse transcriptase inhibitor, an ARV is antiretroviral treatments for H.I.V. infection, such as abacavir. 
  medication, branded as Ziagen, which is used in the prevention and constraint of AIDS is acquired auto-immune deficiency syndrome, a pandemic disease caused by the HIV.  It also amplifies the threat of tuberculosis.   Initially deadly, infecting and destroying the T-lymphocytes of the immune system, it can now be treated with HAART to become a chronic disease.  And with an understanding of HIV's mode of entry into the T-cells, through its binding to CCR5 and CD4 encoded transmembrane proteins, AIDS may be susceptible to treatment with recombinant DNA to alter the CCR5 binding site, or with drugs that bind to the CCR5 cell surface protein preventing binding by the virus.  Future optimization of drug delivery may leverage nanoscale research (May 2016). 
  .  It is a WHO is World Health Organization a United Nations organization.   essential medicine.  Its use is problematic in about 6% of the patient base.  Pharmacogenomics studies how genes affect a person's response to drugs so as to develop personalized drug treatment plans, tailored to a person's specific phenotype.  The process optimizes the treatment process but there are barriers to its deployment:
  • Large scale clinical trials may test 20,000 individuals, but if a toxic response impacts only 0.1% of them there would only be 20 cases found which is often too few to identify the cause of the response.  Instead a process for capturing adverse drug reactions after approval and marketing must be used along with the ability to take a blood sample in these cases.  
  • Simplified studies on a subset of individuals that have the target allele should be cheaper but are unattractive to pharmaceutical companies which typically want to maximize their target market (Aug 2016).  
  • F.D.A. has not required genomic testing for most drug developments.  
  • Health care providers are being slow to use pharmacogenomics.  Often third-party payers are unwilling to reimburse the tests. 
    
  • Transportation to centralized laboratories for genomic testing causes delays which makes some drug therapy applications impractical.  An alternative solution would be to have a patient's EHR contain their genome sequence for immediate genomic implications.  
  allows these patients to be identified and treated with an alternative ARV. 
  
• Abhidhamma is a guided theory of meditation includes a variety of practices with the contemplative goal of altering traits to free the subject of suffering.  Goleman & Davidson see three distinct levels of practice: beginner, long term meditator, Yogi; with radically different levels of commitment.  Beginners typically do a limited-time-investment mindfulness meditation such as MBSR.  Long term meditators typically practice vipassana meditation.  Yogis practice Tibetan meditations Dzogchen and Mahamudra, which start like vipassana but in a non-dual stance developing a more subtle meta-awareness.  Richard Davidson, Cortland Dahl and Antoine Lutz developed a typology of the practices:
  • Attentional - train aspects of attention. 
    
  • Constructive - cultivate virtuous qualities: loving-kindness;
    
  • Destructive - use self-observation to pierce the nature of experience.  These include non-dual approaches where ordinary cognition no longer dominates. 
    
  practice is a fifth-century text, which is still the definitive guidebook for Burmese and Thai Theravada meditators explain Goleman and Davidson.  It provides the fundamental template for insight meditation, popularly called mindfulness.  It details the progression of meditative states to nirvana.  It tells of the need to develop a keenly concentrated mind and sharply mindful awareness.  The practices for both aspects are described:
  • Concentration - starts with focus on breath, or any other point of focus, attention on our natural state reveals the monkey mind, As concentration strengthens wandering thoughts subside, and an observable river of thoughts slows to a still lake.  Sustained focus brings access concentration where attention stays focused on the target - which may be accompanied by feelings of delight and calm.  Jhana first occurs when all distracting thoughts cease and the mind fills with rapture.  There are seven more levels of jhana.  
  • Mindful awareness, looking into the mechanics of consciousness, was a goal of Gautama Buddha, where awareness is left open to whatever arises in the mind, notes what arises and lets it go.  A shift to insight meditation occurs where we see the mind as a set of processes.  Each shift yields more insights into consciousness.  At the highest level strong negative feelings like greed and anger fade away, replaced by traits of equanimity, kindness, compassion and joy. 
    
  .  It presents a
  The agents in complex adaptive systems (CAS) must model their environment to respond effectively to it.  Evolution's schematic operators and Samuel modeling together support the indirect recording of past successes and their strategic use by the current agent to learn how to succeed in the proximate environment. 
  
  model of the
  Computational theory of the mind and evolutionary psychology provide Steven Pinker with a framework on which to develop his psychological arguments about the mind and its relationship to the brain.  Humans captured a cognitive niche by natural selection 'building out' specialized aspects of their bodies and brains resulting in a system of mental organs we call the mind. 
  
  He garnishes and defends the framework with findings from psychology regarding: The visual system - an example of natural selections solutions to the sensory challenges of inverse modeling of our environment; Intensions - where he highlights the challenges of hunter-gatherers - making sense of the objects they perceive and predicting what they imply and natural selections powerful solutions; Emotions - which Pinker argues are essential to human prioritizing and decision making; Relationships - natural selection's strategies for coping with the most dangerous competitors, other people.  He helps us understand marriage, friendships and war. 
  
  These conclusions allow him to understand the development and maintenance of higher callings: Art, Music, Literature, Humor, Religion, & Philosophy; and develop a position on the meaning of life. 
  
  Complex adaptive system (CAS) modeling allows RSS to frame Pinker's arguments within humanity's current situation, induced by powerful evolved amplifiers: Globalization, Cliodynamics, The green revolution and resource bottlenecks; melding his powerful predictions of the drivers of human behavior with system wide constraints.  The implications are discussed. 
  
  
  conscious mind, including a map and methods of transformation: altered traits reflect changes to four neural pathways that Goleman & Davidson identify in Altered Traits.  These networks support: stress reactions - induced experimentally with the TSST, compassion and empathy, attention, sense of self; and are altered by different types of meditation.  An altered state refers to changes that occur only during meditation.  All meditation has the contemplative goal of altered traits leading to being free of suffering by revealing our Bhudda nature.  An altered trait indicates that the practice of meditation has tranformed the brain so the induced changes are seen before beginning to meditate.  Goleman & Davidson developed a robust behavioral measure for attention: the ability to maintain focus while counting breaths.  The test requires pressing a keyboard's down arrow on each outbreath except on the nineth when a different key is pressed and counting restarts at one.  The objective metric is the difference between the subjective count and the actual number of breaths taken.  ; of the core being.  It describes a theory where healthy: even-mindedness, composure, ongoing mindfulness, realistic confidence, buoyancy, flexibility, adaptability, pliancy; and unhealthy: desires, self-centeredness, sluggishness, agitation;
  Flows of different kinds are essential to the operation of complex adaptive systems (CAS). 
  Example flows are outlined.  Constraints on flows support the emergence of the systems.  Examples of constraints are discussed. 
  
  flows push against and
  Terrence Deacon explores how constraints on dynamic flows can induce emergent phenomena which can do real work.  He shows how these phenomena are sustained.  The mechanism enables the development of Darwinian competition. 
  
  constrain each other.  A meditator in deep concentration suppresses the unhealthy traits.  Deepening levels of insight practice lead to a radical transformation, ultimately freeing the meditator's mind of the unhealthy mix. 
  
• ABIGAIL is Geisinger's patient experience standards, after founder Abigail Geisinger:
  
• Accountable
• Befriend
• Inform
  
• Genuine
  
• Acknowledge
  
• Involve
  
• Listen
  
• ABL is a gene on human chromosole 22.  In the majority of cases of CML is chronic myelogenous leukemia.  It is a leukemia characterized by the unregulated growth of myeloid cells in the bone marrow.  The growth is encouraged by the cellular signalling system (gene change that generates a faulty tyrosine kinase) being locked on.  Visual methods allowed Dr. Janet Rowley's team to recognize that most CML includes the Philadelphia chromosome.  It encodes the chimeric always on tyrosine kinase protein seen only in CML.  Targeted treatments such as Gleevec block the pathway for the tyrosine kinase. 
  part of ABL is coppied into a merged chromosome with part of BCR is a gene on chromosome 22 which normally codes the breakpoint cluster region protein which is a GTPase-activating protein for RAC1 and CDC42.  In many cases of CML part of the BCR gene gets translated onto an additional Philadelphia chromosome along with part of gene ABL from chromosome 9.   from chromosome 9, in a transformation initially noted by Dr. Janet Rowley and colleagues and called the Philadelphia chromosome is a chromosome fragment generated by a mutation copying bits of chromosome 9 including part of gene BCR and part of gene ABL from chromosome 22.  In the majority of cases of CML Philadelphia chromosome is present and generates an aways on tyrosine kinase signalling protein which causes vast proliferation of white blood cells.  Since the protein is aberrant blocking its production pathway with drugs such as Gleevec stop the excessive white blood cell production. 
  .  
• ABS is an asset-backed security defined as backed by nonconforming loans rather than Fannie Mae is the coloquial name for the FNMA which is:
  • The federal national mortgage association, a GSE.  It was made a publically traded company by the HUD act of 1968 to remove its debt from the federal budget.  
  • In 1970 FNMA was authorized to purchase conventional mortgages.  FHLMC was setup to ensure competition for FNMA in this task. 
    
  • In 1981 FNMA issued its first designated MBS. 
    
  • In 1992 the Democratic Congress and President Bush established HCDA which gave FNMA affordable housing goals set annually by HUD with Congressional approval.  
  • In 1999 the Clinton administration put pressure on FNMA to expand loans to low and moderate income borrowers.  FNMA took on additional subprime risk. 
    
  • In 2000 HUD placed anti-predatory lending rules on the affordable housing goals, but these constraints were dropped in 2004.  In effect they just pushed mortgage originators to Wall Street finance. 
    
  • Once mortgage originators started to use warehouse loans, the GSEs lost visibility and control of origination.  
  • The GSEs purchased AAA mortgages from commercial banks.  Many of these classifications were fraudulent leaving the GSEs with bad debt.  In 2008 to maintain the stability of the global economy the George W. Bush administration seized the GSEs and placed them in conservatorship under the FHFA, ensuring they could not collapse.  
  • In 2010 FNMA's stock was delisted from the NYSE.  They still trade over-the-counter. 
    
  or Freddie Mac quality loans used in original MBS is mortgage backed security, a bond backed by the monthly payments homeowners make on their residences.  It was initially developed by Lew Ranieri at Salomon Brothers. 
  or CMO is a:
  
  • Chief medical officer or a
    
  • Care maintenance organization or in finance a
    
  • Collateralized mortgage obligation.  The collateralized mortgage obligation was invented by Larry Fink (BlackRock) and team while they were at First Boston in 1983.  The key innovation was that the risk in these contracts was more predictable than in an MBS due to the presence of a trust that guaranteed payments to the bond holders.  The risk was separated into tranches with different credit ratings and yields.  The structure was used by the banking and securities companies to finance the subprime housing boom. 
    
  . 
  
• Abulia is an incapacity to generate voluntary actions. 
  
• ACA is the Patient Protection and Affordable Care Act amended by the Health Care and Education Reconciliation is a fast-track Senate procedure defined in title III of the CBIC act.  In response to a stagnant economy and President Nixon's spending controls it was hoped this process would help with acting rapidly on the rising budget deficit and increasing entitlement spending.  The process is constrained by Senate rules that limit its use to provisions that deal with government tax and spending activities, but not policy:
  • Senators can object to a reconciliation bill if they see the rules being broken & ask for the parliamentarian to judge if a provision of a bill fails the rules. 
    
  • If the parliamentarian judges the proposal does fail the rules, the bill must be passed by 60 votes to overcome the objections, rather than a simple majority of the Senate or the provision must be stripped from the bill. 
    
  Act of 2010 (Obama care).  In part it is designed to make the health care system costs grow slower.  It aims to do this by: increasing competition between insurers and providers, offering free preventative services to limit the development of serious illnesses, constraining patients' use of expensive services, constraining the growth of payments to Medicare is a social insurance program that guarantees access to health insurance for Americans aged 65 and over, and younger people with disabilities and end stage renal disease or ALS.  Medicare is currently missing a cap on out-of-pocket costs and direct prescription drug coverage.  It includes:
  
  • Benefits
  • Part A: Hospital inpatient insurance.  As of Dec 2013 Medicare pays for home care in only limited circumstances, such as when a person needs temporary nursing care after a hospitalization.  Part A covers 20 days of inpatient rehabilitation at a SNF after discharge from inpatient care at a hospital. 
    
  • Part B: Medical insurance for non-hospital services including: doctor visits, tests, injectable drugs, ambulances, physical therapy;
    
  • Part C: Medicare Advantage 
  • Part D: indirect prescription drug coverage The MMA prohibits Medicare from directly negotiating drug prices. 
    
  • Eligibility
    
  • All persons 65 years of age or older who are legal residents for at least 5 years.  If they or a spouse have paid Medicare taxes for 10 years the Medicare part A payments are waived.  Medicare is legislated to become the primary health plan. 
    
  • Persons under 65 with disabilities who receive SSDI. 
    
  • Persons with specific medical conditions:
  • Have end stage renal disease or need a kidney transplant. 
    
  • They have ALS. 
    
  • Some beneficiaries are dual eligible. 
    
  • Part A requires the person has been admitted as an inpatient at a hospital.  This is constrained by a rule that they stay for three days after admission.  
    
  • Sign-up
  • Part A has automatic sign-up if the person is drawing social security.  Otherwise the person must sign-up for Part A and Part B. 
    
  • Should sign-up for Part B during the Initial Enrollment Period, of seven months centered around 65th birthday, online or at a social security office.  But if still covered by spouse's insurance or not yet retired then may only join during the 3 month general enrollment period (January to March) each year, with coverage initiated the following July.  Incremental yearly 10% penalties apply for not signing up at 65.  These penalties apply to all subsequent premiums. 
    
  • Premiums
  • Part A premium
  • Part B insurance premium
    
  • Part C & D premiums are set by the commercial insurer.  
  providers and piloting new ways for PCP is a Primary Care Physician.  PCPs are viewed by legislators and regulators as central to the effective management of care.  When coordinated care had worked the PCP is a key participant.  In most successful cases they are central.  In certain Medicare ACO models (Pioneer) PCPs are committed to achieve meaningful use requirements.  Working against this is the: replacement of diagnostic skills by technological solutions, low FFS leverage of the PCP compared to specialists, demotivation of battling prior authorization for expensive treatments. 
  s to manage patient care to keep patients away from costly E.D. is emergency department.  Pain is the main reason (75%) patients go to an E.D.  It has traditionally been part of an acute care hospital but recently is being deployed standalone as a catchment funnel to the owning hospital.  The EMTALA legislation requires E.D. treatment to stabilize every person seeking treatment by most hospitals.  Unreimbursed care is supported from federal government funds.  E. D. profitability has been helped by hospitals contracting with 3rd party companies who are able to improve margins through surprise billing.  The standalone E.D. competes with the positioning and brand power of lower cost urgent care clinics.  Commercial nature of care requires walk-ins to register to gain access to care.  With the focus on treatment of pain, E.D.s are a major distributor of opioids (5% of opioid prescriptions) and a major starting point of addiction in patients but are cutting back (Jun 2016). 
  s.  It funds these changes with increased taxes on the wealthy is schematically useful information and its equivalent, schematically useful energy, to paraphrase Beinhocker.  It is useful because an agent has schematic strategies that can utilize the information or energy to extend or leverage control of the cognitive niche.   .  It follows an architecture developed by Heritage Action's Butler, Moffit, Haislmaier extended by White House OMB is the Office of Management and Budget.  It:
  • Creates and promotes the President's federal budget and hence indirectly his priorities. 
    
  • Has the power to advance or constrain federal regulation as many proposed rules must be signed off by the O.M.B. (OIRA) before they are issued.  The rules it can constrain include those relating to:
  • Energy
  • Environmental standards
  • Labor protections
  • Food safety
  • All administration policies affect the budget directly or indirectly so they are constrained by the O.M.B.  
  health policy advisor Ezekiel Emanuel & architect Jeanne Lambrew.  The Obama administration drafting team included: Bob Kocher; allowing it to integrate ideas from: Dartmouth Institute's Elliot Fischer (ACO is an Accountable Care Organization. These are accredited bundles of companies which together try to offer Dartmouth-Hitchcock like business models (Dec 2015, Sep 2016) focused on wellness, improving the provision of primary care to a large group of Medicare patients, and rewarding doctors for preventing problems.  Advocate health illustrates the idea.  Robert Pearl notes that the transition is difficult: hospitals that find their efficiency improving should reduce the number of doctors they utilize.  But any doctors that are pushed out of the ACO will likely take their patients with them, undermining the revenues that support the FFV business.  The ACA regulates qualification to be a Medicare ACO.  Individual organizations within a Medicare shared savings ACO continue to submit their own claims and are paid by Medicare for FFS.  But the ACO is eligible for shared savings.  Within the shared savings program the CMS innovation center has setup advanced payment ACOs.  As an alternative to shared savings, in a Pioneer ACO, over time 50% of the FFS payments flow directly to the ACO as a bundled payment.  CMS has established quality measures for ACOs for Medicare.  The CMS program's purpose is to reward providers for reducing total cost of care for patients through prevention, disease management, and coordination. 
  
  • CMS initiated its Physician Group Practice Demonstration in 2005.  By 2008 the congressional budget office reported on Bonus-eligible organizations. 
    
  • CMS defines ACOs as organizations that "create incentives for health care providers to work together to treat an individual patient across care settings - including doctors' offices, hospitals and long-term care facilities."
  • CMS has developed APMs which include ACOs, and advanced APMs where the ACOs must be risk bearing. 
    
  • CMMI accepts providers' proposals to test various payment systems including shared savings and partial capitation.  
  • Private market ACOs have formed including: Providence Health & Services, Blue Shield California, Anthem Blue Cross, United Health Care, BCBS Minnesota, BCBS Illinois, Humana, CIGNA, Main Health Management Coalition, BCBS Massachusetts, Aetna.  
  ).  The ACA did not include a Medicare is a social insurance program that guarantees access to health insurance for Americans aged 65 and over, and younger people with disabilities and end stage renal disease or ALS.  Medicare is currently missing a cap on out-of-pocket costs and direct prescription drug coverage.  It includes:
  
  • Benefits
  • Part A: Hospital inpatient insurance.  As of Dec 2013 Medicare pays for home care in only limited circumstances, such as when a person needs temporary nursing care after a hospitalization.  Part A covers 20 days of inpatient rehabilitation at a SNF after discharge from inpatient care at a hospital. 
    
  • Part B: Medical insurance for non-hospital services including: doctor visits, tests, injectable drugs, ambulances, physical therapy;
    
  • Part C: Medicare Advantage 
  • Part D: indirect prescription drug coverage The MMA prohibits Medicare from directly negotiating drug prices. 
    
  • Eligibility
    
  • All persons 65 years of age or older who are legal residents for at least 5 years.  If they or a spouse have paid Medicare taxes for 10 years the Medicare part A payments are waived.  Medicare is legislated to become the primary health plan. 
    
  • Persons under 65 with disabilities who receive SSDI. 
    
  • Persons with specific medical conditions:
  • Have end stage renal disease or need a kidney transplant. 
    
  • They have ALS. 
    
  • Some beneficiaries are dual eligible. 
    
  • Part A requires the person has been admitted as an inpatient at a hospital.  This is constrained by a rule that they stay for three days after admission.  
    
  • Sign-up
  • Part A has automatic sign-up if the person is drawing social security.  Otherwise the person must sign-up for Part A and Part B. 
    
  • Should sign-up for Part B during the Initial Enrollment Period, of seven months centered around 65th birthday, online or at a social security office.  But if still covered by spouse's insurance or not yet retired then may only join during the 3 month general enrollment period (January to March) each year, with coverage initiated the following July.  Incremental yearly 10% penalties apply for not signing up at 65.  These penalties apply to all subsequent premiums. 
    
  • Premiums
  • Part A premium
  • Part B insurance premium
    
  • Part C & D premiums are set by the commercial insurer.  
  buy in (May 2016).  The law includes:
• Alterations, in title I is ACA quality affordable care for all Americans.  It mandates community rating & essential health benefits.  It includes:
  • Subtitle A: Immediate improvements in health care for all Americans. 
    
  • Subtitle B: Immediate actions to preserve and expand coverage. 
    
  • Subtitle C: Quality health insurance coverage for all Americans.  Which reforms the health insurance markets and prohibits preexisting condition exclusions and forms of health status discrimination.  
  • Subtitle D: Available coverage choices for all Americans. 
    
  • Subtitle E: Affordable coverage choices for all Americans. 
    
  • Subtitle F: Shared responsibility for health care which mandates individuals and employers to pay for insurance.  
  • The employer mandate requires employers with more than 50 full-time workers to offer most of their employees insurance or face penalties. 
    
  , to how health care is paid for and who is covered.  This has been altered to ensure
  
• Americans with preexisting conditions get health insurance cover - buttressed by mandating community rating mandates health insurers charge the same price to people of the same age living in the same geographic area. 
  and
  
• That they are constrained by the individual mandate to have insurance but the requirement was supported by subsidies for the poor (those with incomes between 100 & 400% of the federal poverty line is based on the Johnson War on Poverty valuation of $3000 as the relative needed income.  It was justified using Mollie Orshansky's modelling of the price of food to limit hunger.  It was adopted as an official US poverty line in August 1969 and has remained unchanged except for adjustments for price inflation.  ).  
• Children, allowed to, stay on their parents insurance until 26 years of age. 
  
• Medicare solvency improvements. 
  
• Medicaid is the state-federal program for the poor.  Originally part of Lyndon Johnson's 1965 Bill, eligibility and services vary by state.  Medicaid currently pays less for care than Medicare, resulting in many care providers refusing to participate in the program.  Less than 10 percent of Medicaid recipients, those in long-term care including nursing homes where 64% are dependent on Medicaid, use one-third of all Medicaid spending which is a problem.  The ACA's Medicaid expansion program, made state optional by the SCOTUS decision, was initially taken up by fifty percent of states.  As of 2016 it covers 70 million Americans at a federal cost of $350 billion a year.  In 2017 it pays for 40% of new US births. 
  expansion, in title II is ACA role of public programs.  It includes:
  • Subtitle A: Improved access to Medicaid. 
    
  • Subtitle B: Enhanced support for children's health insurance program. 
    
  • Subtitle C: Medicaid and CHIP enrolment simplification. 
    
  • Subtitle D: Improvements to Medicaid services. 
    
  • Subtitle E: New options for states to provide long-term services and support. 
    
  • Subtitle F: Medicaid prescription drug coverage. 
    
  • Subtitle G: Medicaid disproportionate share hospital (DSH) payments.  
  • Subtitle H: Improved coordination for dual eligibles. 
    
  • Subtitle I: Improving the quality of Medicaid for patients and providers
    
  • Subtitle J: Improvements to the Medicaid and CHIP payment and access commission (MACPAC)
    
  • Subtitle K: Protections for American Indians and Alaska natives. 
    
  • Subtitle L: Maternal and child health services. 
    
  : to poor with incomes below 138% of the federal poverty line; an expansion which was subsequently constrained by the Supreme Court's ruling making expansion an optional state government decision. 
  
• Hospital Readmissions have become a source of increased revenue for hospitals.  But with government interested in reducing the US health care cost curve ACA's HRRP (pay-for-performance), BPCI and CTI and Interact discharge initiative have all increased the focus on unnecessary readmissions.  Now the end-to-end process is under scrutiny with hospitals reengineering discharge (RED) and PAC providers using RAI and TCN. 
  Reduction Program (HRRP is the Hospital Readmissions Reduction Program of the ACA.  It imposes payment penalties on high readmitting IPPS hospitals.  Such hospitals with higher than expected readmissions rates will receive reduced Medicare payments for all Medicare discharges relating to three medical conditions: heart failure, acute myocardial infarction, and pneumonia.  The reductions will be driven by an adjustment factor of 1% in 2013, 2% in 2014, and 3% subsequently.  The incentives/penalties induce complex adaptive responses (Dec 2018)
  ) which was enforced by CMS is the centers for Medicare and Medicaid services.   mandated rules finalized in 2011 and effected starting Oct 2012.  
• Medical home models are primary care architectures which deliver: patient-centered, accessible, coordinated, comprehensive care of high quality and safety (Dec 2015).  The models have been made more significant due to Affordable Care Act payment reform requirements.  The goal is to reduce treatment costs and improve population health by reengineering of the traditional silo'd provider network.  See PCMH. 
  .  
• Community transformation grants support the transformation of low income stressed neighborhoods to improve their lifestyles and health. 
  
• Qualifications for ACO is an Accountable Care Organization. These are accredited bundles of companies which together try to offer Dartmouth-Hitchcock like business models (Dec 2015, Sep 2016) focused on wellness, improving the provision of primary care to a large group of Medicare patients, and rewarding doctors for preventing problems.  Advocate health illustrates the idea.  Robert Pearl notes that the transition is difficult: hospitals that find their efficiency improving should reduce the number of doctors they utilize.  But any doctors that are pushed out of the ACO will likely take their patients with them, undermining the revenues that support the FFV business.  The ACA regulates qualification to be a Medicare ACO.  Individual organizations within a Medicare shared savings ACO continue to submit their own claims and are paid by Medicare for FFS.  But the ACO is eligible for shared savings.  Within the shared savings program the CMS innovation center has setup advanced payment ACOs.  As an alternative to shared savings, in a Pioneer ACO, over time 50% of the FFS payments flow directly to the ACO as a bundled payment.  CMS has established quality measures for ACOs for Medicare.  The CMS program's purpose is to reward providers for reducing total cost of care for patients through prevention, disease management, and coordination. 
  
  • CMS initiated its Physician Group Practice Demonstration in 2005.  By 2008 the congressional budget office reported on Bonus-eligible organizations. 
    
  • CMS defines ACOs as organizations that "create incentives for health care providers to work together to treat an individual patient across care settings - including doctors' offices, hospitals and long-term care facilities."
  • CMS has developed APMs which include ACOs, and advanced APMs where the ACOs must be risk bearing. 
    
  • CMMI accepts providers' proposals to test various payment systems including shared savings and partial capitation.  
  • Private market ACOs have formed including: Providence Health & Services, Blue Shield California, Anthem Blue Cross, United Health Care, BCBS Minnesota, BCBS Illinois, Humana, CIGNA, Main Health Management Coalition, BCBS Massachusetts, Aetna.  
  s.  Organizations must:
  
• Establish a formal legal structure with shared governance which allows the ACO to distribute shared savings is the Medicare Shared Savings Program.  The program began in 2012 with 3 year term contracts.  ACO Physician groups and hospitals are eligible to participate but there must be primary care physicians in the ACO.  Participating ACOs must serve > 5000 Medicare beneficiaries.  The potential for a bonus payment is based on Medicare cost savings and quality metrics.  Two payment models are available.  Only one has downside risk involved.  CMS included 'robust' quality measures to monitor the quality of care provided and beneficiary satisfaction (see fact sheet 'Improving Quality of Care for Medicare Patients: Accountable Care Organizations'). 
  payments to participating providers and suppliers. 
  
• Participate in the MSSP is the Medicare Shared Savings Program.  The program began in 2012 with 3 year term contracts.  ACO Physician groups and hospitals are eligible to participate but there must be primary care physicians in the ACO.  Participating ACOs must serve > 5000 Medicare beneficiaries.  The potential for a bonus payment is based on Medicare cost savings and quality metrics.  Two payment models are available.  Only one has downside risk involved.  CMS included 'robust' quality measures to monitor the quality of care provided and beneficiary satisfaction (see fact sheet 'Improving Quality of Care for Medicare Patients: Accountable Care Organizations'). 
  for three or more years. 
  
• Have a management structure. 
  
• Have clinical and administrative systems. 
  
• Include enough PCP is a Primary Care Physician.  PCPs are viewed by legislators and regulators as central to the effective management of care.  When coordinated care had worked the PCP is a key participant.  In most successful cases they are central.  In certain Medicare ACO models (Pioneer) PCPs are committed to achieve meaningful use requirements.  Working against this is the: replacement of diagnostic skills by technological solutions, low FFS leverage of the PCP compared to specialists, demotivation of battling prior authorization for expensive treatments. 
  s to care for Medicare is a social insurance program that guarantees access to health insurance for Americans aged 65 and over, and younger people with disabilities and end stage renal disease or ALS.  Medicare is currently missing a cap on out-of-pocket costs and direct prescription drug coverage.  It includes:
  
  • Benefits
  • Part A: Hospital inpatient insurance.  As of Dec 2013 Medicare pays for home care in only limited circumstances, such as when a person needs temporary nursing care after a hospitalization.  Part A covers 20 days of inpatient rehabilitation at a SNF after discharge from inpatient care at a hospital. 
    
  • Part B: Medical insurance for non-hospital services including: doctor visits, tests, injectable drugs, ambulances, physical therapy;
    
  • Part C: Medicare Advantage 
  • Part D: indirect prescription drug coverage The MMA prohibits Medicare from directly negotiating drug prices. 
    
  • Eligibility
    
  • All persons 65 years of age or older who are legal residents for at least 5 years.  If they or a spouse have paid Medicare taxes for 10 years the Medicare part A payments are waived.  Medicare is legislated to become the primary health plan. 
    
  • Persons under 65 with disabilities who receive SSDI. 
    
  • Persons with specific medical conditions:
  • Have end stage renal disease or need a kidney transplant. 
    
  • They have ALS. 
    
  • Some beneficiaries are dual eligible. 
    
  • Part A requires the person has been admitted as an inpatient at a hospital.  This is constrained by a rule that they stay for three days after admission.  
    
  • Sign-up
  • Part A has automatic sign-up if the person is drawing social security.  Otherwise the person must sign-up for Part A and Part B. 
    
  • Should sign-up for Part B during the Initial Enrollment Period, of seven months centered around 65th birthday, online or at a social security office.  But if still covered by spouse's insurance or not yet retired then may only join during the 3 month general enrollment period (January to March) each year, with coverage initiated the following July.  Incremental yearly 10% penalties apply for not signing up at 65.  These penalties apply to all subsequent premiums. 
    
  • Premiums
  • Part A premium
  • Part B insurance premium
    
  • Part C & D premiums are set by the commercial insurer.  
  FFS is fee-for-service payment.  For health care providers the high profits were made in hospitalizations, imaging and surgery.  Due to its inducing excessive treatment activity it may be replaced by FFV bundled payment.   patient population (> 5000) assigned to the ACO. 
  
• Be accountable for the quality and cost of care provided to the Medicare FFS patient population. 
  
• Have defined processes to promote: Evidence-based medicine is evidence based medicine where explicit and judicious use of current best practice evidence is used in making decisions about the care of patients.  There are differences in the application to individuals and populations.  Still the goal was to replace subjective use of basic and clinical research with:
  
  • Prioritization of clinical trial results to build conclusions. 
    
  • Adoption of processes that translated epidemiological methods to physician decision making. 
    
  • Widely used but innapropriate procedures were abandoned.  
  • There is now explicit evaluation of evidence of effectiveness before issuing practice guidelines.  A rational for adoption is required.  
  • HHS appointed USPSTF to develop evidence based recommendations. 
    
  , Patient-centeredness, Quality reporting, Cost management, Coordination of care aims to transfer information between the patient and each care participant as required and establish accountability by defining who is responsible for each care delivery activity, the extent of that responsibility and when that responsibility will be transferred to other care participants or the patient and family.  Successful care coordination requires face-to-face interactions.  It also requires aligned incentives (ACO, Bundled payments).  AHRQ defines quality measures for care coordination.  The situation is usually complex and adaptive due to the interactions of all the providers, settings, the patients' preferences, and the number of physical health problems, treatments, and the patients' social situation.  The potentially exponential increase in complexity as the number of these factors present increases leads to patient hot spots requiring explicit proactive coordination of care.  It is argued that care coordination must include six specific activities:
  1. Determination and updating of care coordination needs: Needs assessment should identify preferences and goals, current situation and past history.  It needs to be updated periodically and after new diagnosis and other changes in health or functional status. 
     
  2. Creation and updating of proactive plan of care
     
  3. Communication
  4. Facilitation of transitions: typical transition problems are detailed by Project Boost.  A challenging issue with transitions is what to do when there is no resource to take over the coordination role in the handoff. 
     
  5. Connection to community resources: Community resources are any service or program outside the health care system that may support a patient's health and wellness. 
     
  6. Alignment of resources with population needs: need to see the system-level, assess the needs of populations to identify and address gaps in services.  
  ; 
• Demonstrate it meets HHS is the U.S. Department of Health and Human Services.   patient-centeredness criteria including use of patient and caregiver assessments and individualized care plans outline the patient's current and long-term needs and goals for care, identifies coordination needs, and addresses potential gaps.  This is consistant with the biopsychosocial model.  It also clarifies how the patient will reach the goals and who is responsible for implementing each part of the plan.  HL7's FHIR has defined a CarePlan resource.  .  
• CMMI is the center for Medicare and Medicaid Innovation.  It is a test bed for new ways of financing and delivering care.  It allowed Congress to institutionalize innovation sending a signal to providers that they would be participating in CMS driven programs that could become mainstream.  It funds evaluations of innovative health care models.  Under the ACA if the HHS secretary finds any of its projects would reduce Medicare spending without harming the quality of care the projects may be expanded nationwide.  The CBO estimates the CMMI will save $34 billion between 2016 and 2026.  CMMI projects include:
  • Medicare will make a bundled payment for hip and knee replacement surgery (CJR) and 90 days of follow-up care forcing hospitals to work closely with doctors, nursing homes and home health agencies.  
  • New ways to pay for prescription drugs, medical devices, cancer care (OCM).  
  • HHS secretary has invoked his 3021 authority to institute DPP. 
    
  Medicare payment experimentation.  
• Requirements that pharmaceutical companies must report payments made to physicians (Sunshine Act is the physician payments sunshine act of 2010.  It is:
  • Section 6002 of the ACA.  
  • It requires pharmaceutical and medical device companies to release details of payments to doctors and US teaching hospitals.  
  ). 
  
• A requirement that chain restaurants must report calorie counts on their menus. 
  
• ACA title II is ACA is the Patient Protection and Affordable Care Act amended by the Health Care and Education Reconciliation Act of 2010 (Obama care).  In part it is designed to make the health care system costs grow slower.  It aims to do this by: increasing competition between insurers and providers, offering free preventative services to limit the development of serious illnesses, constraining patients' use of expensive services, constraining the growth of payments to Medicare providers and piloting new ways for PCPs to manage patient care to keep patients away from costly E.D.s.  It funds these changes with increased taxes on the wealthy.  It follows an architecture developed by Heritage Action's Butler, Moffit, Haislmaier extended by White House OMB health policy advisor Ezekiel Emanuel & architect Jeanne Lambrew.  The Obama administration drafting team included: Bob Kocher; allowing it to integrate ideas from: Dartmouth Institute's Elliot Fischer (ACO).  The ACA did not include a Medicare buy in (May 2016).  The law includes:
  • Alterations, in title I, to how health care is paid for and who is covered.  This has been altered to ensure
    
  • Americans with preexisting conditions get health insurance cover - buttressed by mandating community rating and
    
  • That they are constrained by the individual mandate to have insurance but the requirement was supported by subsidies for the poor (those with incomes between 100 & 400% of the federal poverty line).  
  • Children, allowed to, stay on their parents insurance until 26 years of age. 
    
  • Medicare solvency improvements. 
    
  • Medicaid expansion, in title II: to poor with incomes below 138% of the federal poverty line; an expansion which was subsequently constrained by the Supreme Court's ruling making expansion an optional state government decision. 
    
  • Hospital Readmissions Reduction Program (HRRP) which was enforced by CMS mandated rules finalized in 2011 and effected starting Oct 2012.  
  • Medical home models.  
  • Community transformation grants support the transformation of low income stressed neighborhoods to improve their lifestyles and health. 
    
  • Qualifications for ACOs.  Organizations must:
    
  • Establish a formal legal structure with shared governance which allows the ACO to distribute shared savings payments to participating providers and suppliers. 
    
  • Participate in the MSSP for three or more years. 
    
  • Have a management structure. 
    
  • Have clinical and administrative systems. 
    
  • Include enough PCPs to care for Medicare FFS patient population (> 5000) assigned to the ACO. 
    
  • Be accountable for the quality and cost of care provided to the Medicare FFS patient population. 
    
  • Have defined processes to promote: Evidence-based medicine, Patient-centeredness, Quality reporting, Cost management, Coordination of care; 
  • Demonstrate it meets HHS patient-centeredness criteria including use of patient and caregiver assessments and individualized care plans.  
  • CMMI Medicare payment experimentation.  
  • Requirements that pharmaceutical companies must report payments made to physicians (Sunshine Act). 
    
  • A requirement that chain restaurants must report calorie counts on their menus. 
    
  role of public programs.  It includes:
• Subtitle A: Improved access to Medicaid is the state-federal program for the poor.  Originally part of Lyndon Johnson's 1965 Bill, eligibility and services vary by state.  Medicaid currently pays less for care than Medicare, resulting in many care providers refusing to participate in the program.  Less than 10 percent of Medicaid recipients, those in long-term care including nursing homes where 64% are dependent on Medicaid, use one-third of all Medicaid spending which is a problem.  The ACA's Medicaid expansion program, made state optional by the SCOTUS decision, was initially taken up by fifty percent of states.  As of 2016 it covers 70 million Americans at a federal cost of $350 billion a year.  In 2017 it pays for 40% of new US births. 
  . 
  
• Subtitle B: Enhanced support for children's health insurance program. 
  
• Subtitle C: Medicaid and CHIP is:
  
  • The Children's Health Insurance Program started in 1997 as part of the BBA as SCHIP.  It provides health insurance coverage for children in families with income below 200 percent of the poverty line.  The coverage is focused on care specialized for children including: developmental delays, chronic conditions including asthma and obesity.  CHIP's funding must be iteratively re-authorized by Congress.  CHIP is financed federally, but states must enroll eligible children.  In many states one agency administers CHIP and Medicaid.  CHIP is leveraged by families that have employer based insurance with costly premiums, so the families only cover the adults.  
  • Clonal Hematopoiesis of Indeterminate Potential, where stem cells develop a somatic mutation cluster pair often found in leukemia, which is expressed in white blood cells they produce.  The mutation clusters give these stem cells a competitive advantage and they accumulate over time.  The white blood cells form inflammatory plaques.  CHIP increases with age, increasing the risk of dying, of clot fragment induced heart attacks and stroke, over the subsequent 10 years by 54%
  enrolment simplification. 
  
• Subtitle D: Improvements to Medicaid services. 
  
• Subtitle E: New options for states to provide long-term services and support. 
  
• Subtitle F: Medicaid prescription drug coverage. 
  
• Subtitle G: Medicaid disproportionate share hospital (DSH is disproportionate share hospital ACA program providing federal government Medicare compensation for a provider treating indigent patients. 
  ) payments.  
• Subtitle H: Improved coordination for dual eligibles. 
  
• Subtitle I: Improving the quality of Medicaid for patients and providers
  
• Subtitle J: Improvements to the Medicaid and CHIP payment and access commission (MACPAC is the Medicaid CHIP payment and access commission, a federal level body of 17 commissioners, chartered, as part of CHIPRA, to advise Congress.  
  )
  
• Subtitle K: Protections for American Indians and Alaska natives. 
  
• Subtitle L: Maternal and child health services. 
  
• ACA title I is ACA is the Patient Protection and Affordable Care Act amended by the Health Care and Education Reconciliation Act of 2010 (Obama care).  In part it is designed to make the health care system costs grow slower.  It aims to do this by: increasing competition between insurers and providers, offering free preventative services to limit the development of serious illnesses, constraining patients' use of expensive services, constraining the growth of payments to Medicare providers and piloting new ways for PCPs to manage patient care to keep patients away from costly E.D.s.  It funds these changes with increased taxes on the wealthy.  It follows an architecture developed by Heritage Action's Butler, Moffit, Haislmaier extended by White House OMB health policy advisor Ezekiel Emanuel & architect Jeanne Lambrew.  The Obama administration drafting team included: Bob Kocher; allowing it to integrate ideas from: Dartmouth Institute's Elliot Fischer (ACO).  The ACA did not include a Medicare buy in (May 2016).  The law includes:
  • Alterations, in title I, to how health care is paid for and who is covered.  This has been altered to ensure
    
  • Americans with preexisting conditions get health insurance cover - buttressed by mandating community rating and
    
  • That they are constrained by the individual mandate to have insurance but the requirement was supported by subsidies for the poor (those with incomes between 100 & 400% of the federal poverty line).  
  • Children, allowed to, stay on their parents insurance until 26 years of age. 
    
  • Medicare solvency improvements. 
    
  • Medicaid expansion, in title II: to poor with incomes below 138% of the federal poverty line; an expansion which was subsequently constrained by the Supreme Court's ruling making expansion an optional state government decision. 
    
  • Hospital Readmissions Reduction Program (HRRP) which was enforced by CMS mandated rules finalized in 2011 and effected starting Oct 2012.  
  • Medical home models.  
  • Community transformation grants support the transformation of low income stressed neighborhoods to improve their lifestyles and health. 
    
  • Qualifications for ACOs.  Organizations must:
    
  • Establish a formal legal structure with shared governance which allows the ACO to distribute shared savings payments to participating providers and suppliers. 
    
  • Participate in the MSSP for three or more years. 
    
  • Have a management structure. 
    
  • Have clinical and administrative systems. 
    
  • Include enough PCPs to care for Medicare FFS patient population (> 5000) assigned to the ACO. 
    
  • Be accountable for the quality and cost of care provided to the Medicare FFS patient population. 
    
  • Have defined processes to promote: Evidence-based medicine, Patient-centeredness, Quality reporting, Cost management, Coordination of care; 
  • Demonstrate it meets HHS patient-centeredness criteria including use of patient and caregiver assessments and individualized care plans.  
  • CMMI Medicare payment experimentation.  
  • Requirements that pharmaceutical companies must report payments made to physicians (Sunshine Act). 
    
  • A requirement that chain restaurants must report calorie counts on their menus. 
    
  quality affordable care for all Americans.  It mandates community rating mandates health insurers charge the same price to people of the same age living in the same geographic area. 
  & essential health benefits are the minimum mandated set of benefits that insurers must cover under the ACA.  These include:
  • Mental health care,
  • Emergency services,
    
  • maternity and newborn care,
    
  • prescription drugs;
    
  .  It includes:
• Subtitle A: Immediate improvements in health care for all Americans. 
  
• Subtitle B: Immediate actions to preserve and expand coverage. 
  
• Subtitle C: Quality health insurance coverage for all Americans.  Which reforms the health insurance markets and prohibits preexisting condition exclusions and forms of health status discrimination.  
• Subtitle D: Available coverage choices for all Americans. 
  
• Subtitle E: Affordable coverage choices for all Americans. 
  
• Subtitle F: Shared responsibility for health care which mandates individuals and employers to pay for insurance.  
• The employer mandate requires employers with more than 50 full-time workers to offer most of their employees insurance or face penalties. 
  
• ACC is either the
  
• Anterior cingulate cortex which:
• Includes the subgenual ACC and the paragenual ACC, and Brodmann areas 24, 25 is the Subcallosal Cingulate Cortex, an area of the ACC, which Kandel explains, is a region where thought, motor control and drive come together.  It is rich in neurons generating serotonin transporters.  It is directly involved in a signalling network with: amydala, hypothalamus, hippocampus, insula cortex; that integrates thinking and emotion to plan and respond effectively.  Kandel notes whenever area 25 becomes hyperactive, the components of this circuit associated with emotion are disconnected from the thinking brain resulting in a loss of personal identity.  , 32 and 33. 
  
• The gyrus of the ACC has two functional components, which both operate abnormally in mood disorders: depression is a debilitating episodic state of extreme sadness, typically beginning in late teens or early twenties. This is accompanied by a lack of energy and emotion, which is facilitated by genetic predisposition - for example genes coding for relatively low serotonin levels, estrogen sensitive CREB-1 gene which increases women's incidence of depression at puberty; and an accumulation of traumatic events.  There is a significant risk of suicide: depression is involved in 50% of the 43,000 suicides in the US, and 15% of people with depression commit suicide.  Depression is the primary cause of disability with about 20 million Americans impacted by depression at any time.  There is evidence of shifts in the sleep/wake cycle in affected individuals (Dec 2015).  The affected person will experience a pathological sense of loss of control, prolonged sadness with feelings of hopelessness, helplessness & worthlessness, irritability, sleep disturbances, loss of appetite, and inability to experience pleasure.  Michael Pollan concludes depression is fear of the past.  It affects 12% of men and 20% of women.  It appears to be associated with androgen deprivation therapy treatment for prostate cancer (Apr 2016).  Chronic stress depletes the nucleus accumbens of dopamine, biasing humans towards depression.  Depression easily leads to following unhealthy pathways: drinking, overeating; which increase the risk of heart disease.   It has been associated with an aging related B12 deficiency (Sep 2016).  During depression, stress mediates inhibition of dopamine signalling.  Both depression and stress activate the adrenal glands' release of cortisol, which will, over the long term, impact the PFC.  There is an association between depression and additional brain regions: Enlarged & more active amygdala, Hippocampal dendrite and spine number reductions & in longer bouts hippocampal volume reductions and memory problems, Dorsal raphe nucleus linked to loneliness, Defective functioning of the hypothalamus undermining appetite and sex drive, Abnormalities of the ACC.  Mayberg notes ACC area 25: serotonin transporters are particularly active in depressed people and lower the serotonin in area 25 impacting the emotion circuit it hubs, inducing bodily sensations that patients can't place or consciously do anything about; and right anterior insula: which normally generates emotions from internal feelings instead feel dead inside; are critical in depression.  Childhood adversity can increase depression risk by linking recollections of uncontrollable situations to overgeneralizations that life will always be terrible and uncontrollable.  Sufferers of mild autism often develop depression.  Treatments include: CBT which works well for cases with below average activity of the right anterior insula (mild and moderate depression), UMHS depression management, deep-brain stimulation of the anterior insula to slow firing of area 25.  Drug treatments are required for cases with above average activity of the right anterior insula.  As of 2010 drug treatments: SSRIs (Prozac), MAO, monoamine reuptake inhibitors; take weeks to facilitate a response & many patients do not respond to the first drug applied, often prolonging the agony.  By 2018, Kandel notes, Ketamine is being tested as a short term treatment, as it acts much faster, reversing the effect of cortisol in stimulating glutamate signalling, and because it reverses the atrophy induced by chronic stress.   Genomic predictions of which treatment will be effective have not been possible because: Not all clinical depressions are the same, a standard definition of drug response is difficult;, anxiety is manifested in the amygdala mediating inhibition of dopamine rewards.  Anxiety disorders are now seen as a related cluster, including PTSD, panic attacks, and phobias.  Major anxiety, is typically episodic, correlated with increased activity in the amygdala, results in elevated glucocorticoids and reduces hippocampal dendrite & spine density.  Some estrogen receptor variants are associated with anxiety in women.  Women are four times more likely to suffer from anxiety.  Louann Brizendine concludes this helps prepare mothers, so they are ready to protect their children.  Michael Pollan concludes anxiety is fear of the future.  Sufferers of mild autism often develop anxiety disorders.  Treatments for anxiety differ.  50 to 70% of people with generalized anxiety respond to drugs increasing serotonin concentrations, where there is relief from symptoms: worry, guilt; linked to depression, which are treated with SSRIs (Prozac).  Cognitive anxiety (extreme for worries and anxious thoughts) is also helped by yoga.  But many fear-related disorders respond better to psychotherapy: psychoanalysis, and intensive CBT.  Tara Brach notes that genuine freedom from fear is enabled by taking refuge. 
  & bipolar also termed manic-depression is an episodic developmental disorder beginning in late adolescence, which can stimulate great creativity during the manic phase and suicide in the depressive phase.  Vincent van Gough suffered from depression for much of his adult life, and killed himself at thirty seven.  He produced three hundred of his greatest art works, using color to convey mood, while struggling with psychotic depression and mania in the last two years of his life.  Only the first manic phase requires a significant positive or negative stressful situation.  Type I bipolar includes more manic situations which may include psychosis.  Type II does not include psychosis.  Some people suffer 'mixed state' where mania and depression occur at the same time.  Sleep deprivation activates the amygdala and can induce mania in some people with bipolar disorder.  It affects 3 million Americans.  The amygdala is more active in people with bipolar disorder.  Franz Kallman found identical twins are likely (70% chance) to share the disorder.  Swedish researchers studying thousands of families in 2009 showed a strong hereditary link between bipolar disorder and schizophrenia, which was corroborated in 2012.  Genetic analysis of 2.3 million different regions of DNA of 9,747 people with bipolar disorder and 14,278 comparable people without, found five regions that appear connected with bipolar disorder.  Gene ADCY2, was identified, supports production of an enzyme facilitating neural signalling, and correlates with observed impairment of communication in certain brain regions in bipolar disorder.  GWAS implicate ANK3 and CACNA1C SNPs in bipolar disorder.  And de Novo mutations increase the risk.  Lithium limits the extremes of the mood swings in some patients but has side effects.  Anti-psychotic medications are prescribed.  .  The
  
• Rostral/ventral part is involved in emotional are low level fast unconscious agents distributed across the brain and body which associate, via the amygdala and rich club hubs, important environmental signals with encoded high speed sensors, and distributed programs of action to model: predict, prioritize guidance signals, select and respond effectively, coherently and rapidly to the initial signal.  The majority of emotion centered brain regions interface to the midbrain through the hypothalamus.  The cerebellum and basal ganglia support the integration of emotion and motor functions, rewarding rhythmic movement.  The most accessible signs of emotions are the hard to control and universal facial expressions.  Emotions provide prioritization for conscious access given that an animal has only one body, but possibly many cells, with which to achieve its highest level goals.  Because of this, base emotions clash with group goals and are disparaged by the powerful.  Pinker notes a set of group selected emotions which he classes as: other-condemning, other-praising, other-suffering and self-conscious emotions.  Evolutionary psychology argues evolution shaped human emotions during the long period of hunter-gatherer existence in the African savanna.  Human emotions are universal and include: Anger, Appreciation of natural beauty, Contempt, Disgust, Embarrassment, Fear, Gratitude, Grief, Guilt, Happiness, Honor, Jealousy, Liking, Love, Moral awe, Rage, Romantic love, Lust for revenge, Passion, Sadness, Self-control, Shame, Sympathy, Surprise; and the sham emotions and distrust induced by reciprocal altruism. 
  processes and autonomic functions.  It connects to the hippocampus is a part of the medial temporal lobe of the brain involved in the temporary storage or coding of long-term episodic memory.  It includes the dentate gyrus.  Memory formation in the cells of the hippocampus uses the MAP kinase signalling network which is impacted by sleep deprivation.  The hippocampus dependent memory system is directly affected by cholinergic changes throughout the wake-sleep cycle.  Increased acetylcholine during REM sleep promotes information attained during wakefulness to be stored in the hippocampus by suppressing previous excitatory connections while facilitating encoding without interference from previously stored information.  During slow-wave sleep low levels of acetylcholine cause the release of the suppression and allow for spontaneous recovery of hippocampal neurons resulting in memory consolidation.  It was initially associated with memory formation by McGill University's Dr. Brenda Milner, via studies of 'HM' Henry Molaison, whose medial temporal lobes had been surgically destroyed leaving him unable to create new explicit memories.  The size of neurons' dendritic trees expands and contracts over a female rat's ovulatory cycle, with the peak in size and cognitive skills at the estrogen high point.  Adult neurogenesis occurs in the hippocampus (3% of neurons are replaced each month) where the new neurons integrate into preexisting circuits.  It is enhanced by learning, exercise, estrogen, antidepressants, environmental enrichment, and brain injury and inhibited by various stressors explains Sapolsky.  Prolonged stress makes the hippocampus atrophy.  He notes the new neurons are essential for integrating new information into preexisting schemas -- learning that two things you thought were the same are actually different.  Specific cells within the hippocampus and its gateway, the entorhinal cortex, are compromised by Alzheimer's disease.  It directly signals area 25. 
  , amygdala contains > 12 distinct areas: Central, Lateral.  It receives simple signals from the lower parts of the brain: pain from the PAG; and abstract complex information from the highest areas: Disgust, heart rate, and suffering from the insula cortex, allowing it to orchestrate emotion.  It connects strongly to attention focusing networks.  It sends signals to almost every other part of the brain, including to the decision making circuitry of the frontal lobes.  It has high levels of D(1) dopamine receptors.  During extreme fear the amygdala drives the hippocampus into fear learning.  It outputs directly to subcortical reflexive motor pathways when speed is required.  Its central nucleus projects to the BNST.  It signals the locus ceruleus.  It directly signals area 25.  The amygdala:
  
  • Promotes aggression.  Stimulating the amygdala promotes rage.  It converts anger into aggression and when impaired it impacts the ability to detect angry facial expressions.  
  • Participates in disgust
  • Perceives fear promoting stimuli, focusing our attention on these.  In PTSD sufferers the Amygdala overreacts to mildly fearful stimuli and is slow to calm down and the amygdala expands in size over a period of months.  Fear is processed by the lateral nucleus which serves as the input from various senses, and the central nucleus which outputs to the brain stem (central grey - freezing, lateral hypothalamus - blood pressure, activates paraventricular hypothalamus => crf -> hormone adjustments). 
    
  • Has lots of receptors for and is highly sensitive to glucocorticoids.  Stress inhibits the GABA interneurons in the basolateral amygdala (BLA) allowing the excitatory glutamate releasing neurons to excite more. 
    
  • Is sensitive to unsettling/uncertain social situations where it promotes anxiety and makes us distracted.  It is also interested in uncertain but potentially painful situations.  The amygdala contributes to social and emotional decision making where the BLA supports rejecting an unacceptable offer, as allowed in the Ultimatum Game, by injecting implicit mistrust and vigilance, generating an anger driven rejection that is used as punishment.  The amygdala is very rapidly excited by subliminal signals from the thalamus of outgroup skin color.  The amygdala subsequently tips social emotions against outgroups unless restrained by the frontal lobe or influenced by subliminal priming to prioritize inclusion.  The fast path from the thalamus rapidly but inaccurately signals its identified a weapon. 
    
  • Sees suffering of others as increasingly salient with loving-kindness meditation practice, Goleman & Davidson explain. 
    
  • Promotes male, but not female, sexual motivation when it is an uncertain potential pleasure. 
    
  • Responds to the longing for uncertain potential pleasures and fear that the reward will not be worth it if it happens.  The amygdala turns off during orgasm. 
    
  • Uses but is not directly involved in vision.  
  , orbital prefrontal cortex is a rich club hub region of the prefrontal cortex, involved in representing emotion & reward in decision making.  It is positioned immediately above the orbits where the eyes sit.  The medial part judges the beauty of faces, minds and acts and will conflate them in social emotion evaluations.  The orbitofrontal cortex receives projections from the: hippocampus & associated areas of the cingulate, retrosplenial & entorhinal cortices, anterior thalamus, amygdala, midline thalamus, non-isocortical insula, mediodorsal thalamus. 
  , anterior insula is a rich club hub within the insula cortex.  It is anatomically subdivided by sulci into gyri.  It is where self-awareness and social experience integrate.  Feelings from the internal state of the body are used to generate emotions.  It includes a direct projection from the: thalamus's ventral medial nucleus, central nucleus of the amygdala.  The anterior insula projects into the amygdala.  It includes spindle neurons. 
  , nucleus accumbens is a region of the basal forebrain (striatum) rostral to the preoptic area and immediately adjacent to the septum.  The nucleus accumbens was closely associated with the limbic system, mediates the impact of emotion and plays an important role in reinforcement.  If a rodent wins a fight on his home territory, there are long-lasting increases in levels of testosterone receptors enhancing pleasurable effects.  When prairie voles first mate, epi-genetic state changes are induced in the accumbens to support pair-bonding.  The accumbens projects to brain regions associated with movement.  The major pathways of dopaminergic neurons begin in the substantia nigra and the ventral tegmental area.  The amygdala projects back to the accumbens.  The tegmentostriatal system begins in the ventral tegmental area and projects to the nucleus accumbens.  The nucleus accumbens includes high levels of D1, D2 and D3 dopamine receptors located on the spine & shafts of dendrites of excitatory cells reduce the transfer of excitation from the dendrites to the cell bodies, so only especially strong excitatory inputs get through to the cell body to elicit excitation.  It also has D4 dopamine receptors which are highly variable.  The accumbens responds differently to rewards depending on maturity: In juveniles all reward levels result in the same response activity level, During adolescence the accumbens responds to small rewards negatively, and large rewards hugely, In adults the rewards result in measured scaled positive responses.  Chronic stress depletes dopamine from the nucleus accumbens biasing humans towards depression.  .  It is overactive during regular or bipolar depression. 
  
• Caudal part is involved in cognition and the control of behavior.  It connects with the dorsal PFC is prefrontal cortex which is:
  • The front part of the frontal lobe of the cerebral cortex.  It evolved most recently.  During adolescence when the PFC is still deploying, older brain agents provide equivalent strategies: ventral striatum.  The PFC has been implicated in planning, working memory: dorsolateral; decision making: Orbitofrontal cortex; and social behavior.  It regulates feelings.  Different PFC circuits track internal reward driven strategies and externally signalled advice.  The PFC chooses between conflicting options, letting go or restraint, especially between cognition and emotions.  It imposes an overarching strategy for managing working memory.  It is essential for thinking about multiple items with different labels.  It includes neurons that are interested in particular sub-categories: Dog, Cat.  Once it has made a decision it signals the rest of the frontal lobe just behind it.  Glucocorticoids decrease excitability of the PFC.  
  , secondary motor cortex is the posterior precentral gyrus region of the frontal lobe of the cerebral cortex involved with planning, control and execution of voluntary movements. 
  , and posterior cingulate cortex (PCC) is a brain region where invariant-location cells dwell.  It is closely connected to the parahippocampal gyrus.  It activates during self-focused thought.  University of Massachusetts Medical School Center for Mindfulness research director, Judson Brewer, sees the PCC participation in: distraction, wandering attention, thinking about ourselves, liking an immoral choice, feeling guilty, and craving.  Its activation was reduced by mindfulness meditation explain Goleman & Davidson. 
  
  
• Is a central focus of empathy is the capability to relate to another person from their perspective.  It is implemented by spindle neurons.  Empathy towards others is controlled by the right-hemisphere supramarginal gyrus.  Empathy is context dependently mediated by estrogen.  It develops over time: Piaget's preoperational stage includes rudimentary empathy, Theory of mind supports the development; initially feeling someone's pain as one integrated being, then for them and eventually as them.  In adults, when someone else is hurt the anterior cingulate cortex, amygdala & insula activates projecting [scapegoating] to the vmPFC.  If the pain is physical the PAG activates and motor neurons for the area where the other person was injured.  The intertwining of the ACC amygdala & insula in adults results in attribution of fault even when there is none which can make it hard to step in and actually help.  But in seven-year-olds the activation is concrete: PAG and sensory & motor cortexes with minimal coupling to the rudimentary vmPFC.  In older children the vmPFC is coupled to limbic structures.  Ten to twelve year olds abstract empathy to classes of people.  Brizendine asserts young girls develop empathy earlier than boys, because their evolved greater neuronal investment in communication and emotion networks.  Year old girls are much more responsive to the distress of other people than boys are.  At 18 months girls are experiencing infantile puberty.  By adolescence the vmPFC is coupled to theory of mind regions and intentional harm induces disgust via the amygdala.  Sapolsky explains adolescent boys are utilitarian and tend to accept inequality more than girls do.  But both sexes accept inequality as the way it is.  Sociopaths do not develop empathy.   supporting people relating to other's pain.  This is dependent on oxytocin is a peptide hormone which makes humans more prosocial to and socially competent in their in-group and more antisocial to everyone else.  The effects are contingent; changing during stress and in the presence of a threatening out-group.  Oxytocin makes people look at eyes longer, encouraging improved accuracy at perceiving emotions.  It enhances activity in the TPJ supporting modeling of other people's thinking.  Dogs and their owners secrete oxytocin increasing the amount of eye contact between them.  It is associated with pair bonding.  Brizendine explains that oxytocin and dopamine production are stimulated by ovarian estrogen at the onset of puberty, encouraging girls to connect and bond with their girlfriends, reducing stress, and exclude the out-group.  It is central to female mammals wanting to nurse, nursing, and remembering their child.  Its effects are context dependent and so is the regulation of the genes that control oxytocin.  Variants of a gene CD38 which facilitates oxytocin secretion from neurons are associated with differing levels of activation of the fusiform face area when looking at faces.  Sapolsky describes an oxytocin receptor gene variant that is associated with children showing: Extreme aggression, A callous unemotional style; foreshadowing adult psychopathy.  And another receptor gene variant is associated with childhood social disconnection and unstable adult relationships.  Gene/environment interactions complicate the interpretation of the presence of particular gene variants.  Hypothalamic neurons send projections to: ventral tegmentum which also becomes more receptive during child birth, nucleus accumbens, hippocampus, amygdala where it inhibits the central amygdala suppressing fear & anxiety consistently in men while still allowing women to respond to threats to their infants, frontal cortex, olfactory network where it helps new rat mums to learn the smell of their offspring; where oxytocin prepares the brain for in-group bonding, out-grouping, birth and maternal behavior.  Outside the brain hypothalamic neurons in females send oxytocin to the posterior pituitary where it enters the blood stream stimulating uterine contraction during labor & supporting milk production for weaning.  Disorders associated with oxytocin abnormalities include ASD. 
  . 
  
• In non-human mammals it processes interoceptive signals indicate the body's internal homeostatic state: Pain, Fatigue; seconds to minutes before.  The signals are conveyed to the CNS via unmyelinated C fibers or lightly myelinated A delta fibers.  Damasio suggests this is key to the fabrication of feelings, allowing interaction with the surrounding chemical environment and cross talk between axons.  These signals operate unconsciously unless mapped by feelings into consciousness.  The interoceptive 'networks': default mode network; project to brain regions that implement social emotions. 
  .  The ACC focuses the internal signals into high level 'gut intuitions.'  Pain emerged as a mental experience, Damasio asserts, constructed by the mind using mapping structures and events provided by nervous systems.  But feeling pain is supported by older biological functions that support homeostasis.  These capabilities reflect the organism's underlying emotive processes that respond to wounds: antibacterial and analgesic chemical deployment, flinching and evading actions; that occur in organisms without nervous systems.  Later in evolution, after organisms with nervous systems were able to map non-neural events, the components of this complex response were 'imageable'.  Today, a wound induced by an internal disease is reported by old, unmyelinated C nerve fibers.  A wound created by an external cut is signalled by evolutionarily recent myelinated fibers that result in a sharp well-localized report, that initially flows to the dorsal root ganglia, then to the spinal cord, where the signals are mixed within the dorsal and ventral horns, and then are transmitted to the brain stem nuclei, thalamus and cerebral cortex.  The pain of a cut is located, but it is also felt through an emotive response that stops us in our tracks.  Pain amplifies the aggression response of people by interoceptive signalling of brain regions providing social emotions including the PAG projecting to the amygdala; making aggressive people more so and less aggressive people less so.  Fear of pain is a significant contributor to female anxiety.  Pain is the main reason people visit the ED in the US.  Pain is mediated by the thalamus and nucleus accumbens, unless undermined by sleep deprivation. 
  catches the ACC's attention. 
  
• Performs discrepancy detection from the outcome that was predicted - at a high level.  The ACC cares about the meaning of what is predicted. 
  
• If the ACC has been convinced that a pain killer placebo has inhibited pain signals, the ACC will stay silent about actual pain that is signalled from interoceptive networks.  
• The ACC will signal: physical pain, emotional pain, metaphorical pain, anxiety is manifested in the amygdala mediating inhibition of dopamine rewards.  Anxiety disorders are now seen as a related cluster, including PTSD, panic attacks, and phobias.  Major anxiety, is typically episodic, correlated with increased activity in the amygdala, results in elevated glucocorticoids and reduces hippocampal dendrite & spine density.  Some estrogen receptor variants are associated with anxiety in women.  Women are four times more likely to suffer from anxiety.  Louann Brizendine concludes this helps prepare mothers, so they are ready to protect their children.  Michael Pollan concludes anxiety is fear of the future.  Sufferers of mild autism often develop anxiety disorders.  Treatments for anxiety differ.  50 to 70% of people with generalized anxiety respond to drugs increasing serotonin concentrations, where there is relief from symptoms: worry, guilt; linked to depression, which are treated with SSRIs (Prozac).  Cognitive anxiety (extreme for worries and anxious thoughts) is also helped by yoga.  But many fear-related disorders respond better to psychotherapy: psychoanalysis, and intensive CBT.  Tara Brach notes that genuine freedom from fear is enabled by taking refuge. 
  , disgust is a universal human emotion.  Pinker notes it has its own facial expression and is codified in food taboos.  The mind must be associated with the proximate environment and parents minimize the risk for their omnivorous children by teaching them what foods to eat and what to avoid.  The children's minds are initially receptive to trying all foods but their brains subsequently lock in on the foods they have experienced.  These parental choices are affected by schematic influence on what has been beneficial.  Adolescent's brain developments undermine these constraints enabling intergroup transfers.  Disgust is modulated by the insula cortex which projects signals to the amygdala.  Adult humans merge moral and physical disgust enabling metaphorical out grouping. 
  , embarrassment, social exclusion especially in adolescence in humans supports the transition from a juvenile configuration, dependent on parents and structured to learn & logistically transform, to adult optimized to the proximate environment.  And it is staged, encouraging male adolescents to escape the hierarchy they grew up in and enter other groups where they may bring in: fresh ideas, risk taking; and alter the existing hierarchy: Steve Jobs & Steve Wozniak, Bill Gates & Paul Allen; while females become highly focused on friendships and communications.  It marks the beginning of Piaget's formal operational stage of cognitive development.  The limbic, autonomic and hormone networks are already deployed and functioning effectively.  The frontal cortex has to be pruned: winning neurons move to their final highly connected positions, and are myelinated over time.  The rest dissolve.  So the frontal lobe does not obtain its adult configuration and networked integration until the mid-twenties when prefrontal cortex control becomes optimal.  The evolutionarily oldest areas of the frontal cortex mature first.  The PFC must be iteratively customized by experience to do the right thing as an adult.  Adolescents:
  • Don't detect irony effectively.  They depend on the DMPFC to do this, unlike adults who leverage the fusiform face area.  
  • Regulate emotions with the ventral striatum while the prefrontal cortex is still being setup.  Dopamine projection density and signalling increase from the ventral tegmentum catalyzing increased interest in dopamine based rewards.  Novelty seeking allows for creative exploration which was necessary to move beyond the familial pack.  Criticisms do not get incorporated into learning models by adolescents leaving their risk assessments very poor.  The target of the dopamine networks, the adolescent accumbens, responds to rewards like a gyrating top - hugely to large rewards, and negatively to small rewards.  Eventually as the frontal regions increase in contribution there are steady improvements in: working memory, flexible rule use, executive organization and task shifting.  And adolescents start to see other people's perspective. 
    
  • Drive the cellular transformations with post-pubescent high levels of testosterone in males, and high but fluctuating estrogen & progesterone levels in females.  Blood flow to the frontal cortex is also diverted on occasion to the groin.  
  • Peer pressure is exceptionally influential in adolescents.  Admired peer comments reduce vmPFC activity and enhance ventral striatal activity.  Adults modulate the mental impact of socially mean treatment: the initial activation of the PAG, anterior cingulate, amygdala, insula cortex; which generate feelings of pain, anger, and disgust, with the VLPFC but that does not occur in adolescents.  
  • Feel empathy intensely, supported by their rampant emotions, interest in novelty, ego.  But feeling the pain of others can induce self-oriented avoidance of the situations. 
    
  ; as one and the same.  The ACC's abnormalities being associated with major depression is a debilitating episodic state of extreme sadness, typically beginning in late teens or early twenties. This is accompanied by a lack of energy and emotion, which is facilitated by genetic predisposition - for example genes coding for relatively low serotonin levels, estrogen sensitive CREB-1 gene which increases women's incidence of depression at puberty; and an accumulation of traumatic events.  There is a significant risk of suicide: depression is involved in 50% of the 43,000 suicides in the US, and 15% of people with depression commit suicide.  Depression is the primary cause of disability with about 20 million Americans impacted by depression at any time.  There is evidence of shifts in the sleep/wake cycle in affected individuals (Dec 2015).  The affected person will experience a pathological sense of loss of control, prolonged sadness with feelings of hopelessness, helplessness & worthlessness, irritability, sleep disturbances, loss of appetite, and inability to experience pleasure.  Michael Pollan concludes depression is fear of the past.  It affects 12% of men and 20% of women.  It appears to be associated with androgen deprivation therapy treatment for prostate cancer (Apr 2016).  Chronic stress depletes the nucleus accumbens of dopamine, biasing humans towards depression.  Depression easily leads to following unhealthy pathways: drinking, overeating; which increase the risk of heart disease.   It has been associated with an aging related B12 deficiency (Sep 2016).  During depression, stress mediates inhibition of dopamine signalling.  Both depression and stress activate the adrenal glands' release of cortisol, which will, over the long term, impact the PFC.  There is an association between depression and additional brain regions: Enlarged & more active amygdala, Hippocampal dendrite and spine number reductions & in longer bouts hippocampal volume reductions and memory problems, Dorsal raphe nucleus linked to loneliness, Defective functioning of the hypothalamus undermining appetite and sex drive, Abnormalities of the ACC.  Mayberg notes ACC area 25: serotonin transporters are particularly active in depressed people and lower the serotonin in area 25 impacting the emotion circuit it hubs, inducing bodily sensations that patients can't place or consciously do anything about; and right anterior insula: which normally generates emotions from internal feelings instead feel dead inside; are critical in depression.  Childhood adversity can increase depression risk by linking recollections of uncontrollable situations to overgeneralizations that life will always be terrible and uncontrollable.  Sufferers of mild autism often develop depression.  Treatments include: CBT which works well for cases with below average activity of the right anterior insula (mild and moderate depression), UMHS depression management, deep-brain stimulation of the anterior insula to slow firing of area 25.  Drug treatments are required for cases with above average activity of the right anterior insula.  As of 2010 drug treatments: SSRIs (Prozac), MAO, monoamine reuptake inhibitors; take weeks to facilitate a response & many patients do not respond to the first drug applied, often prolonging the agony.  By 2018, Kandel notes, Ketamine is being tested as a short term treatment, as it acts much faster, reversing the effect of cortisol in stimulating glutamate signalling, and because it reverses the atrophy induced by chronic stress.   Genomic predictions of which treatment will be effective have not been possible because: Not all clinical depressions are the same, a standard definition of drug response is difficult;. 
  
• Has a bridging role between the empathetic and self-interested pain monitor.  Sapolsky notes the ACC is essential for learning fear is an emotion which prepares the body for time sensitive action: Blood is sent to the muscles from the gut and skin, Adrenalin is released stimulating: Fuel to be released from the liver, Blood is encouraged to clot, and Face is wide-eyed and fearful.  The short-term high priority goal, experienced as a sense of urgency, is to flee, fight or deflect the danger.  There are both 'innate' - really high priority learning - which are mediated by the central amygdala and learned fears which are mediated by the BLA which learns to fear a stimulus and then signals the central amygdala.  Tara Brach notes we experience fear as a painfully constricted throat, chest and belly, and racing heart.  The mind can build stories of the future which include fearful situations making us anxious about current ideas and actions that we associate with the potential future scenario.  And it can associate traumatic events from early childhood with our being at fault.  Consequent assumptions of our being unworthy can result in shame and fear of losing friendships.  The mechanism for human fear was significantly evolved to protect us in the African savanna.  This does not align perfectly with our needs in current environments: U.S. Grant was unusually un-afraid of the noise or risk of guns and trusted his horses' judgment, which mostly benefited his agency as a modern soldier. 
  and conditioned avoidance by observation alone through an intermediate step of shared representation of self.  He concludes "At its core the ACC is about self-interest, with caring about the other person in pain as an add-on." 
  
• American College of Cardiology
  
• ACE is
  
• An acute care episode.  CMS is the centers for Medicare and Medicaid services.   has used an ACE demonstrator to explore the value of bundled payments is where the purchaser disburses a single predefined payment to cover certain combinations of hospital, physician, post-acute, or other services performed during an episode of care relating to a particular condition (unlike capitation).  This bundling is assumed (Sep 2018) to allow the value delivery system to optimize around low cost high quality long term health care.  With one bundled payment physicians & hospitals must coordinate care and reduce the unit costs to remain profitable.  And to avoid taking on risk of expensive complications physicians & hospitals are incented to standardize and focus on quality.  This optimization is dependent on quantifying the value of the outcome of the episode of care.  Previously FFS payments induced excessive treatment activity.  Bundled payment is included in CMS ACE demonstrations and BPCI initiatives.  There are significant impacts on IT. 
  
  1. It is argued that effective pricing of the bundle requires marketing data which must be extracted from the historic transaction base.  
  2. Billing and payment systems must be updated to handle the receipt and distribution of the bundled payments. 
     
  3. Care delivery must be re-architected to reduce costs and improve quality. 
     
  4. Monitoring sensors can be used to feed reports to ensure re-architected operations conform.  
  .  The demonstrator covered 37 cardiac is the diagnosis and treatment of: Congenital heart defects, CAD, Heart failure, Valvular heart disease; by cardiologists.   and orthopedic is the treatment of the musculoskeletal system which supports multi-cell higher animals and allows them to move about: including correcting deformities, breaks, tears, compression, tendonitis, disc failures, misalignment, fusion to treat damaged discs. 
  procedures including: bypass surgery, hip replacements, pacemakers, and cardiac stents is a small wire cage that can be inserted into an artery to prop it open.  They were introduced as an alternative to bypass surgery in the 1990s.  Stents are expensive.  Medicare payments vary depending on what kind of stent is used and how many, but are generally in the range $10,000 to $17,000 in 2015.   Double blind trials show that stents have no effect on chest pain relief (Nov 2017)
  ; in 11 hospitals.  It saved $319 per person, across over 12,000 cases, on average.  
• Angiotensin-converting-enzyme. 
  
• ACE inhibitor is angiotensin-converting-enzyme inhibitor.  They help relax blood vessels and are used to treat hypertension and CHF is congestive heart failure which occurs when the heart is unable to generate enough blood flow to meet the body's demands.  There are two main types: failure due to left ventricular dysfunction and abnormal diastolic function increasing the stiffness of the left ventricle and decreasing its relaxation.  Heart expansion in CHF distorts the mitral valve which exacerbates the problems.  MitraClip surgery trials found effective in correcting the mitral valve damage (Sep 2018).  Treatments include: digoxin; .  
• ACHC is the accreditation commission for health care.  It is recognized by the federal government for:
• HHA is home health agency. 
  accreditation along with the CHAP is the community health accrediation program, one of three federally recognized HHA focused programs along with those provided by the Joint Commission and ACHC. 
  and the Joint Commission, JC or JCAHO is a nonprofit that accredits more than 19,000 health care organizations and programs in the United States. 
  
  • Home health care: The JC is one of three groups (JC, CHAP, ACHC) recognized by the federal government as accreditors of HHAs.  The JC requires its accredited HHAs receive payment from Medicare.  To become accredited an HHA must undergo detailed reviews and onsite visits, including direct observation of patient caregiving, every three years. 
    
  • Hospitals: In 1965 the federal government decided that a hospital that met joint commission accreditation met the Medicare conditions of participation.  MIPPA removed the joint commission's accreditation authority requiring it to submit accreditations to CMS which subsequently determines the granting of accreditation. 
    
  • Rehabilitation: Joint Commission accreditation is an alternative to CARF certification for rehabilitation.  
  .  
• ACI is advanced care information. 
  
• ACID transactions are Atomic, Consistent, Isolated and Durable, allowing the user of the transaction a simple operating paradigm.  In particular if the transaction fails there are no ramifications outside of the local transaction.  
• ACO is an Accountable Care Organization. These are accredited bundles of companies which together try to offer Dartmouth-Hitchcock like business models (Dec 2015, Sep 2016) focused on wellness is a health care oriented employer based strategy for reducing health care costs and encouraging wellbeing.  Wellbeing has traditionally been a focus of public health.  , improving the provision of primary care to a large group of Medicare is a social insurance program that guarantees access to health insurance for Americans aged 65 and over, and younger people with disabilities and end stage renal disease or ALS.  Medicare is currently missing a cap on out-of-pocket costs and direct prescription drug coverage.  It includes:
  
  • Benefits
  • Part A: Hospital inpatient insurance.  As of Dec 2013 Medicare pays for home care in only limited circumstances, such as when a person needs temporary nursing care after a hospitalization.  Part A covers 20 days of inpatient rehabilitation at a SNF after discharge from inpatient care at a hospital. 
    
  • Part B: Medical insurance for non-hospital services including: doctor visits, tests, injectable drugs, ambulances, physical therapy;
    
  • Part C: Medicare Advantage 
  • Part D: indirect prescription drug coverage The MMA prohibits Medicare from directly negotiating drug prices. 
    
  • Eligibility
    
  • All persons 65 years of age or older who are legal residents for at least 5 years.  If they or a spouse have paid Medicare taxes for 10 years the Medicare part A payments are waived.  Medicare is legislated to become the primary health plan. 
    
  • Persons under 65 with disabilities who receive SSDI. 
    
  • Persons with specific medical conditions:
  • Have end stage renal disease or need a kidney transplant. 
    
  • They have ALS. 
    
  • Some beneficiaries are dual eligible. 
    
  • Part A requires the person has been admitted as an inpatient at a hospital.  This is constrained by a rule that they stay for three days after admission.  
    
  • Sign-up
  • Part A has automatic sign-up if the person is drawing social security.  Otherwise the person must sign-up for Part A and Part B. 
    
  • Should sign-up for Part B during the Initial Enrollment Period, of seven months centered around 65th birthday, online or at a social security office.  But if still covered by spouse's insurance or not yet retired then may only join during the 3 month general enrollment period (January to March) each year, with coverage initiated the following July.  Incremental yearly 10% penalties apply for not signing up at 65.  These penalties apply to all subsequent premiums. 
    
  • Premiums
  • Part A premium
  • Part B insurance premium
    
  • Part C & D premiums are set by the commercial insurer.  
  patients, and rewarding doctors for preventing problems.  Advocate health illustrates the idea.  Robert Pearl notes that the transition is difficult: hospitals that find their efficiency improving should reduce the number of doctors they utilize.  But any doctors that are pushed out of the ACO will likely take their patients with them, undermining the revenues that support the FFV is fee-for-value payment.  It may be a bundled payment for a set of services provided by a group of doctors and facilities, or full capitation.  In each case the risk has shifted from the payer to the providers of care. 
  business.  The ACA is the Patient Protection and Affordable Care Act amended by the Health Care and Education Reconciliation Act of 2010 (Obama care).  In part it is designed to make the health care system costs grow slower.  It aims to do this by: increasing competition between insurers and providers, offering free preventative services to limit the development of serious illnesses, constraining patients' use of expensive services, constraining the growth of payments to Medicare providers and piloting new ways for PCPs to manage patient care to keep patients away from costly E.D.s.  It funds these changes with increased taxes on the wealthy.  It follows an architecture developed by Heritage Action's Butler, Moffit, Haislmaier extended by White House OMB health policy advisor Ezekiel Emanuel & architect Jeanne Lambrew.  The Obama administration drafting team included: Bob Kocher; allowing it to integrate ideas from: Dartmouth Institute's Elliot Fischer (ACO).  The ACA did not include a Medicare buy in (May 2016).  The law includes:
  • Alterations, in title I, to how health care is paid for and who is covered.  This has been altered to ensure
    
  • Americans with preexisting conditions get health insurance cover - buttressed by mandating community rating and
    
  • That they are constrained by the individual mandate to have insurance but the requirement was supported by subsidies for the poor (those with incomes between 100 & 400% of the federal poverty line).  
  • Children, allowed to, stay on their parents insurance until 26 years of age. 
    
  • Medicare solvency improvements. 
    
  • Medicaid expansion, in title II: to poor with incomes below 138% of the federal poverty line; an expansion which was subsequently constrained by the Supreme Court's ruling making expansion an optional state government decision. 
    
  • Hospital Readmissions Reduction Program (HRRP) which was enforced by CMS mandated rules finalized in 2011 and effected starting Oct 2012.  
  • Medical home models.  
  • Community transformation grants support the transformation of low income stressed neighborhoods to improve their lifestyles and health. 
    
  • Qualifications for ACOs.  Organizations must:
    
  • Establish a formal legal structure with shared governance which allows the ACO to distribute shared savings payments to participating providers and suppliers. 
    
  • Participate in the MSSP for three or more years. 
    
  • Have a management structure. 
    
  • Have clinical and administrative systems. 
    
  • Include enough PCPs to care for Medicare FFS patient population (> 5000) assigned to the ACO. 
    
  • Be accountable for the quality and cost of care provided to the Medicare FFS patient population. 
    
  • Have defined processes to promote: Evidence-based medicine, Patient-centeredness, Quality reporting, Cost management, Coordination of care; 
  • Demonstrate it meets HHS patient-centeredness criteria including use of patient and caregiver assessments and individualized care plans.  
  • CMMI Medicare payment experimentation.  
  • Requirements that pharmaceutical companies must report payments made to physicians (Sunshine Act). 
    
  • A requirement that chain restaurants must report calorie counts on their menus. 
    
  regulates qualification to be a Medicare is a social insurance program that guarantees access to health insurance for Americans aged 65 and over, and younger people with disabilities and end stage renal disease or ALS.  Medicare is currently missing a cap on out-of-pocket costs and direct prescription drug coverage.  It includes:
  
  • Benefits
  • Part A: Hospital inpatient insurance.  As of Dec 2013 Medicare pays for home care in only limited circumstances, such as when a person needs temporary nursing care after a hospitalization.  Part A covers 20 days of inpatient rehabilitation at a SNF after discharge from inpatient care at a hospital. 
    
  • Part B: Medical insurance for non-hospital services including: doctor visits, tests, injectable drugs, ambulances, physical therapy;
    
  • Part C: Medicare Advantage 
  • Part D: indirect prescription drug coverage The MMA prohibits Medicare from directly negotiating drug prices. 
    
  • Eligibility
    
  • All persons 65 years of age or older who are legal residents for at least 5 years.  If they or a spouse have paid Medicare taxes for 10 years the Medicare part A payments are waived.  Medicare is legislated to become the primary health plan. 
    
  • Persons under 65 with disabilities who receive SSDI. 
    
  • Persons with specific medical conditions:
  • Have end stage renal disease or need a kidney transplant. 
    
  • They have ALS. 
    
  • Some beneficiaries are dual eligible. 
    
  • Part A requires the person has been admitted as an inpatient at a hospital.  This is constrained by a rule that they stay for three days after admission.  
    
  • Sign-up
  • Part A has automatic sign-up if the person is drawing social security.  Otherwise the person must sign-up for Part A and Part B. 
    
  • Should sign-up for Part B during the Initial Enrollment Period, of seven months centered around 65th birthday, online or at a social security office.  But if still covered by spouse's insurance or not yet retired then may only join during the 3 month general enrollment period (January to March) each year, with coverage initiated the following July.  Incremental yearly 10% penalties apply for not signing up at 65.  These penalties apply to all subsequent premiums. 
    
  • Premiums
  • Part A premium
  • Part B insurance premium
    
  • Part C & D premiums are set by the commercial insurer.  
  ACO.  Individual organizations within a Medicare is a social insurance program that guarantees access to health insurance for Americans aged 65 and over, and younger people with disabilities and end stage renal disease or ALS.  Medicare is currently missing a cap on out-of-pocket costs and direct prescription drug coverage.  It includes:
  
  • Benefits
  • Part A: Hospital inpatient insurance.  As of Dec 2013 Medicare pays for home care in only limited circumstances, such as when a person needs temporary nursing care after a hospitalization.  Part A covers 20 days of inpatient rehabilitation at a SNF after discharge from inpatient care at a hospital. 
    
  • Part B: Medical insurance for non-hospital services including: doctor visits, tests, injectable drugs, ambulances, physical therapy;
    
  • Part C: Medicare Advantage 
  • Part D: indirect prescription drug coverage The MMA prohibits Medicare from directly negotiating drug prices. 
    
  • Eligibility
    
  • All persons 65 years of age or older who are legal residents for at least 5 years.  If they or a spouse have paid Medicare taxes for 10 years the Medicare part A payments are waived.  Medicare is legislated to become the primary health plan. 
    
  • Persons under 65 with disabilities who receive SSDI. 
    
  • Persons with specific medical conditions:
  • Have end stage renal disease or need a kidney transplant. 
    
  • They have ALS. 
    
  • Some beneficiaries are dual eligible. 
    
  • Part A requires the person has been admitted as an inpatient at a hospital.  This is constrained by a rule that they stay for three days after admission.  
    
  • Sign-up
  • Part A has automatic sign-up if the person is drawing social security.  Otherwise the person must sign-up for Part A and Part B. 
    
  • Should sign-up for Part B during the Initial Enrollment Period, of seven months centered around 65th birthday, online or at a social security office.  But if still covered by spouse's insurance or not yet retired then may only join during the 3 month general enrollment period (January to March) each year, with coverage initiated the following July.  Incremental yearly 10% penalties apply for not signing up at 65.  These penalties apply to all subsequent premiums. 
    
  • Premiums
  • Part A premium
  • Part B insurance premium
    
  • Part C & D premiums are set by the commercial insurer.  
  shared savings is the Medicare Shared Savings Program.  The program began in 2012 with 3 year term contracts.  ACO Physician groups and hospitals are eligible to participate but there must be primary care physicians in the ACO.  Participating ACOs must serve > 5000 Medicare beneficiaries.  The potential for a bonus payment is based on Medicare cost savings and quality metrics.  Two payment models are available.  Only one has downside risk involved.  CMS included 'robust' quality measures to monitor the quality of care provided and beneficiary satisfaction (see fact sheet 'Improving Quality of Care for Medicare Patients: Accountable Care Organizations'). 
  ACO continue to submit their own claims and are paid by Medicare for FFS is fee-for-service payment.  For health care providers the high profits were made in hospitalizations, imaging and surgery.  Due to its inducing excessive treatment activity it may be replaced by FFV bundled payment.  .  But the ACO is eligible for shared savings is the Medicare Shared Savings Program.  The program began in 2012 with 3 year term contracts.  ACO Physician groups and hospitals are eligible to participate but there must be primary care physicians in the ACO.  Participating ACOs must serve > 5000 Medicare beneficiaries.  The potential for a bonus payment is based on Medicare cost savings and quality metrics.  Two payment models are available.  Only one has downside risk involved.  CMS included 'robust' quality measures to monitor the quality of care provided and beneficiary satisfaction (see fact sheet 'Improving Quality of Care for Medicare Patients: Accountable Care Organizations'). 
  .  Within the shared savings program the CMS is the centers for Medicare and Medicaid services.   innovation center is the CMS Innovation Center.  It was created by the ACA to test new models of health care delivery and payment including the Pioneer ACO and the Advance Payment ACO.  It also offers technical support to providers to improve the coordination of care and share lessons learned and best practices.  In 2016 Andy Slavitt proposed testing a new Medicare part B drug pricing rule, which was furiously resisted by PhRMA and blocked by Representative Skimkus collection of 242 Representative's signatures. 
  has setup advanced payment ACOs is a CMS Innovation center has developed a model of an ACO for physician-owned and rural providers participating in the Shared Savings Program who would benefit from additional start-up resources to build the necessary infrastructure, such as new staff or information technology systems.  .  As an alternative to shared savings, in a Pioneer ACO is a CMS Innovation Center initiative to support ACOs in providing more coordinated care to beneficiaries (individuals and populations) at lower cost to Medicare.  It leverages the ACA shared savings program and tests an alternative 'pioneer ACO' model.  Pioneers are assumed to be organizations with experience offering coordinated, patient-centered care, and operating in ACO-like arrangements.  A first performance period Jan 1 2012 - 2014 tests a shared savings and shared losses payment arrangement with higher levels of reward and risk than in the shared savings program.  In year three Pioneer ACOs that have showed savings over the first two years can move to a population based payment model.  Two alternative payment models were added which allow pioneer ACOs more flexibility in the speed at which they assume financial risk.  Pioneers must also commit to having greater than 50% of primary care providers meet meaningful use of certified EHRs for receipt of payments through Medicare and Medicaid EHR Incentive Programs.  Pioneers must have > 15000 beneficiaries enrolled in original FFS part A and part B Medicare.  Organizations were selected using these criteria. 
  , over time 50% of the FFS payments flow directly to the ACO as a bundled payment is where the purchaser disburses a single predefined payment to cover certain combinations of hospital, physician, post-acute, or other services performed during an episode of care relating to a particular condition (unlike capitation).  This bundling is assumed (Sep 2018) to allow the value delivery system to optimize around low cost high quality long term health care.  With one bundled payment physicians & hospitals must coordinate care and reduce the unit costs to remain profitable.  And to avoid taking on risk of expensive complications physicians & hospitals are incented to standardize and focus on quality.  This optimization is dependent on quantifying the value of the outcome of the episode of care.  Previously FFS payments induced excessive treatment activity.  Bundled payment is included in CMS ACE demonstrations and BPCI initiatives.  There are significant impacts on IT. 
  
  1. It is argued that effective pricing of the bundle requires marketing data which must be extracted from the historic transaction base.  
  2. Billing and payment systems must be updated to handle the receipt and distribution of the bundled payments. 
     
  3. Care delivery must be re-architected to reduce costs and improve quality. 
     
  4. Monitoring sensors can be used to feed reports to ensure re-architected operations conform.  
  .  CMS is the centers for Medicare and Medicaid services.   has established quality measures for ACOs for Medicare is a social insurance program that guarantees access to health insurance for Americans aged 65 and over, and younger people with disabilities and end stage renal disease or ALS.  Medicare is currently missing a cap on out-of-pocket costs and direct prescription drug coverage.  It includes:
  
  • Benefits
  • Part A: Hospital inpatient insurance.  As of Dec 2013 Medicare pays for home care in only limited circumstances, such as when a person needs temporary nursing care after a hospitalization.  Part A covers 20 days of inpatient rehabilitation at a SNF after discharge from inpatient care at a hospital. 
    
  • Part B: Medical insurance for non-hospital services including: doctor visits, tests, injectable drugs, ambulances, physical therapy;
    
  • Part C: Medicare Advantage 
  • Part D: indirect prescription drug coverage The MMA prohibits Medicare from directly negotiating drug prices. 
    
  • Eligibility
    
  • All persons 65 years of age or older who are legal residents for at least 5 years.  If they or a spouse have paid Medicare taxes for 10 years the Medicare part A payments are waived.  Medicare is legislated to become the primary health plan. 
    
  • Persons under 65 with disabilities who receive SSDI. 
    
  • Persons with specific medical conditions:
  • Have end stage renal disease or need a kidney transplant. 
    
  • They have ALS. 
    
  • Some beneficiaries are dual eligible. 
    
  • Part A requires the person has been admitted as an inpatient at a hospital.  This is constrained by a rule that they stay for three days after admission.  
    
  • Sign-up
  • Part A has automatic sign-up if the person is drawing social security.  Otherwise the person must sign-up for Part A and Part B. 
    
  • Should sign-up for Part B during the Initial Enrollment Period, of seven months centered around 65th birthday, online or at a social security office.  But if still covered by spouse's insurance or not yet retired then may only join during the 3 month general enrollment period (January to March) each year, with coverage initiated the following July.  Incremental yearly 10% penalties apply for not signing up at 65.  These penalties apply to all subsequent premiums. 
    
  • Premiums
  • Part A premium
  • Part B insurance premium
    
  • Part C & D premiums are set by the commercial insurer.  
  .  The CMS program's purpose is to reward providers for reducing total cost of care for patients through prevention, disease management, and coordination aims to transfer information between the patient and each care participant as required and establish accountability by defining who is responsible for each care delivery activity, the extent of that responsibility and when that responsibility will be transferred to other care participants or the patient and family.  Successful care coordination requires face-to-face interactions.  It also requires aligned incentives (ACO, Bundled payments).  AHRQ defines quality measures for care coordination.  The situation is usually complex and adaptive due to the interactions of all the providers, settings, the patients' preferences, and the number of physical health problems, treatments, and the patients' social situation.  The potentially exponential increase in complexity as the number of these factors present increases leads to patient hot spots requiring explicit proactive coordination of care.  It is argued that care coordination must include six specific activities:
  1. Determination and updating of care coordination needs: Needs assessment should identify preferences and goals, current situation and past history.  It needs to be updated periodically and after new diagnosis and other changes in health or functional status. 
     
  2. Creation and updating of proactive plan of care
     
  3. Communication
  4. Facilitation of transitions: typical transition problems are detailed by Project Boost.  A challenging issue with transitions is what to do when there is no resource to take over the coordination role in the handoff. 
     
  5. Connection to community resources: Community resources are any service or program outside the health care system that may support a patient's health and wellness. 
     
  6. Alignment of resources with population needs: need to see the system-level, assess the needs of populations to identify and address gaps in services.  
  . 
  
• CMS initiated its Physician Group Practice in health care is physician group practice a CMS demonstrator program that led to the promotion of ACOs. 
  Demonstration in 2005.  By 2008 the congressional budget office reported on Bonus-eligible organizations. 
  
• CMS defines ACOs as organizations that "create incentives for health care providers to work together to treat an individual patient across care settings - including doctors' offices, hospitals and long-term care facilities."
• CMS has developed APM is alternative payment model, Medicare's risk based payments to organizations set up as ACOs.  It includes track 1 ACOs which are not risk bearing.  APMs have to report various measures to CMS. 
  s which include ACOs, and advanced APM is a CMS regulated group of APMs that effectively uses FFV.  The list includes: Risk-bearing ACOs, Comprehensive end stage renal disease care, Comprehensive primary care plus, Oncology care model. 
  s where the ACOs must be risk bearing. 
  
• CMMI is the center for Medicare and Medicaid Innovation.  It is a test bed for new ways of financing and delivering care.  It allowed Congress to institutionalize innovation sending a signal to providers that they would be participating in CMS driven programs that could become mainstream.  It funds evaluations of innovative health care models.  Under the ACA if the HHS secretary finds any of its projects would reduce Medicare spending without harming the quality of care the projects may be expanded nationwide.  The CBO estimates the CMMI will save $34 billion between 2016 and 2026.  CMMI projects include:
  • Medicare will make a bundled payment for hip and knee replacement surgery (CJR) and 90 days of follow-up care forcing hospitals to work closely with doctors, nursing homes and home health agencies.  
  • New ways to pay for prescription drugs, medical devices, cancer care (OCM).  
  • HHS secretary has invoked his 3021 authority to institute DPP. 
    
  accepts providers' proposals to test various payment systems including shared savings is the Medicare Shared Savings Program.  The program began in 2012 with 3 year term contracts.  ACO Physician groups and hospitals are eligible to participate but there must be primary care physicians in the ACO.  Participating ACOs must serve > 5000 Medicare beneficiaries.  The potential for a bonus payment is based on Medicare cost savings and quality metrics.  Two payment models are available.  Only one has downside risk involved.  CMS included 'robust' quality measures to monitor the quality of care provided and beneficiary satisfaction (see fact sheet 'Improving Quality of Care for Medicare Patients: Accountable Care Organizations'). 
  and partial capitation is a global payment for all care for a patient during a specified time period.  It forces the provider of care to take a high risk.  Managing the risk implies successful population health management. 
  .  
• Private market ACOs have formed including: Providence Health & Services, Blue Shield California, Anthem Blue Cross, United Health Care, BCBS Minnesota, BCBS Illinois, Humana, CIGNA, Main Health Management Coalition, BCBS Massachusetts, Aetna.  
• ACOG is the American Congress of Obstetricians and Gynecologists. 
  
• ACR is the American College of Radiology.  It is HHS is the U.S. Department of Health and Human Services.  's PAMA is the Protecting Access to Medicare Act of 2014.  It includes:
  • Delays of the SGR cut to Medicare until March 2015 ('doc fix').  The delay is partly funded with cuts to Medicare's funding of SNF, lab tests, physician and other provider services.  The rest is offset by moving Medicare sequester cuts from 2025 to 2024.  This SGR cut has been iteratively delayed for 10 years and was finally removed in 2015. 
  • Helps states establish CCBHCs through section 223 the Excellence in Mental Health Act demonstration program.  This stipulated that CCBHCs may receive an enhanced Medicaid reimbursement rate based on their anticipated cost of care. 
    
  • Directs HHS to develop VBP and readmissions strategies for SNFs
  • Directs HHS to: Develop, Promote the use by ordering and furnishing agents of, Make the interfaces public of; rules for imaging services appropriateness criteria.  The rules held in a radiology CDSS will remove the need for pre-authorization of the procedure. 
    
  • Enhances clinical diagnostic laboratory tests coverage, payment rates;
  • Alters end stage renal disease payments, audits;
  applicable imaging services are advanced diagnostic imaging services for which appropriate use criteria apply.   appropriate use criteria are those:
  
  • Which assist ordering and furnishing professionals in making the most appropriate treatment decision per condition for this individual
    
  • Developed or endorsed by national medical specialty societies or other provider led entities.  For imaging services this is the ACR. 
    
  standards body. 
  
• Acrophonic principle where each shape of a mnemonic leveraged a word that began with the corresponding consonant.  This
  This page discusses the impact of random events which once they occur encourage a particular direction forward for a complex adaptive system (CAS). 
  
  frozen accident resulted in the names and representations of the alphabetic characters we now use as the Greeks and Phoenicians turned them into modern letters.  Greek and Roman letters have distorted Semitic names of the two dozen images that gave our letters their shape, name and pronunciation of their first consonant:
• 'A' when rotated 90 degrees looks like the ox head that it initially represented - aleph (ox). 
  
• 'b' is the outline of a house termed beth in Semitic languages include Arabic, Amharic and Hebrew.  They have an unusual morphology that emphasizes consonants.  The designers of Proto-Sinaitic writing exploited this building a representation of an abstract consonant grid that only required about two dozen shapes in the consonant lexicon.  They also used the acrophonic priciple to leverage mnemonics. 
  .  It became the Greek beta.  
  
• 'I' is a goad (lamd). 
  
• 'k' is a hand with outstretched fingers (kaf). 
  
• 'm' symbolizes waves (mayyuma). 
  
• 'n' is a snake (nahasu).  
• 'R' is a head (res). 
  
• ACTH is adrenocorticotropic hormone are signalling molecules: ACTH, TRH, Melanocyte stimulating hormone, Testosterone, Oxytocin, Vasopressin, Insulin, Growth hormone, Estrogen, Progesterone, Angiotensin II, Asprosin, EPO, Irisin, Leptin, FGF21 hormone, Prostaglandins, TSH, Thyroxine, Glococorticoids: Cortisol; that are transported by the circulatory system to interact with target organs having appropriate receptors.  The levels of hormones can fluctuate massively, as in pregnancy. 
  which stimulates the adrenal glands are endocrine glands, situated above the kidneys, that produce: adrenaline, aldosterone and cortisol. 
  to release glucocorticoids are corticosteroids which bind the glucocorticoid receptor.  They decrease excitability of prefrontal cortical neurons.  They have adverse effects in fetal/infant development having organizational effects on fetal brain construction and decreasing levels of: growth factors, neurons, synapses; resulting in an adult brain that is more sensitive to environmental triggers of depression and anxiety.  Glucocorticoids affect gene control structures and induce epi-genetic changes.  They have been found associated with high sodium chloride consumption (May 2017). 
  . 
  
• Action potentials are the actively generated waves of voltage change was formulated by Julius Bernstein to describe the generation and propagation of an action potential along a neuron's cell membrane.  It elegantly established how a resting potential of -70 millivolts was maintained until the selective permeability of the membrane is broken down briefly (0 millivolts) during the action potential, utilizing energy stored in concentration gradients of ions. 
  across the neuron's, specialized eukaryotic cells include channels which control flows of sodium and potassium ions across the massively extended cell membrane supporting an electro-chemical wave which is then converted into an outgoing chemical signal transmission from synapses which target nearby neuron or muscle cell receptors.  Neurons are supported by glial cells.  Neurons include a:
  • Receptive element - dendrites
    
  • Transmitting element - axon and synaptic terminals.  The axon may be myelinated, focusing the signals through synaptic transmission, or unmyelinated - where crosstalk is leveraged. 
  • Highly variable DNA schema using transposons. 
    
  membrane, formed from a lipid (fat) bilayer which creates a barrier between aqueous (water soluble) media.  In AWF a key property of membranes - their providing a catalytic environment and supporting the suspension of enzymatically active proteins within the membrane; is simulated with a Workspace list where 'active' structures can be inserted and codelets can detect and act on the structure's active promise configured as an association in the Slipnet.   that
  Flows of different kinds are essential to the operation of complex adaptive systems (CAS). 
  Example flows are outlined.  Constraints on flows support the emergence of the systems.  Examples of constraints are discussed. 
  
  flow down a neuron, specialized eukaryotic cells include channels which control flows of sodium and potassium ions across the massively extended cell membrane supporting an electro-chemical wave which is then converted into an outgoing chemical signal transmission from synapses which target nearby neuron or muscle cell receptors.  Neurons are supported by glial cells.  Neurons include a:
  • Receptive element - dendrites
    
  • Transmitting element - axon and synaptic terminals.  The axon may be myelinated, focusing the signals through synaptic transmission, or unmyelinated - where crosstalk is leveraged. 
  • Highly variable DNA schema using transposons. 
    
  's axon, a long extension of a neuron which has a membrane constructed to support the uni-directional flow of action potential from the dendritic tree and cell body to the synaptic terminals.  .  Helmholtz noted that while they propagate far more slowly than electrical transmissions action potentials do not attenuate.  Lord Adrian showed the action potential to be an all-or-nothing signal, is an emergent capability which is used by cooperating agents to support coordination & rival agents to support control and dominance.  In eukaryotic cells signalling is used extensively.  A signal interacts with the exposed region of a receptor molecule inducing it to change shape to an activated form.  Chains of enzymes interact with the activated receptor relaying, amplifying and responding to the signal to change the state of the cell.  Many of the signalling pathways pass through the nuclear membrane and interact with the DNA to change its state.  Enzymes sensitive to the changes induced in the DNA then start to operate generating actions including sending further signals.  Cell signalling is reviewed by Helmreich.  Signalling is a fundamental aspect of CAS theory and is discussed from the abstract CAS perspective in signals and sensors.  In AWF the eukaryotic signalling architecture has been abstracted in a codelet based implementation.  To be credible signals must be hard to fake.  To be effective they must be easily detected by the target recipient.  To be efficient they are low cost to produce and destroy. 
  .  Consequently Adrian extended the neuron doctrine is cell theory applied to the brain.  Anatomist Santiago Cajal developed ground breaking strategies to view individual neurons and concluded that nerve cells (neurons) are the fundamental building blocks and signalling units of the brain.  
  • Looking at newborn brains helped Cajal to see individual neurons because there were less present than in mature higher animals. 
    
  • Using Golgi's silver stain only 1% of neurons are stained but that 1% is fully stained revealing the full anatomy of single neurons.  This allowed Cajal to develop observations which he used to formulate the four principles of the neuron doctrine:
  1. Neuron is the fundamental structural and functional element of the brain with the dendrites and axon having different roles. 
     
  2. The terminals of one neuron's axon communicate with the dendrites of other neurons via specialized sites that include a small gap.  
  3. Connection specificity argues that neurons only form synapses and communicate with certain targets to construct a neural circuit.  Typically a single neuron makes contact with dendrites of many target cells, allowing broad dissemination of information. 
     
  4. Dynamic polarization Cajal argued was provided by signals only traveling in one direction in a neural circuit. 
     
  from anatomy to function demonstrating:
• Sensitivity is indicated by the frequency of transmission of action potentials. 
  
• Anatomy indicates the meaning of the signal.  Hodgkin and Huxley's ionic hypothesis proposes the mechanism for generating action potentials that can propagate long distances within a given neuron.  Extending Bernstein's membrane hypothesis about breakdown of the resting potential (-70 millivolts) Hodgkin and Huxley's studies on squid giant axons showed that the action potential was actively generated by transport of sodium ions into the cell (+40 millivolts) and then potassium ions out to restore the resting potential.   completed the characterization of the action potential.  
• Activation function provides an artificial neural network node with its output given a set of inputs with a weight and bias.  Typical activation functions are the sigmoid function generates an s curve.  It is f(x) = 1/(1+exp(-x)).  It is a simple function that may be selected for classifying a novel instance x as belonging to a particular class within the training data in machine learning.  The hyperplane (bias + x(t) weight) = 0 forms the decision boundary.  The orientation of the decision boundary is determined by the vector weight.  The bias shifts the decision boundary by a constant amount.  The sigmoid function is one activation function for use with neural networks which does not suffer unstable convergence (like the linear activation function), or produce a limiting binary output (like a binary function).  One effective alternative to selecting a direct sigmoid function is to apply a class conditional density estimation and Bayes rule to form the classifier. 
  and the hyperbolic tangent.  The Rectified linear function is given by f (z) = max (0, x)  often works better in practice for DNN are representational models that achieve high performance on difficult pattern recognition problems in vision and speech.  But they need specialized training methods such as greedy layerwise pre-training or HF optimization.  Researchers are gaining access to the participation of the individual 'neurons' using: visualization, attribution, dimensionality reduction, interpretability; (Mar 2018)
  s. 
  
• Active sites, on the external surface of folded proteins, a relatively long chain (polymer) of peptides.  Shorter chains of peptides are termed polypeptides.   present amino acids are the building blocks of proteins.  The 20 main variants differ by the nature of their side chain.  Some are positively charged, others negatively charged.  Some are water seeking while others are fat seeking.  The genetic code mapping of DNA base pair triplets thus specifies the primary sequence of amino-acids in any protein polymer. 
  which become catalytic structures, an infrastructure amplifier. 
  .  
• Activity based cost accounting identifies the process based flow of activities used to perform a task and the cost of each activity to effectively apportion costs. 
  
• AD is Anno Domini also referred to as common era (CE).  
• Ada refers to Ada Byron, Countess of Lovelace and, in deference to her memory, is the name of a computer programming language used in developing military systems during the late 1970s and beyond. 
  
• ADA is either the Americans with Disabilities Act of 1990 or a label for the gene that encodes the enzyme, a protein with a structure which allows it to operate as a chemical catalyst and a control switch. 
  adenosine deaminase. 
  
• Adair three-circles model is a tool for leadership now aims to develop plans and strategies which ensure effective coordination to improve the common good of the in-group.  Pinker notes the evolved pressure of social rivalry associating power with leadership.  Saposky observes the disconnect between power hierarchies and wisdom in apes.  John Adair developed a modern leadership methodology based on the three-circles model. 
  described in Effective Leadership.  It argues an effective team has distinct but interacting:
• Individual needs - which must be supported by the leader to ensure the team member's self-motivation is not undermined. 
  
• Group needs - Each member's social emotions are emotions that are induced in response to other people's signals, are implemented by specific brain regions including: Prefrontal cortex, Insula cortex, Anterior cingulate cortex, Amygdala; receive lots of projections from interoceptive networks.  Sapolsky asserts in the moments just before we prioritize a consequential act the process is less rational and autonomous than we assume.  There are many significant signals from the prior seconds to minutes that effect social emotions:
  
  • Our brains respond subliminally to skin color very quickly: Amygdala activates, Fusiform face area activates; prior to the conscious stream activating the anterior cingulate and DLPFC which then inhibit the amygdala. 
    
  • Social dominance is culture independent and accurately subliminally assessed after a 40-millisecond exposure.  Stable status relations activate the ventromedial prefrontal cortex and DLPFC, while a dynamic situation also activates the amygdala.  
  • People who are subliminally judged attractive by the medial orbitofrontal cortex are considered kinder, smarter and more honest.  They are given more breaks. 
    
  • Faces and eyes in particular are most important subliminal cues.  They are monitored by the fusiform.  People respond more appropriately under the subliminal influence of eyes. 
    
  • Olfactory sensors send more direct projections to the limbic network than other sensory networks.  Pheromones signal fear activating the amygdala. 
    
  • Observing pain responses in others results in empathy even among young children. 
    
  • Words are important emotional signals providing unconscious priming of social responses.  Kahneman & Tversky demonstrated how the phrase '95% survival rate' is found to be a more acceptable choice than '5% death rate'.  Sapolsky notes that prosocial word priming fosters cooperation with antisocial word priming doing the opposite.  
  • Cultural objects such as visible: flags, team badges; subliminally modify in-group outgroup decisions. 
    
  • The presence of women in a situation alters the responses of men: Increased risk-taking, more focus on luxuries, increased aggression; in circumstances where conflict is already encouraged but not when status is achieved prosocially.  
  • Physical environment shapes behavior as demonstrated by Philip Zimbardo and leveraged in broken windows policing.  
  • Bodily adjustments to sensory structures introduce adaptive complexity, with the brain being influenced to become more sensitive and alter the sensor networks to make some more sensitive.  But these adaptations also vary culturally.  Collectivist cultures focus on a visual scene's surrounding contextual information while people from individualistic cultures focus on the focal object!  
    
  are supported by being part of a cohesive group or organization performing a worthwhile and demanding task. 
  
• Task needs - A task that is too big for an individual, which is agreed to be valuable and achievable, at a stretch, by the group within expected timescales.  Tasks can be seen to be valuable to the organization when they are clearly derived from the corporate Hoshin - Hoshin (direction) Kanri (management) is a planning process which was popularized by Professor Kaoru Ishikawa which helped align goals and objectives across an organization.  It argues:
  1. Focus on a few breakthrough ideas.  As a method to focus an organization on lean management it can be used to drive cost cutting.  However, if the measures are poor the results can undermine the operation of an effective system, as at Laguna Honda Hospital.  
     
  2. Cascade of goals and strategies is developed by top down and bottom up discussions allowing detail to be added along with alignment and buy in.  In Japan, lifelong employment supported this process.  The individual focused merit ratings used in Western management practice undermines the process in Deming's view (deadly disease 3). 
     
  3. The goals, strategies and success measures should be rigorously documented.  In the original paper and fax processes in Japan each goal, its strategies, measures and resources were documented in a planning table.  The whole activity became coordinated by a house of quality.  In AWF the planning table is replaced by a bullet point infinite labelled goal in the execution schematic plan with a structured status block allowing easy visualization of the goal network. 
     
  4. Regular review process based on a Shewhart cycle.  
  . 
  
• Adaptation in evolutionary biology argues that the human genome and phenotypes developed during the relatively long period when our ancestors were hunter-gatherers.  These biologists argue we can best understand ourselves by observing the remaining hunter-gatherer tribes including the Hadza. 
  is a trait that increased the number of surviving offspring in an
  This page reviews the implications of reproduction initially generating a single initialized child cell.  For multi-cellular organisms this 'cell' must contain all the germ-line schematic structures including for organelles and multi-generational epi-genetic state.  Any microbiome is subsequently integrated during the innovative deployment of this creative event.  Organisms with skeletal infrastructure cannot complete the process of creation of an associated adult mind, until the proximate environment has been sampled during development.  The mechanism and resulting strategic options are discussed. 
  
  organism's ancestral lineage.  Holland argues: complex adaptive systems (
  This page introduces the complex adaptive system (CAS) theory frame.  The theory provides an organizing framework that is used by 'life.'  It can be used to evaluate and rank models that claim to describe our perceived reality.  It catalogs the laws and strategies which underpin the operation of systems that are based on the interaction of emergent agents.  It highlights the constraints that shape CAS and so predicts their form.  A proposal that does not conform is wrong. 
  
  John Holland's framework for representing complexity is outlined.  Links to other key aspects of CAS theory discussed at the site are presented. 
  
  CAS) adapt due to the influence of
  Plans emerge in complex adaptive systems (CAS) to provide the instructions that agents use to perform actions.  The component architecture and structure of the plans is reviewed. 
  
  schematic strings on
  Plans are interpreted and implemented by agents.  This page discusses the properties of agents in a complex adaptive system (CAS). 
  It then presents examples of agents in different CAS.  The examples include a computer program where modeling and actions are performed by software agents.  These software agents are aggregates. 
  The participation of agents in flows is introduced and some implications of this are outlined. 
  
  agents. 
  This page reviews the implications of selection, variation and heredity in a complex adaptive system (CAS).  The mechanism and its emergence are discussed. 
  
  Evolution indicates fitness is, according to Dawkins, a suitcase word with at least five meanings in biology:
  1. Darwin and Wallace thought in terms of the capacity to survive and reproduce, but they were considering discrete aspects such as chewing grass - where hard enamel would improve the relative fitness. 
     
  2. Population geneticists: Ronald Fisher, Sewall Wright, J.B.S. Haldane; consider selection at a locus where for a genotype: green eyes vs blue eyes; one with higher fitness can be identified from genotypic frequencies and gene frequencies, with all other variations averaged out. 
     
  3. Whole organism 'integrated' fitness.  Dawkins notes there is only ever one instance of a specific organism.  Being unique, comparing the relative success of its offspring makes little sense.  Over a huge number of generations the individual is likely to have provided a contribution to everyone in the pool or no one. 
     
  4. Inclusive fitness, where according to Hamilton, fitness depends on an organism's actions or effects on its children or its relative's children, a model where natural selection favors organs and behaviors that cause the individual's genes to be passed on.  It is easy to mistakenly count an offspring in multiple relative's fitness assessments. 
     
  5. Personal fitness represents the effects a person's relatives have on the individual's fitness [3].  When interpreted correctly fitness [4] and fitness [5] are the same. 
     
  when an
  This page reviews the implications of reproduction initially generating a single initialized child cell.  For multi-cellular organisms this 'cell' must contain all the germ-line schematic structures including for organelles and multi-generational epi-genetic state.  Any microbiome is subsequently integrated during the innovative deployment of this creative event.  Organisms with skeletal infrastructure cannot complete the process of creation of an associated adult mind, until the proximate environment has been sampled during development.  The mechanism and resulting strategic options are discussed. 
  
  organism survives and reproduces.  For his genetic algorithm, Holland separated the adaptive process into credit assignment and rule discovery.  He assigned a strength to each of the rules (alternate hypothesis) used by his artificial agents, by credit assignment - each accepted message being paid for by the recipient, increasing the sender agent's rule's strength (
  The agents in complex adaptive systems (CAS) must model their environment to respond effectively to it.  Evolution's schematic operators and Samuel modeling together support the indirect recording of past successes and their strategic use by the current agent to learn how to succeed in the proximate environment. 
  
  implicit modeling) and reducing the recipient's.  When an agent achieved an explicit goal they obtained a final reward.  Rule discovery used the genetic algorithm to select strong rule schemas from a pair of agents to be included in the next generation, with
  Plans change in complex adaptive systems (CAS) due to the action of genetic operations such as mutation, splitting and recombination.  The nature of the operations is described. 
  
  crossing over and mutation applied, and the resulting schematic strategies used to replace weaker schemas.  The crossing over
  Plans change in complex adaptive systems (CAS) due to the action of genetic operations such as mutation, splitting and recombination.  The nature of the operations is described. 
  
  genetic operator is unlikely to break up a short schematic sequence that provides a building block retained because of its 'fitness';  In
  Terrence Deacon explores how constraints on dynamic flows can induce emergent phenomena which can do real work.  He shows how these phenomena are sustained.  The mechanism enables the development of Darwinian competition. 
  
  Deacon's conception of evolution, an adaptation is the realization of a set of constraints on candidate mechanisms, and so long as these constraints are maintained, other features are arbitrary. 
  
• Adaptive unconscious is Timothy Wilson's idea of a set of high-level cognitive processes, which interpret 'information' quickly without conscious awareness.  It supports: decision making integrates situational context, state and signals to prioritize among strategies and respond in a timely manner.  It occurs in all animals, including us and our organizations: 
  
  • Individual human decision making includes conscious and unconscious aspects.  Situational context is highly influential: supplying meaning to our general mechanisms, & for robots too.  Emotions are important in providing a balanced judgement.  The adaptive unconscious interprets percepts quickly supporting 'fast' decision making.  Conscious decision making, supported by the: DLPFC, vmPFC and limbic system; can use slower autonomy.  The amygdala, during unsettling or uncertain social situations, signals the decision making regions of the frontal lobe, including the orbitofrontal cortex.  The BLA supports rejecting unacceptable offers.  Moral decisions are influenced by a moral decision switch.  Sleeping before making an important decision is useful in obtaining the support of the unconscious in developing a preference.  Word framing demonstrates the limitations of our fast intuitive decision making processes.  And prior positive associations detected by the hippocampus, can be reactivated with the support of the striatum linking it to the memory of a reward, inducing a bias into our choices.  Prior to the development of the PFC, the ventral striatum supports adolescent decision making.  Neurons involved in decision making in the association areas of the cortex are active for much longer than neurons participating in the sensory areas of the cortex.  This allows them to link perceptions with a provisional action plan.  Association neurons can track probabilities connected to a choice.  As evidence is accumulated and a threshold is reached a choice is made, making fast thinking highly adaptive.  Diseases including: schizophrenia and anorexia; highlight aspects of human decision making. 
    
  • Organisations often struggle to balance top down and distributed decision making: parliamentry government must use a process, health care is attempting to improve the process: checklists, end-to-end care; and include more participants, but has systemic issues, business leaders struggle with strategy. 
    
  - where it's operation suggests prior gathering of details consciously and then allowing
  Carlo Rovelli resolves the paradox of time. 
  Rovelli initially explains that low level physics does not include time:
  

  • A present that is common throughout the universe does not exist
    
  • Events are only partially ordered.  The present is localized
  • The difference between past and future is not foundational.  It occurs because of state that through our blurring appears particular to us
  • Time passes at different speeds dependent on where we are and how fast we travel
    
  • Time's rhythms are due to the gravitational field
    
  • Our quantized physics shows neither space nor time, just processes transforming physical variables. 
    
  • Fundamentally there is no time.  The basic equations evolve together with events, not things 

  Then he explains how in a physical world without time its perception can emerge:
  

  • Our familiar time emerges
    
  • Our interaction with the world is partial, blurred, quantum indeterminate
    
  • The ignorance determines the existence of thermal time and entropy that quantifies our uncertainty
    
  • Directionality of time is real but perspectival.  The entropy of the world in relation to us increases with our thermal time.  The growth of entropy distinguishes past from future: resulting in traces and memories
    
  • Each human is a unified being because: we reflect the world, we formed an image of a unified entity by interacting with our kind, and because of the perspective of memory
    
  • The variable time: is one of the variables of the gravitational field.  With our scale we don't register quantum fluctuations, making space-time appear determined.  At our speed we don't perceive differences in time of different clocks, so we experience a single time: universal, uniform, ordered; which is helpful to our decisions

  
  
  time, including sleeping facilitates salient memory formation and removal of non-salient memories.  The five different stages of the nightly sleep cycles support different aspects of memory formation.  The sleep stages follow Pre-sleep and include: Stage one characterized by light sleep and lasting 10 minutes, Stage two where theta waves and sleep spindles occur, Stage three and Stage four together represent deep slow-wave sleep (SWS) with delta waves, Stage five is REM sleep; sleep cycles last between 90-110 minutes each and as the night progresses SWS times reduce and REM times increase.   Sleep includes the operation of synapse synthesis and maintenance through DNA based activity including membrane trafficking, synaptic vesicle recycling, myelin structural protein formation and cholesterol and protein synthesis.  Sleep also controls inflammation (Jan 2019)  Sleep deprivation undermines the thalamus & nucleus accumbens management of pain. 
  , for the adaptive unconscious to generate a preference, although it is quick to categorize and rigid and may be overruled by the slower acting consciousness; Kahneman views adaptive unconscious decision making as part of fast thinking. 
  
• Adaptive web supports the agents writing and using the dark webs is a web site that is not open to the Internet.  It is a set of deployed HTML files in a directory which refer to each other via file based references relative to the directory.   by:
  
• Leveraging unstructured HTML documents to allow clusters of related information to be juxtaposed.  
• Allowing source data to be private to a particular agent or shared and jointly edited within a team. 
  
• Allowing the writers to define streams of information (signals) within the source HTML. 
  
• Supporting the linkage of the signals to other streams of information deployed into specific dark webs. 
  
• Genetic operations can be applied to the source data.  Key items are labelled.  They are prioritized.  But they should never be deleted from the source documents. 
  
• Transforming the streams of information as they are gathered for deployment into target dark webs.  Aspects like checklist are signals which remind the reader of highly significant aspects of a process.  They are designed to be consulted at a point in the process where forgetting about the aspect will have a significantly detrimental effect.  Often the processes are being used to respond to failures in the regular operation.  Atul Gawande argues that effective use of checklists is vital to coping with situations that are complex. 
  and glossary references can be augmented with details.  Changes in one area of the dark web can be signalled in other pages. 
  
• Constraining which dark webs the information streams will deploy too.  
  
• Adaptive walk is a
  This web page reviews opportunities to find and capture new niches, based on studying fitness landscapes using complex adaptive system (CAS) theory.  CAS SuperOrganisms are able to capture rich niches.  A variety of CAS are included: chess, prokaryotes, nation states, businesses, economies; along with change mechanisms: evolution and artificial intelligence; agency effects and environmental impacts. 
  
  Genetic algorithms supported by fitness functions are compared to genetic operators. 
  
  Early evolution of life and its inbuilt constraints are discussed. 
  
  Strategic clustering, goals, flexibility and representation of state are considered. 
  
  fitness landscape search strategy that picks its direction of search randomly, and then selects for ascending steps, and backtracks if it starts to descend.  It gets
  This page discusses the methods of avoiding traps.  Genetic selection and learning to avoid traps are reviewed. 
  
  trapped in local maxima and must be augmented with other strategies, such as a short random jump is a fitness landscape search strategy that picks its direction of search randomly, and jumps a random distance in that direction. It is risky since it can jump into danger where the searcher may die. 
  . 
  
• ADCY2 is a gene which encodes the enzyme, a protein with a structure which allows it to operate as a chemical catalyst and a control switch. 
  adenylyl cyclase type 2 is a transmembrane enzyme, encoded by the ADCY2 gene, which generates the second messenger, cyclic AMP, from ATP.  It is highly regulated by G-proteins, calcium, calmodulin, and Raf kinase.  It includes six membraine segments and two cytoplasmic domains. 
  .  
• Addcltag is a filter file contains filter statements that alter the merge process executed by the dark web generator.  In particular it describes:
  • Dontunload filters statement (dontunload 'filters' = 't').  By default the statements are unloaded. 
    
  • Map statements which replace a link found in the active source stream with the mapped equivalent (mapf '../web/awfbur01.html' = 'awfbur01.html'). 
    
  • Purge statements which remove the HTML link structure from the active source stream (purge 'http://www.reinventures.com' = 't').  The purge will only be executed if the right hand side of the command equates to true in Perl.  
  • Region dominance statements, which request the dark web generator to replace the regular stream source tagged with the identified start and end stream tag names with a replacement with the same name in the merge stream (region '<stream name>' = 'dom') from a source file with a 'dom' suffix to the file name.  For example:
    
  • The source file awffwbusitdom.html would be dominant to AWF provided source file awffwbusit.html.  
  • The file awffwbusit.htm includes the sub-stream tagged with start tag 'anhp1' and end tag 'anhp1'. 
    
  • If the file awffwbusitdom.htm is created and includes an HTML stream identified by 'anhp1' its source will be included instead of the recessive source once the filter file includes the statement:
  • region 'anhp1' = 'dom'
  • Region co-dominance statements, which request the dark web generator to prepend an additional stream identified in the statements to the regular stream being deployed at the html name specified.  For example:
  • The source file awffwbusitext.html would be co-dominant with the AWF provided source file awffwbusit.html.  
  • The file awffwbusit.htm includes the sub-stream tagged with start tag 'sgen132' and end tag 'sgen132'. Within this stream is HTML named 'Impact_of_socio-cultural_complexity'. 
    
  • If the file awffwbusitext.htm is created and includes an HTML stream identified by 'dsgen132Impact_of_socio-cultural_complexity' start and end tags its source will be included immediately before the HTML source named 'Impact_of_socio-cultural_complexity', once the filter file includes the ordered pair of statements:
  • regionexttnlist 'sgen132' = 't'
  • regionexthnlist 'sgen132' = 'Impact_of_socio-cultural_complexity'
    
  • Glossary mouse over text source file statement (addgltext 'hover' = 'html/awfhelphomeplan.html').  When a glossary reference is detected in the source stream it is enhanced so that in the target HTML file on a mouse over JavaScript will display the glossary item details. 
    
  • Glossary HTML tag start string statement (addgltag 'id' = 'gl').  
  • Glossary target file statement (glfile 'name' = '<target glossary page name>').  
  • Glossary source file (addglstream 'file0' = '<path to>/<glossary source file>')
  • Glossary element (addglkey 'gl_Hoshin' = '1') with key gl_Hoshin will be included from addglstream file1. 
    
  • Checklist mouse over text source file statement (addcltext 'hover' = 'html/awfhelphomeplan.html').  Checklists are structured lists that conform to Atul Gawande's description in The Checklist Manifesto.  When a checklist reference is detected in the source stream it is enhanced so that in the target HTML file on a mouse over JavaScript will display the checklist item details. 
    
  • Checklist HTML tag start string statement (addcltag 'id' = 'cl').  
  • Checklist target file statement (clfile 'name' = 'awfhcl.htm'). 
    
  • State link generation statements (addstatelink 'awffwpwcxprad.htm' = 'http://localhost:3000/openstage/randd/randmgr/awffwpwcxprad.htm') which link one dark web to another via an execution link. 
    
  • Summary item text source file statement (addsumtext 'hover' = 'html/awfhelphomeplan.html').  On mouse over items specified in sumfile descriptions will display the summary information, which occurs after the summary heading and before the next heading, from the source file. 
    
  • Statements of each summary source file to include in summary mouse over (sumfile 'pwhp' = 'awfhpwhp.htm').  
  • Name list statement (namelist 'name' = 'nam').  
  • Statefile commands which allow a dark web execution plan to include a strategy status description, and for the dark web to be associated via an execution link with the dark web containing the delegates implementation actions. 
    
  • Strategy contents list statement (lablist 'name' = 'cxp'). 
  • Strategy label priority statement (labpr '1.1.0.1' = '1').
  • Link error report suppression statement (linkerror 'usetext' = 't').  
  • Setup shared source developer Git status web report generation with (gitstateweb '<web file name>' = 't')
  • Setup shared source maintainer Git status web report generation with (gitsourcestateweb 'web file name>' = 't')
  • Setup indicator of names of Git status web pages with (addgitst 'id' = '<Git status page file name prefix>')
    
  command which specifies the AWF is the adaptive web framework.   tag are structures which are used by the dark web generator to filter the current source stream.  Once a start tag for the current case selector is detected the source data is merged into the HTML template.  This continues until a terminating end tag for the current case selector is detected.  The generator becomes a filter of the source. 
  that marks the start and end of the checklist are signals which remind the reader of highly significant aspects of a process.  They are designed to be consulted at a point in the process where forgetting about the aspect will have a significantly detrimental effect.  Often the processes are being used to respond to failures in the regular operation.  Atul Gawande argues that effective use of checklists is vital to coping with situations that are complex. 
  definition source stream.  It is also the identifier that must be prepended to checklist are signals which remind the reader of highly significant aspects of a process.  They are designed to be consulted at a point in the process where forgetting about the aspect will have a significantly detrimental effect.  Often the processes are being used to respond to failures in the regular operation.  Atul Gawande argues that effective use of checklists is vital to coping with situations that are complex. 
  entry names in the source documents and hence the target dark web is a web site that is not open to the Internet.  It is a set of deployed HTML files in a directory which refer to each other via file based references relative to the directory.   checklist page.  For example:
  
• The command triple addcltag 'id' = 'cl' tells the generator is a Perl script, typically launched as a child process within the configuration editor, by clicking 'generate web', which executes frame configuration file instructions merging the configuration variables with an HTML template file to generate target web pages.  The configuration instructions can be tailored by filters from the configuration file specified filter file. 
  to include items from the checklist page (identified to the dark web generator is a Perl script, typically launched as a child process within the configuration editor, by clicking 'generate web', which executes frame configuration file instructions merging the configuration variables with an HTML template file to generate target web pages.  The configuration instructions can be tailored by filters from the configuration file specified filter file. 
  by the filter file contains filter statements that alter the merge process executed by the dark web generator.  In particular it describes:
  • Dontunload filters statement (dontunload 'filters' = 't').  By default the statements are unloaded. 
    
  • Map statements which replace a link found in the active source stream with the mapped equivalent (mapf '../web/awfbur01.html' = 'awfbur01.html'). 
    
  • Purge statements which remove the HTML link structure from the active source stream (purge 'http://www.reinventures.com' = 't').  The purge will only be executed if the right hand side of the command equates to true in Perl.  
  • Region dominance statements, which request the dark web generator to replace the regular stream source tagged with the identified start and end stream tag names with a replacement with the same name in the merge stream (region '<stream name>' = 'dom') from a source file with a 'dom' suffix to the file name.  For example:
    
  • The source file awffwbusitdom.html would be dominant to AWF provided source file awffwbusit.html.  
  • The file awffwbusit.htm includes the sub-stream tagged with start tag 'anhp1' and end tag 'anhp1'. 
    
  • If the file awffwbusitdom.htm is created and includes an HTML stream identified by 'anhp1' its source will be included instead of the recessive source once the filter file includes the statement:
  • region 'anhp1' = 'dom'
  • Region co-dominance statements, which request the dark web generator to prepend an additional stream identified in the statements to the regular stream being deployed at the html name specified.  For example:
  • The source file awffwbusitext.html would be co-dominant with the AWF provided source file awffwbusit.html.  
  • The file awffwbusit.htm includes the sub-stream tagged with start tag 'sgen132' and end tag 'sgen132'. Within this stream is HTML named 'Impact_of_socio-cultural_complexity'. 
    
  • If the file awffwbusitext.htm is created and includes an HTML stream identified by 'dsgen132Impact_of_socio-cultural_complexity' start and end tags its source will be included immediately before the HTML source named 'Impact_of_socio-cultural_complexity', once the filter file includes the ordered pair of statements:
  • regionexttnlist 'sgen132' = 't'
  • regionexthnlist 'sgen132' = 'Impact_of_socio-cultural_complexity'
    
  • Glossary mouse over text source file statement (addgltext 'hover' = 'html/awfhelphomeplan.html').  When a glossary reference is detected in the source stream it is enhanced so that in the target HTML file on a mouse over JavaScript will display the glossary item details. 
    
  • Glossary HTML tag start string statement (addgltag 'id' = 'gl').  
  • Glossary target file statement (glfile 'name' = '<target glossary page name>').  
  • Glossary source file (addglstream 'file0' = '<path to>/<glossary source file>')
  • Glossary element (addglkey 'gl_Hoshin' = '1') with key gl_Hoshin will be included from addglstream file1. 
    
  • Checklist mouse over text source file statement (addcltext 'hover' = 'html/awfhelphomeplan.html').  Checklists are structured lists that conform to Atul Gawande's description in The Checklist Manifesto.  When a checklist reference is detected in the source stream it is enhanced so that in the target HTML file on a mouse over JavaScript will display the checklist item details. 
    
  • Checklist HTML tag start string statement (addcltag 'id' = 'cl').  
  • Checklist target file statement (clfile 'name' = 'awfhcl.htm'). 
    
  • State link generation statements (addstatelink 'awffwpwcxprad.htm' = 'http://localhost:3000/openstage/randd/randmgr/awffwpwcxprad.htm') which link one dark web to another via an execution link. 
    
  • Summary item text source file statement (addsumtext 'hover' = 'html/awfhelphomeplan.html').  On mouse over items specified in sumfile descriptions will display the summary information, which occurs after the summary heading and before the next heading, from the source file. 
    
  • Statements of each summary source file to include in summary mouse over (sumfile 'pwhp' = 'awfhpwhp.htm').  
  • Name list statement (namelist 'name' = 'nam').  
  • Statefile commands which allow a dark web execution plan to include a strategy status description, and for the dark web to be associated via an execution link with the dark web containing the delegates implementation actions. 
    
  • Strategy contents list statement (lablist 'name' = 'cxp'). 
  • Strategy label priority statement (labpr '1.1.0.1' = '1').
  • Link error report suppression statement (linkerror 'usetext' = 't').  
  • Setup shared source developer Git status web report generation with (gitstateweb '<web file name>' = 't')
  • Setup shared source maintainer Git status web report generation with (gitsourcestateweb 'web file name>' = 't')
  • Setup indicator of names of Git status web pages with (addgitst 'id' = '<Git status page file name prefix>')
    
  command addcltext is a filter file command which describes to the dark web generator the source file from which the checklist description is loaded.  If this command is not present in the filter file no hover substitution will be performed. 
  ) that have names starting with 'cl_'. 
  
• Addcltext is a filter file contains filter statements that alter the merge process executed by the dark web generator.  In particular it describes:
  • Dontunload filters statement (dontunload 'filters' = 't').  By default the statements are unloaded. 
    
  • Map statements which replace a link found in the active source stream with the mapped equivalent (mapf '../web/awfbur01.html' = 'awfbur01.html'). 
    
  • Purge statements which remove the HTML link structure from the active source stream (purge 'http://www.reinventures.com' = 't').  The purge will only be executed if the right hand side of the command equates to true in Perl.  
  • Region dominance statements, which request the dark web generator to replace the regular stream source tagged with the identified start and end stream tag names with a replacement with the same name in the merge stream (region '<stream name>' = 'dom') from a source file with a 'dom' suffix to the file name.  For example:
    
  • The source file awffwbusitdom.html would be dominant to AWF provided source file awffwbusit.html.  
  • The file awffwbusit.htm includes the sub-stream tagged with start tag 'anhp1' and end tag 'anhp1'. 
    
  • If the file awffwbusitdom.htm is created and includes an HTML stream identified by 'anhp1' its source will be included instead of the recessive source once the filter file includes the statement:
  • region 'anhp1' = 'dom'
  • Region co-dominance statements, which request the dark web generator to prepend an additional stream identified in the statements to the regular stream being deployed at the html name specified.  For example:
  • The source file awffwbusitext.html would be co-dominant with the AWF provided source file awffwbusit.html.  
  • The file awffwbusit.htm includes the sub-stream tagged with start tag 'sgen132' and end tag 'sgen132'. Within this stream is HTML named 'Impact_of_socio-cultural_complexity'. 
    
  • If the file awffwbusitext.htm is created and includes an HTML stream identified by 'dsgen132Impact_of_socio-cultural_complexity' start and end tags its source will be included immediately before the HTML source named 'Impact_of_socio-cultural_complexity', once the filter file includes the ordered pair of statements:
  • regionexttnlist 'sgen132' = 't'
  • regionexthnlist 'sgen132' = 'Impact_of_socio-cultural_complexity'
    
  • Glossary mouse over text source file statement (addgltext 'hover' = 'html/awfhelphomeplan.html').  When a glossary reference is detected in the source stream it is enhanced so that in the target HTML file on a mouse over JavaScript will display the glossary item details. 
    
  • Glossary HTML tag start string statement (addgltag 'id' = 'gl').  
  • Glossary target file statement (glfile 'name' = '<target glossary page name>').  
  • Glossary source file (addglstream 'file0' = '<path to>/<glossary source file>')
  • Glossary element (addglkey 'gl_Hoshin' = '1') with key gl_Hoshin will be included from addglstream file1. 
    
  • Checklist mouse over text source file statement (addcltext 'hover' = 'html/awfhelphomeplan.html').  Checklists are structured lists that conform to Atul Gawande's description in The Checklist Manifesto.  When a checklist reference is detected in the source stream it is enhanced so that in the target HTML file on a mouse over JavaScript will display the checklist item details. 
    
  • Checklist HTML tag start string statement (addcltag 'id' = 'cl').  
  • Checklist target file statement (clfile 'name' = 'awfhcl.htm'). 
    
  • State link generation statements (addstatelink 'awffwpwcxprad.htm' = 'http://localhost:3000/openstage/randd/randmgr/awffwpwcxprad.htm') which link one dark web to another via an execution link. 
    
  • Summary item text source file statement (addsumtext 'hover' = 'html/awfhelphomeplan.html').  On mouse over items specified in sumfile descriptions will display the summary information, which occurs after the summary heading and before the next heading, from the source file. 
    
  • Statements of each summary source file to include in summary mouse over (sumfile 'pwhp' = 'awfhpwhp.htm').  
  • Name list statement (namelist 'name' = 'nam').  
  • Statefile commands which allow a dark web execution plan to include a strategy status description, and for the dark web to be associated via an execution link with the dark web containing the delegates implementation actions. 
    
  • Strategy contents list statement (lablist 'name' = 'cxp'). 
  • Strategy label priority statement (labpr '1.1.0.1' = '1').
  • Link error report suppression statement (linkerror 'usetext' = 't').  
  • Setup shared source developer Git status web report generation with (gitstateweb '<web file name>' = 't')
  • Setup shared source maintainer Git status web report generation with (gitsourcestateweb 'web file name>' = 't')
  • Setup indicator of names of Git status web pages with (addgitst 'id' = '<Git status page file name prefix>')
    
  command which describes to the dark web generator is a Perl script, typically launched as a child process within the configuration editor, by clicking 'generate web', which executes frame configuration file instructions merging the configuration variables with an HTML template file to generate target web pages.  The configuration instructions can be tailored by filters from the configuration file specified filter file. 
  the source file from which the checklist are signals which remind the reader of highly significant aspects of a process.  They are designed to be consulted at a point in the process where forgetting about the aspect will have a significantly detrimental effect.  Often the processes are being used to respond to failures in the regular operation.  Atul Gawande argues that effective use of checklists is vital to coping with situations that are complex. 
  description is loaded.  If this command is not present in the filter file no hover substitution will be performed. 
  
• Addgitst is a filter file contains filter statements that alter the merge process executed by the dark web generator.  In particular it describes:
  • Dontunload filters statement (dontunload 'filters' = 't').  By default the statements are unloaded. 
    
  • Map statements which replace a link found in the active source stream with the mapped equivalent (mapf '../web/awfbur01.html' = 'awfbur01.html'). 
    
  • Purge statements which remove the HTML link structure from the active source stream (purge 'http://www.reinventures.com' = 't').  The purge will only be executed if the right hand side of the command equates to true in Perl.  
  • Region dominance statements, which request the dark web generator to replace the regular stream source tagged with the identified start and end stream tag names with a replacement with the same name in the merge stream (region '<stream name>' = 'dom') from a source file with a 'dom' suffix to the file name.  For example:
    
  • The source file awffwbusitdom.html would be dominant to AWF provided source file awffwbusit.html.  
  • The file awffwbusit.htm includes the sub-stream tagged with start tag 'anhp1' and end tag 'anhp1'. 
    
  • If the file awffwbusitdom.htm is created and includes an HTML stream identified by 'anhp1' its source will be included instead of the recessive source once the filter file includes the statement:
  • region 'anhp1' = 'dom'
  • Region co-dominance statements, which request the dark web generator to prepend an additional stream identified in the statements to the regular stream being deployed at the html name specified.  For example:
  • The source file awffwbusitext.html would be co-dominant with the AWF provided source file awffwbusit.html.  
  • The file awffwbusit.htm includes the sub-stream tagged with start tag 'sgen132' and end tag 'sgen132'. Within this stream is HTML named 'Impact_of_socio-cultural_complexity'. 
    
  • If the file awffwbusitext.htm is created and includes an HTML stream identified by 'dsgen132Impact_of_socio-cultural_complexity' start and end tags its source will be included immediately before the HTML source named 'Impact_of_socio-cultural_complexity', once the filter file includes the ordered pair of statements:
  • regionexttnlist 'sgen132' = 't'
  • regionexthnlist 'sgen132' = 'Impact_of_socio-cultural_complexity'
    
  • Glossary mouse over text source file statement (addgltext 'hover' = 'html/awfhelphomeplan.html').  When a glossary reference is detected in the source stream it is enhanced so that in the target HTML file on a mouse over JavaScript will display the glossary item details. 
    
  • Glossary HTML tag start string statement (addgltag 'id' = 'gl').  
  • Glossary target file statement (glfile 'name' = '<target glossary page name>').  
  • Glossary source file (addglstream 'file0' = '<path to>/<glossary source file>')
  • Glossary element (addglkey 'gl_Hoshin' = '1') with key gl_Hoshin will be included from addglstream file1. 
    
  • Checklist mouse over text source file statement (addcltext 'hover' = 'html/awfhelphomeplan.html').  Checklists are structured lists that conform to Atul Gawande's description in The Checklist Manifesto.  When a checklist reference is detected in the source stream it is enhanced so that in the target HTML file on a mouse over JavaScript will display the checklist item details. 
    
  • Checklist HTML tag start string statement (addcltag 'id' = 'cl').  
  • Checklist target file statement (clfile 'name' = 'awfhcl.htm'). 
    
  • State link generation statements (addstatelink 'awffwpwcxprad.htm' = 'http://localhost:3000/openstage/randd/randmgr/awffwpwcxprad.htm') which link one dark web to another via an execution link. 
    
  • Summary item text source file statement (addsumtext 'hover' = 'html/awfhelphomeplan.html').  On mouse over items specified in sumfile descriptions will display the summary information, which occurs after the summary heading and before the next heading, from the source file. 
    
  • Statements of each summary source file to include in summary mouse over (sumfile 'pwhp' = 'awfhpwhp.htm').  
  • Name list statement (namelist 'name' = 'nam').  
  • Statefile commands which allow a dark web execution plan to include a strategy status description, and for the dark web to be associated via an execution link with the dark web containing the delegates implementation actions. 
    
  • Strategy contents list statement (lablist 'name' = 'cxp'). 
  • Strategy label priority statement (labpr '1.1.0.1' = '1').
  • Link error report suppression statement (linkerror 'usetext' = 't').  
  • Setup shared source developer Git status web report generation with (gitstateweb '<web file name>' = 't')
  • Setup shared source maintainer Git status web report generation with (gitsourcestateweb 'web file name>' = 't')
  • Setup indicator of names of Git status web pages with (addgitst 'id' = '<Git status page file name prefix>')
    
  command which describes to the dark web generator is a Perl script, typically launched as a child process within the configuration editor, by clicking 'generate web', which executes frame configuration file instructions merging the configuration variables with an HTML template file to generate target web pages.  The configuration instructions can be tailored by filters from the configuration file specified filter file. 
  the file name prefix that when appended with a Git is a source control system created to support the development of the Linux operating system.  Linus Torvalds was not happy with the source control systems that he and the other Linux developers used so he designed and developed Git.  AWF uses Git as a way to share the HTML sources and istrings library files of group developed dark webs. 
  branch name is an AWF Git workflow based on the SPIMWF where:
  • Branches are long lived and associated with individual participants in the shared plan development. 
    
  • Only the Integration Manager has to understand Git terminal tools or perform merges and fix conflicts. 
    
  • All other team members use AWFCE's Git integration facilities to gitpull the latest sources, add and commit edits, and then gitpush the updates back to their own branch of a source repository that is accessible by the intrgration manager. 
    
  and .htm will match a page of the git status web frame.  This allows the <rhlgitsourcestatus is a filter file command which specifies the name of the report html web page in the Git status frame that will be generated by the dark web generator for this shared source maintainer.  With 'gitsourcestateweb' activated and an html source stream that includes the key word <rhlgitsourcestatus> a report will be generated detailing the current merge state of the master and other branches of the shared and maintainer repositories. 
  > generation process to use Git memo information from the branch page in reporting the merge state of the branch in the Git source maintainer's master branch. 
  
• Addglkey is a filter file contains filter statements that alter the merge process executed by the dark web generator.  In particular it describes:
  • Dontunload filters statement (dontunload 'filters' = 't').  By default the statements are unloaded. 
    
  • Map statements which replace a link found in the active source stream with the mapped equivalent (mapf '../web/awfbur01.html' = 'awfbur01.html'). 
    
  • Purge statements which remove the HTML link structure from the active source stream (purge 'http://www.reinventures.com' = 't').  The purge will only be executed if the right hand side of the command equates to true in Perl.  
  • Region dominance statements, which request the dark web generator to replace the regular stream source tagged with the identified start and end stream tag names with a replacement with the same name in the merge stream (region '<stream name>' = 'dom') from a source file with a 'dom' suffix to the file name.  For example:
    
  • The source file awffwbusitdom.html would be dominant to AWF provided source file awffwbusit.html.  
  • The file awffwbusit.htm includes the sub-stream tagged with start tag 'anhp1' and end tag 'anhp1'. 
    
  • If the file awffwbusitdom.htm is created and includes an HTML stream identified by 'anhp1' its source will be included instead of the recessive source once the filter file includes the statement:
  • region 'anhp1' = 'dom'
  • Region co-dominance statements, which request the dark web generator to prepend an additional stream identified in the statements to the regular stream being deployed at the html name specified.  For example:
  • The source file awffwbusitext.html would be co-dominant with the AWF provided source file awffwbusit.html.  
  • The file awffwbusit.htm includes the sub-stream tagged with start tag 'sgen132' and end tag 'sgen132'. Within this stream is HTML named 'Impact_of_socio-cultural_complexity'. 
    
  • If the file awffwbusitext.htm is created and includes an HTML stream identified by 'dsgen132Impact_of_socio-cultural_complexity' start and end tags its source will be included immediately before the HTML source named 'Impact_of_socio-cultural_complexity', once the filter file includes the ordered pair of statements:
  • regionexttnlist 'sgen132' = 't'
  • regionexthnlist 'sgen132' = 'Impact_of_socio-cultural_complexity'
    
  • Glossary mouse over text source file statement (addgltext 'hover' = 'html/awfhelphomeplan.html').  When a glossary reference is detected in the source stream it is enhanced so that in the target HTML file on a mouse over JavaScript will display the glossary item details. 
    
  • Glossary HTML tag start string statement (addgltag 'id' = 'gl').  
  • Glossary target file statement (glfile 'name' = '<target glossary page name>').  
  • Glossary source file (addglstream 'file0' = '<path to>/<glossary source file>')
  • Glossary element (addglkey 'gl_Hoshin' = '1') with key gl_Hoshin will be included from addglstream file1. 
    
  • Checklist mouse over text source file statement (addcltext 'hover' = 'html/awfhelphomeplan.html').  Checklists are structured lists that conform to Atul Gawande's description in The Checklist Manifesto.  When a checklist reference is detected in the source stream it is enhanced so that in the target HTML file on a mouse over JavaScript will display the checklist item details. 
    
  • Checklist HTML tag start string statement (addcltag 'id' = 'cl').  
  • Checklist target file statement (clfile 'name' = 'awfhcl.htm'). 
    
  • State link generation statements (addstatelink 'awffwpwcxprad.htm' = 'http://localhost:3000/openstage/randd/randmgr/awffwpwcxprad.htm') which link one dark web to another via an execution link. 
    
  • Summary item text source file statement (addsumtext 'hover' = 'html/awfhelphomeplan.html').  On mouse over items specified in sumfile descriptions will display the summary information, which occurs after the summary heading and before the next heading, from the source file. 
    
  • Statements of each summary source file to include in summary mouse over (sumfile 'pwhp' = 'awfhpwhp.htm').  
  • Name list statement (namelist 'name' = 'nam').  
  • Statefile commands which allow a dark web execution plan to include a strategy status description, and for the dark web to be associated via an execution link with the dark web containing the delegates implementation actions. 
    
  • Strategy contents list statement (lablist 'name' = 'cxp'). 
  • Strategy label priority statement (labpr '1.1.0.1' = '1').
  • Link error report suppression statement (linkerror 'usetext' = 't').  
  • Setup shared source developer Git status web report generation with (gitstateweb '<web file name>' = 't')
  • Setup shared source maintainer Git status web report generation with (gitsourcestateweb 'web file name>' = 't')
  • Setup indicator of names of Git status web pages with (addgitst 'id' = '<Git status page file name prefix>')
    
  command which specifies that an item with the key specified from an additional included glossary stream (addglstream is a filter file command which specifies a path and file name of a source file containing glossary items delineated by the AWF tag that marks the start and end of the glossary definition source stream.  A number of streams can be included.  The first should have a key 'file0', the second 'file1' etc.  If an addglstream statement is used in a filter file:
  
  • No glossary items should be declared in the source file containing the basic glossary source within start and end tags.  
  • The basic glossary page should include the target <gltarget> which the merged and sorted glossary items will be deployed into. 
    
  ) should be merged into the target glossary stream. 
  
• Addglstream is a filter file contains filter statements that alter the merge process executed by the dark web generator.  In particular it describes:
  • Dontunload filters statement (dontunload 'filters' = 't').  By default the statements are unloaded. 
    
  • Map statements which replace a link found in the active source stream with the mapped equivalent (mapf '../web/awfbur01.html' = 'awfbur01.html'). 
    
  • Purge statements which remove the HTML link structure from the active source stream (purge 'http://www.reinventures.com' = 't').  The purge will only be executed if the right hand side of the command equates to true in Perl.  
  • Region dominance statements, which request the dark web generator to replace the regular stream source tagged with the identified start and end stream tag names with a replacement with the same name in the merge stream (region '<stream name>' = 'dom') from a source file with a 'dom' suffix to the file name.  For example:
    
  • The source file awffwbusitdom.html would be dominant to AWF provided source file awffwbusit.html.  
  • The file awffwbusit.htm includes the sub-stream tagged with start tag 'anhp1' and end tag 'anhp1'. 
    
  • If the file awffwbusitdom.htm is created and includes an HTML stream identified by 'anhp1' its source will be included instead of the recessive source once the filter file includes the statement:
  • region 'anhp1' = 'dom'
  • Region co-dominance statements, which request the dark web generator to prepend an additional stream identified in the statements to the regular stream being deployed at the html name specified.  For example:
  • The source file awffwbusitext.html would be co-dominant with the AWF provided source file awffwbusit.html.  
  • The file awffwbusit.htm includes the sub-stream tagged with start tag 'sgen132' and end tag 'sgen132'. Within this stream is HTML named 'Impact_of_socio-cultural_complexity'. 
    
  • If the file awffwbusitext.htm is created and includes an HTML stream identified by 'dsgen132Impact_of_socio-cultural_complexity' start and end tags its source will be included immediately before the HTML source named 'Impact_of_socio-cultural_complexity', once the filter file includes the ordered pair of statements:
  • regionexttnlist 'sgen132' = 't'
  • regionexthnlist 'sgen132' = 'Impact_of_socio-cultural_complexity'
    
  • Glossary mouse over text source file statement (addgltext 'hover' = 'html/awfhelphomeplan.html').  When a glossary reference is detected in the source stream it is enhanced so that in the target HTML file on a mouse over JavaScript will display the glossary item details. 
    
  • Glossary HTML tag start string statement (addgltag 'id' = 'gl').  
  • Glossary target file statement (glfile 'name' = '<target glossary page name>').  
  • Glossary source file (addglstream 'file0' = '<path to>/<glossary source file>')
  • Glossary element (addglkey 'gl_Hoshin' = '1') with key gl_Hoshin will be included from addglstream file1. 
    
  • Checklist mouse over text source file statement (addcltext 'hover' = 'html/awfhelphomeplan.html').  Checklists are structured lists that conform to Atul Gawande's description in The Checklist Manifesto.  When a checklist reference is detected in the source stream it is enhanced so that in the target HTML file on a mouse over JavaScript will display the checklist item details. 
    
  • Checklist HTML tag start string statement (addcltag 'id' = 'cl').  
  • Checklist target file statement (clfile 'name' = 'awfhcl.htm'). 
    
  • State link generation statements (addstatelink 'awffwpwcxprad.htm' = 'http://localhost:3000/openstage/randd/randmgr/awffwpwcxprad.htm') which link one dark web to another via an execution link. 
    
  • Summary item text source file statement (addsumtext 'hover' = 'html/awfhelphomeplan.html').  On mouse over items specified in sumfile descriptions will display the summary information, which occurs after the summary heading and before the next heading, from the source file. 
    
  • Statements of each summary source file to include in summary mouse over (sumfile 'pwhp' = 'awfhpwhp.htm').  
  • Name list statement (namelist 'name' = 'nam').  
  • Statefile commands which allow a dark web execution plan to include a strategy status description, and for the dark web to be associated via an execution link with the dark web containing the delegates implementation actions. 
    
  • Strategy contents list statement (lablist 'name' = 'cxp'). 
  • Strategy label priority statement (labpr '1.1.0.1' = '1').
  • Link error report suppression statement (linkerror 'usetext' = 't').  
  • Setup shared source developer Git status web report generation with (gitstateweb '<web file name>' = 't')
  • Setup shared source maintainer Git status web report generation with (gitsourcestateweb 'web file name>' = 't')
  • Setup indicator of names of Git status web pages with (addgitst 'id' = '<Git status page file name prefix>')
    
  command which specifies a path and file name of a source file containing glossary items delineated by the AWF is the adaptive web framework.   tag are structures which are used by the dark web generator to filter the current source stream.  Once a start tag for the current case selector is detected the source data is merged into the HTML template.  This continues until a terminating end tag for the current case selector is detected.  The generator becomes a filter of the source. 
  that marks the start and end of the glossary definition source stream.  A number of streams can be included.  The first should have a key 'file0', the second 'file1' etc.  If an addglstream statement is used in a filter file:
  
• No glossary items should be declared in the source file containing the basic glossary source within start acts as a start operon initiating the sourcing of an AWF stream, by the dark web generator from the current schematic structure being traversed, when the:
  
  • Tag label value matches the case selector being actioned by the generator, and  
    
  • The generator's target path does not include any of the exclusion terms of the form -<exclusion pathname fragment>. 
    
  • There are two visible forms deployed into the visual editor text stream: the list form (see '(cxpradjames2 -randd -open)' within an HTML unnumbered list with two path exclusion terms) and the start of body text form (see '(cxpradjames1)' within yellow highlights - cut and paste the highlighted line and one above and below and then change the selector value to the string you require); and a low level html comment form (see 'start tag paral' in the linked example within an html inclusion of a Perl code stream and hence the html comment follows a Perl comment '#' character) deployed into the raw HTML tag stream. 
    
  and end tags acts as a terminator of an AWF stream as long as the:
  • Tag label value matches the case selector being actioned by the dark web generator. 
    
  .  
• The basic glossary page should include the target <gltarget> which the merged and sorted glossary items will be deployed into. 
  
• Addgltag is a filter file contains filter statements that alter the merge process executed by the dark web generator.  In particular it describes:
  • Dontunload filters statement (dontunload 'filters' = 't').  By default the statements are unloaded. 
    
  • Map statements which replace a link found in the active source stream with the mapped equivalent (mapf '../web/awfbur01.html' = 'awfbur01.html'). 
    
  • Purge statements which remove the HTML link structure from the active source stream (purge 'http://www.reinventures.com' = 't').  The purge will only be executed if the right hand side of the command equates to true in Perl.  
  • Region dominance statements, which request the dark web generator to replace the regular stream source tagged with the identified start and end stream tag names with a replacement with the same name in the merge stream (region '<stream name>' = 'dom') from a source file with a 'dom' suffix to the file name.  For example:
    
  • The source file awffwbusitdom.html would be dominant to AWF provided source file awffwbusit.html.  
  • The file awffwbusit.htm includes the sub-stream tagged with start tag 'anhp1' and end tag 'anhp1'. 
    
  • If the file awffwbusitdom.htm is created and includes an HTML stream identified by 'anhp1' its source will be included instead of the recessive source once the filter file includes the statement:
  • region 'anhp1' = 'dom'
  • Region co-dominance statements, which request the dark web generator to prepend an additional stream identified in the statements to the regular stream being deployed at the html name specified.  For example:
  • The source file awffwbusitext.html would be co-dominant with the AWF provided source file awffwbusit.html.  
  • The file awffwbusit.htm includes the sub-stream tagged with start tag 'sgen132' and end tag 'sgen132'. Within this stream is HTML named 'Impact_of_socio-cultural_complexity'. 
    
  • If the file awffwbusitext.htm is created and includes an HTML stream identified by 'dsgen132Impact_of_socio-cultural_complexity' start and end tags its source will be included immediately before the HTML source named 'Impact_of_socio-cultural_complexity', once the filter file includes the ordered pair of statements:
  • regionexttnlist 'sgen132' = 't'
  • regionexthnlist 'sgen132' = 'Impact_of_socio-cultural_complexity'
    
  • Glossary mouse over text source file statement (addgltext 'hover' = 'html/awfhelphomeplan.html').  When a glossary reference is detected in the source stream it is enhanced so that in the target HTML file on a mouse over JavaScript will display the glossary item details. 
    
  • Glossary HTML tag start string statement (addgltag 'id' = 'gl').  
  • Glossary target file statement (glfile 'name' = '<target glossary page name>').  
  • Glossary source file (addglstream 'file0' = '<path to>/<glossary source file>')
  • Glossary element (addglkey 'gl_Hoshin' = '1') with key gl_Hoshin will be included from addglstream file1. 
    
  • Checklist mouse over text source file statement (addcltext 'hover' = 'html/awfhelphomeplan.html').  Checklists are structured lists that conform to Atul Gawande's description in The Checklist Manifesto.  When a checklist reference is detected in the source stream it is enhanced so that in the target HTML file on a mouse over JavaScript will display the checklist item details. 
    
  • Checklist HTML tag start string statement (addcltag 'id' = 'cl').  
  • Checklist target file statement (clfile 'name' = 'awfhcl.htm'). 
    
  • State link generation statements (addstatelink 'awffwpwcxprad.htm' = 'http://localhost:3000/openstage/randd/randmgr/awffwpwcxprad.htm') which link one dark web to another via an execution link. 
    
  • Summary item text source file statement (addsumtext 'hover' = 'html/awfhelphomeplan.html').  On mouse over items specified in sumfile descriptions will display the summary information, which occurs after the summary heading and before the next heading, from the source file. 
    
  • Statements of each summary source file to include in summary mouse over (sumfile 'pwhp' = 'awfhpwhp.htm').  
  • Name list statement (namelist 'name' = 'nam').  
  • Statefile commands which allow a dark web execution plan to include a strategy status description, and for the dark web to be associated via an execution link with the dark web containing the delegates implementation actions. 
    
  • Strategy contents list statement (lablist 'name' = 'cxp'). 
  • Strategy label priority statement (labpr '1.1.0.1' = '1').
  • Link error report suppression statement (linkerror 'usetext' = 't').  
  • Setup shared source developer Git status web report generation with (gitstateweb '<web file name>' = 't')
  • Setup shared source maintainer Git status web report generation with (gitsourcestateweb 'web file name>' = 't')
  • Setup indicator of names of Git status web pages with (addgitst 'id' = '<Git status page file name prefix>')
    
  command which specifies the AWF is the adaptive web framework.   tag are structures which are used by the dark web generator to filter the current source stream.  Once a start tag for the current case selector is detected the source data is merged into the HTML template.  This continues until a terminating end tag for the current case selector is detected.  The generator becomes a filter of the source. 
  that marks the start and end of the glossary definition source stream.  It is also the identifier that must be prepended to glossary entry names in the source documents and hence the target dark web is a web site that is not open to the Internet.  It is a set of deployed HTML files in a directory which refer to each other via file based references relative to the directory.   glossary page.  For example:
  The command triple addgltag 'id' = 'gl' tells the generator is a Perl script, typically launched as a child process within the configuration editor, by clicking 'generate web', which executes frame configuration file instructions merging the configuration variables with an HTML template file to generate target web pages.  The configuration instructions can be tailored by filters from the configuration file specified filter file. 
  to include items from the glossary page (identified to the dark web generator is a Perl script, typically launched as a child process within the configuration editor, by clicking 'generate web', which executes frame configuration file instructions merging the configuration variables with an HTML template file to generate target web pages.  The configuration instructions can be tailored by filters from the configuration file specified filter file. 
  by the filter file contains filter statements that alter the merge process executed by the dark web generator.  In particular it describes:
  • Dontunload filters statement (dontunload 'filters' = 't').  By default the statements are unloaded. 
    
  • Map statements which replace a link found in the active source stream with the mapped equivalent (mapf '../web/awfbur01.html' = 'awfbur01.html'). 
    
  • Purge statements which remove the HTML link structure from the active source stream (purge 'http://www.reinventures.com' = 't').  The purge will only be executed if the right hand side of the command equates to true in Perl.  
  • Region dominance statements, which request the dark web generator to replace the regular stream source tagged with the identified start and end stream tag names with a replacement with the same name in the merge stream (region '<stream name>' = 'dom') from a source file with a 'dom' suffix to the file name.  For example:
    
  • The source file awffwbusitdom.html would be dominant to AWF provided source file awffwbusit.html.  
  • The file awffwbusit.htm includes the sub-stream tagged with start tag 'anhp1' and end tag 'anhp1'. 
    
  • If the file awffwbusitdom.htm is created and includes an HTML stream identified by 'anhp1' its source will be included instead of the recessive source once the filter file includes the statement:
  • region 'anhp1' = 'dom'
  • Region co-dominance statements, which request the dark web generator to prepend an additional stream identified in the statements to the regular stream being deployed at the html name specified.  For example:
  • The source file awffwbusitext.html would be co-dominant with the AWF provided source file awffwbusit.html.  
  • The file awffwbusit.htm includes the sub-stream tagged with start tag 'sgen132' and end tag 'sgen132'. Within this stream is HTML named 'Impact_of_socio-cultural_complexity'. 
    
  • If the file awffwbusitext.htm is created and includes an HTML stream identified by 'dsgen132Impact_of_socio-cultural_complexity' start and end tags its source will be included immediately before the HTML source named 'Impact_of_socio-cultural_complexity', once the filter file includes the ordered pair of statements:
  • regionexttnlist 'sgen132' = 't'
  • regionexthnlist 'sgen132' = 'Impact_of_socio-cultural_complexity'
    
  • Glossary mouse over text source file statement (addgltext 'hover' = 'html/awfhelphomeplan.html').  When a glossary reference is detected in the source stream it is enhanced so that in the target HTML file on a mouse over JavaScript will display the glossary item details. 
    
  • Glossary HTML tag start string statement (addgltag 'id' = 'gl').  
  • Glossary target file statement (glfile 'name' = '<target glossary page name>').  
  • Glossary source file (addglstream 'file0' = '<path to>/<glossary source file>')
  • Glossary element (addglkey 'gl_Hoshin' = '1') with key gl_Hoshin will be included from addglstream file1. 
    
  • Checklist mouse over text source file statement (addcltext 'hover' = 'html/awfhelphomeplan.html').  Checklists are structured lists that conform to Atul Gawande's description in The Checklist Manifesto.  When a checklist reference is detected in the source stream it is enhanced so that in the target HTML file on a mouse over JavaScript will display the checklist item details. 
    
  • Checklist HTML tag start string statement (addcltag 'id' = 'cl').  
  • Checklist target file statement (clfile 'name' = 'awfhcl.htm'). 
    
  • State link generation statements (addstatelink 'awffwpwcxprad.htm' = 'http://localhost:3000/openstage/randd/randmgr/awffwpwcxprad.htm') which link one dark web to another via an execution link. 
    
  • Summary item text source file statement (addsumtext 'hover' = 'html/awfhelphomeplan.html').  On mouse over items specified in sumfile descriptions will display the summary information, which occurs after the summary heading and before the next heading, from the source file. 
    
  • Statements of each summary source file to include in summary mouse over (sumfile 'pwhp' = 'awfhpwhp.htm').  
  • Name list statement (namelist 'name' = 'nam').  
  • Statefile commands which allow a dark web execution plan to include a strategy status description, and for the dark web to be associated via an execution link with the dark web containing the delegates implementation actions. 
    
  • Strategy contents list statement (lablist 'name' = 'cxp'). 
  • Strategy label priority statement (labpr '1.1.0.1' = '1').
  • Link error report suppression statement (linkerror 'usetext' = 't').  
  • Setup shared source developer Git status web report generation with (gitstateweb '<web file name>' = 't')
  • Setup shared source maintainer Git status web report generation with (gitsourcestateweb 'web file name>' = 't')
  • Setup indicator of names of Git status web pages with (addgitst 'id' = '<Git status page file name prefix>')
    
  command addgltext is a filter file command which describes to the dark web generator the source file from which the glossary description is loaded.  If this command is not present in the filter file no hover substitution will be performed.  ) that have names starting with 'gl_'. 
• Addgltext is a filter file contains filter statements that alter the merge process executed by the dark web generator.  In particular it describes:
  • Dontunload filters statement (dontunload 'filters' = 't').  By default the statements are unloaded. 
    
  • Map statements which replace a link found in the active source stream with the mapped equivalent (mapf '../web/awfbur01.html' = 'awfbur01.html'). 
    
  • Purge statements which remove the HTML link structure from the active source stream (purge 'http://www.reinventures.com' = 't').  The purge will only be executed if the right hand side of the command equates to true in Perl.  
  • Region dominance statements, which request the dark web generator to replace the regular stream source tagged with the identified start and end stream tag names with a replacement with the same name in the merge stream (region '<stream name>' = 'dom') from a source file with a 'dom' suffix to the file name.  For example:
    
  • The source file awffwbusitdom.html would be dominant to AWF provided source file awffwbusit.html.  
  • The file awffwbusit.htm includes the sub-stream tagged with start tag 'anhp1' and end tag 'anhp1'. 
    
  • If the file awffwbusitdom.htm is created and includes an HTML stream identified by 'anhp1' its source will be included instead of the recessive source once the filter file includes the statement:
  • region 'anhp1' = 'dom'
  • Region co-dominance statements, which request the dark web generator to prepend an additional stream identified in the statements to the regular stream being deployed at the html name specified.  For example:
  • The source file awffwbusitext.html would be co-dominant with the AWF provided source file awffwbusit.html.  
  • The file awffwbusit.htm includes the sub-stream tagged with start tag 'sgen132' and end tag 'sgen132'. Within this stream is HTML named 'Impact_of_socio-cultural_complexity'. 
    
  • If the file awffwbusitext.htm is created and includes an HTML stream identified by 'dsgen132Impact_of_socio-cultural_complexity' start and end tags its source will be included immediately before the HTML source named 'Impact_of_socio-cultural_complexity', once the filter file includes the ordered pair of statements:
  • regionexttnlist 'sgen132' = 't'
  • regionexthnlist 'sgen132' = 'Impact_of_socio-cultural_complexity'
    
  • Glossary mouse over text source file statement (addgltext 'hover' = 'html/awfhelphomeplan.html').  When a glossary reference is detected in the source stream it is enhanced so that in the target HTML file on a mouse over JavaScript will display the glossary item details. 
    
  • Glossary HTML tag start string statement (addgltag 'id' = 'gl').  
  • Glossary target file statement (glfile 'name' = '<target glossary page name>').  
  • Glossary source file (addglstream 'file0' = '<path to>/<glossary source file>')
  • Glossary element (addglkey 'gl_Hoshin' = '1') with key gl_Hoshin will be included from addglstream file1. 
    
  • Checklist mouse over text source file statement (addcltext 'hover' = 'html/awfhelphomeplan.html').  Checklists are structured lists that conform to Atul Gawande's description in The Checklist Manifesto.  When a checklist reference is detected in the source stream it is enhanced so that in the target HTML file on a mouse over JavaScript will display the checklist item details. 
    
  • Checklist HTML tag start string statement (addcltag 'id' = 'cl').  
  • Checklist target file statement (clfile 'name' = 'awfhcl.htm'). 
    
  • State link generation statements (addstatelink 'awffwpwcxprad.htm' = 'http://localhost:3000/openstage/randd/randmgr/awffwpwcxprad.htm') which link one dark web to another via an execution link. 
    
  • Summary item text source file statement (addsumtext 'hover' = 'html/awfhelphomeplan.html').  On mouse over items specified in sumfile descriptions will display the summary information, which occurs after the summary heading and before the next heading, from the source file. 
    
  • Statements of each summary source file to include in summary mouse over (sumfile 'pwhp' = 'awfhpwhp.htm').  
  • Name list statement (namelist 'name' = 'nam').  
  • Statefile commands which allow a dark web execution plan to include a strategy status description, and for the dark web to be associated via an execution link with the dark web containing the delegates implementation actions. 
    
  • Strategy contents list statement (lablist 'name' = 'cxp'). 
  • Strategy label priority statement (labpr '1.1.0.1' = '1').
  • Link error report suppression statement (linkerror 'usetext' = 't').  
  • Setup shared source developer Git status web report generation with (gitstateweb '<web file name>' = 't')
  • Setup shared source maintainer Git status web report generation with (gitsourcestateweb 'web file name>' = 't')
  • Setup indicator of names of Git status web pages with (addgitst 'id' = '<Git status page file name prefix>')
    
  command which describes to the dark web generator is a Perl script, typically launched as a child process within the configuration editor, by clicking 'generate web', which executes frame configuration file instructions merging the configuration variables with an HTML template file to generate target web pages.  The configuration instructions can be tailored by filters from the configuration file specified filter file. 
  the source file from which the glossary description is loaded.  If this command is not present in the filter file no hover substitution will be performed.  
• Addiction results from changes in the operation of the brain's reward network includes: the nucleus accumbens, which responds to dopamine signalling, the striatum & the PFC which control and motivate using rewards. 
  's regulatory regions, altering the anticipation of rewards.  Addictive drugs mediate the receptors, in biological cells these proteins are able to span the cell membrane and present an active site which is tailored to interact with a specific signal.  When the receptor pairs with its signal, its overall shape changes resulting in changes in the part internal to the cell which can be relayed by the cells signalling infrastructure.  In neuron synapses one type of receptor (fast) is associated with an ion channel.  The other (slow) is associated with a signalling enzyme chain and modulates the neuron's response. 
  of the reward network, increasing dopamine is a synaptic signal supporting generalized goal-directed behavior & anticipation of reward.  Its significance is that the receptors that detect the signal are of the slow acting type and are used to alter (modulate) the response of fast acting dopaminergic neural circuits in which the receptors are deployed (LTP).  The signal detects significant changes including predictions of models and actual results which differ unexpectedly.  Dopamine is released primarily by neurons of the ventral tegmental area and the substantia nigra.  The dopamine network architecture is designed to signal the possibility of any type of reward: Norm violation punishment, Winning a lottery, & Misfortune of an envied competitor.  Dopamine signalling:
  
  • Rescales continuously to accommodate the range of intensity offered by different stimuli.  So dopamine's responses to any reward habituate.  GABA is released by some tegmental neurons to induce habituation.  This allows addictions to develop. 
    
  • Reflects the anticipation of reward.  It supports establishment of a relationship between a signal, working for a reward and obtaining the reward, but subsequently dopamine is mainly released encouraging the work, right after the signal supporting anticipation of the reward.  Anticipation requires learning and is reflected in hippocampus activity.  That explains context dependent cravings.  And the learning architecture means reliable cues become rewarding.  The accumbens supports willpower.  And dopamine
    
  • Promotes goal-oriented behavior needed to obtain & likely to achieve the reward - through the dopamine projections to the prefrontal cortex.  That makes dopamine central to:
    
  • Motivation.  This binding fails in depression - due to stress and in anxiety - due to signals from the amygdala.  
  • The prefrontal cortex's mesocortically stimulated support for willpower to act to delay rewards.  To sustain work for delayed rewards additional dopamine is released based on the length of the delay and the rewards uncertainty (modelled in the dorsolateral prefrontal cortex - which promotes the long term and the ventromedial prefrontal cortex - which promotes the short term) and the anticipated size of the reward (modelled in the accumbens).  Impulsiveness in ADHD is reflected in abnormal dopamine processing.  Addictive drugs bias the dopamine network towards impulsiveness.  
  • Is lowered by certain gene variants which induce: less dopamine in the synapse, fewer receptors, lower responsiveness of receptors; associated with (as tiny effects in hugely varying social scenarios): sensation seeking, risk taking, attentional problems, extroversion; where:
    
  • The receptor D4's gene shows high variability.  The D47R form is relatively unresponsive to dopamine.  
  • Dopamine is degraded by COMT.  The COMT gene includes a variant which is highly efficient reducing dopamine signalling but with complicating gene/environment interactions.  
  • Dopamine is removed from the synapse by a reuptake transporter DAT. 
    
  in the pleasure centers of the cortex includes the paleocortex a thin sheet of cells that mostly process smell, archicortex and the neocortex.  The cerebral cortex is a pair of large folded sheets of brain tissue, one on either side of the top of the head connected by the corpus callosum.  It includes the occipital, parietal, temporal and frontal lobes. 
  .  The learned association of the situation with the reward makes addiction highly prone to relapse, when the situation is subsequently experienced.  This makes addiction a chronic disease, where the sufferer must remain vigilant to avoid relapse inducing situations.  Repeated exposure to the addictive drug alters the reward network.  The neurons, specialized eukaryotic cells include channels which control flows of sodium and potassium ions across the massively extended cell membrane supporting an electro-chemical wave which is then converted into an outgoing chemical signal transmission from synapses which target nearby neuron or muscle cell receptors.  Neurons are supported by glial cells.  Neurons include a:
  • Receptive element - dendrites
    
  • Transmitting element - axon and synaptic terminals.  The axon may be myelinated, focusing the signals through synaptic transmission, or unmyelinated - where crosstalk is leveraged. 
  • Highly variable DNA schema using transposons. 
    
  that produce dopamine are impaired, no longer sending dopamine to the reward target areas, reducing the feeling of pleasure.  But the situational association remains strong driving the addict to repeat the addictive activity.  Destroying the memory of the pleasure inducer may provide a treatment for addiction in the future.  Addiction has a genetic component, which supports inheritance.  Some other compulsive disorders: eating include anorexia, bulimia & obesity. 
  , gambling, sexual behavior; are similar to drug addiction. 
  
• Addstatelink is a filter file contains filter statements that alter the merge process executed by the dark web generator.  In particular it describes:
  • Dontunload filters statement (dontunload 'filters' = 't').  By default the statements are unloaded. 
    
  • Map statements which replace a link found in the active source stream with the mapped equivalent (mapf '../web/awfbur01.html' = 'awfbur01.html'). 
    
  • Purge statements which remove the HTML link structure from the active source stream (purge 'http://www.reinventures.com' = 't').  The purge will only be executed if the right hand side of the command equates to true in Perl.  
  • Region dominance statements, which request the dark web generator to replace the regular stream source tagged with the identified start and end stream tag names with a replacement with the same name in the merge stream (region '<stream name>' = 'dom') from a source file with a 'dom' suffix to the file name.  For example:
    
  • The source file awffwbusitdom.html would be dominant to AWF provided source file awffwbusit.html.  
  • The file awffwbusit.htm includes the sub-stream tagged with start tag 'anhp1' and end tag 'anhp1'. 
    
  • If the file awffwbusitdom.htm is created and includes an HTML stream identified by 'anhp1' its source will be included instead of the recessive source once the filter file includes the statement:
  • region 'anhp1' = 'dom'
  • Region co-dominance statements, which request the dark web generator to prepend an additional stream identified in the statements to the regular stream being deployed at the html name specified.  For example:
  • The source file awffwbusitext.html would be co-dominant with the AWF provided source file awffwbusit.html.  
  • The file awffwbusit.htm includes the sub-stream tagged with start tag 'sgen132' and end tag 'sgen132'. Within this stream is HTML named 'Impact_of_socio-cultural_complexity'. 
    
  • If the file awffwbusitext.htm is created and includes an HTML stream identified by 'dsgen132Impact_of_socio-cultural_complexity' start and end tags its source will be included immediately before the HTML source named 'Impact_of_socio-cultural_complexity', once the filter file includes the ordered pair of statements:
  • regionexttnlist 'sgen132' = 't'
  • regionexthnlist 'sgen132' = 'Impact_of_socio-cultural_complexity'
    
  • Glossary mouse over text source file statement (addgltext 'hover' = 'html/awfhelphomeplan.html').  When a glossary reference is detected in the source stream it is enhanced so that in the target HTML file on a mouse over JavaScript will display the glossary item details. 
    
  • Glossary HTML tag start string statement (addgltag 'id' = 'gl').  
  • Glossary target file statement (glfile 'name' = '<target glossary page name>').  
  • Glossary source file (addglstream 'file0' = '<path to>/<glossary source file>')
  • Glossary element (addglkey 'gl_Hoshin' = '1') with key gl_Hoshin will be included from addglstream file1. 
    
  • Checklist mouse over text source file statement (addcltext 'hover' = 'html/awfhelphomeplan.html').  Checklists are structured lists that conform to Atul Gawande's description in The Checklist Manifesto.  When a checklist reference is detected in the source stream it is enhanced so that in the target HTML file on a mouse over JavaScript will display the checklist item details. 
    
  • Checklist HTML tag start string statement (addcltag 'id' = 'cl').  
  • Checklist target file statement (clfile 'name' = 'awfhcl.htm'). 
    
  • State link generation statements (addstatelink 'awffwpwcxprad.htm' = 'http://localhost:3000/openstage/randd/randmgr/awffwpwcxprad.htm') which link one dark web to another via an execution link. 
    
  • Summary item text source file statement (addsumtext 'hover' = 'html/awfhelphomeplan.html').  On mouse over items specified in sumfile descriptions will display the summary information, which occurs after the summary heading and before the next heading, from the source file. 
    
  • Statements of each summary source file to include in summary mouse over (sumfile 'pwhp' = 'awfhpwhp.htm').  
  • Name list statement (namelist 'name' = 'nam').  
  • Statefile commands which allow a dark web execution plan to include a strategy status description, and for the dark web to be associated via an execution link with the dark web containing the delegates implementation actions. 
    
  • Strategy contents list statement (lablist 'name' = 'cxp'). 
  • Strategy label priority statement (labpr '1.1.0.1' = '1').
  • Link error report suppression statement (linkerror 'usetext' = 't').  
  • Setup shared source developer Git status web report generation with (gitstateweb '<web file name>' = 't')
  • Setup shared source maintainer Git status web report generation with (gitsourcestateweb 'web file name>' = 't')
  • Setup indicator of names of Git status web pages with (addgitst 'id' = '<Git status page file name prefix>')
    
  command which connects the same execution plan are lists of strategies.  Each strategy is numbered with a unique infinite label. 
  page in two dark web is a web site that is not open to the Internet.  It is a set of deployed HTML files in a directory which refer to each other via file based references relative to the directory.  s together providing a mechanism to construct a network of 'open' dark webs.  The command specifies that when generating the target page matching the 'key' any http name associated strategy should have an execution link are http references deployed by the dark web generator from each http id associated infinite labelled execution plan goal, via its primary resource to an equivalent page and goal in another dark web.  The links are deployed in response to the filter file command addstatelink. 
  . 
  
• The command triple addstatelink 'fwpwcxprad.htm' = 'http://localhost:3000/fwpwcxprad.htm' would add execution links from the generating page in the target dark web to the same page in another dark web via the internal web server. 
  
• Addstatepref is a filter file contains filter statements that alter the merge process executed by the dark web generator.  In particular it describes:
  • Dontunload filters statement (dontunload 'filters' = 't').  By default the statements are unloaded. 
    
  • Map statements which replace a link found in the active source stream with the mapped equivalent (mapf '../web/awfbur01.html' = 'awfbur01.html'). 
    
  • Purge statements which remove the HTML link structure from the active source stream (purge 'http://www.reinventures.com' = 't').  The purge will only be executed if the right hand side of the command equates to true in Perl.  
  • Region dominance statements, which request the dark web generator to replace the regular stream source tagged with the identified start and end stream tag names with a replacement with the same name in the merge stream (region '<stream name>' = 'dom') from a source file with a 'dom' suffix to the file name.  For example:
    
  • The source file awffwbusitdom.html would be dominant to AWF provided source file awffwbusit.html.  
  • The file awffwbusit.htm includes the sub-stream tagged with start tag 'anhp1' and end tag 'anhp1'. 
    
  • If the file awffwbusitdom.htm is created and includes an HTML stream identified by 'anhp1' its source will be included instead of the recessive source once the filter file includes the statement:
  • region 'anhp1' = 'dom'
  • Region co-dominance statements, which request the dark web generator to prepend an additional stream identified in the statements to the regular stream being deployed at the html name specified.  For example:
  • The source file awffwbusitext.html would be co-dominant with the AWF provided source file awffwbusit.html.  
  • The file awffwbusit.htm includes the sub-stream tagged with start tag 'sgen132' and end tag 'sgen132'. Within this stream is HTML named 'Impact_of_socio-cultural_complexity'. 
    
  • If the file awffwbusitext.htm is created and includes an HTML stream identified by 'dsgen132Impact_of_socio-cultural_complexity' start and end tags its source will be included immediately before the HTML source named 'Impact_of_socio-cultural_complexity', once the filter file includes the ordered pair of statements:
  • regionexttnlist 'sgen132' = 't'
  • regionexthnlist 'sgen132' = 'Impact_of_socio-cultural_complexity'
    
  • Glossary mouse over text source file statement (addgltext 'hover' = 'html/awfhelphomeplan.html').  When a glossary reference is detected in the source stream it is enhanced so that in the target HTML file on a mouse over JavaScript will display the glossary item details. 
    
  • Glossary HTML tag start string statement (addgltag 'id' = 'gl').  
  • Glossary target file statement (glfile 'name' = '<target glossary page name>').  
  • Glossary source file (addglstream 'file0' = '<path to>/<glossary source file>')
  • Glossary element (addglkey 'gl_Hoshin' = '1') with key gl_Hoshin will be included from addglstream file1. 
    
  • Checklist mouse over text source file statement (addcltext 'hover' = 'html/awfhelphomeplan.html').  Checklists are structured lists that conform to Atul Gawande's description in The Checklist Manifesto.  When a checklist reference is detected in the source stream it is enhanced so that in the target HTML file on a mouse over JavaScript will display the checklist item details. 
    
  • Checklist HTML tag start string statement (addcltag 'id' = 'cl').  
  • Checklist target file statement (clfile 'name' = 'awfhcl.htm'). 
    
  • State link generation statements (addstatelink 'awffwpwcxprad.htm' = 'http://localhost:3000/openstage/randd/randmgr/awffwpwcxprad.htm') which link one dark web to another via an execution link. 
    
  • Summary item text source file statement (addsumtext 'hover' = 'html/awfhelphomeplan.html').  On mouse over items specified in sumfile descriptions will display the summary information, which occurs after the summary heading and before the next heading, from the source file. 
    
  • Statements of each summary source file to include in summary mouse over (sumfile 'pwhp' = 'awfhpwhp.htm').  
  • Name list statement (namelist 'name' = 'nam').  
  • Statefile commands which allow a dark web execution plan to include a strategy status description, and for the dark web to be associated via an execution link with the dark web containing the delegates implementation actions. 
    
  • Strategy contents list statement (lablist 'name' = 'cxp'). 
  • Strategy label priority statement (labpr '1.1.0.1' = '1').
  • Link error report suppression statement (linkerror 'usetext' = 't').  
  • Setup shared source developer Git status web report generation with (gitstateweb '<web file name>' = 't')
  • Setup shared source maintainer Git status web report generation with (gitsourcestateweb 'web file name>' = 't')
  • Setup indicator of names of Git status web pages with (addgitst 'id' = '<Git status page file name prefix>')
    
  command which specifies the prefix used by the dark web generator is a Perl script, typically launched as a child process within the configuration editor, by clicking 'generate web', which executes frame configuration file instructions merging the configuration variables with an HTML template file to generate target web pages.  The configuration instructions can be tailored by filters from the configuration file specified filter file. 
  execution plan are lists of strategies.  Each strategy is numbered with a unique infinite label. 
  monitored region is a part of a child execution plan that has a link from the 'update' or 'PDCA' keyword within a strategy's status description in the associated parent execution plan.  With appropriate filter file settings (addstatepref, addstatetag, statecase, statefile, statelist) the dark web generator will monitor changes to the region starting at the infinite label for the strategy in the child plan and each line following it until a higher labeled strategy is detected.  Any changes within the region will be indicated by linking the parent's status description 'done' keyword to a status file description and changing the 'done' link status to unused. 
  state change processor to help it reconstruct the child execution plan filenames in conjunction with the statelist is a filter file command which associates a list of child execution plan case selectors with a parent execution plan's state dark web page.   data items and '.htm'.  
  
• Addstatetag is a filter file contains filter statements that alter the merge process executed by the dark web generator.  In particular it describes:
  • Dontunload filters statement (dontunload 'filters' = 't').  By default the statements are unloaded. 
    
  • Map statements which replace a link found in the active source stream with the mapped equivalent (mapf '../web/awfbur01.html' = 'awfbur01.html'). 
    
  • Purge statements which remove the HTML link structure from the active source stream (purge 'http://www.reinventures.com' = 't').  The purge will only be executed if the right hand side of the command equates to true in Perl.  
  • Region dominance statements, which request the dark web generator to replace the regular stream source tagged with the identified start and end stream tag names with a replacement with the same name in the merge stream (region '<stream name>' = 'dom') from a source file with a 'dom' suffix to the file name.  For example:
    
  • The source file awffwbusitdom.html would be dominant to AWF provided source file awffwbusit.html.  
  • The file awffwbusit.htm includes the sub-stream tagged with start tag 'anhp1' and end tag 'anhp1'. 
    
  • If the file awffwbusitdom.htm is created and includes an HTML stream identified by 'anhp1' its source will be included instead of the recessive source once the filter file includes the statement:
  • region 'anhp1' = 'dom'
  • Region co-dominance statements, which request the dark web generator to prepend an additional stream identified in the statements to the regular stream being deployed at the html name specified.  For example:
  • The source file awffwbusitext.html would be co-dominant with the AWF provided source file awffwbusit.html.  
  • The file awffwbusit.htm includes the sub-stream tagged with start tag 'sgen132' and end tag 'sgen132'. Within this stream is HTML named 'Impact_of_socio-cultural_complexity'. 
    
  • If the file awffwbusitext.htm is created and includes an HTML stream identified by 'dsgen132Impact_of_socio-cultural_complexity' start and end tags its source will be included immediately before the HTML source named 'Impact_of_socio-cultural_complexity', once the filter file includes the ordered pair of statements:
  • regionexttnlist 'sgen132' = 't'
  • regionexthnlist 'sgen132' = 'Impact_of_socio-cultural_complexity'
    
  • Glossary mouse over text source file statement (addgltext 'hover' = 'html/awfhelphomeplan.html').  When a glossary reference is detected in the source stream it is enhanced so that in the target HTML file on a mouse over JavaScript will display the glossary item details. 
    
  • Glossary HTML tag start string statement (addgltag 'id' = 'gl').  
  • Glossary target file statement (glfile 'name' = '<target glossary page name>').  
  • Glossary source file (addglstream 'file0' = '<path to>/<glossary source file>')
  • Glossary element (addglkey 'gl_Hoshin' = '1') with key gl_Hoshin will be included from addglstream file1. 
    
  • Checklist mouse over text source file statement (addcltext 'hover' = 'html/awfhelphomeplan.html').  Checklists are structured lists that conform to Atul Gawande's description in The Checklist Manifesto.  When a checklist reference is detected in the source stream it is enhanced so that in the target HTML file on a mouse over JavaScript will display the checklist item details. 
    
  • Checklist HTML tag start string statement (addcltag 'id' = 'cl').  
  • Checklist target file statement (clfile 'name' = 'awfhcl.htm'). 
    
  • State link generation statements (addstatelink 'awffwpwcxprad.htm' = 'http://localhost:3000/openstage/randd/randmgr/awffwpwcxprad.htm') which link one dark web to another via an execution link. 
    
  • Summary item text source file statement (addsumtext 'hover' = 'html/awfhelphomeplan.html').  On mouse over items specified in sumfile descriptions will display the summary information, which occurs after the summary heading and before the next heading, from the source file. 
    
  • Statements of each summary source file to include in summary mouse over (sumfile 'pwhp' = 'awfhpwhp.htm').  
  • Name list statement (namelist 'name' = 'nam').  
  • Statefile commands which allow a dark web execution plan to include a strategy status description, and for the dark web to be associated via an execution link with the dark web containing the delegates implementation actions. 
    
  • Strategy contents list statement (lablist 'name' = 'cxp'). 
  • Strategy label priority statement (labpr '1.1.0.1' = '1').
  • Link error report suppression statement (linkerror 'usetext' = 't').  
  • Setup shared source developer Git status web report generation with (gitstateweb '<web file name>' = 't')
  • Setup shared source maintainer Git status web report generation with (gitsourcestateweb 'web file name>' = 't')
  • Setup indicator of names of Git status web pages with (addgitst 'id' = '<Git status page file name prefix>')
    
  command which specifies the AWF is the adaptive web framework.   tag are structures which are used by the dark web generator to filter the current source stream.  Once a start tag for the current case selector is detected the source data is merged into the HTML template.  This continues until a terminating end tag for the current case selector is detected.  The generator becomes a filter of the source. 
  that defines the file name appended string used to name an execution plans are lists of strategies.  Each strategy is numbered with a unique infinite label. 
  associated execution state dark web is a web site that is not open to the Internet.  It is a set of deployed HTML files in a directory which refer to each other via file based references relative to the directory.   page.  For example the command triple addstatetag 'id' = 'st' tells the dark web generator is a Perl script, typically launched as a child process within the configuration editor, by clicking 'generate web', which executes frame configuration file instructions merging the configuration variables with an HTML template file to generate target web pages.  The configuration instructions can be tailored by filters from the configuration file specified filter file. 
  to name any state is a filter file command which associates a state dark web page with its parent execution plan.  For example with an addstatetag 'id' of 'st' the statefile 'prefixparentcasest.htm' = 'prefixparentcase.htm' requests the dark web generator to create the 'prefixparentcasest.htm' file and provide state links to it about the monitored regions in the child execution plans. 
  dark web is a web site that is not open to the Internet.  It is a set of deployed HTML files in a directory which refer to each other via file based references relative to the directory.   page it associates with a parent execution plan 'parentplan.htm' with the dark web is a web site that is not open to the Internet.  It is a set of deployed HTML files in a directory which refer to each other via file based references relative to the directory.   page name 'parentplanst.htm'. 
  
• Addsumtext is a filter file contains filter statements that alter the merge process executed by the dark web generator.  In particular it describes:
  • Dontunload filters statement (dontunload 'filters' = 't').  By default the statements are unloaded. 
    
  • Map statements which replace a link found in the active source stream with the mapped equivalent (mapf '../web/awfbur01.html' = 'awfbur01.html'). 
    
  • Purge statements which remove the HTML link structure from the active source stream (purge 'http://www.reinventures.com' = 't').  The purge will only be executed if the right hand side of the command equates to true in Perl.  
  • Region dominance statements, which request the dark web generator to replace the regular stream source tagged with the identified start and end stream tag names with a replacement with the same name in the merge stream (region '<stream name>' = 'dom') from a source file with a 'dom' suffix to the file name.  For example:
    
  • The source file awffwbusitdom.html would be dominant to AWF provided source file awffwbusit.html.  
  • The file awffwbusit.htm includes the sub-stream tagged with start tag 'anhp1' and end tag 'anhp1'. 
    
  • If the file awffwbusitdom.htm is created and includes an HTML stream identified by 'anhp1' its source will be included instead of the recessive source once the filter file includes the statement:
  • region 'anhp1' = 'dom'
  • Region co-dominance statements, which request the dark web generator to prepend an additional stream identified in the statements to the regular stream being deployed at the html name specified.  For example:
  • The source file awffwbusitext.html would be co-dominant with the AWF provided source file awffwbusit.html.  
  • The file awffwbusit.htm includes the sub-stream tagged with start tag 'sgen132' and end tag 'sgen132'. Within this stream is HTML named 'Impact_of_socio-cultural_complexity'. 
    
  • If the file awffwbusitext.htm is created and includes an HTML stream identified by 'dsgen132Impact_of_socio-cultural_complexity' start and end tags its source will be included immediately before the HTML source named 'Impact_of_socio-cultural_complexity', once the filter file includes the ordered pair of statements:
  • regionexttnlist 'sgen132' = 't'
  • regionexthnlist 'sgen132' = 'Impact_of_socio-cultural_complexity'
    
  • Glossary mouse over text source file statement (addgltext 'hover' = 'html/awfhelphomeplan.html').  When a glossary reference is detected in the source stream it is enhanced so that in the target HTML file on a mouse over JavaScript will display the glossary item details. 
    
  • Glossary HTML tag start string statement (addgltag 'id' = 'gl').  
  • Glossary target file statement (glfile 'name' = '<target glossary page name>').  
  • Glossary source file (addglstream 'file0' = '<path to>/<glossary source file>')
  • Glossary element (addglkey 'gl_Hoshin' = '1') with key gl_Hoshin will be included from addglstream file1. 
    
  • Checklist mouse over text source file statement (addcltext 'hover' = 'html/awfhelphomeplan.html').  Checklists are structured lists that conform to Atul Gawande's description in The Checklist Manifesto.  When a checklist reference is detected in the source stream it is enhanced so that in the target HTML file on a mouse over JavaScript will display the checklist item details. 
    
  • Checklist HTML tag start string statement (addcltag 'id' = 'cl').  
  • Checklist target file statement (clfile 'name' = 'awfhcl.htm'). 
    
  • State link generation statements (addstatelink 'awffwpwcxprad.htm' = 'http://localhost:3000/openstage/randd/randmgr/awffwpwcxprad.htm') which link one dark web to another via an execution link. 
    
  • Summary item text source file statement (addsumtext 'hover' = 'html/awfhelphomeplan.html').  On mouse over items specified in sumfile descriptions will display the summary information, which occurs after the summary heading and before the next heading, from the source file. 
    
  • Statements of each summary source file to include in summary mouse over (sumfile 'pwhp' = 'awfhpwhp.htm').  
  • Name list statement (namelist 'name' = 'nam').  
  • Statefile commands which allow a dark web execution plan to include a strategy status description, and for the dark web to be associated via an execution link with the dark web containing the delegates implementation actions. 
    
  • Strategy contents list statement (lablist 'name' = 'cxp'). 
  • Strategy label priority statement (labpr '1.1.0.1' = '1').
  • Link error report suppression statement (linkerror 'usetext' = 't').  
  • Setup shared source developer Git status web report generation with (gitstateweb '<web file name>' = 't')
  • Setup shared source maintainer Git status web report generation with (gitsourcestateweb 'web file name>' = 't')
  • Setup indicator of names of Git status web pages with (addgitst 'id' = '<Git status page file name prefix>')
    
  command which describes to the dark web generator is a Perl script, typically launched as a child process within the configuration editor, by clicking 'generate web', which executes frame configuration file instructions merging the configuration variables with an HTML template file to generate target web pages.  The configuration instructions can be tailored by filters from the configuration file specified filter file. 
  the source file from which the summary text descriptions are the lines of HTML between the Summary heading and the next heading in a source stream. 
  are loaded.  If this command is not present in the filter file no hover substitution will be performed. 
  
• Adenocarcinoma is a cancer of mucus is used to cover tissues that are exposed.  It is made from mucins.  Mucous membranes may secrete mucus to generate a robust barrier. 
  -secreting glands.  It can occur thoughout the body including the lungs affects 200,000 Americans each year.  Inflammation is a driver of lung cancer spread (Aug 2017).  All these cancers are carcinomas.  There are two main hystological types:
  • Non-small-cell carcinomas are of three sub-types:
  • Adenocarcinomas (40% of lung cancers) are typically peripherally situated and mostly induced by smoking.
    
  • Squamous-cell carcinomas (30% of lung cancers) arise in the large bronchi an are highly correlated with smoking. 
    
  • Large-cell carcinomas (5 to 10% of lung cancers).
    
  • Small-cell carcinomas.
    
  , where 40% of cancers are adenocarcinomas.  Genes ERBB2 is a gene, often termed HER2, that encodes RTK erbB-2, a proto-oncogene. 
  and VEGF is vascular endothelial growth factor, a signalling protein used by cells to stimulate angiogenesis.   are often amplified in this cancer. 
  
• Adenylyl cyclase type 2 is a transmembrane enzyme, a protein with a structure which allows it to operate as a chemical catalyst and a control switch. 
  , encoded by the ADCY2 is a gene which encodes the enzyme adenylyl cyclase type 2.   gene, which generates the second messenger, provide an amplified form of signals within a cell.  Since cells need to stabilize their overall state with many operations happening in parallel second messengers are useful in clarifying the signals effect.  The second messenger strategy is seen repeatedly in CAS including: neuro-transmitter guidance signals such as dopamine distribution in the brain, corporate positioning email messages in response to new situations, newspaper articles aligning the population; , cyclic AMP, from ATP.  It is highly regulated by G-proteins are guanine nucleotide-binding proteins.  There are two major classes of G proteins: Monomeric such as Ras, Heterotrimeric; both existing in active GTP-bound state and an inactive GDP-bound state.  The heterotrimeric proteins couple to heptahelical receptors.  The receptor bound active heterotrimeric proteins dissociate into alpha and beta-gama subunits which both transmit signals to targets. 
  , calcium, calmodulin, and Raf is a serine/threonine protein kinase homologous with PKC.  It is a key signalling protein.  Growth factor signalling flows through Raf to the MAP Kinase cascade.   kinase.  It includes six membraine segments and two cytoplasmic domains. 
  
• ADHD is attention-deficit/hyperactivity disorder, a chronic condition including hyperactivity, impulsiveness and low attention.  Dopamine is a synaptic signal supporting generalized goal-directed behavior & anticipation of reward.  Its significance is that the receptors that detect the signal are of the slow acting type and are used to alter (modulate) the response of fast acting dopaminergic neural circuits in which the receptors are deployed (LTP).  The signal detects significant changes including predictions of models and actual results which differ unexpectedly.  Dopamine is released primarily by neurons of the ventral tegmental area and the substantia nigra.  The dopamine network architecture is designed to signal the possibility of any type of reward: Norm violation punishment, Winning a lottery, & Misfortune of an envied competitor.  Dopamine signalling:
  
  • Rescales continuously to accommodate the range of intensity offered by different stimuli.  So dopamine's responses to any reward habituate.  GABA is released by some tegmental neurons to induce habituation.  This allows addictions to develop. 
    
  • Reflects the anticipation of reward.  It supports establishment of a relationship between a signal, working for a reward and obtaining the reward, but subsequently dopamine is mainly released encouraging the work, right after the signal supporting anticipation of the reward.  Anticipation requires learning and is reflected in hippocampus activity.  That explains context dependent cravings.  And the learning architecture means reliable cues become rewarding.  The accumbens supports willpower.  And dopamine
    
  • Promotes goal-oriented behavior needed to obtain & likely to achieve the reward - through the dopamine projections to the prefrontal cortex.  That makes dopamine central to:
    
  • Motivation.  This binding fails in depression - due to stress and in anxiety - due to signals from the amygdala.  
  • The prefrontal cortex's mesocortically stimulated support for willpower to act to delay rewards.  To sustain work for delayed rewards additional dopamine is released based on the length of the delay and the rewards uncertainty (modelled in the dorsolateral prefrontal cortex - which promotes the long term and the ventromedial prefrontal cortex - which promotes the short term) and the anticipated size of the reward (modelled in the accumbens).  Impulsiveness in ADHD is reflected in abnormal dopamine processing.  Addictive drugs bias the dopamine network towards impulsiveness.  
  • Is lowered by certain gene variants which induce: less dopamine in the synapse, fewer receptors, lower responsiveness of receptors; associated with (as tiny effects in hugely varying social scenarios): sensation seeking, risk taking, attentional problems, extroversion; where:
    
  • The receptor D4's gene shows high variability.  The D47R form is relatively unresponsive to dopamine.  
  • Dopamine is degraded by COMT.  The COMT gene includes a variant which is highly efficient reducing dopamine signalling but with complicating gene/environment interactions.  
  • Dopamine is removed from the synapse by a reuptake transporter DAT. 
    
  response profiles to temporal discounting tasks are abnormal for ADHD sufferers.  Imaging studies show differences in the brains of ADHD sufferers.  Stimulants have been found to have a calming effect on ADHD sufferers.  However, overdiagnosis is identification of disease when no symptoms or impacts will occur.  It typically results from false positives during screening (Aug 2016).  It can result in unnecessary and problematic treatment. 
  seems likely, with a strong correlation of diagnosis to age at time of school admission!  Causally associated factors include:
• Family history
• Genetics
• May be influenced by high doses of Tylenol during pregnancy (Sep 2016). 
  
• Environmental factors - a consistant daily schedule, praise for good behavior, clear bondaries, enough sleep and limiting distractions are all part of behavioral therapy for ADHD.  
  
• CNS developmental is a phase during the operation of a CAS agent.  It allows for schematic strategies to be iteratively blended with environmental signals to solve the logistical issues of migrating newly built and transformed sub-agents.  That is needed to achieve the adult configuration of the agent and optimize it for the proximate environment.  Smiley includes examples of the developmental phase agents required in an emergent CAS.  In situations where parents invest in the growth and memetic learning of their offspring the schematic grab bag can support optimizations to develop models, structures and actions to construct an adept adult.  In humans, adolescence leverages neural plasticity, elder sibling advice and adult coaching to help prepare the deploying neuronal network and body to successfully compete. 
  problems.   
• Adjacent possible.  
• Adjuvant is a strategy or tool that modifies a primary plan.  In cancer is the out-of-control growth of cells, which have stopped obeying their cooperative schematic planning and signalling infrastructure.  It results from compounded: oncogene, tumor suppressor, DNA caretaker; mutations in the DNA.  In 2010 one third of Americans are likely to die of cancer.  Cell division rates did not predict likelihood of cancer.  Viral infections are associated.  Radiation and carcinogen exposure are associated.  Lifestyle impacts the likelihood of cancer occurring: Drinking alcohol to excess, lack of exercise, Obesity, Smoking, More sun than your evolved melanin protection level; all significantly increase the risk of cancer occurring (Jul 2016). 
  treatment adjuvant pharmaceutical and immunological agents modify the effects of other treatments. 
  
• Adolescence in humans supports the transition from a juvenile configuration, dependent on parents and structured to
  The agents in complex adaptive systems (CAS) must model their environment to respond effectively to it.  Evolution's schematic operators and Samuel modeling together support the indirect recording of past successes and their strategic use by the current agent to learn how to succeed in the proximate environment. 
  
  learn & logistically transform, to
  In a post disruption environment there is a race to capture network effects.  Once the network effects have been obtained the winner will ensure further advantage until the next round of disruption. 
  
  adult optimized to the proximate environment.  And it is staged, encouraging male adolescents to escape the hierarchy they grew up in and enter other groups where they may bring in: fresh ideas, risk taking; and alter the existing hierarchy: Steve Jobs was an innovative entrepreneur who integrated art and culture with engineering, and is responsible for: the strong sexual selection force of the: Macintosh, iPod, iPad and iPhone; and their dedicated fan base.  He cofounded Apple Computer with Steve Wozniak where Wozniak designed a particularly simple microprocessor based computer, the Apple 1 and Jobs made it elegant.  Struck by the relative simplicity and ease of use of PARC's Alto, Jobs and Wozniak began building the Lisa.  But Jobs decided it was flawed and took a small group aside to build the Macintosh which the whole team were happy to sign their names on the inside.  Born February 24th 1955, Steve's birth mother Joanne Schieble was forced by her father to have the boy adopted rather than allow her to marry his Muslim Syrian birth father, Abdulfattah Jandali, the last of nine children of a hugely wealthy trader, Walter Isaacson explains.  The baby was adopted by Paul Reinhold Jobs, a highly practical mechanic and a mild kind father, and Clara Hagopian, also sweet-humored, and when Steve was two they adopted Patty.  The Jobs lived in an Eichler (a design inspired by Frank Lloyd Wright), in Mountain View, California, which had a strong influence on Steve, as he explained to Isaacson, "Eichler did a great thing.  His houses were smart and cheap and good.  They brought clean design and simple taste to lower income people.  They had awesome little features, like radiant heating in the floors.  You put carpet on them, and we had nice toasty floors when we were kids."  Steve Jobs knew early on that he was adopted, which pained him supporting development of his Challenger personality type.  It was also clear to Steve that he was unlike his adopted parents, Paul and Clara Jobs, who stressed to him that they picked him specifically and that he was special.  They tolerated Steve's high risk activities and ensured he was safe when problems occurred.  Paul Jobs impressed Steve as a child, with his valuing quality workmanship, and his practical capabilities.  Paul could repair any car and Steve became interested in the electronics aspects.  He was helped by neighbors who were electrical engineers: Larry Lang; the geographic cluster that formed around Hewlett Packard and Intel.  And he then joined a neighborhood electronics club where he was introduced to Steve Wozniak.  But the young Steve Jobs was shocked when he discovered his father did not correctly understand some aspects of the world, and Steve realized he was much more intelligent than his parents Paul and Clara.  With their support he followed his curiosity and resisted any attempt to stop him.  His powerful drive made his parents, teachers, local business leaders: Bill Hewlett, Nolan Bushnell; and coaches go along.  At Reed College he pushed to attend courses he was interested in: calligraphy; rather than follow the syllabus, and they let him.  They even allowed him to continue when he stopped his parents from paying more tuition.  His stressed idealist continually sought out gurus: Shunryu Suzuki, Neem Karoli Baba; and visionaries who might help Steve understand who he really was. 
  & Steve Wozniak, Bill Gates & Paul Allen; while females become highly focused on friendships and communications.  It marks the beginning of Piaget's formal operational stage of cognitive development.  The limbic supports emotional circuits: Amygdala, Hippocampus, Septum, Habenula, Mammillary bodies; all of which signals the midbrain through the hypothalamus. The broad interconnections of these regions with a part of the frontal lobe suggested to Walle Nauta that it (ventromedial prefrontal cortex) is a quasi-member of the limbic network.  , autonomic and hormone are signalling molecules: ACTH, TRH, Melanocyte stimulating hormone, Testosterone, Oxytocin, Vasopressin, Insulin, Growth hormone, Estrogen, Progesterone, Angiotensin II, Asprosin, EPO, Irisin, Leptin, FGF21 hormone, Prostaglandins, TSH, Thyroxine, Glococorticoids: Cortisol; that are transported by the circulatory system to interact with target organs having appropriate receptors.  The levels of hormones can fluctuate massively, as in pregnancy. 
  
  This page discusses the effect of the network on the agents participating in a complex adaptive system (CAS).  Small world and scale free networks are considered. 
  
  networks are already deployed and functioning effectively.  The frontal cortex of the cerebral cortex is at the front of the brain.  It includes the: prefrontal cortex, motor cortex.  Sapolsky asserts it makes you do the harder thing when it's the right thing to do.  The frontal cortex supports working memory to sustain focus on a task.  It also coordinates the strategic actions necessary to achieve success.  It provides impulse control, regulation of emotion, and willpower.  The prefrontal cortex maintains focus by deprioritizing currently irrelevant streams of information.  The frontal cortex tracks rules.  Over a lifetime, that builds into a costly activity.  Once it tires, responses become less prosocial.  But practice shifts operation of tasks to the cerebellum.  The frontal cortex signals the tegmentum and accumbens with the conclusions of its expectancy/discrepancy calculations.  The frontal lobe provides executive function, considering bits of information, assessing patterns and then prioritizing the strategies.  The frontal lobe is the most recent part of the brain to evolve and involves a disproportionate percentage of primate-unique genes in its development and operation.  It does not complete development until the mid-20s.  It includes spindle neurons.  It is easily damaged.  Sapolsky (Nauta) notes that its ventromedial prefrontal cortex is a quasi-member of the limbic system. 
  has to be pruned: winning neurons, specialized eukaryotic cells include channels which control flows of sodium and potassium ions across the massively extended cell membrane supporting an electro-chemical wave which is then converted into an outgoing chemical signal transmission from synapses which target nearby neuron or muscle cell receptors.  Neurons are supported by glial cells.  Neurons include a:
  • Receptive element - dendrites
    
  • Transmitting element - axon and synaptic terminals.  The axon may be myelinated, focusing the signals through synaptic transmission, or unmyelinated - where crosstalk is leveraged. 
  • Highly variable DNA schema using transposons. 
    
  move to their final highly connected positions, and are myelinated is the fatty insulating material deployed by Schwann cells & oligodendrocytes, both types of glial cells, around axons to improve their conduction rate.  In humans it is still occurring 25 years after birth.  It has great impact on long axons, in neurons that project over long distances, where it helps brain inter-region signalling.  The long development time of myelination allows for the later myelinated brain regions to be particularly shaped by the proximate environment. 
  over
  Carlo Rovelli resolves the paradox of time. 
  Rovelli initially explains that low level physics does not include time:
  

  • A present that is common throughout the universe does not exist
    
  • Events are only partially ordered.  The present is localized
  • The difference between past and future is not foundational.  It occurs because of state that through our blurring appears particular to us
  • Time passes at different speeds dependent on where we are and how fast we travel
    
  • Time's rhythms are due to the gravitational field
    
  • Our quantized physics shows neither space nor time, just processes transforming physical variables. 
    
  • Fundamentally there is no time.  The basic equations evolve together with events, not things 

  Then he explains how in a physical world without time its perception can emerge:
  

  • Our familiar time emerges
    
  • Our interaction with the world is partial, blurred, quantum indeterminate
    
  • The ignorance determines the existence of thermal time and entropy that quantifies our uncertainty
    
  • Directionality of time is real but perspectival.  The entropy of the world in relation to us increases with our thermal time.  The growth of entropy distinguishes past from future: resulting in traces and memories
    
  • Each human is a unified being because: we reflect the world, we formed an image of a unified entity by interacting with our kind, and because of the perspective of memory
    
  • The variable time: is one of the variables of the gravitational field.  With our scale we don't register quantum fluctuations, making space-time appear determined.  At our speed we don't perceive differences in time of different clocks, so we experience a single time: universal, uniform, ordered; which is helpful to our decisions

  
  
  time.  The rest dissolve, programmed cell death is a signal initiated DNA controlled process which results in eukaryotic cells self-destructing.  .  So the frontal lobe does not obtain its adult configuration and networked integration until the mid-twenties when prefrontal cortex (PFC) is
  
  • The front part of the frontal lobe of the cerebral cortex.  It evolved most recently.  During adolescence when the PFC is still deploying, older brain agents provide equivalent strategies: ventral striatum.  The PFC has been implicated in planning, working memory: dorsolateral; decision making: Orbitofrontal cortex; and social behavior.  It regulates feelings.  Different PFC circuits track internal reward driven strategies and externally signalled advice.  The PFC chooses between conflicting options, letting go or restraint, especially between cognition and emotions.  It imposes an overarching strategy for managing working memory.  It is essential for thinking about multiple items with different labels.  It includes neurons that are interested in particular sub-categories: Dog, Cat.  Once it has made a decision it signals the rest of the frontal lobe just behind it.  Glucocorticoids decrease excitability of the PFC.  
  control becomes optimal.  The evolutionarily oldest areas of the frontal cortex mature first.  The PFC is prefrontal cortex which is:
  • The front part of the frontal lobe of the cerebral cortex.  It evolved most recently.  During adolescence when the PFC is still deploying, older brain agents provide equivalent strategies: ventral striatum.  The PFC has been implicated in planning, working memory: dorsolateral; decision making: Orbitofrontal cortex; and social behavior.  It regulates feelings.  Different PFC circuits track internal reward driven strategies and externally signalled advice.  The PFC chooses between conflicting options, letting go or restraint, especially between cognition and emotions.  It imposes an overarching strategy for managing working memory.  It is essential for thinking about multiple items with different labels.  It includes neurons that are interested in particular sub-categories: Dog, Cat.  Once it has made a decision it signals the rest of the frontal lobe just behind it.  Glucocorticoids decrease excitability of the PFC.  
  must be iteratively customized by experience to do the right thing as an adult.  Adolescents:
• Don't detect irony effectively.  They depend on the DMPFC is dorsomedial prefrontal cortex which is:
  • A major agent of the sense of self and theory of mind in human adults. 
    
  • It participates in altruism.  
  to do this, unlike adults who leverage the fusiform is a region of the brain which supports advanced mechanisms of shape recognition and implements the early stages of reading.  Subliminal priming with words did not depend on the shape of the word.  The fusiform gyrus was able to process the abstract identity of a word without caring if it was upper or lower case.   While high up in the cortex it can operate below the level of conscious experience.  It contributes to social emotions with:
  
  • Its face area being more activated by faces with in-group skin color.  
  • It activating when shown pictures of cars in automobile aficionados. 
    
  • It activating when shown pictures of birds in birdwatchers; since it really recognizes examples of items from an individual's emotionally salient categories. 
    
  face area.  
• Regulate emotions are low level fast unconscious agents distributed across the brain and body which associate, via the amygdala and rich club hubs, important environmental signals with encoded high speed sensors, and distributed programs of action to model: predict, prioritize guidance signals, select and respond effectively, coherently and rapidly to the initial signal.  The majority of emotion centered brain regions interface to the midbrain through the hypothalamus.  The cerebellum and basal ganglia support the integration of emotion and motor functions, rewarding rhythmic movement.  The most accessible signs of emotions are the hard to control and universal facial expressions.  Emotions provide prioritization for conscious access given that an animal has only one body, but possibly many cells, with which to achieve its highest level goals.  Because of this, base emotions clash with group goals and are disparaged by the powerful.  Pinker notes a set of group selected emotions which he classes as: other-condemning, other-praising, other-suffering and self-conscious emotions.  Evolutionary psychology argues evolution shaped human emotions during the long period of hunter-gatherer existence in the African savanna.  Human emotions are universal and include: Anger, Appreciation of natural beauty, Contempt, Disgust, Embarrassment, Fear, Gratitude, Grief, Guilt, Happiness, Honor, Jealousy, Liking, Love, Moral awe, Rage, Romantic love, Lust for revenge, Passion, Sadness, Self-control, Shame, Sympathy, Surprise; and the sham emotions and distrust induced by reciprocal altruism. 
  with the ventral striatum is a region within the basal ganglia.   It is a target of the tegmentostriatal dopamine pathway.  It has been captured by brain imaging assigning values to subliminal symbols experimentally associated with winning (highly valued) and losing (low valuation) money.  During adolescence, prior to the deployment of the prefrontal cortex, the ventral striatum helps balance/control emotional decision making. 
  while the prefrontal cortex is still being setup.  Dopamine is a synaptic signal supporting generalized goal-directed behavior & anticipation of reward.  Its significance is that the receptors that detect the signal are of the slow acting type and are used to alter (modulate) the response of fast acting dopaminergic neural circuits in which the receptors are deployed (LTP).  The signal detects significant changes including predictions of models and actual results which differ unexpectedly.  Dopamine is released primarily by neurons of the ventral tegmental area and the substantia nigra.  The dopamine network architecture is designed to signal the possibility of any type of reward: Norm violation punishment, Winning a lottery, & Misfortune of an envied competitor.  Dopamine signalling:
  
  • Rescales continuously to accommodate the range of intensity offered by different stimuli.  So dopamine's responses to any reward habituate.  GABA is released by some tegmental neurons to induce habituation.  This allows addictions to develop. 
    
  • Reflects the anticipation of reward.  It supports establishment of a relationship between a signal, working for a reward and obtaining the reward, but subsequently dopamine is mainly released encouraging the work, right after the signal supporting anticipation of the reward.  Anticipation requires learning and is reflected in hippocampus activity.  That explains context dependent cravings.  And the learning architecture means reliable cues become rewarding.  The accumbens supports willpower.  And dopamine
    
  • Promotes goal-oriented behavior needed to obtain & likely to achieve the reward - through the dopamine projections to the prefrontal cortex.  That makes dopamine central to:
    
  • Motivation.  This binding fails in depression - due to stress and in anxiety - due to signals from the amygdala.  
  • The prefrontal cortex's mesocortically stimulated support for willpower to act to delay rewards.  To sustain work for delayed rewards additional dopamine is released based on the length of the delay and the rewards uncertainty (modelled in the dorsolateral prefrontal cortex - which promotes the long term and the ventromedial prefrontal cortex - which promotes the short term) and the anticipated size of the reward (modelled in the accumbens).  Impulsiveness in ADHD is reflected in abnormal dopamine processing.  Addictive drugs bias the dopamine network towards impulsiveness.  
  • Is lowered by certain gene variants which induce: less dopamine in the synapse, fewer receptors, lower responsiveness of receptors; associated with (as tiny effects in hugely varying social scenarios): sensation seeking, risk taking, attentional problems, extroversion; where:
    
  • The receptor D4's gene shows high variability.  The D47R form is relatively unresponsive to dopamine.  
  • Dopamine is degraded by COMT.  The COMT gene includes a variant which is highly efficient reducing dopamine signalling but with complicating gene/environment interactions.  
  • Dopamine is removed from the synapse by a reuptake transporter DAT. 
    
  projection density and signalling, is an emergent capability which is used by cooperating agents to support coordination & rival agents to support control and dominance.  In eukaryotic cells signalling is used extensively.  A signal interacts with the exposed region of a receptor molecule inducing it to change shape to an activated form.  Chains of enzymes interact with the activated receptor relaying, amplifying and responding to the signal to change the state of the cell.  Many of the signalling pathways pass through the nuclear membrane and interact with the DNA to change its state.  Enzymes sensitive to the changes induced in the DNA then start to operate generating actions including sending further signals.  Cell signalling is reviewed by Helmreich.  Signalling is a fundamental aspect of CAS theory and is discussed from the abstract CAS perspective in signals and sensors.  In AWF the eukaryotic signalling architecture has been abstracted in a codelet based implementation.  To be credible signals must be hard to fake.  To be effective they must be easily detected by the target recipient.  To be efficient they are low cost to produce and destroy. 
  increase from the ventral tegmentum is part of the tegmentum which contains dopamine long system cell bodies (high levels of D(2)).  Their axons branch extensively and reach many areas including: Mesolimbic to the limbic system: amygdala, hippocampus; Tegmentostriatal to the nucleus accumbens, Mesocortical to the forebrain including the prefrontal cortex.  The terminals are fairly evenly distributed through out layers 1 - 6.  So dopamine can modulate input and output excitatory and inhibitory transmissions.  If a rodent wins a fight on his home territory, there are long-lasting increases in levels of testosterone receptors enhancing pleasurable effects.  The lateral ventral tegmental area is now known to be one of two large adrenergic pathways, along with the locus ceruleus.  During child birth the ventral tegmentum deploys more oxytocin receptors increasing its sensitivity to the neuropeptide.  
  catalyzing, an infrastructure amplifier. 
  increased interest in dopamine is a synaptic signal supporting generalized goal-directed behavior & anticipation of reward.  Its significance is that the receptors that detect the signal are of the slow acting type and are used to alter (modulate) the response of fast acting dopaminergic neural circuits in which the receptors are deployed (LTP).  The signal detects significant changes including predictions of models and actual results which differ unexpectedly.  Dopamine is released primarily by neurons of the ventral tegmental area and the substantia nigra.  The dopamine network architecture is designed to signal the possibility of any type of reward: Norm violation punishment, Winning a lottery, & Misfortune of an envied competitor.  Dopamine signalling:
  
  • Rescales continuously to accommodate the range of intensity offered by different stimuli.  So dopamine's responses to any reward habituate.  GABA is released by some tegmental neurons to induce habituation.  This allows addictions to develop. 
    
  • Reflects the anticipation of reward.  It supports establishment of a relationship between a signal, working for a reward and obtaining the reward, but subsequently dopamine is mainly released encouraging the work, right after the signal supporting anticipation of the reward.  Anticipation requires learning and is reflected in hippocampus activity.  That explains context dependent cravings.  And the learning architecture means reliable cues become rewarding.  The accumbens supports willpower.  And dopamine
    
  • Promotes goal-oriented behavior needed to obtain & likely to achieve the reward - through the dopamine projections to the prefrontal cortex.  That makes dopamine central to:
    
  • Motivation.  This binding fails in depression - due to stress and in anxiety - due to signals from the amygdala.  
  • The prefrontal cortex's mesocortically stimulated support for willpower to act to delay rewards.  To sustain work for delayed rewards additional dopamine is released based on the length of the delay and the rewards uncertainty (modelled in the dorsolateral prefrontal cortex - which promotes the long term and the ventromedial prefrontal cortex - which promotes the short term) and the anticipated size of the reward (modelled in the accumbens).  Impulsiveness in ADHD is reflected in abnormal dopamine processing.  Addictive drugs bias the dopamine network towards impulsiveness.  
  • Is lowered by certain gene variants which induce: less dopamine in the synapse, fewer receptors, lower responsiveness of receptors; associated with (as tiny effects in hugely varying social scenarios): sensation seeking, risk taking, attentional problems, extroversion; where:
    
  • The receptor D4's gene shows high variability.  The D47R form is relatively unresponsive to dopamine.  
  • Dopamine is degraded by COMT.  The COMT gene includes a variant which is highly efficient reducing dopamine signalling but with complicating gene/environment interactions.  
  • Dopamine is removed from the synapse by a reuptake transporter DAT. 
    
  based
  Read Montague explores how brains make decisions.  In particular he explains how:
  

  • Evolution can create indirect abstract models, such as the dopamine system, that allow
    
  • Life changing real-time decisions to be made, and how
    
  • Schematic structures provide encodings of computable control structures which operate through and on incomputable, schematically encoded, physically active structures and operationally associated production functions. 
  rewards.  Novelty seeking allows for creative exploration which was necessary to move beyond the familial pack.  Criticisms do not get incorporated into learning models by adolescents leaving their risk, is an assessment of the likelihood of an independent problem occurring.  It can be assigned an accurate probability since it is independent of other variables in the system.  As such it is different from uncertainty. 
  assessments very poor.  The target of the dopamine networks are categorized anatomically into three key types:
  • Ultra-short systems,
    
  • Intermediate length systems,
    
  • Long systems. 
    
  , the adolescent accumbens is a region of the basal forebrain (striatum) rostral to the preoptic area and immediately adjacent to the septum.  The nucleus accumbens was closely associated with the limbic system, mediates the impact of emotion and plays an important role in reinforcement.  If a rodent wins a fight on his home territory, there are long-lasting increases in levels of testosterone receptors enhancing pleasurable effects.  When prairie voles first mate, epi-genetic state changes are induced in the accumbens to support pair-bonding.  The accumbens projects to brain regions associated with movement.  The major pathways of dopaminergic neurons begin in the substantia nigra and the ventral tegmental area.  The amygdala projects back to the accumbens.  The tegmentostriatal system begins in the ventral tegmental area and projects to the nucleus accumbens.  The nucleus accumbens includes high levels of D1, D2 and D3 dopamine receptors located on the spine & shafts of dendrites of excitatory cells reduce the transfer of excitation from the dendrites to the cell bodies, so only especially strong excitatory inputs get through to the cell body to elicit excitation.  It also has D4 dopamine receptors which are highly variable.  The accumbens responds differently to rewards depending on maturity: In juveniles all reward levels result in the same response activity level, During adolescence the accumbens responds to small rewards negatively, and large rewards hugely, In adults the rewards result in measured scaled positive responses.  Chronic stress depletes dopamine from the nucleus accumbens biasing humans towards depression.  , responds to rewards like a gyrating top - hugely to large rewards, and negatively to small rewards.  Eventually as the frontal regions increase in contribution there are steady improvements in: working memory is a dominant function of the dorsolateral prefrontal cortex and the areas it connects with.  Prefrontal neurons implement an active memory continuing to fire after the signal is gone for potentially dozens of seconds from the inferior temporal cortex (multi-sensory integration area) and lower level sensory neurons characterized by Hubel & Weisel, while the short-term memory task continues.  If the prefrontal cortex gets distracted the memory is lost from consciousness.  Earl Miller argues the prefrontal cortex implements the rules that decide which working memory neurons will fire (Spring 2017).  Working memory develops from childhood through the late teens, and depends on pyramidal neurons within the PFC. 
  , flexible rule use, executive organization and task shifting.  And adolescents start to see other people's perspective. 
  
• Drive the cellular transformations with post-pubescent high levels of testosterone is a hormone secreted by the testes, ovaries, and adrenal glands, in response to stimulation from the hypothalamic/pituitary/testicular cascade, that makes humans more willing to do what it takes to attain and maintain status, according to Sapolsky.  That means players of the Ultimatum Game, if previously given testosterone can become more generous.  High testosterone in a fetus masculinizes the brain.  Males generate 10 times the amount.  It is the trigger for sexual desire in males and females, stimulating the hypothalamus.  Testosterone's effect is highly socially contextual so it may encourage acts of kindness or aggression (when challenged).  The level of testosterone does not predict which individuals will be aggressive in: Birds, Fish, Mammals including primates.  Genes impact the potency of testosterone by altering the enzymes that: Construct it, Convert it to estrogen, code the androgen receptor.   This androgen receptor includes a variable polyglutamine repeat which alters the sensitivity to the testosterone signal.  The more potent form is associated with boys showing more dramatic 'masculinization' of the cortex.  But the detected genetic influences are small.  Testosterone decreases activity in the prefrontal cortex and its functional coupling to the amygdala while increasing the coupling between the amygdala & the thalamus.  Testosterone shortens the refactory period of amygdaloid & amygdaloid target neurons.  This results in impulsive risk taking and more focus on unfamiliar faces and distrust of them.  Testosterone increases activity in the ventral tegmentum projecting dopamine to enhance place preference.  Winners of fights become more willing to fight in part due to testosterone increasing confidence and optimism and reducing fear and anxiety.  And winning at: Chess, Athletics, Stock trades; induces the BNST to add testosterone receptors increasing its sensitivity to the hormone.  People become overconfident and overly optimistic. 
  in males, and high but fluctuating estrogen is a generic term for a number of related steroid hormones each of which works differently.  Estrogen:
  • Is generated in the ovaries.  It supports the generation of oxytocin, and so is associated with attachment, nurturing and other affiliative behaviors. 
    
  • Supports verbal memory.  Removal of ovaries without immediate estrogen replacement therapy degrades verbal memory performance.  The HT reduces age-related shrinkage of the PFC, parietal cortex, and temporal lobe in women, and made them less depressed and angry. 
    
  • Supports mitochondrial operation in the blood vessels of the brain. 
    
  • Contributes to maternal aggression but it can reduce aggression and enhance empathy, depending on brain state.  There are two different estrogen receptor types which mediate these conflicting effects.  The level of each type of receptor is independently regulated.  Different receptor variants are associated with:
  • Higher rates of anxiety among women
  • Higher rates of antisocial behavior and conduct disorder in men
  • Is essential for vaginal lubrication 
  • Facilitates the elimination of cholesterol
    
  • Has anti-inflammatory and anti-oxidative properties improving response to stress
    
  & progesterone is a steroid hormone.  It:
  • Rarely directly effects areas of the brain.  Instead it is converted into other sterioids which have different actions in different brain areas. 
    
  • Increases maternal aggression in concert with estrogen by increasing oxytocin release in certain brain regions.  However, on its own progresterone decreases aggression and anxiety.  It decreases anxiety by entering neurons where it is converted to allopregnanolone which binds to GABA receptors increasing their sensitivity to GABA.  
  • Decreases female sex drive during the second half of the menstrual cycle.  
  levels in females.  Blood flow to the frontal cortex is also diverted on occasion to the groin.  
• Peer pressure is exceptionally influential in adolescents is Robert Trivers theory to explain the allocation of parental resources to various offspring, from the implications of genetics on the family.  Observing that children want to take more than what their parents want to give Trivers concluded a parent should aim to transfer resources depending on the relative benefits to each child and the costs, since each child has the same percentage of the parent's genes.  But each child shares only fifty percent of their genes with their siblings so should aim to get resources until the benefit to the others is twice the cost to the child.  And the parent may keep back some resources for allocation to further planned offspring.  A variety of conflicts ensue:
  • In the womb the fetus tries to capture nutrients from the mother at the expense of future children.  It ties up the mother's insulin to increase the blood sugar available to it and placing the mother at risk of diabetes.  Fathers can assist their offspring in this 'fight with the mother' by supplying imprinted genes that help the offspring capture resources. 
    
  • At birth mothers must decide whether to let the baby die.  This practice is cross cultural but is considered a depravity by present Western culture.  That is probably due to the West having captured a majority of the world's resources for centuries.  
  • Infants use cuteness to encourage parental investment.  A mother's attachment delays until it is clear that the baby will live.  
  • Infants cry to demand milk.  Until weaned the mother won't ovulate limiting her future reproductive potential. 
    
  • Young children are in conflict with their father over access to their mother. 
    
  • Children are in a position to develop paradoxical tactics to push for more resource allocation. 
    
  • Older children may have sexual conflicts with their parents, especially their fathers.  Fathers compete with sons for sexual partners in many societies.  But this competition is not for their mother.  
  • Adult children may conflict with their parents over allocation of family resources.  This has led to murder. 
    
  • Parents attempt to train children to assist the parent's social interests.  The implication is that children are wary of their parent's suggestions and typically pay more attention to the advice of their peer group according to Judith Harris.  
  • Parents sell or trade their children.  The price paid for a daughter will likely depend on her virginity.  Hence fathers take an interest in their daughters' sexuality.  
  .  Admired peer comments reduce vmPFC is ventromedial prefrontal cortex which is:
  • Focused on the impact of emotion on decision making
    
  • A participant in limbic system operations 
  • Many human behaviors involve interactions between the vmPFC, the limbic system & the dorsolateral prefrontal cortex.  Part of decision making is for the limbic system to internally simulate (often with the help of the sympathetic nervous system) what alternative outcomes of a decision will feel like with the results of these somatic marker analyses being reported to the vmPFC.  
    
  • Damage to the vmPFC results in bad decision making: Poor judgement in choosing friends & partners, Failure to respond to negative feedback; because they can't feel the issues; and are overly controlled by the logical contribution of the DLPFC. 
    
  activity and enhance ventral striatal is a region within the basal ganglia.   It is a target of the tegmentostriatal dopamine pathway.  It has been captured by brain imaging assigning values to subliminal symbols experimentally associated with winning (highly valued) and losing (low valuation) money.  During adolescence, prior to the deployment of the prefrontal cortex, the ventral striatum helps balance/control emotional decision making. 
  activity.  Adults modulate the mental impact of socially mean treatment: the initial activation of the PAG is periaqueductal gray, an ancient core brain structure that projects pain sensations to the amygdala, has a high density of vasopressin and oxytocin receptors and a direct connection to the orbitofrontal cortex, potentially supporting maternal love.  It has a critical role in autonomic function, motivated behavior and responses to threats - the dorsal PAG activates during defensive behaviors: freezing immobility, running, jumping, increased blood pressure; while caudal ventrolateral PAG activation results in an immobile relaxed posture.  The PAG's enkephalin-producing cells suppress pain. 
  , anterior cingulate is the cingulate gyrus, a rich club hub.  Contains many sub-parts:
  
  • The anterior cingulate cortex ACC:
  • Includes the subgenual ACC and the paragenual ACC, and Brodmann areas 24, 25, 32 and 33. 
    
  • The gyrus of the ACC has two functional components, which both operate abnormally in mood disorders: depression, anxiety & bipolar.  The
    
  • Rostral/ventral part is involved in emotional processes and autonomic functions.  It connects to the hippocampus, amygdala, orbital prefrontal cortex, anterior insula, nucleus accumbens.  It is overactive during regular or bipolar depression. 
    
  • Caudal part is involved in cognition and the control of behavior.  It connects with the dorsal PFC, secondary motor cortex, and posterior cingulate cortex
    
  • Is a central focus of empathy supporting people relating to other's pain.  This is dependent on oxytocin. 
    
  • In non-human mammals it processes interoceptive signals.  The ACC focuses the internal signals into high level 'gut intuitions.'  Pain catches the ACC's attention. 
    
  • Performs discrepancy detection from the outcome that was predicted - at a high level.  The ACC cares about the meaning of what is predicted. 
    
  • If the ACC has been convinced that a pain killer placebo has inhibited pain signals, the ACC will stay silent about actual pain that is signalled from interoceptive networks.  
  • The ACC will signal: physical pain, emotional pain, metaphorical pain, anxiety, disgust, embarrassment, social exclusion especially in adolescence; as one and the same.  The ACC's abnormalities being associated with major depression. 
    
  • Has a bridging role between the empathetic and self-interested pain monitor.  Sapolsky notes the ACC is essential for learning fear and conditioned avoidance by observation alone through an intermediate step of shared representation of self.  He concludes "At its core the ACC is about self-interest, with caring about the other person in pain as an add-on." 
    
  • The midcingulate cortex was formerly judged part of the 'emotional' limbic system in MacLean's discredited triune brain model.  
  • The posterior cingulate cortex
    
  • The retrosplenial cingulate cortex
    
  , amygdala contains > 12 distinct areas: Central, Lateral.  It receives simple signals from the lower parts of the brain: pain from the PAG; and abstract complex information from the highest areas: Disgust, heart rate, and suffering from the insula cortex, allowing it to orchestrate emotion.  It connects strongly to attention focusing networks.  It sends signals to almost every other part of the brain, including to the decision making circuitry of the frontal lobes.  It has high levels of D(1) dopamine receptors.  During extreme fear the amygdala drives the hippocampus into fear learning.  It outputs directly to subcortical reflexive motor pathways when speed is required.  Its central nucleus projects to the BNST.  It signals the locus ceruleus.  It directly signals area 25.  The amygdala:
  
  • Promotes aggression.  Stimulating the amygdala promotes rage.  It converts anger into aggression and when impaired it impacts the ability to detect angry facial expressions.  
  • Participates in disgust
  • Perceives fear promoting stimuli, focusing our attention on these.  In PTSD sufferers the Amygdala overreacts to mildly fearful stimuli and is slow to calm down and the amygdala expands in size over a period of months.  Fear is processed by the lateral nucleus which serves as the input from various senses, and the central nucleus which outputs to the brain stem (central grey - freezing, lateral hypothalamus - blood pressure, activates paraventricular hypothalamus => crf -> hormone adjustments). 
    
  • Has lots of receptors for and is highly sensitive to glucocorticoids.  Stress inhibits the GABA interneurons in the basolateral amygdala (BLA) allowing the excitatory glutamate releasing neurons to excite more. 
    
  • Is sensitive to unsettling/uncertain social situations where it promotes anxiety and makes us distracted.  It is also interested in uncertain but potentially painful situations.  The amygdala contributes to social and emotional decision making where the BLA supports rejecting an unacceptable offer, as allowed in the Ultimatum Game, by injecting implicit mistrust and vigilance, generating an anger driven rejection that is used as punishment.  The amygdala is very rapidly excited by subliminal signals from the thalamus of outgroup skin color.  The amygdala subsequently tips social emotions against outgroups unless restrained by the frontal lobe or influenced by subliminal priming to prioritize inclusion.  The fast path from the thalamus rapidly but inaccurately signals its identified a weapon. 
    
  • Sees suffering of others as increasingly salient with loving-kindness meditation practice, Goleman & Davidson explain. 
    
  • Promotes male, but not female, sexual motivation when it is an uncertain potential pleasure. 
    
  • Responds to the longing for uncertain potential pleasures and fear that the reward will not be worth it if it happens.  The amygdala turns off during orgasm. 
    
  • Uses but is not directly involved in vision.  
  , insula cortex is part of the cerebral cortex folded deep within the lateral sulcus.  It includes: anterior, posterior insula; and is overlaid by the operculum.  Kandel notes the anterior insula is where feelings are calibrated by evaluating and integrating the importance of the stimuli.  It directly signals area 25.  LeDoux showed there are two routes for signals of feelings and emotions to the amygdala: a fast unconscious one and a slow one that involves the anterior insula.  So the insula is assumed to participate in consciousness where it has been linked to emotion, salience & body homeostasis functions:
  
  • Perception,
    
  • Motor control: Hand-&-eye motor movement, Swallowing, Gastric motility, Speech articulation;
    
  • Self-awareness,
    
  • Inter-personal experiences: Disgust at smells, contamination & mutilation which generate visceral responses, that are projected to the amygdala; binding physical and moral aspects of purity (Macbeth effect)
  • Suffering of others can be projected by the insula to the amygdala and made increasingly salient with loving-kindness meditation practice, Goleman & Davidson explain. 
    
  • Homeostatic regulation of the sympathetic network, parasympathetic network, and immune system.  Heart rate and sweat gland activity are monitored.   When the amygdala signals concern, the insula prepares the body for action, increasing blood flow to the muscles etc.
    
  ; which generate feelings of pain emerged as a mental experience, Damasio asserts, constructed by the mind using mapping structures and events provided by nervous systems.  But feeling pain is supported by older biological functions that support homeostasis.  These capabilities reflect the organism's underlying emotive processes that respond to wounds: antibacterial and analgesic chemical deployment, flinching and evading actions; that occur in organisms without nervous systems.  Later in evolution, after organisms with nervous systems were able to map non-neural events, the components of this complex response were 'imageable'.  Today, a wound induced by an internal disease is reported by old, unmyelinated C nerve fibers.  A wound created by an external cut is signalled by evolutionarily recent myelinated fibers that result in a sharp well-localized report, that initially flows to the dorsal root ganglia, then to the spinal cord, where the signals are mixed within the dorsal and ventral horns, and then are transmitted to the brain stem nuclei, thalamus and cerebral cortex.  The pain of a cut is located, but it is also felt through an emotive response that stops us in our tracks.  Pain amplifies the aggression response of people by interoceptive signalling of brain regions providing social emotions including the PAG projecting to the amygdala; making aggressive people more so and less aggressive people less so.  Fear of pain is a significant contributor to female anxiety.  Pain is the main reason people visit the ED in the US.  Pain is mediated by the thalamus and nucleus accumbens, unless undermined by sleep deprivation. 
  , anger is an emotion which protects a person who has been cheated by a supposed friend.  When the exploitation of the altruism is discovered, Steven Pinker explains, the result is a drive for moralistic aggression to hurt the cheater.  Anger is mostly experienced as a rapid wave that then quickly dissipates.  When it is repressed, for example by a strong moral sense (superego), it can sustain, inducing long term stress. 
  , and disgust is a universal human emotion.  Pinker notes it has its own facial expression and is codified in food taboos.  The mind must be associated with the proximate environment and parents minimize the risk for their omnivorous children by teaching them what foods to eat and what to avoid.  The children's minds are initially receptive to trying all foods but their brains subsequently lock in on the foods they have experienced.  These parental choices are affected by schematic influence on what has been beneficial.  Adolescent's brain developments undermine these constraints enabling intergroup transfers.  Disgust is modulated by the insula cortex which projects signals to the amygdala.  Adult humans merge moral and physical disgust enabling metaphorical out grouping. 
  , with the VLPFC is ventrolateral prefrontal cortex
  but that does not occur in adolescents.  
• Feel empathy is the capability to relate to another person from their perspective.  It is implemented by spindle neurons.  Empathy towards others is controlled by the right-hemisphere supramarginal gyrus.  Empathy is context dependently mediated by estrogen.  It develops over time: Piaget's preoperational stage includes rudimentary empathy, Theory of mind supports the development; initially feeling someone's pain as one integrated being, then for them and eventually as them.  In adults, when someone else is hurt the anterior cingulate cortex, amygdala & insula activates projecting [scapegoating] to the vmPFC.  If the pain is physical the PAG activates and motor neurons for the area where the other person was injured.  The intertwining of the ACC amygdala & insula in adults results in attribution of fault even when there is none which can make it hard to step in and actually help.  But in seven-year-olds the activation is concrete: PAG and sensory & motor cortexes with minimal coupling to the rudimentary vmPFC.  In older children the vmPFC is coupled to limbic structures.  Ten to twelve year olds abstract empathy to classes of people.  Brizendine asserts young girls develop empathy earlier than boys, because their evolved greater neuronal investment in communication and emotion networks.  Year old girls are much more responsive to the distress of other people than boys are.  At 18 months girls are experiencing infantile puberty.  By adolescence the vmPFC is coupled to theory of mind regions and intentional harm induces disgust via the amygdala.  Sapolsky explains adolescent boys are utilitarian and tend to accept inequality more than girls do.  But both sexes accept inequality as the way it is.  Sociopaths do not develop empathy.   intensely, supported by their rampant emotions, interest in novelty, ego.  But feeling the pain of others can induce self-oriented avoidance of the situations. 
  
• Adrenal glands are endocrine glands, situated above the kidneys provides multiple vital functions.  It: Produces renin which supports negative feedback, Removes excess organic molecules from the blood, Regulates electrolytes in the blood, Maintains pH homeostasis, Regulates fluid balance, Regulates blood pressure, monitors blood oxygen concentration and signals erythropoiesis with EPO, Reabsorbs water, glucose (SGLT2) and amino acids.  Kidney function is monitored with the GFR.  Kidneys can fail acutely or chronically.  Kidneys are affected by a variety of cancers including: advanced kidney cancer, von Hippel Landau; some of which are induced by PFAS.    Multiple myeloma, type 2 diabetes, TB and drug treatments for MDR TB place a strain on the kidneys and can induce failure.  , that produce: adrenaline, aldosterone and cortisol is a glucocorticoid produced in the adrenal cortex of the adrenal glands.  It:
  
  • Stimulates
    
  • Gluconeogenesis to increase production of blood sugar
    
  • Metabolism of fats, proteins and carbohydrates
    
  • Suppresses the immune system.  
  • Decreases bone formation
  • In excessive concentrations destroy synaptic connections in the: hippocampus, and prefrontal cortex; leading to flattened emotions and impaired memory. 
    
  . 
  
• ADT is admit, discharge, transfer, a backbone HIS Health care information systems.  There were traditionally four backbone services:
  • ADT,
  • Financial,
    
  • Scheduling,
  • Acuity (EDIS);
    
  allowing the sharing of patient information with other health care providers.  It has a corresponding HL7 is health level 7 (name implying focused on application level protocols in health care).  It includes a variety of standards: Arden Syntax, RIM, CDA, CCOW, claims attachments, FHIR, SPL and messaging and has developed a EHR system functional model providing a standardized description of the functions provided.  The formation of HL7 messaging communications streams has a relatively high overhead.  HL7 version 2 is generally deployed.  The version 2 messaging standardizes health care data interchange with messages originally based on character delimited '|' segments (containing character delimited '^' composite fields (containing character delimited '&' subcomponents) in a non XML structure interchanged widely over a secure network stack.  The first field in a message segment is the 3 character segment name.  HL7 is generally transmitted over MLLP.  HL7 v2 has been extended with an XML encoding.  HL7 v2 messages have to be augmented to transmit over TCP/IP.  The US Government mandate that licenced recipients of HL7 messages understand all aspects of the information transferred.  That is point-to-point specific since each sender has their own interpretation of what information goes in what HL7 fields.  The usual solution to this situation and rule is (1) an interface engine placed between the two points which maps the sender's information from the fields it uses for transmission to the recipients interpretation of HL7 field usage and (2) a lot of testing to show the mappings are correct and reliable.  Because of the impact of changing the interpretation of use of HL7 (on all the interface engines of point connected partners) operational adjustments to HL7 are difficult.  Version 3 of HL7 adopts a different strategy.  It introduces a Meta model (RIM) of the data and so when adopted changes the strategies available for interconnection.  It is XML based.  But the operational difficulty of switching to version 3 has left most systems tied to version 2.   message that reports a status change for a patient.  
• Advance payment ACO is a CMS is the centers for Medicare and Medicaid services.   Innovation center is the CMS Innovation Center.  It was created by the ACA to test new models of health care delivery and payment including the Pioneer ACO and the Advance Payment ACO.  It also offers technical support to providers to improve the coordination of care and share lessons learned and best practices.  In 2016 Andy Slavitt proposed testing a new Medicare part B drug pricing rule, which was furiously resisted by PhRMA and blocked by Representative Skimkus collection of 242 Representative's signatures. 
  has developed a model of an ACO for physician-owned and rural providers participating in the Shared Savings is the Medicare Shared Savings Program.  The program began in 2012 with 3 year term contracts.  ACO Physician groups and hospitals are eligible to participate but there must be primary care physicians in the ACO.  Participating ACOs must serve > 5000 Medicare beneficiaries.  The potential for a bonus payment is based on Medicare cost savings and quality metrics.  Two payment models are available.  Only one has downside risk involved.  CMS included 'robust' quality measures to monitor the quality of care provided and beneficiary satisfaction (see fact sheet 'Improving Quality of Care for Medicare Patients: Accountable Care Organizations'). 
  Program who would benefit from additional start-up resources to build the necessary infrastructure, such as new staff or information technology systems.  
• Advanced APM is a CMS is the centers for Medicare and Medicaid services.   regulated group of APM is alternative payment model, Medicare's risk based payments to organizations set up as ACOs.  It includes track 1 ACOs which are not risk bearing.  APMs have to report various measures to CMS. 
  s that effectively uses FFV is fee-for-value payment.  It may be a bundled payment for a set of services provided by a group of doctors and facilities, or full capitation.  In each case the risk has shifted from the payer to the providers of care. 
  .  The list includes: Risk-bearing ACO is an Accountable Care Organization. These are accredited bundles of companies which together try to offer Dartmouth-Hitchcock like business models (Dec 2015, Sep 2016) focused on wellness, improving the provision of primary care to a large group of Medicare patients, and rewarding doctors for preventing problems.  Advocate health illustrates the idea.  Robert Pearl notes that the transition is difficult: hospitals that find their efficiency improving should reduce the number of doctors they utilize.  But any doctors that are pushed out of the ACO will likely take their patients with them, undermining the revenues that support the FFV business.  The ACA regulates qualification to be a Medicare ACO.  Individual organizations within a Medicare shared savings ACO continue to submit their own claims and are paid by Medicare for FFS.  But the ACO is eligible for shared savings.  Within the shared savings program the CMS innovation center has setup advanced payment ACOs.  As an alternative to shared savings, in a Pioneer ACO, over time 50% of the FFS payments flow directly to the ACO as a bundled payment.  CMS has established quality measures for ACOs for Medicare.  The CMS program's purpose is to reward providers for reducing total cost of care for patients through prevention, disease management, and coordination. 
  
  • CMS initiated its Physician Group Practice Demonstration in 2005.  By 2008 the congressional budget office reported on Bonus-eligible organizations. 
    
  • CMS defines ACOs as organizations that "create incentives for health care providers to work together to treat an individual patient across care settings - including doctors' offices, hospitals and long-term care facilities."
  • CMS has developed APMs which include ACOs, and advanced APMs where the ACOs must be risk bearing. 
    
  • CMMI accepts providers' proposals to test various payment systems including shared savings and partial capitation.  
  • Private market ACOs have formed including: Providence Health & Services, Blue Shield California, Anthem Blue Cross, United Health Care, BCBS Minnesota, BCBS Illinois, Humana, CIGNA, Main Health Management Coalition, BCBS Massachusetts, Aetna.  
  s, Comprehensive end stage renal disease care, Comprehensive primary care plus, Oncology care model. 
  
• Advanced kidney cancer - There are expected to be 61,560 new cases of kidney cancer includes any cancer initiated in the kidney.  In adults the most common form is an RCC.  In children Wilms tumors are most common.  Transitional cell cancer is the other common form.  It develops in the renal pelvis and ureter in adults.  It is associated with obesity. 
  in the US is the United States of America.   and 14,080 deaths in 2015.  Drug treatments have increased survival from 10 - 12 months to up to 30.  Exact causes are unknown but risk factors are: smoking, obesity is an addictive disorder where the brain is induced to require more eating, often because of limits to the number of fat cells available to report satiation (Jul 2016).  Brain images of drug-addicted people and obese people have found similar changes in the brain.  Obese people's reward network tends to be less responsive to dopamine and have a lower density of dopamine receptors.  Obesity spreads like a virus through a social network with a 171% likelihood that a friend of someone who becomes obese will also become so.  Obesity is associated with: metabolic syndrome including inflammation, cancer (Aug 2016), high cholesterol, hypertension, type-2-diabetes, asthma and heart disease.  It is suspected that this is contributing to the increase in maternal deaths in the US (Sep 2016).  Obesity is a complex condition best viewed as representing many different diseases, which is affected by the: Amount of brown adipose tissue (Oct 2016), Asprosin signalling by white adipose tissue (Nov 2016), Genetic alleles including 25 which guarantee an obese outcome, side effects of some pharmaceuticals for: Psychiatric disorders, Diabetes, Seizure, Hypertension, Auto-immunity; Acute diseases: Hypothyroidism, Cushing's syndrome, Hypothalamus disorders; State of the gut microbiome.  Infections, but not antibiotics, appear associated with childhood obesity (Nov 2016). 
  , high blood pressure is high blood pressure.  It is directly associated with death rate due to pressure induced damage to the left ventricle and in general to cardiovascular diseases.  Treated with antihypertensives: Diuretics, Calcium channel blockers, Angiotensin receptor blockers or Beta blockers.  , genetic mutations and heredity.  
• Adverse drug reactions result from various causes of drug treatments including:
• Individual pharmacogenomics studies how genes affect a person's response to drugs so as to develop personalized drug treatment plans, tailored to a person's specific phenotype.  The process optimizes the treatment process but there are barriers to its deployment:
  • Large scale clinical trials may test 20,000 individuals, but if a toxic response impacts only 0.1% of them there would only be 20 cases found which is often too few to identify the cause of the response.  Instead a process for capturing adverse drug reactions after approval and marketing must be used along with the ability to take a blood sample in these cases.  
  • Simplified studies on a subset of individuals that have the target allele should be cheaper but are unattractive to pharmaceutical companies which typically want to maximize their target market (Aug 2016).  
  • F.D.A. has not required genomic testing for most drug developments.  
  • Health care providers are being slow to use pharmacogenomics.  Often third-party payers are unwilling to reimburse the tests. 
    
  • Transportation to centralized laboratories for genomic testing causes delays which makes some drug therapy applications impractical.  An alternative solution would be to have a patient's EHR contain their genome sequence for immediate genomic implications.  
  differences altering the metabolic processing chain of each drug. 
  
• Pharmacists' miss-understanding handwritten prescriptions. 
  
• Patient's miss-interpreting their treatment instructions. 
  
• Complex interactions of multiple drugs being taken by a patient. 
  
• Underlying illnesses, especially of the liver is an emergent cellular system providing metabolic: Dietary compound metabolism and signalling: After gorging on sugar-rich foods the liver releases FGF21 hormone to dampen further eating activity; Detoxification, Regulation of glucose through glycogen storage (asprosin signalling from white adipose tissue); clotting, immune, exocrine and endocrine functions.  It is supplied with oxygen-rich blood via the hepatic artery and blood rich in semi-processed foodstuffs from the intestines & spleen via the hepatic portal vein.  It is constructed from: Hepatocytes which swim in the blood to process it, BECs, Stromal cells, Hepatic stellate cells, Kupffer cells, and blood vessels.  The embryonic endoderm cells invade the mesoderm to form the liver bud.  Subsequently the liver bud vascularizes and is colonized by hematopoietic cells.  The liver operates on a daily cycle (Aug 2018) allowing it time to recover from the stress of processing toxic substances.  In a healthy adult liver cells do not divide significantly.  But in a damaged liver, the liver cells shift back to a neonatal state to re-enter the cell cycle and rebuild the liver.  There are over 100 disorders of the liver.  Obesity and diabetes are associated with increased prevalence of these liver disorders worldwide. 
  & kidneys provides multiple vital functions.  It: Produces renin which supports negative feedback, Removes excess organic molecules from the blood, Regulates electrolytes in the blood, Maintains pH homeostasis, Regulates fluid balance, Regulates blood pressure, monitors blood oxygen concentration and signals erythropoiesis with EPO, Reabsorbs water, glucose (SGLT2) and amino acids.  Kidney function is monitored with the GFR.  Kidneys can fail acutely or chronically.  Kidneys are affected by a variety of cancers including: advanced kidney cancer, von Hippel Landau; some of which are induced by PFAS.    Multiple myeloma, type 2 diabetes, TB and drug treatments for MDR TB place a strain on the kidneys and can induce failure.   altering the metabolism and clearing of drugs in the body. 
  
• Aether-drift was a prediction of physicists attempting to align the Galileian transformation is a set of equations relating one place (x,y,z) and time (t) to another place (x',y',z') and time (t'):
  • x' = x - vt
  • y' = y
  • z' = z
  • t' = t
    
  with a set of reference bodies moving uniformally.  It was proposed that one body K was at rest with respect to an aether in space.  More complicated laws of other reference bodies in motion relative to the aether would demonstrate aether drift. 
• AF is atrial fibrillation, an abnormal heart rhythm: rapid, irregular.  It:
• Can lead to blood clots or coagulation is formation of a clot:
  • Platlets become activated, adhere and aggregate supported by
  • Fibrin polymerization, deposition and maturation.  
  , stroke is when brain cells are deprived of oxygen and begin to die.  750,000 patients a year suffer strokes in the US.  85% of those strokes are caused by clots.  There are two structural types: Ischemic and hemorrhagic.  Thrombectomy has been found to be a highly effective treatment for some stroke situations (Jan 2018). 
  , CHF is congestive heart failure which occurs when the heart is unable to generate enough blood flow to meet the body's demands.  There are two main types: failure due to left ventricular dysfunction and abnormal diastolic function increasing the stiffness of the left ventricle and decreasing its relaxation.  Heart expansion in CHF distorts the mitral valve which exacerbates the problems.  MitraClip surgery trials found effective in correcting the mitral valve damage (Sep 2018).  Treatments include: digoxin; , dementia is a classification of memory impairment, constrained feelings and enfeebled or extinct intellect.  The most common form for people under 60 is FTD.  Dementia has multiple causes including: vascular disease (inducing VCI) including strokes, head trauma, syphilis and mercury poisoning for treating syphilis, alcoholism, B12 deficiency (Sep 2016), privation, Androgen deprivation therapy (Oct 2016), stress, Parkinson's disease, Alzheimer's disease, and prion infections such as CJD and kuru.  The condition is typically chronic and treatment long term (Laguna Honda ward) and is predicted by Stanley Prusiner to become a major burden on the health system.  It may be possible to constrain the development some forms of dementia by: physical activity, hypertension management, and ongoing cognitive training.  Dementia appears to develop faster in women than men.   and other complications.  
• Fibrillations allow blood to pool in the heart chambers and form small clots which can then lodge in small arteries and block blood flow. 
  
• Has become much more common being induced by endemic diseases: hypertension is high blood pressure.  It is directly associated with death rate due to pressure induced damage to the left ventricle and in general to cardiovascular diseases.  Treated with antihypertensives: Diuretics, Calcium channel blockers, Angiotensin receptor blockers or Beta blockers.  , obesity is an addictive disorder where the brain is induced to require more eating, often because of limits to the number of fat cells available to report satiation (Jul 2016).  Brain images of drug-addicted people and obese people have found similar changes in the brain.  Obese people's reward network tends to be less responsive to dopamine and have a lower density of dopamine receptors.  Obesity spreads like a virus through a social network with a 171% likelihood that a friend of someone who becomes obese will also become so.  Obesity is associated with: metabolic syndrome including inflammation, cancer (Aug 2016), high cholesterol, hypertension, type-2-diabetes, asthma and heart disease.  It is suspected that this is contributing to the increase in maternal deaths in the US (Sep 2016).  Obesity is a complex condition best viewed as representing many different diseases, which is affected by the: Amount of brown adipose tissue (Oct 2016), Asprosin signalling by white adipose tissue (Nov 2016), Genetic alleles including 25 which guarantee an obese outcome, side effects of some pharmaceuticals for: Psychiatric disorders, Diabetes, Seizure, Hypertension, Auto-immunity; Acute diseases: Hypothyroidism, Cushing's syndrome, Hypothalamus disorders; State of the gut microbiome.  Infections, but not antibiotics, appear associated with childhood obesity (Nov 2016). 
  and type-2-diabetes is the leading cause of blindness, limb amputations and kidney failure.  It is a risk factor for Alzheimer's disease.  Insulin and glucose levels are regulated by the pancreas, liver, muscle, brain and fat.  Diabetes occurs when the insulin level is insufficient to regulate the glucose in the system.  As we age our muscles become less sensitive to insulin and the pancreas responds by increasing the amount generated.  Increased fat levels in obesity demand more insulin overloading the pancreas.  Persistent high glucose levels are also toxic to the pancreas beta cells.  High glucocorticoid levels have been associated with type 2 diabetes.  There are genetic risk factors since siblings of someone with the disease have three times the baseline risk (about 50% of the risk of getting type 2 diabetes is genetic).  The inheritance is polygenic.  More than 20 genes have been identified as risk factors, but that is too few to account for the 50% weighting so many more will be identified.  Of those identified so far many are associated with the beta cells.  The one with the strongest relative risk is TCF7L2.  The disease can be effectively controlled through a diligent application of treatments and regular checkups.  Doctors are monitored for how under control their patients' diabetes is (Sep 2015).  Treatments include:
  • Metformin - does not change the course of pre-diabetes - if you stop taking it, it is as if it hasn't been taken. 
    
  • Diet
  • Exercise
  . 
  
• Cocoa reduces risk of AF (May 2017)
• Treatments include: digoxin is a WHO essential medicine for treating heart conditions including: AF, atrial flutter and CHF.  It typically makes the heart beat more strongly, slowly and regularly.  But in one patient in ten a gut bacterium, Eggerthella lenta with two specific gene variants, inactivates the digoxin.  Digoxin was initially isolated from the foxglove, Digitalis lanata. 
  ;
  
• AFB is Air Force Base. 
  
• AFDC is Aid to Families with Dependent Children program, created by the SSA is the social securities act of 1935 was part of the second New Deal.  It attempted to limit risks of old age, poverty and unemployment.  It is funded through payroll taxes via FICA and SECA into the social security trust funds.  Title IV of the original SSA created what became the AFDC.  The Social Security Administration controls the OASI and DI trust funds.  The funds are administered by the trustees.  The SSA was amended in 1965 to include:
  • Title V is Maternal and child health services. 
    
  • Title XVIII is Medicare.  
  , that ran from 1935 to 1996 when it was replaced by TANF.  The values provided declined over the years. 
  
• Affective facial display is a face expressing strong emotions are low level fast unconscious agents distributed across the brain and body which associate, via the amygdala and rich club hubs, important environmental signals with encoded high speed sensors, and distributed programs of action to model: predict, prioritize guidance signals, select and respond effectively, coherently and rapidly to the initial signal.  The majority of emotion centered brain regions interface to the midbrain through the hypothalamus.  The cerebellum and basal ganglia support the integration of emotion and motor functions, rewarding rhythmic movement.  The most accessible signs of emotions are the hard to control and universal facial expressions.  Emotions provide prioritization for conscious access given that an animal has only one body, but possibly many cells, with which to achieve its highest level goals.  Because of this, base emotions clash with group goals and are disparaged by the powerful.  Pinker notes a set of group selected emotions which he classes as: other-condemning, other-praising, other-suffering and self-conscious emotions.  Evolutionary psychology argues evolution shaped human emotions during the long period of hunter-gatherer existence in the African savanna.  Human emotions are universal and include: Anger, Appreciation of natural beauty, Contempt, Disgust, Embarrassment, Fear, Gratitude, Grief, Guilt, Happiness, Honor, Jealousy, Liking, Love, Moral awe, Rage, Romantic love, Lust for revenge, Passion, Sadness, Self-control, Shame, Sympathy, Surprise; and the sham emotions and distrust induced by reciprocal altruism. 
  as interpreted by an observer's brain.  In:
• Adult observers this activates that amygdala contains > 12 distinct areas: Central, Lateral.  It receives simple signals from the lower parts of the brain: pain from the PAG; and abstract complex information from the highest areas: Disgust, heart rate, and suffering from the insula cortex, allowing it to orchestrate emotion.  It connects strongly to attention focusing networks.  It sends signals to almost every other part of the brain, including to the decision making circuitry of the frontal lobes.  It has high levels of D(1) dopamine receptors.  During extreme fear the amygdala drives the hippocampus into fear learning.  It outputs directly to subcortical reflexive motor pathways when speed is required.  Its central nucleus projects to the BNST.  It signals the locus ceruleus.  It directly signals area 25.  The amygdala:
  
  • Promotes aggression.  Stimulating the amygdala promotes rage.  It converts anger into aggression and when impaired it impacts the ability to detect angry facial expressions.  
  • Participates in disgust
  • Perceives fear promoting stimuli, focusing our attention on these.  In PTSD sufferers the Amygdala overreacts to mildly fearful stimuli and is slow to calm down and the amygdala expands in size over a period of months.  Fear is processed by the lateral nucleus which serves as the input from various senses, and the central nucleus which outputs to the brain stem (central grey - freezing, lateral hypothalamus - blood pressure, activates paraventricular hypothalamus => crf -> hormone adjustments). 
    
  • Has lots of receptors for and is highly sensitive to glucocorticoids.  Stress inhibits the GABA interneurons in the basolateral amygdala (BLA) allowing the excitatory glutamate releasing neurons to excite more. 
    
  • Is sensitive to unsettling/uncertain social situations where it promotes anxiety and makes us distracted.  It is also interested in uncertain but potentially painful situations.  The amygdala contributes to social and emotional decision making where the BLA supports rejecting an unacceptable offer, as allowed in the Ultimatum Game, by injecting implicit mistrust and vigilance, generating an anger driven rejection that is used as punishment.  The amygdala is very rapidly excited by subliminal signals from the thalamus of outgroup skin color.  The amygdala subsequently tips social emotions against outgroups unless restrained by the frontal lobe or influenced by subliminal priming to prioritize inclusion.  The fast path from the thalamus rapidly but inaccurately signals its identified a weapon. 
    
  • Sees suffering of others as increasingly salient with loving-kindness meditation practice, Goleman & Davidson explain. 
    
  • Promotes male, but not female, sexual motivation when it is an uncertain potential pleasure. 
    
  • Responds to the longing for uncertain potential pleasures and fear that the reward will not be worth it if it happens.  The amygdala turns off during orgasm. 
    
  • Uses but is not directly involved in vision.  
  and subsequently the vmPFC is ventromedial prefrontal cortex which is:
  • Focused on the impact of emotion on decision making
    
  • A participant in limbic system operations 
  • Many human behaviors involve interactions between the vmPFC, the limbic system & the dorsolateral prefrontal cortex.  Part of decision making is for the limbic system to internally simulate (often with the help of the sympathetic nervous system) what alternative outcomes of a decision will feel like with the results of these somatic marker analyses being reported to the vmPFC.  
    
  • Damage to the vmPFC results in bad decision making: Poor judgement in choosing friends & partners, Failure to respond to negative feedback; because they can't feel the issues; and are overly controlled by the logical contribution of the DLPFC. 
    
  as they become habituated to the emotional content. 
  
• Adolescents the vmPFC responds less allowing the amygdala's activation to keep growing. 
  
• AFIT is the US is the United States of America.   Air Force Institute of Technology, a scholarship program to support personnel studying to obtain advanced degrees.  The Sputnik crisis identified a need to train engineers for a US response, which forced a broadening of the AFIT program to include undergraduate engineering degrees and a loosening of the
  Terrence Deacon explores how constraints on dynamic flows can induce emergent phenomena which can do real work.  He shows how these phenomena are sustained.  The mechanism enables the development of Darwinian competition. 
  
  constraints. 
  
• Aflatoxins are a family of complex aromatic toxins and carcinogens produced by certain Aspergillus molds.  They are amongst the most carcinogenic substances known.  They are metabolized in the liver is an emergent cellular system providing metabolic: Dietary compound metabolism and signalling: After gorging on sugar-rich foods the liver releases FGF21 hormone to dampen further eating activity; Detoxification, Regulation of glucose through glycogen storage (asprosin signalling from white adipose tissue); clotting, immune, exocrine and endocrine functions.  It is supplied with oxygen-rich blood via the hepatic artery and blood rich in semi-processed foodstuffs from the intestines & spleen via the hepatic portal vein.  It is constructed from: Hepatocytes which swim in the blood to process it, BECs, Stromal cells, Hepatic stellate cells, Kupffer cells, and blood vessels.  The embryonic endoderm cells invade the mesoderm to form the liver bud.  Subsequently the liver bud vascularizes and is colonized by hematopoietic cells.  The liver operates on a daily cycle (Aug 2018) allowing it time to recover from the stress of processing toxic substances.  In a healthy adult liver cells do not divide significantly.  But in a damaged liver, the liver cells shift back to a neonatal state to re-enter the cell cycle and rebuild the liver.  There are over 100 disorders of the liver.  Obesity and diabetes are associated with increased prevalence of these liver disorders worldwide. 
  to reactive intermediates that mutate p53 is a tumor suppressor which improves the specificity of transcription's DNA binding and promotes the transcriptional activity of E2F.  P53's activity is controlled by phosphorylation by cyclin Cdk complexes allowing indirect control of the cell cycle.  Among the many genes controlled by p53 are cyclin genes, genes for an inhibitor of cyclin-dependent kinases (Cdk), and the bax gene, which promotes apoptosis.  p53 can thus promote cell proliferation.  It can drive cells into apoptosis.  But it can also stop cell proliferation by arresting the cell cycle.  Normally there is a dynamic balance between proliferation of cells and their death.  In cancer proliferation may become unregulated due to oncogenic mutations or over expression of key regulatory signalling G proteins such as Ras.  Mutations of the p53 suppressor gene are the most frequent suppressor gene mutations in human cancers.  Elephants like humans, have a relatively low buildup of cancer with age.  Elephant's cells have twenty copies of p53 gene pairs which ensure cells with damaged DNA go into apoptosis blocking cancer onset.  P53 has been shown to be involved in irregular brain cell activity in epilepsy and ASD. 
  .  They are regularly found in improperly stored commodities such as chillis, peanuts, rice and wheat.  And they flow through the food distribution system when contaminated food is processed.  Higher animals fed on contaminated food can pass aflatoxin transformation products into the food chain.  They have been found in feed stock, eggs, milk products and meat.  The most toxic aflatoxin can permeate the skin.  
• African savanna is the environment where hunter-gatherers is a lifestyle organized around a band of relatives, evolved in humans focused on capturing the cognitive niche in the African savanna.  It is of great significance in shaping our minds: behaviors, emotions, creativity, intelligence; and developing survival strategies including use of fire and language, according to evolutionary psychologists.  It was practiced by all humans, for most of Homo sapiens existence, until the emergence of farming, and still is by some isolated bands: Ju/'hoansi, New Guinea: Gebusi, Mae Enga; & Borneo head hunters, Maasai & Zulu warriors from Africa, Amazonians: Waorani, Jivaro; Brazilian and Venezuelan Yanomamo.  Since the band moves on when it has depleted the resources in an area of land, the soil remains vibrant, but the large animals were typically placed in a position of stress from which they did not recover. 
  primarily
  This page reviews the implications of selection, variation and heredity in a complex adaptive system (CAS).  The mechanism and its emergence are discussed. 
  
  evolved.  Its grassland supported large herbivores that could be hunted easily across the plains.  Clumps of Acacia trees: with short trunks, and broad bows; & rocks supported places to hide from large carnivores.  Streams, especially important in times of drought, and paths add to the signals, is an emergent capability which is used by cooperating agents to support coordination & rival agents to support control and dominance.  In eukaryotic cells signalling is used extensively.  A signal interacts with the exposed region of a receptor molecule inducing it to change shape to an activated form.  Chains of enzymes interact with the activated receptor relaying, amplifying and responding to the signal to change the state of the cell.  Many of the signalling pathways pass through the nuclear membrane and interact with the DNA to change its state.  Enzymes sensitive to the changes induced in the DNA then start to operate generating actions including sending further signals.  Cell signalling is reviewed by Helmreich.  Signalling is a fundamental aspect of CAS theory and is discussed from the abstract CAS perspective in signals and sensors.  In AWF the eukaryotic signalling architecture has been abstracted in a codelet based implementation.  To be credible signals must be hard to fake.  To be effective they must be easily detected by the target recipient.  To be efficient they are low cost to produce and destroy. 
  enabling orientation. 
  
• AFSC is Air Force Systems Command which includes Eglin and Wright-Patterson AFB in Dayton, Ohio, includes Wright Field and Patterson AFB.  It is part of the US AFSC and includes the Air Force Museum, Propulsion Laboratory and the Flight Dynamics Laboratory, where the Air Force conducts basic research into aircraft and engines.  The concentration of research and status undermines the end-to-end architecture and iterative cycles needed to evolve effective aircraft and associated services. 
  organizations. 
  
• Age-related memory loss, also called benign senescent forgetfulness, is a different condition from Alzheimer's disease is a dementia which correlates with deposition of amyloid plaques in the neurons.  As of 2015 there are 5 million Alzheimer's patients in the USA.  It was originally defined as starting in middle age which is rare, so it was a rare dementia.  But in 1980s it was redefined as any dementia without another known cause. Early indications include mood and behavioral changes (MBI) and declarative memory and thinking problems (MCI).  Specific cells within the hippocampal circuitry and its gateway, the entorhinal cortex, are damaged.  The amygdala, cerebelum and other areas supporting implicit memory are not impacted during the early stages of the disease.  Grid cell destruction results in a sense of being lost.  The default mode network is disrupted.  Variants include: late-onset sporadic; with risk factors - ApoE4 for late onset Alzheimer's, presenilin, androgen deprivation therapy (Dec 2015), type 2 diabetes.  There are multiple theories of the mechanism of Alzheimer's during aging: Allen Roses argues that it is due to gene alleles that limit the capacity of mitochondria to support neuron operation, Neurons of sporadic Alzheimer's sufferers show greater APP gene diversity due to somatic recombination; It may be initiated by: stress induced HHV-6a, HHV7 herpes activation (Jun 2018) and or an increasingly leaky blood-brain barrier; and a subsequent innate immune response to the infections (May 2016).  The Alzheimer's pathway follows:
  • Plaques form.  These are seen in fMRIs 10 to 15 years prior to detecting memory and thinking changes.  APP deployed in the cell membrane is cut into three parts.  The external part becomes amyloid-beta peptide which aggregates into Amyloid plaques, external to the neurons, if too much is generated or it is not removed fast enough. 
    
  • Solanezumab aimed to inhibit plaque formation but clinical trials failed (Nov 2016). 
    
  • Encouraging the garbage collection of amyloid and tau with gamma rhythms stimulation retards Alzheimer's in mice studies (Mar 2019)
    
  • BACE inhibitors block an enzyme needed to form amyloid. 
    
  • Mutation driven misfolded Tau proteins can form tangles within the cytoplasm of neurons.  The Tau tangles kill nerve cells.  LMTX is a drug treatment targeted at these tangles. 
    
  • The brain becomes inflamed resulting in the killing of many more nerve cells.  The hippocampus disintegrates and the brain loses critical functions and memory loss becomes noticeable. 
    
  .  It initially occurs in the dentate gyrus is a structure within the hippocampus.  It is involved early on in age-related declarative memory loss. 
  , reflecting osteocalcin is a hormone generated by bone.  It acts on many organs including the brain where it influences the production of serotonin, dopamine, GABA and other neurotransmitters, promoting spatial memory and learning. 
  related reduced synthesis of CREB complex is a group of proteins that are required for turning on gene expression for the conversion of short-term memory into long-term memory.  The complex includes: RbAp48; proteins. 
  's RbAp48 protein.  CREB is critical for controlling the conversion of short-term memory in the brain includes functionally different types: Declarative, or explicit, (episodic and semantic), Implicit, Procedural, Spatial, Temporal, Verbal; Hebb suggested that glutamate receptive neurons learn by (NMDA channel based) synaptic strengthening: short term memory.  This was shown to happen for explicit memory formation in the hippocampus.  This strengthening is sustained by subsequent LTP.  The non-real-time learning and planning processes operate through consciousness using the working memory structures, and then via sleep, the salient ones are consolidated while the rest are destroyed and garbage collected.   to long-term memory.  Ramping up RbAp48 production in old mice eliminated age-related memory loss.  This suggests that vigorous exercise, which maintains bone density and osteocalcin levels, can help limit age-related memory loss. 
  
• Plans are interpreted and implemented by agents.  This page discusses the properties of agents in a complex adaptive system (CAS). 
  It then presents examples of agents in different CAS.  The examples include a computer program where modeling and actions are performed by software agents.  These software agents are aggregates. 
  The participation of agents in flows is introduced and some implications of this are outlined. 
  
  Agent. 
• Aggregation is when a number of actions become coordinated and operate together.  In the adaptive web framework's
  This page describes the Adaptive Web framework (AWF) test system and the agent programming framework (Smiley) that supports its operation. 
  Example test system statements are included.  To begin a test a test statement is loaded into Smiley while Smiley executes on the Perl interpreter. 
  Part of Smiley's Perl code focused on setting up the infrastructure is included bellow. 
  The setup includes:
  

  • Loading the 'Meta file' specification,
    
  • Initializing the Slipnet, and Workspaces and loading them
    
  • So that the Coderack can be called. 

  The Coderack, which is the focus of a separate page of the Perl frame then schedules and runs the codelets that are invoked by the test statement structures. 
  
  Smiley, codelets become coordinated by their relative position in the deployment cascade.  The cascade's dynamics are dependent on the situation, the operating codelets responses to that situation and the grouping, in Copycat grouping codelets can group two or more bonded Workspace objects (WSO) together.  In effect grouping adjusts the system to reflect the presence of a chemically active molecule in the molecules local environment. 
  of
  Plans emerge in complex adaptive systems (CAS) to provide the instructions that agents use to perform actions.  The component architecture and structure of the plans is reviewed. 
  
  schematic strings they are
  This page describes the Smiley infrastructure that supports the associative binding of schematic strings to codelets defined in the Meta file and Slipnet. 
  The infrastructure supporting the associations is introduced. 
  The role of Jeff Hawkins neocortical attributes is discussed. 
  Relevant Slipnet configurations are included. 
  The codelets and supporting functions are included. 
  
  associated with.  The aggregate effect is a phenotype is the system that results from the controlled expression of the genes.  It is typically represented by a prokaryotic cell or the body of a multi-cell animal or plant.  The point is that the genes provide the control surface and the abstract recipe that has been used to generate the cell.   the adaptive in evolutionary biology is a trait that increased the number of surviving offspring in an organism's ancestral lineage.  Holland argues: complex adaptive systems (CAS) adapt due to the influence of schematic strings on agents.  Evolution indicates fitness when an organism survives and reproduces.  For his genetic algorithm, Holland separated the adaptive process into credit assignment and rule discovery.  He assigned a strength to each of the rules (alternate hypothesis) used by his artificial agents, by credit assignment - each accepted message being paid for by the recipient, increasing the sender agent's rule's strength (implicit modeling) and reducing the recipient's.  When an agent achieved an explicit goal they obtained a final reward.  Rule discovery used the genetic algorithm to select strong rule schemas from a pair of agents to be included in the next generation, with crossing over and mutation applied, and the resulting schematic strategies used to replace weaker schemas.  The crossing over genetic operator is unlikely to break up a short schematic sequence that provides a building block retained because of its 'fitness';  In Deacon's conception of evolution, an adaptation is the realization of a set of constraints on candidate mechanisms, and so long as these constraints are maintained, other features are arbitrary. 
  
  Plans are interpreted and implemented by agents.  This page discusses the properties of agents in a complex adaptive system (CAS). 
  It then presents examples of agents in different CAS.  The examples include a computer program where modeling and actions are performed by software agents.  These software agents are aggregates. 
  The participation of agents in flows is introduced and some implications of this are outlined. 
  
  agent. 
  
• AHA is the American_hospital association. 
  
• AHP is association health plan:
• Allow small businesses and individuals in particular professions, trades or interest groups to join associations that offer insurance to members. 
  
• Are a form of MEWA is a multiple-employer welfare arrangement which is state regulated. 
  
  
• AHRQ is the Agency for Healthcare Research and Quality.  It provided the definition of a medical home are primary care architectures which deliver: patient-centered, accessible, coordinated, comprehensive care of high quality and safety (Dec 2015).  The models have been made more significant due to Affordable Care Act payment reform requirements.  The goal is to reduce treatment costs and improve population health by reengineering of the traditional silo'd provider network.  See PCMH. 
  (PCMH is patient centered medical homes:
  • Describes a reorganization of the health care delivery system to focus on the patient and care giver supported by EHR infrastructure and some form of process management which will be necessary to coordinate interventions by each of the functional entities resources to treat the patients specific problems.   The disadvantage of a PCMH is the administrative and technology cost needed to support its complex processes.  The PCMH
    
  • Was promoted as a way to incent more PCP which had been seen as a low reward role by medical students.  HCI3 argues this use of PCMH is flawed.  PCMH is driven by the medical home models of the ACA.  In this model the PCMH is accountable for meeting the vast majority of each patients physical and mental health care needs including prevention and wellness, acute care, and chronic care.  It is focused on treating the whole person.  It is tasked with coordinating the care across all elements of the health care system, including transitions and building clear and open communications.  It must ensure extended access and availability of its services and patients preferences about access.  It must continuously improve quality by monitoring evidence-based medicine and clinical decision support tools (NCQA).  Many argue that to be effective it must be connected to a 'medical neighborhood'.  The PCMH brings together the specialized resources and infrastructure required to develop and iteratively maintain the care plans and population oriented system descriptions that are central to ACA care coordination. 
    
   
  ) as both a place and a model of the organization of primary care consists of providing accessible, comprehensive, longitudinal, and coordinated care in the context of families and community.  Interpreting the meaning of many streams of information and working together with the patient to make decisions based on the fullest understanding of this information relative to the patient's values and preferences is key to PCP providing value. 
  that delivers core functions of primary health care. 
  
• AIDA - activities that initially create awareness and then interest, desire and subsequently action.  
• AIDS is acquired auto-immune deficiency syndrome, a pandemic disease caused by the HIV is human immunodeficiency virus, an RNA retrovirus which causes AIDS.  It infects T-lymphocytes helper cells slowly destroying the host's immune system.  The main pandemic form of HIV is HIV-1 M which has been traced back to a spillover to Cameroon/Congolese forest Chimpanzees of SIVs that weakly infected proximate humans and then was amplified by social conditions in expanding towns: Ouesso, Brazzaville, Leopoldville; down river from these forests during the 1900 - 1920s.  Additional amplification occurred through public health programs: Trypanosomiasis, STDs; which cross-infected subpopulations of Leopoldville/Kinshasa around the same time.  UNESCO organized Haitian support for the DRC in the 1960s vectored HIV-1 M back to Haiti where the blood plasma trade provided an evolved amplifier for HIV-1 M infected plasma to flow into the US healthcare supply chain through Miami.  Some HIV's enter the lymphocytes by leveraging the T cells CCR5 protein.  The HIV X4 variant leverages CXCR4. 
  .  It also amplifies the threat of tuberculosis, consumption or otherwise TB, is mostly an airborn bacterial lung infection, but it can also infect the brain, kidneys and other parts of the body.  The only vaccine is still the BCG.  The deployment of antibiotics during the 1940s allowed effective treatment: Streptomycin.  In 1963 epidemiologist George Comstock realized why 30% of Alaskan adults were infected with TB - it grows slowly and is transmitted to other people before symptoms occur.  Treatment was expanded to all contacts of a person with symptoms, who tested positive for TB.  This strategy eradicated TB in the West, but was considered impractical in poor countries.  Diagnostic tools for TB are insufficient.  And because TB grows slowly in walled off pockets in the lungs it takes many months of treatment for antibiotics to eradicate the infection.  TB benefits from compromised hosts and has benefited from HIV/AIDS.  TB is also leveraging the plasmids that now carry immunity to all current antibiotics.  In 2016 it is estimated to latently infect two billion people.  9.6 million worldwide became infected in 2014.  1.5 million people will die from TB in 2016.  Deaths from the disease have fallen drastically since 2000.  TB has been halted or reversed in 16 of the 22 countries: India (Sep 2016, Infection base estimate increased Oct 2016), Vietnam, Indonesia; that have the majority of cases.  But it is still the infectious disease causing the most deaths world-wide.  In 2018 W.H.O. asserts there is a $3.5 billion shortfall in funding for TB public health control efforts, a gap that will double by 2023.  Nano scale drug delivery has the potential to push back on TB and is being actively researched (May 2016).   .   Initially deadly, infecting and destroying the T-lymphocytes are a type of leukocyte.  They appear mainly in the lymphatic network.  Their are various types:
  • B cells which make antibodies that bind to pathogens, and activate the complement system.  When malignant these cells can produce multiple myeloma. 
    
  • Natural killer cells can kill body cells that do not display MHC class 1 molecules, or do display stress markers including MIC-A. 
    
  • T cells including CD4+ helper cells, Cytotoxic T cells, Gamma 5 T cells; 
    
  of the immune system has to support and protect an inventory of host cell types, detect and respond to invaders and maintain the symbiont equilibrium within the microbiome.  It detects microbes which have breached the secreted mucus barrier, driving them back and fortifying the barrier.  It culls species within the microbiome that are expanding beyond requirements.  It destroys invaders who make it into the internal transport networks.  As part of its initialization it has immune cells which suppress the main system to allow the microbiome to bootstrap.  The initial microbiome is tailored by the antibodies supplied from the mother's milk while breastfeeding.  The immune system consists of two main parts the older non-adaptive part and the newer adaptive part.  The adaptive part achieves this property by being schematically specified by DNA which is highly variable.  By rapid reproduction the system recombines the DNA variable regions in vast numbers of offspring cells which once they have been shown not to attack the host cell lines are used as templates for interacting with any foreign body (antigen).  When the immune cell's DNA hyper-variable regions are expressed as y-shaped antibody proteins they typically include some receptor like structures which match the surfaces of the typical antigen.  Once the antibody becomes bound to the antigen the immune system cells can destroy the invader. 
  , it can now be treated with HAART is highly active ARV therapy using a combination of at least three drugs that supress HIV replication. 
  to become a chronic disease.  And with an understanding of HIV's mode of entry into the T-cells, through its binding to CCR5 is a gene that encodes the CD195 cell membrane receptor.  The receptor is part of the target cell binding strategy of HIV.  Phase shift mutations of CCR5 have provided immunity to AIDS. 
  and CD4 is a gene that encodes a cell surface glycoprotein called CD4.  It is expressed on the surface of T-lymphocytes.  It is part of the binding target strategy of HIV. 
  encoded transmembrane proteins, AIDS may be susceptible to treatment with recombinant DNA (DNA), a polymer composed of a chain of deoxy ribose sugars with purine or pyrimidine side chains.  DNA naturally forms into helical pairs with the side chains stacked in the center of the helix.  It is a natural form of schematic string.  The purines and pyrimidines couple so that AT and GC pairs make up the stackable items.  A code of triplets of base pairs (enabling 64 separate items to be named) has evolved which now redundantly represents each of the 20 amino-acids that are deployed into proteins, along with triplets representing the termination sequence.  Chemical modifications and histone binding (chromatin) allow cells to represent state directly on the DNA schema.  To cope with inconsistencies in the cell wide state second messenger and evolved amplification strategies are used.   to alter the CCR5 binding site, or with drugs that bind to the CCR5 cell surface protein preventing binding by the virus is a relatively small capsule containing genetic material: RNA, DNA; which utilizes the cellular infrastructure of its target host to replicate its genetic material and operational proteins.  David Quammen explains the four key challenges of viruses: Getting from one host to another, penetrating a cell within the host, commandeering the cell's infrastructure, escaping from the cell and organism; Single-stranded RNA viruses: Coronavirus, chickungunya, dengue, Ebola, Hantas, Hendra, Influenzas, Junin, Lassa, Machupo, Marburg, Measles, Mumps, Nipah, Rabies, Retrovirus (HIV), Rhinovirus, yellow fever; are subject to more mutation events than DNA viruses, but limits the size of the genetic string.  Double stranded DNA viruses: baculoviruses, hepadnaviruses, Herpesviruses, iridoviruses, papillomavirses, poxviruses; can leverage relatively far larger genetic payloads.  The relationship with the reservoir host is long-term, a parasitic or symbiotic relationship, developing over millions of years.  But opportunistically, it may spillover into a secondary host, with the virus entering the host cell, leveraging the host infrastructure to replicate its self massively and then exiting the host cell by rupturing it and killing the organism. 
  .  Future optimization of drug delivery may leverage nanoscale research (May 2016). 
  
• Aire is the autoimmune regulator protein.  It is a specialized transcription factor are enzymes which associate with a transcription complex to bind to the DNA and control its transcription and hence translation into proteins.  The regulation of DNA transcription and protein synthesis are reviewed by Tsonis.  Transcription factors allow environmental state to become reflected in the control of DNA transcription.  Transcription factors can regulate multiple genes, allowing network effects & multiple transcription factors can regulate a gene allowing sophisticated control processes.  In AWF the transcription, translation and deployment infrastructure of the eukaryotic cell has been abstracted in a codelet based implementation. 
  targeting specific histone, in the eukaryotic cell are enzymes which bind to the DNA polymers supporting them and controlling their interactions with other enzymes.  In particular sets of DNA operons can be enabled or disabled by histone induced changes in the DNA polymers shape.  In AWF the histone control of DNA has been abstracted in a codelet based implementation of operon controlled programmed case control.   markers that indicate transcriptionally inactive chromatin, expressed in the thymus and lymph nodes.  In cooperation with 50 other partner molecules it causes T-cells to be exposed to self-antigens presented by mTEC is medullary thymic epithelial cells, a set of thymus cells that ensure immune system tolerance.  They can express 80% of the genome.   Their expression is controlled by AIRE driven by the NF-kappa B signalling pathway, or Fezf2 another AIRE independent regulator. 
  in the thymus.  Any T-cells that react are signalled to destroy themselves.  In the lymph nodes other Aire dependent tissue-restricted antigens are presented and reactive T-cells are inactivated. 
  
• Akinetic mutism is an inability to generate spontaneous verbal reports.  Repetition is often still possible.  
• Aleksander's Axioms were proposed by Aleksander & Dunmall to define a minimal set of material preconditions for a conscious biological or non-biological agent.  These axioms are:
1. Depiction - Internal perceptual states depict the external world and the self 
   
2. Imagination - internal state that imagines depiction
   
3. Attention is the mutli-faceted capability allowing access to consciousness.  It includes selective attention, vigilance, allocating attention, goal focus, and meta-awareness. 
   
   
4. Planning - imagines future actions and selects among the alternatives
   
5. Emotion - affective states that evaluate planned actions and prioritize for selection
   
• All-or-nothing measures set is used by Geisinger because it closely matches the wants and needs of patients to slow chronic disease progression and prevent additional diseases and their impacts by delivery of optimal treatment, and drives care givers to achieve all goals.  It also provides a sensitive scale for measuring improvements.  Not all patients will achieve every measure, but the set encourages the patient, their family, the PCP is a Primary Care Physician.  PCPs are viewed by legislators and regulators as central to the effective management of care.  When coordinated care had worked the PCP is a key participant.  In most successful cases they are central.  In certain Medicare ACO models (Pioneer) PCPs are committed to achieve meaningful use requirements.  Working against this is the: replacement of diagnostic skills by technological solutions, low FFS leverage of the PCP compared to specialists, demotivation of battling prior authorization for expensive treatments. 
  and specialists to engage and develop a shared understanding. 
  
• Allele, one of multiple alternative forms of a schematic sequence with the same address on a
  Plans emerge in complex adaptive systems (CAS) to provide the instructions that agents use to perform actions.  The component architecture and structure of the plans is reviewed. 
  
  schematic string.  
• Allergies include various conditions: hay fever, food allergies: MMA is:
  
  • The Medicare Modernization Act of 2003.  It includes Medicare part D, the Medicare prescription drug benefit, which constrains Medicare from negotiation of its drug prices and created MAC and RAC.  It was sponsored by Senator Bill Tauzin and implemented by Tom Scully.  
  • Mammalian meat allergy which is induced by a month prior tick bite that introduced the allergen alpha-gal.  About 1% of bitten humans develop the allergy & prevalence is increasing.  Humans & old world primates & monkeys don't make alpha-gal (Jul 2018).  Symptoms can include: hives, anaphylactic shock, low blood pressure. 
    
  , Peanut; atopic dermatitis, asthma is inflammation of the airways resulting in their narrowing, swelling and generating additional mucus which inhibits breathing.  Its prevalence doubled in the US between 1980 and 2000.  Asthma is the most common chronic disease in childhood, the most common reason for being away from school and the most common reason for hospitalization.  10 to 13% of children's asthma cases are due to obesity.  Among obese children 23 to 27% of asthma cases are due to obesity.  Diagnosis: Propeller Health; Treatments include: Xolair;
  , and anaphylaxis; caused by over activity of the immune system has to support and protect an inventory of host cell types, detect and respond to invaders and maintain the symbiont equilibrium within the microbiome.  It detects microbes which have breached the secreted mucus barrier, driving them back and fortifying the barrier.  It culls species within the microbiome that are expanding beyond requirements.  It destroys invaders who make it into the internal transport networks.  As part of its initialization it has immune cells which suppress the main system to allow the microbiome to bootstrap.  The initial microbiome is tailored by the antibodies supplied from the mother's milk while breastfeeding.  The immune system consists of two main parts the older non-adaptive part and the newer adaptive part.  The adaptive part achieves this property by being schematically specified by DNA which is highly variable.  By rapid reproduction the system recombines the DNA variable regions in vast numbers of offspring cells which once they have been shown not to attack the host cell lines are used as templates for interacting with any foreign body (antigen).  When the immune cell's DNA hyper-variable regions are expressed as y-shaped antibody proteins they typically include some receptor like structures which match the surfaces of the typical antigen.  Once the antibody becomes bound to the antigen the immune system cells can destroy the invader. 
  in response to antigens in the proximate environment.  Initially associated with the English upper-class, allergies have spread across the population with general adoption of: small family size, cleanliness, antibiotic are compounds which kill bacteria, molds, etc.  Sulfur dye stuffs were found to be effective antibiotics.  The first evolved antibiotic discovered was penicillin.  Antibiotics are central to modern health care supporting the processes of: Surgery, Wound management, Infection control; which makes the development of antibiotic resistance worrying.  Antibiotics are:
  • Economically problematic to develop and sell. 
    
  • Congress enacted GAIN to encourage development of new antibiotics.  But it has not developed any market-entry award scheme, which seems necessary to encourage new antibiotic R&D. 
    
  • Medicare has required hospitals and SNFs to execute plans to ensure correct use of antibiotics & prevent the spread of drug-resistant infections.  
  • C.D.C. is acting to stop the spread of resistant infections and reduce unnecessary use of antibiotics.  
    
  • F.D.A. has simplified approval standards.  It is working with industry to limit use of antibiotics in livestock. 
    
  • BARDA is promoting public-private partnerships to support promising research.
    
  • Impacting the microbiome of the recipient.  Stool banking is a solution  (Sloan-Kettering stool banking).  
  • Associated with obesity, although evidence suggests childhood obesity relates to the infections not the antibiotic treatments (Nov 2016). 
    
  • Monitored globally by W.H.O.
    
  • Regulated in the US by the F.D.A. who promote voluntary labeling by industry to discourage livestock fattening (Dec 2013).  
  • Customer demands have more effect - Perdue shifts to no antibiotics in premier chickens (Aug 2015). 
    
  use, public health is the proactive planning, coordination and execution of strategies to improve and safeguard the wellbeing of the public.  Its global situation is discussed in The Great Escape by Deaton.  Public health in the US is coordinated by the PHS federally but is mainly executed at the state and local levels.  Public health includes:
  • Awareness campaigns about health threatening activities including: Smoking, Over-eating, Alcohol consumption, Contamination with poisons: lead; Joint damage from over-exercise;
    
  • Research, monitoring and control of: disease agents, reservoir and amplifier hosts, spillover and other processes, and vectors; by agencies including the CDC. 
    
  • Monitoring of the public's health by institutes including the NIH.  This includes screening for cancer & heart disease. 
    
  • Development, deployment and maintenance of infrastructure including: sewers, water plants and pipes.  
  • Development, deployment and maintenance of vaccination strategies.  
  • Development, deployment and maintenance of fluoridation. 
    
  • Development, deployment and maintenance of family planning services. 
    
  • Regulation and constraint of foods, drugs and devices by agencies including the FDA.  
  programs; in line with the hygiene hypothesis argues that to avoid hyper-reactive tendencies in the immune response that underlie autoimmune and allergic diseases need stimulation early in life.  Lifestyle is assumed to be a major aspect:
  • How the way you live guarantees exposure to a rich variety of microbes that favorably impact the immune system.  
  , with newborns no longer getting exposed to antigens by their older siblings and proximate higher animals. 
  
• Allocating attention allows for noticing small or rapid shifts in what we experience, according to Goleman & Davidson. 
  
• Alpha-gal is short for galactose-alpha-1,3-galactose.  It is a sugar which is a component of cell membranes. 
  
• Alpha-synuclein is a protein found mainly in the presynaptic, a neuron structure which provides a junction with other neurons.  It generates signal molecules, either excitatory or inhibitory, which are kept in vesicles until the synapse is stimulated when the signal molecules are released across the synaptic cleft from the neuron.  The provisioning of synapses is under genetic control and is part of long term memory formation as identified by Eric Kandel.  Modulation signals (from slow receptors) initiate the synaptic strengthening which occurs in memory. 
  terminals of neurons, specialized eukaryotic cells include channels which control flows of sodium and potassium ions across the massively extended cell membrane supporting an electro-chemical wave which is then converted into an outgoing chemical signal transmission from synapses which target nearby neuron or muscle cell receptors.  Neurons are supported by glial cells.  Neurons include a:
  • Receptive element - dendrites
    
  • Transmitting element - axon and synaptic terminals.  The axon may be myelinated, focusing the signals through synaptic transmission, or unmyelinated - where crosstalk is leveraged. 
  • Highly variable DNA schema using transposons. 
    
  .  It is important in maintaining the supply of synaptic vesicles - it interacts with tubulin.  It simultaneously binds to phospolipids of the plasma membrane and to synaptobrevin is a component of the core SNARE complex that drives fusion of membranes in exocytosis.  -2 becoming a chaperone.  It is encoded by the SNCA gene.  It is a major constituent of Parkinson's disease corresponds to the breakdown of certain interneurons in the brain.  It is not fully understood why this occurs.  Dopamine system neuron breakdown generates the classical symptoms of tremors and rigidity.  In some instances an uncommon LRRK2 gene mutation confers a high risk of Parkinson's disease.  In rare cases Italian and Greek families are impacted in their early forties and fifties resulting from a single letter mutation in alpha-synuclein which alters the alpha-synuclein protein causing degeneration in the substantia nigra, after a build up of Lewy bodies in the neurons.  But poisoning from MPTP has also been shown to destroy dopamine system neurons.  DeLong showed that MPTP poisoning results in overactivity in the subthalamic nucleus.  People who have an appendectomy in their 20s are at lower risk of developing Parkinson's disease.  The Alpha-synuclein protein is known to build up in the appendix in association with changes in the gut microbiome.  This buildup may support the 'flow' of alpha-synuclein from the gut along neurons that route to the brain.  Paraquat has also been linked to Parkinson's disease.  Parkinson's disease does not directly kill many sufferers.  But it impacts swallowing which encourages development of pneumonia through inhaling or aspirating food.  And it undermines balance which can increase the possibility of falls.  Dememtia can also develop.  Treatment with deep-brain stimulation, after surgical implantation of electrodes in the subthalamic nucleus removes the symptoms of Parkinson's disease in some patients. 
  Lewy bodies are protein clumps that are a pathological mark of Parkinson's disease and Lewy body dementia.  A major component of the clumps is alpha-synuclein.  .  Knockout mice with targeted inactivation of the expression of alpha-synuclein show impaired spatial learning and working memory.  
• Alpha helix provides a structural building block (a helical tube) that can be conserved and used by
  Richard Dawkin's explores how nature has created implementations of designs, without any need for planning or design, through the accumulation of small advantageous changes. 
  
  natural selection. 
• Alpha oscillations are brain waves of 8 - 13 hertz that occur during periods of relaxation, long distance signalling, is an emergent capability which is used by cooperating agents to support coordination & rival agents to support control and dominance.  In eukaryotic cells signalling is used extensively.  A signal interacts with the exposed region of a receptor molecule inducing it to change shape to an activated form.  Chains of enzymes interact with the activated receptor relaying, amplifying and responding to the signal to change the state of the cell.  Many of the signalling pathways pass through the nuclear membrane and interact with the DNA to change its state.  Enzymes sensitive to the changes induced in the DNA then start to operate generating actions including sending further signals.  Cell signalling is reviewed by Helmreich.  Signalling is a fundamental aspect of CAS theory and is discussed from the abstract CAS perspective in signals and sensors.  In AWF the eukaryotic signalling architecture has been abstracted in a codelet based implementation.  To be credible signals must be hard to fake.  To be effective they must be easily detected by the target recipient.  To be efficient they are low cost to produce and destroy. 
  in the cortex includes the paleocortex a thin sheet of cells that mostly process smell, archicortex and the neocortex.  The cerebral cortex is a pair of large folded sheets of brain tissue, one on either side of the top of the head connected by the corpus callosum.  It includes the occipital, parietal, temporal and frontal lobes. 
  and during presleep is the period of transition from being awake to stage one of sleep.  It is characterized by alpha waves.   . 
  
• Alphabet is a writing process where representational signals (letters and graphemes is a series of one or more letters that maps onto a phoneme in the target language.  The grapheme 'tt' in 'button' maps to the phoneme 't'.  Dehaene notes that English has an extensive set of:
  
  • Simple frequently used graphemes including 't', 'k' and 'a'. 
    
  • Simple but less frequent graphemes including 'b', 'm', 'f'. 
    
  • Irregular ones including 'i', 'o'. 
    
  • Complex graphemes including 'un', 'ch', 'ough', 'oi' and 'au.'   The human visual system treats learned graphemes as units.  
  ) refer to speech sounds (phonemes are the smallest speech units explicitly representing discrete speech sounds.  The phoneme 't' is a part of Tuna, stop and foot. 
  ) rather than meanings.  Dehaene asserts the principle probably emerged in small groups of people on the fringes of mainstream society.  The first example is Proto-Sinaitic is the earliest alphabetic writing system.  It dates from 1700 BC in the Sinai Peninsula.  It used shapes from Egyptian characters but used them to represent sounds of the Semitic language.  This allowed for a dramatic reduction in the required number of symbols used: two dozen were enough to represent all the existing speech sounds. 
  .  Alphabets allow for a drastic reduction in the number of signs required to be learnt. 
  
• ALS is amyotrophic lateral sclerosis which selectively destroys motor neurons, specialized eukaryotic cells include channels which control flows of sodium and potassium ions across the massively extended cell membrane supporting an electro-chemical wave which is then converted into an outgoing chemical signal transmission from synapses which target nearby neuron or muscle cell receptors.  Neurons are supported by glial cells.  Neurons include a:
  • Receptive element - dendrites
    
  • Transmitting element - axon and synaptic terminals.  The axon may be myelinated, focusing the signals through synaptic transmission, or unmyelinated - where crosstalk is leveraged. 
  • Highly variable DNA schema using transposons. 
    
  . 
  
• Alternative quality contract (AQC) is:
  
• A 2009 payment arrangement developed by Blue Cross Blue Shield of Massachusetts.  It was developed to support change.  It differs from capitation is a global payment for all care for a patient during a specified time period.  It forces the provider of care to take a high risk.  Managing the risk implies successful population health management. 
  in including upside measures for patient safety, appropriateness of care and patient satisfaction.  Its key components are:
• Integration across the care continuum
• Accountability for performance measures for ambulatory and inpatient care.  Includes a 10% incentive for performing. 
  
• Performance measures are selected that are: Nationally accepted, Vary across providers, Include sufficient data on provider being measured, measured at the level that can influence the outcome. 
  
• Global payment for all medical services with health status adjustment and with margin retention. 
  
• Five year contract to create a sustained partnership 
• Altruism, is the property that since kin share genes
  This page reviews the implications of selection, variation and heredity in a complex adaptive system (CAS).  The mechanism and its emergence are discussed. 
  
  natural selection will improve the replicator is Richard Dawkin's name for the genotype since it has the evolutionary goal of surviving long enough to reproduce its schematic plan effectively.  The action of genetic operators means that the results of successful reproduction may be different to the parental genotypes and phenotypes (Dawkin's vehicle). 
  's selfish goals, Richard Dawkins's postulate described in 'The Selfish Gene' that genes are self-interested, meaning they include strategies for their agent's which promote the genes survival and replication.  Families will act altruistically to one another since they include a percentage of shared genes, allowing kin selection.  All other situations are viewed as competitive. 
  by supporting the survival of such relatives.  Improving the chances of survival of non-kin is hard to explain with a gene preservation theory.  Why help a competitive gene?  Trivers explanation of reciprocal altruism benefits another organism at a cost to the behaver.  It is differentiated from kin altruism, by Williams and Trivers, since it can apply between unrelated individuals.  It can be induced by natural selection when there is mutual survival benefit in group activities and cheating can be detected and discouraged.  Humans, leveraging the cognitive niche, can particularly easily, build an evolved amplifier, through sharing information at little cost and significant benefit.  But African savanna hunters similarly gain from sharing large game meat with other un-related altruistic group members since the meat would otherwise spoil before it could be eaten. 
  shows the special conditions under which it can occur. 
  
• Alveolate are eukaryotes is a relatively large multi-component cell type.  It initially emerged from prokaryotic archaea subsuming eubacteria, from which single and multi-celled plants, multi celled fungi, including single-cell variant yeast, drips, protozoa and metazoa, including humans, are constructed.  A eukaryotic cell contains modules including a nucleus and production functions such as chloroplasts and mitochondria. 
  which include flattened vesicles in the outer cortical region. 
  
• Alzheimer's disease is a dementia is a classification of memory impairment, constrained feelings and enfeebled or extinct intellect.  The most common form for people under 60 is FTD.  Dementia has multiple causes including: vascular disease (inducing VCI) including strokes, head trauma, syphilis and mercury poisoning for treating syphilis, alcoholism, B12 deficiency (Sep 2016), privation, Androgen deprivation therapy (Oct 2016), stress, Parkinson's disease, Alzheimer's disease, and prion infections such as CJD and kuru.  The condition is typically chronic and treatment long term (Laguna Honda ward) and is predicted by Stanley Prusiner to become a major burden on the health system.  It may be possible to constrain the development some forms of dementia by: physical activity, hypertension management, and ongoing cognitive training.  Dementia appears to develop faster in women than men.   which correlates with deposition of amyloid plaques in the neurons, specialized eukaryotic cells include channels which control flows of sodium and potassium ions across the massively extended cell membrane supporting an electro-chemical wave which is then converted into an outgoing chemical signal transmission from synapses which target nearby neuron or muscle cell receptors.  Neurons are supported by glial cells.  Neurons include a:
  • Receptive element - dendrites
    
  • Transmitting element - axon and synaptic terminals.  The axon may be myelinated, focusing the signals through synaptic transmission, or unmyelinated - where crosstalk is leveraged. 
  • Highly variable DNA schema using transposons. 
    
  .  As of 2015 there are 5 million Alzheimer's patients in the USA is the United States of America.  .  It was originally defined as starting in middle age which is rare, so it was a rare dementia.  But in 1980s it was redefined as any dementia without another known cause. Early indications include mood and behavioral changes (MBI is mild behavioral impairment, a proposed early diagnosis for dementia.  It recognizes and measures something that some experts say is often overlooked: Sharp changes in mood and behavior can precede the memory and thinking problems of dementia.  But there is a risk of over diagnosis which could leave many people unnecessarily fearful about their futures and seeking more tests.  And the diagnosis could affect insurance premiums.  To imply MBI the symptoms must last for more than six months and be a fundamental change in behavior.  
  ) and declarative memory , or explicit memory, allows higher animals to consciously remember people, places and objects.  It includes episodic and semantic memory.  It is supported by the medial region of the temporal lobe, explains Kandel.   and thinking problems (MCI is mild cognitive impairment, a sense of memory loss despite normal performance on memory tests.  It is often associated with Alzheimer's disease. 
  ).  Specific cells within the hippocampal is a part of the medial temporal lobe of the brain involved in the temporary storage or coding of long-term episodic memory.  It includes the dentate gyrus.  Memory formation in the cells of the hippocampus uses the MAP kinase signalling network which is impacted by sleep deprivation.  The hippocampus dependent memory system is directly affected by cholinergic changes throughout the wake-sleep cycle.  Increased acetylcholine during REM sleep promotes information attained during wakefulness to be stored in the hippocampus by suppressing previous excitatory connections while facilitating encoding without interference from previously stored information.  During slow-wave sleep low levels of acetylcholine cause the release of the suppression and allow for spontaneous recovery of hippocampal neurons resulting in memory consolidation.  It was initially associated with memory formation by McGill University's Dr. Brenda Milner, via studies of 'HM' Henry Molaison, whose medial temporal lobes had been surgically destroyed leaving him unable to create new explicit memories.  The size of neurons' dendritic trees expands and contracts over a female rat's ovulatory cycle, with the peak in size and cognitive skills at the estrogen high point.  Adult neurogenesis occurs in the hippocampus (3% of neurons are replaced each month) where the new neurons integrate into preexisting circuits.  It is enhanced by learning, exercise, estrogen, antidepressants, environmental enrichment, and brain injury and inhibited by various stressors explains Sapolsky.  Prolonged stress makes the hippocampus atrophy.  He notes the new neurons are essential for integrating new information into preexisting schemas -- learning that two things you thought were the same are actually different.  Specific cells within the hippocampus and its gateway, the entorhinal cortex, are compromised by Alzheimer's disease.  It directly signals area 25. 
  circuitry and its gateway, the entorhinal cortex is a main limbic association area between the hippocampus and the neocortex, in the medial temporal lobe.  It is a hub for memory and navigation: location awareness is supported by grid cells.  It is the first brain area impacted in Alzheimer's disease. 
  , are damaged.  The amygdala contains > 12 distinct areas: Central, Lateral.  It receives simple signals from the lower parts of the brain: pain from the PAG; and abstract complex information from the highest areas: Disgust, heart rate, and suffering from the insula cortex, allowing it to orchestrate emotion.  It connects strongly to attention focusing networks.  It sends signals to almost every other part of the brain, including to the decision making circuitry of the frontal lobes.  It has high levels of D(1) dopamine receptors.  During extreme fear the amygdala drives the hippocampus into fear learning.  It outputs directly to subcortical reflexive motor pathways when speed is required.  Its central nucleus projects to the BNST.  It signals the locus ceruleus.  It directly signals area 25.  The amygdala:
  
  • Promotes aggression.  Stimulating the amygdala promotes rage.  It converts anger into aggression and when impaired it impacts the ability to detect angry facial expressions.  
  • Participates in disgust
  • Perceives fear promoting stimuli, focusing our attention on these.  In PTSD sufferers the Amygdala overreacts to mildly fearful stimuli and is slow to calm down and the amygdala expands in size over a period of months.  Fear is processed by the lateral nucleus which serves as the input from various senses, and the central nucleus which outputs to the brain stem (central grey - freezing, lateral hypothalamus - blood pressure, activates paraventricular hypothalamus => crf -> hormone adjustments). 
    
  • Has lots of receptors for and is highly sensitive to glucocorticoids.  Stress inhibits the GABA interneurons in the basolateral amygdala (BLA) allowing the excitatory glutamate releasing neurons to excite more. 
    
  • Is sensitive to unsettling/uncertain social situations where it promotes anxiety and makes us distracted.  It is also interested in uncertain but potentially painful situations.  The amygdala contributes to social and emotional decision making where the BLA supports rejecting an unacceptable offer, as allowed in the Ultimatum Game, by injecting implicit mistrust and vigilance, generating an anger driven rejection that is used as punishment.  The amygdala is very rapidly excited by subliminal signals from the thalamus of outgroup skin color.  The amygdala subsequently tips social emotions against outgroups unless restrained by the frontal lobe or influenced by subliminal priming to prioritize inclusion.  The fast path from the thalamus rapidly but inaccurately signals its identified a weapon. 
    
  • Sees suffering of others as increasingly salient with loving-kindness meditation practice, Goleman & Davidson explain. 
    
  • Promotes male, but not female, sexual motivation when it is an uncertain potential pleasure. 
    
  • Responds to the longing for uncertain potential pleasures and fear that the reward will not be worth it if it happens.  The amygdala turns off during orgasm. 
    
  • Uses but is not directly involved in vision.  
  , cerebelum is involved with the efficiency of fine movement. It modulates the force and range of motion and is involved in motor coordination and the learning of motor skills.  Damage to the cerebellum impairs standing, walking, or performance of coordinated movements. A virtuoso pianist or other performing musician depends on their cerebellum.  The cerebellum receives visual, auditory, vestibular, and somatosensory information.  It also receives information about individual muscular movements being directed by the brain.  The cerebellum integrates this information and modifies the motor outflow, exerting a coordinating and smoothing effect on the movements.  However, patients born without a cerebellum have survived reasonably well.  The cerebellum is part of the implicit learning mechanism.  It is required for the rabbit eye-blink to be classically conditioned to respond to a sound, and puff of air (threat to eye).  It integrates the sound and puff and outputs the response to the motor area (blink).  Levitin has shown the cerebellum participates in aspects of emotion and auditory processing.  He found the cerebellum and basal ganglia were active throughout a session listening to music, modeling the beat, rewarding a match between the internal and external rhythm and integrating movement. And he notes the cerebellum providing Williams syndrome sufferers with their capability to play music.   and other areas supporting implicit memory is an unconscious form of memory where previous experiences aid the learning activity, as illustrated by subliminal priming.  This conditioning uses implicit memory to associate prior experience and future predictions with current stimuli.  Kandel showed that this implicit associative learning occurs in Aplysia's simple defensive reflex neural circuit.  Implicit memory is often maintained into old age, including in the early stages of Alzheimer's disease.  Implicit memory depends on regions of the brain that respond to stimuli: amygdala, cerebellum, basal ganglia; and reflex pathways.  Implicit facial memory is supported by the fusiform gyrus and is consolidated during REM sleep.  
  are not impacted during the early stages of the disease.  Grid cell, are neurons in the entorhinal cortex, support location modeling.  Grid cells activate when a higher animal reaches a particular position in a triangular grid mapping the floor of the proximate space.  Grid cells are lost early in Alzheimer's disease corresponding to a sense of being lost. 
  destruction results in a sense of being lost.  The default mode network in Buckner's fMRI based analysis, supports using past experiences to plan for the future, navigate social interactions and maximize the utility of moments when attention is not focused on external events.  It includes the: Medial prefrontal cortex, Medial temporal cortex, Posterior cingulate cortex.  It is disrupted in autism, schizophrenia, Alzheimer's disease.  It becomes quiet under the influence of psychedelics that bind to the serotonin receptor.   is disrupted.  Variants include: late-onset sporadic; with risk factors - ApoE4 is a gene variant which produces the E4 variant of APOE.  It is a risk-factor for late-onset sporadic Alzheimer's disease.  Being homozygote for E4 does not imply getting Alzheimer's but does increase the risk 20 fold.  ApoE2 may reduce the risk of Alzheimer's.  It appears that ApoE4 differentially affects women.  Apoe4 is known to be broken down into fragments which impare mitochondrial operation.  It also promotes amyloid plaque buildup.  Therapies are being developed based on small molecules which reshape ApoE4 to be more like ApoE3 reducing the breakdown.   
  for late onset Alzheimer's, presenilin is a gene which encodes the APP.  John Hardy of UCL followed a family with a history of Alzheimer's disease who inherited the gene with a mutation that supported amyloidosis.  , androgen deprivation therapy lowers the levels of male sex hormones.  These hormones stimulate the growth of prostrate cancer cells.  But the treatment: Bicalutamide, Lupron; is associated with increased rates of: Depression (Apr 2016), Dementia (Oct 2016) including Alzheimer's disease (Dec 2015).   (Dec 2015), type 2 diabetes is the leading cause of blindness, limb amputations and kidney failure.  It is a risk factor for Alzheimer's disease.  Insulin and glucose levels are regulated by the pancreas, liver, muscle, brain and fat.  Diabetes occurs when the insulin level is insufficient to regulate the glucose in the system.  As we age our muscles become less sensitive to insulin and the pancreas responds by increasing the amount generated.  Increased fat levels in obesity demand more insulin overloading the pancreas.  Persistent high glucose levels are also toxic to the pancreas beta cells.  High glucocorticoid levels have been associated with type 2 diabetes.  There are genetic risk factors since siblings of someone with the disease have three times the baseline risk (about 50% of the risk of getting type 2 diabetes is genetic).  The inheritance is polygenic.  More than 20 genes have been identified as risk factors, but that is too few to account for the 50% weighting so many more will be identified.  Of those identified so far many are associated with the beta cells.  The one with the strongest relative risk is TCF7L2.  The disease can be effectively controlled through a diligent application of treatments and regular checkups.  Doctors are monitored for how under control their patients' diabetes is (Sep 2015).  Treatments include:
  • Metformin - does not change the course of pre-diabetes - if you stop taking it, it is as if it hasn't been taken. 
    
  • Diet
  • Exercise
  .  There are multiple theories of the mechanism of Alzheimer's during aging: Allen Roses argues that it is due to gene alleles that limit the capacity of mitochondria are the energy molecule generating production functions of eukaryotic cells.  They are vestigial blue-green bacteria with their own DNA and infrastructure.  Unlike stand-alone bacteria they also use the eukaryotic host DNA and infrastructure for some functions.  The high energy molecules are nucleotides with a high energy phosphate bond.  The most used high energy molecule is Adenosine-tri-phosphate.   to support neuron, specialized eukaryotic cells include channels which control flows of sodium and potassium ions across the massively extended cell membrane supporting an electro-chemical wave which is then converted into an outgoing chemical signal transmission from synapses which target nearby neuron or muscle cell receptors.  Neurons are supported by glial cells.  Neurons include a:
  • Receptive element - dendrites
    
  • Transmitting element - axon and synaptic terminals.  The axon may be myelinated, focusing the signals through synaptic transmission, or unmyelinated - where crosstalk is leveraged. 
  • Highly variable DNA schema using transposons. 
    
  operation, Neurons of sporadic Alzheimer's sufferers show greater APP is Amyloid Precursor Protein.  It is encoded by the gene presenilin. 
  gene diversity due to somatic recombination alters the DNA of somatic cells: Immunoglobulin class switching, B cell receptor gene assembly and T-cell receptor gene V(D)J recombination, neuron genes that encode APP, reused in carcinogenesis; and is inherited by daughter cells. 
  ; It may be initiated by: stress is a multi-faceted condition reflecting high cortisol levels.  Dr. Robert Sapolsky's studies of baboons indicate that stress helps build readiness for fight or flight.  As these actions occur the levels of cortisol return to the baseline rate.  A stressor is anything that disrupts the regular homeostatic balance.  The stress response is the array of neural and endocrine changes that occur to respond effectively to the crisis and reestablish homeostasis. 
  
  • The short term response to the stressor
    
  • activates the amygdala which: Stimulates the brain stem resulting in inhibition of the parasympathetic nervous system and activation of the sympathetic nervous system with the hormones epinephrine and norepinephrine deployed around the body, Activates the PVN which generates a cascade resulting in glucocorticoid secretion to: get energy to the muscles with increased blood pressure for a powerful response.  The brain's acuity and cognition are stimulated.  The immune system is stimulated with beta-endorphin and repair activities curtail.  In order for the body to destroy bacteria in wounds, pro-inflammatory cytokines increase blood flow to the area.  The induced inflammation signals the brain to activate the insula and through it the ACC.  But when the stressor is
    
  • long term: loneliness, debt; and no action is necessary, or possible, long term damage ensues.  Damage from such stress may only occur in specific situations: Nuclear families coping with parents moving in.  Sustained stress provides an evolved amplifier of a position of dominance and status.  It is a strategy in female aggression used to limit reproductive competition.  Sustained stress:
    
  • Stops the frontal cortex from ensuring we do the harder thing, instead substituting amplification of the individual's propensity for risk-taking and impairing risk assessment! 
    
  • Activates the integration between the thalamus and amygdala. 
    
  • Acts differently on the amygdala in comparison to the frontal cortex and hippocampus: Stress strengthens the integration between the Amygdala and the hippocampus, making the hippocampus fearful. 
    
  • BLA & BNST respond with increased BDNF levels and expanded dendrites persistently increasing anxiety and fear conditioning. 
    
  • Makes it easier to learn a fear association and to consolidate it into long-term memory.  Sustained stress makes it harder to unlearn fear by making the prefrontal cortex inhibit the BLA from learning to break the fear association and weakening the prefrontal cortex's hold over the amygdala.  And glucocorticoids decrease activation of the medial prefrontal cortex during processing of emotional faces.  Accuracy of assessing emotions from faces suffers.  A terrified rat generating lots of glucocorticoids will cause dendrites in the hippocampus to atrophy but when it generates the same amount from excitement of running on a wheel the dendrites expand.  The activation of the amygdala seems to determine how the hippocampus responds. 
    
  • Depletes the nucleus accumbens of dopamine biasing rats toward social subordination and biasing humans toward depression. 
    
  • Disrupts working memory by amplifying norepinephrine signalling in the prefrontal cortex and amygdala to prefrontal cortex signalling until they become destructive.  It also desynchronizes activation in different frontal lobe regions impacting shifting of attention.  
  • Increases the risk of autoimmune disease (Jan 2017) 
  • During depression, stress inhibits dopamine signalling.  
  • Strategies for stress reduction include: Mindfulness. 
    
  induced HHV-6a is a double stranded DNA Roseolovirus.  It infects all tested humans and is neuroinflammatory, being seen in diseases such as MS. 
  , HHV7 is a double stranded DNA Roseolovirus. 
  herpes is a family of viruses including: CMV, EBV, varicella zoster (chicken pox), Roseolovirus; 
  activation (Jun 2018) and or an increasingly leaky blood-brain barrier; and a subsequent innate immune response has to support and protect an inventory of host cell types, detect and respond to invaders and maintain the symbiont equilibrium within the microbiome.  It detects microbes which have breached the secreted mucus barrier, driving them back and fortifying the barrier.  It culls species within the microbiome that are expanding beyond requirements.  It destroys invaders who make it into the internal transport networks.  As part of its initialization it has immune cells which suppress the main system to allow the microbiome to bootstrap.  The initial microbiome is tailored by the antibodies supplied from the mother's milk while breastfeeding.  The immune system consists of two main parts the older non-adaptive part and the newer adaptive part.  The adaptive part achieves this property by being schematically specified by DNA which is highly variable.  By rapid reproduction the system recombines the DNA variable regions in vast numbers of offspring cells which once they have been shown not to attack the host cell lines are used as templates for interacting with any foreign body (antigen).  When the immune cell's DNA hyper-variable regions are expressed as y-shaped antibody proteins they typically include some receptor like structures which match the surfaces of the typical antigen.  Once the antibody becomes bound to the antigen the immune system cells can destroy the invader. 
  to the infections (May 2016).  The Alzheimer's pathway follows:
• Plaques form.  These are seen in fMRI is functional magnetic resonance imaging.  Seiji Ogawa leveraged the coupling of neuronal circuit activity and blood flow through the associated glial cells to build a 3 dimensional picture of brain cell activity.  As haemoglobin gives up its oxygen to support the neural activity it becomes magnetic and acts as a signal detected by the fMRI.  fMRI easily visualizes the state of activity in the living human brain at millimeter resolution, up to several times a second but it cannot track the time course of neural firing so it is augmented with EEG.  s 10 to 15 years prior to detecting memory and thinking changes.  APP is Amyloid Precursor Protein.  It is encoded by the gene presenilin. 
  deployed in the cell membrane is cut into three parts.  The external part becomes amyloid-beta peptide which aggregates into Amyloid plaques, external to the neurons, if too much is generated or it is not removed fast enough. 
  
• Solanezumab aimed to inhibit plaque formation but clinical trials failed (Nov 2016). 
  
• Encouraging the garbage collection of amyloid and tau with gamma rhythms are observed as 40 Hz neural activity waves associated with conscious access.  They link different brain regions during alignment and integration of emergent memories aggregated from models in different cortical regions: occipital, temporal, somatosensory, insula, olfactory; meshing 'images' of sight, smells, taste, feel and sound into a single experience.  Yogi's gamma rhythms can last for over a minute, instead of the more typical fifth of a second explain Goleman and Davidson. 
  stimulation retards Alzheimer's in mice studies (Mar 2019)
  
• BACE inhibitors block an enzyme, a protein with a structure which allows it to operate as a chemical catalyst and a control switch. 
  needed to form amyloid. 
  
• Mutation driven misfolded Tau proteins can form tangles within the cytoplasm of neurons.  The Tau tangles kill nerve cells.  LMTX is leucomethylthioninium salts, a second generation tau aggregation inhibitor manufactured by TauRx Therapeutics. 
  is a drug treatment targeted at these tangles. 
  
• The brain becomes inflamed resulting in the killing of many more nerve cells.  The hippocampus disintegrates and the brain loses critical functions and memory loss becomes noticeable. 
  
• AMA is the American Medical Association. 
  
• AMC is Academic medical center.  They perform education, research and patient care.  They include one or more health professions schools, such as a medical school and a hospital.  The major AMCs are represented by the United HealthSystem Consortium.   The costly strategies of the AMCs and increased difficulty of finding enough targeted patients for research studies (Aug 2017) is forcing integration with larger hospital systems is the owner of a set of hospitals and other owned infrastructure and employer of direct staff.  .  AMCs offer researchers clinical research support: Virus is a relatively small capsule containing genetic material: RNA, DNA; which utilizes the cellular infrastructure of its target host to replicate its genetic material and operational proteins.  David Quammen explains the four key challenges of viruses: Getting from one host to another, penetrating a cell within the host, commandeering the cell's infrastructure, escaping from the cell and organism; Single-stranded RNA viruses: Coronavirus, chickungunya, dengue, Ebola, Hantas, Hendra, Influenzas, Junin, Lassa, Machupo, Marburg, Measles, Mumps, Nipah, Rabies, Retrovirus (HIV), Rhinovirus, yellow fever; are subject to more mutation events than DNA viruses, but limits the size of the genetic string.  Double stranded DNA viruses: baculoviruses, hepadnaviruses, Herpesviruses, iridoviruses, papillomavirses, poxviruses; can leverage relatively far larger genetic payloads.  The relationship with the reservoir host is long-term, a parasitic or symbiotic relationship, developing over millions of years.  But opportunistically, it may spillover into a secondary host, with the virus entering the host cell, leveraging the host infrastructure to replicate its self massively and then exiting the host cell by rupturing it and killing the organism. 
  vectors (Nov 2017);
  
• AMD is age related macular degeneration is a disease that results in progressive and complete blindness.  It includes: AMD which has two forms dry and wet. 
  which is the leading cause of vision loss and blindness among Americans over 65.  It is associated with a damaging buildup of drusen pigments in the dry form is the slow destruction of foveal vision.  It is caused by a buildup of drusen pigments due to a failure of the aging cellular infrastructure to remove these metabolic waste products.  The pigments inhibit the flow of oxygen from the choroid blood supply through Bruch's membrane to the RPE and photo-receptor cells.  The drusen damage the RPE causing this layer of the macular to thin.  Over a decade this results in deterioration of perception in the fovea.  In about 20% of sufferers the reduced flows across the RPE result in development of more blood vessels which anomalously push through Bruch's membrane causing the far more rapidly destructive wet macular degeneration.  Dry macular degeneration can be detected using an Amsler grid and confirmed with OCT. 
  and additionally, blood vessels in the wet form is an age related, rapidly irreversible, destruction of foveal vision.  It occurs in 20% of AMD and can damage the retina within a 12 month period.  It is due to aberrant blood vessel development in the choroid, pushing through the RPE and disrupting it.  Treatments using locally deployed VEGF and POGF receptor blockers inhibit the problematic angiogenesis.  .  It is associated with a variety of genetic mutations.  Using HapMap is a genomics project of 2000 scientists in six countries project managed by Francis Collins, which mapped the various haplotypes.  By leveraging the clustering of SNPs in neighborhoods of the genes and knowledge of the boundaries of the neighborhoods you can identify all the SNPs without spending huge amounts of money or laboratory time to test for every one.  HapMap was designed to define the boundaries of the neighborhoods to allow these shortcuts in genome analysis reducing the amount of work by a factor of 40. 
  data it was realized that two gene variations on separate chromosomes, both involved in inflammatory response carry high risk for this disease.  These two genetic factors along with smoking and obesity is an addictive disorder where the brain is induced to require more eating, often because of limits to the number of fat cells available to report satiation (Jul 2016).  Brain images of drug-addicted people and obese people have found similar changes in the brain.  Obese people's reward network tends to be less responsive to dopamine and have a lower density of dopamine receptors.  Obesity spreads like a virus through a social network with a 171% likelihood that a friend of someone who becomes obese will also become so.  Obesity is associated with: metabolic syndrome including inflammation, cancer (Aug 2016), high cholesterol, hypertension, type-2-diabetes, asthma and heart disease.  It is suspected that this is contributing to the increase in maternal deaths in the US (Sep 2016).  Obesity is a complex condition best viewed as representing many different diseases, which is affected by the: Amount of brown adipose tissue (Oct 2016), Asprosin signalling by white adipose tissue (Nov 2016), Genetic alleles including 25 which guarantee an obese outcome, side effects of some pharmaceuticals for: Psychiatric disorders, Diabetes, Seizure, Hypertension, Auto-immunity; Acute diseases: Hypothyroidism, Cushing's syndrome, Hypothalamus disorders; State of the gut microbiome.  Infections, but not antibiotics, appear associated with childhood obesity (Nov 2016). 
  infer 80 percent of the risk.  Treatments can thus target the inflammatory response.  Ranibizumab is a MAB fragment that blocks VEGF binding driven blood vessel formation.  It is marketed under the trade name Lucentis. 
  blocks the VEGF is vascular endothelial growth factor, a signalling protein used by cells to stimulate angiogenesis.   stimulated growth of blood vessels that occur in the wet form. 
• AMI is acute myocardial infarction which means that some of the heart muscle has died from a blocked blood supply.  AMI is hard to measure.  Nanosensors offer a possibility (May 2016).   
• Amino-acids are the building blocks of proteins, a relatively long chain (polymer) of peptides.  Shorter chains of peptides are termed polypeptides.  .  The 20 main variants differ by the nature of their side chain.  Some are positively charged, others negatively charged.  Some are water seeking while others are fat seeking.  The genetic code, the mapping of DNA base triplet sequences, such as AAA and AAT, to amino-acids (AAA maps to the amino-acid lysine for example) and transcription termination sequences (TGA maps to stop transcription for example) that has currently evolved.   mapping of DNA (DNA), a polymer composed of a chain of deoxy ribose sugars with purine or pyrimidine side chains.  DNA naturally forms into helical pairs with the side chains stacked in the center of the helix.  It is a natural form of schematic string.  The purines and pyrimidines couple so that AT and GC pairs make up the stackable items.  A code of triplets of base pairs (enabling 64 separate items to be named) has evolved which now redundantly represents each of the 20 amino-acids that are deployed into proteins, along with triplets representing the termination sequence.  Chemical modifications and histone binding (chromatin) allow cells to represent state directly on the DNA schema.  To cope with inconsistencies in the cell wide state second messenger and evolved amplification strategies are used.   base, a nucleotide base is the side chain purine (A or G) or pyrimidine (T or C).  A is a natural pair for T.  G pairs naturally with C.  These bases have multiple uses in cells including energy transfer, second messenger signalling as well as genetic data storage, transcription and translation.  Deacon argues that the multiple uses are significant to the emergence of evolution. 
  pair triplets thus specifies the primary sequence of amino-acids in any protein polymer. 
  
• Amok is a Malay word describing the homicidal actions occasionally performed by lonely Indochinese men who have suffered a loss of love, money or face.  The syndrome occurs across cultures is how we do and think about things, transmitted by non-genetic means as defined by Frans de Waal.  CAS theory views cultures as operating via memetic schemata evolved by memetic operators to support a cultural superorganism.  Evolutionary psychology asserts that human culture reflects adaptations generated while hunting and gathering.  Dehaene views culture as essentially human, shaped by exaptations and reading, transmitted with support of the neuronal workspace and stabilized by neuronal recycling.  Damasio notes prokaryotes and social insects have developed cultural social behaviors.  Sapolsky argues that parents must show children how to transform their genetically derived capabilities into a culturally effective toolset.  He is interested in the broad differences across cultures of: Life expectancy, GDP, Death in childbirth, Violence, Chronic bullying, Gender equality, Happiness, Response to cheating, Individualist or collectivist, Enforcing honor, Approach to hierarchy; illustrating how different a person's life will be depending on the culture where they are raised.  Culture:
  • Is deployed during pregnancy & childhood, with parental mediation.  Nutrients, immune messages and hormones all affect the prenatal brain.  Hormones: Testosterone with anti-Mullerian hormone masculinizes the brain by entering target cells and after conversion to estrogen binding to intracellular estrogen receptors; have organizational effects producing lifelong changes.  Parenting style typically produces adults who adopt the same approach.  And mothering style can alter gene regulation in the fetus in ways that transfer epigenetically to future generations!  PMS symptoms vary by culture. 
    
  • Is also significantly transmitted to children by their peers during play.  So parents try to control their children's peer group.  
  • Is transmitted to children by their neighborhoods, tribes, nations etc. 
    
  • Influences the parenting style that is considered appropriate. 
    
  • Can transform dominance into honor.  There are ecological correlates of adopting honor cultures.  Parents in honor cultures are typically authoritarian. 
    
  • Is strongly adapted across a meta-ethnic frontier according to Turchin.  
  • Across Europe was shaped by the Carolingian empire. 
    
  • Can provide varying levels of support for innovation.  Damasio suggests culture is influenced by feelings: 
    
  • As motives for intellectual creation: prompting detection and diagnosis of homeostatic deficiencies, identifying desirable states worthy of creative effort.
    
  • As monitors of the success and failure of cultural instruments and practices
  • As participants in the negotiation of adjustments required by the cultural process over time 
  • Produces consciousness according to Dennet. 
    
  .  An amok man responds autonomously and can't be reasoned with.  But Steven Pinkers explains it is:
  
• An emotional are low level fast unconscious agents distributed across the brain and body which associate, via the amygdala and rich club hubs, important environmental signals with encoded high speed sensors, and distributed programs of action to model: predict, prioritize guidance signals, select and respond effectively, coherently and rapidly to the initial signal.  The majority of emotion centered brain regions interface to the midbrain through the hypothalamus.  The cerebellum and basal ganglia support the integration of emotion and motor functions, rewarding rhythmic movement.  The most accessible signs of emotions are the hard to control and universal facial expressions.  Emotions provide prioritization for conscious access given that an animal has only one body, but possibly many cells, with which to achieve its highest level goals.  Because of this, base emotions clash with group goals and are disparaged by the powerful.  Pinker notes a set of group selected emotions which he classes as: other-condemning, other-praising, other-suffering and self-conscious emotions.  Evolutionary psychology argues evolution shaped human emotions during the long period of hunter-gatherer existence in the African savanna.  Human emotions are universal and include: Anger, Appreciation of natural beauty, Contempt, Disgust, Embarrassment, Fear, Gratitude, Grief, Guilt, Happiness, Honor, Jealousy, Liking, Love, Moral awe, Rage, Romantic love, Lust for revenge, Passion, Sadness, Self-control, Shame, Sympathy, Surprise; and the sham emotions and distrust induced by reciprocal altruism. 
  result of lengthy brooding over failure, 
• Carefully planned as a means of deliverance from an unbearable situation
• Cognitive is the ability to orchestrate thought and action in accordance with internal goals according to Princeton's Jonathan Cohen. 
  - It is triggered by an idea, rather than some immediate stimulus or tumor
  
• I am not an important or "big man." 
  
• I possess only my personal sense of dignity
• My life has been reduced to nothing by an intolerable insult which means  
  
• I have nothing to lose except by life, which is nothing, so I trade my life for yours, as your life is favored. 
  
• I will kill many of you which will rehabilitate myself in the eye of the group (amok) of which I am a member even though I might be killed in the process. 
  
• Amortized loans include interest & repayment of principal in the monthly payment.  No lump-sum payment is left when the loan matures.  Varying the number of payments helped limit the size of the monthly payment. 
  
• Amputation is a surgical technique to remove damaged body parts.  The regular method was developed by the 1800s and leaves considerable scope for increasing support for bionic devices: rebuilding agonist antagonist muscle group feedback etc.  
• AMT is alternative minimum tax
  
• Amygdala contains > 12 distinct areas: Central is a relatively ancient evolved part of the amygdala which processes 'innate' fears.  It projects to the BNST to raise the heart rate and blood pressure in preparation for fight and flight. 
  , Lateral is the basolateral amygdala, a relatively recently evolved part of the amygdala which learns stimuli to fear and then signals the central amygdala.  It recieves inputs from all sensory networks.  Some are fast pathways that allow the BLA to detect and respond when the sensory cortex is unaware.  But it is far less accurate than the cortex.  The BLA's learning involves increased excitability of synapses coupling the BLA and central amygdala.  This is due to gene driven: Increased levels of growth factors promoting new connections, more receptors for excitatory neurotransmitters in dendritic spines.  The BLA also responds to signals from the frontal cortex that a stimulus no longer appears frightening.  This subset of BLA cells respond inhibiting the associating subset.  Stress and glucocorticoids increase levels of CRH and BDNF encouraging the building of new dendrites and synapses. 
  .  It receives simple signals from the lower parts of the brain: pain emerged as a mental experience, Damasio asserts, constructed by the mind using mapping structures and events provided by nervous systems.  But feeling pain is supported by older biological functions that support homeostasis.  These capabilities reflect the organism's underlying emotive processes that respond to wounds: antibacterial and analgesic chemical deployment, flinching and evading actions; that occur in organisms without nervous systems.  Later in evolution, after organisms with nervous systems were able to map non-neural events, the components of this complex response were 'imageable'.  Today, a wound induced by an internal disease is reported by old, unmyelinated C nerve fibers.  A wound created by an external cut is signalled by evolutionarily recent myelinated fibers that result in a sharp well-localized report, that initially flows to the dorsal root ganglia, then to the spinal cord, where the signals are mixed within the dorsal and ventral horns, and then are transmitted to the brain stem nuclei, thalamus and cerebral cortex.  The pain of a cut is located, but it is also felt through an emotive response that stops us in our tracks.  Pain amplifies the aggression response of people by interoceptive signalling of brain regions providing social emotions including the PAG projecting to the amygdala; making aggressive people more so and less aggressive people less so.  Fear of pain is a significant contributor to female anxiety.  Pain is the main reason people visit the ED in the US.  Pain is mediated by the thalamus and nucleus accumbens, unless undermined by sleep deprivation. 
  from the PAG is periaqueductal gray, an ancient core brain structure that projects pain sensations to the amygdala, has a high density of vasopressin and oxytocin receptors and a direct connection to the orbitofrontal cortex, potentially supporting maternal love.  It has a critical role in autonomic function, motivated behavior and responses to threats - the dorsal PAG activates during defensive behaviors: freezing immobility, running, jumping, increased blood pressure; while caudal ventrolateral PAG activation results in an immobile relaxed posture.  The PAG's enkephalin-producing cells suppress pain. 
  ; and abstract complex information from the highest areas: Disgust is a universal human emotion.  Pinker notes it has its own facial expression and is codified in food taboos.  The mind must be associated with the proximate environment and parents minimize the risk for their omnivorous children by teaching them what foods to eat and what to avoid.  The children's minds are initially receptive to trying all foods but their brains subsequently lock in on the foods they have experienced.  These parental choices are affected by schematic influence on what has been beneficial.  Adolescent's brain developments undermine these constraints enabling intergroup transfers.  Disgust is modulated by the insula cortex which projects signals to the amygdala.  Adult humans merge moral and physical disgust enabling metaphorical out grouping. 
  , heart rate, and suffering from the insula cortex is part of the cerebral cortex folded deep within the lateral sulcus.  It includes: anterior, posterior insula; and is overlaid by the operculum.  Kandel notes the anterior insula is where feelings are calibrated by evaluating and integrating the importance of the stimuli.  It directly signals area 25.  LeDoux showed there are two routes for signals of feelings and emotions to the amygdala: a fast unconscious one and a slow one that involves the anterior insula.  So the insula is assumed to participate in consciousness where it has been linked to emotion, salience & body homeostasis functions:
  
  • Perception,
    
  • Motor control: Hand-&-eye motor movement, Swallowing, Gastric motility, Speech articulation;
    
  • Self-awareness,
    
  • Inter-personal experiences: Disgust at smells, contamination & mutilation which generate visceral responses, that are projected to the amygdala; binding physical and moral aspects of purity (Macbeth effect)
  • Suffering of others can be projected by the insula to the amygdala and made increasingly salient with loving-kindness meditation practice, Goleman & Davidson explain. 
    
  • Homeostatic regulation of the sympathetic network, parasympathetic network, and immune system.  Heart rate and sweat gland activity are monitored.   When the amygdala signals concern, the insula prepares the body for action, increasing blood flow to the muscles etc.
    
  , allowing it to orchestrate emotion are low level fast unconscious agents distributed across the brain and body which associate, via the amygdala and rich club hubs, important environmental signals with encoded high speed sensors, and distributed programs of action to model: predict, prioritize guidance signals, select and respond effectively, coherently and rapidly to the initial signal.  The majority of emotion centered brain regions interface to the midbrain through the hypothalamus.  The cerebellum and basal ganglia support the integration of emotion and motor functions, rewarding rhythmic movement.  The most accessible signs of emotions are the hard to control and universal facial expressions.  Emotions provide prioritization for conscious access given that an animal has only one body, but possibly many cells, with which to achieve its highest level goals.  Because of this, base emotions clash with group goals and are disparaged by the powerful.  Pinker notes a set of group selected emotions which he classes as: other-condemning, other-praising, other-suffering and self-conscious emotions.  Evolutionary psychology argues evolution shaped human emotions during the long period of hunter-gatherer existence in the African savanna.  Human emotions are universal and include: Anger, Appreciation of natural beauty, Contempt, Disgust, Embarrassment, Fear, Gratitude, Grief, Guilt, Happiness, Honor, Jealousy, Liking, Love, Moral awe, Rage, Romantic love, Lust for revenge, Passion, Sadness, Self-control, Shame, Sympathy, Surprise; and the sham emotions and distrust induced by reciprocal altruism. 
  .  It connects strongly to attention is the mutli-faceted capability allowing access to consciousness.  It includes selective attention, vigilance, allocating attention, goal focus, and meta-awareness. 
  focusing networks.  It sends signals to almost every other part of the brain, including to the decision making integrates situational context, state and signals to prioritize among strategies and respond in a timely manner.  It occurs in all animals, including us and our organizations: 
  
  • Individual human decision making includes conscious and unconscious aspects.  Situational context is highly influential: supplying meaning to our general mechanisms, & for robots too.  Emotions are important in providing a balanced judgement.  The adaptive unconscious interprets percepts quickly supporting 'fast' decision making.  Conscious decision making, supported by the: DLPFC, vmPFC and limbic system; can use slower autonomy.  The amygdala, during unsettling or uncertain social situations, signals the decision making regions of the frontal lobe, including the orbitofrontal cortex.  The BLA supports rejecting unacceptable offers.  Moral decisions are influenced by a moral decision switch.  Sleeping before making an important decision is useful in obtaining the support of the unconscious in developing a preference.  Word framing demonstrates the limitations of our fast intuitive decision making processes.  And prior positive associations detected by the hippocampus, can be reactivated with the support of the striatum linking it to the memory of a reward, inducing a bias into our choices.  Prior to the development of the PFC, the ventral striatum supports adolescent decision making.  Neurons involved in decision making in the association areas of the cortex are active for much longer than neurons participating in the sensory areas of the cortex.  This allows them to link perceptions with a provisional action plan.  Association neurons can track probabilities connected to a choice.  As evidence is accumulated and a threshold is reached a choice is made, making fast thinking highly adaptive.  Diseases including: schizophrenia and anorexia; highlight aspects of human decision making. 
    
  • Organisations often struggle to balance top down and distributed decision making: parliamentry government must use a process, health care is attempting to improve the process: checklists, end-to-end care; and include more participants, but has systemic issues, business leaders struggle with strategy. 
    
  circuitry of the frontal lobes of the cerebral cortex is at the front of the brain.  It includes the: prefrontal cortex, motor cortex.  Sapolsky asserts it makes you do the harder thing when it's the right thing to do.  The frontal cortex supports working memory to sustain focus on a task.  It also coordinates the strategic actions necessary to achieve success.  It provides impulse control, regulation of emotion, and willpower.  The prefrontal cortex maintains focus by deprioritizing currently irrelevant streams of information.  The frontal cortex tracks rules.  Over a lifetime, that builds into a costly activity.  Once it tires, responses become less prosocial.  But practice shifts operation of tasks to the cerebellum.  The frontal cortex signals the tegmentum and accumbens with the conclusions of its expectancy/discrepancy calculations.  The frontal lobe provides executive function, considering bits of information, assessing patterns and then prioritizing the strategies.  The frontal lobe is the most recent part of the brain to evolve and involves a disproportionate percentage of primate-unique genes in its development and operation.  It does not complete development until the mid-20s.  It includes spindle neurons.  It is easily damaged.  Sapolsky (Nauta) notes that its ventromedial prefrontal cortex is a quasi-member of the limbic system. 
  .  It has high levels of D(1) dopamine is a synaptic signal supporting generalized goal-directed behavior & anticipation of reward.  Its significance is that the receptors that detect the signal are of the slow acting type and are used to alter (modulate) the response of fast acting dopaminergic neural circuits in which the receptors are deployed (LTP).  The signal detects significant changes including predictions of models and actual results which differ unexpectedly.  Dopamine is released primarily by neurons of the ventral tegmental area and the substantia nigra.  The dopamine network architecture is designed to signal the possibility of any type of reward: Norm violation punishment, Winning a lottery, & Misfortune of an envied competitor.  Dopamine signalling:
  
  • Rescales continuously to accommodate the range of intensity offered by different stimuli.  So dopamine's responses to any reward habituate.  GABA is released by some tegmental neurons to induce habituation.  This allows addictions to develop. 
    
  • Reflects the anticipation of reward.  It supports establishment of a relationship between a signal, working for a reward and obtaining the reward, but subsequently dopamine is mainly released encouraging the work, right after the signal supporting anticipation of the reward.  Anticipation requires learning and is reflected in hippocampus activity.  That explains context dependent cravings.  And the learning architecture means reliable cues become rewarding.  The accumbens supports willpower.  And dopamine
    
  • Promotes goal-oriented behavior needed to obtain & likely to achieve the reward - through the dopamine projections to the prefrontal cortex.  That makes dopamine central to:
    
  • Motivation.  This binding fails in depression - due to stress and in anxiety - due to signals from the amygdala.  
  • The prefrontal cortex's mesocortically stimulated support for willpower to act to delay rewards.  To sustain work for delayed rewards additional dopamine is released based on the length of the delay and the rewards uncertainty (modelled in the dorsolateral prefrontal cortex - which promotes the long term and the ventromedial prefrontal cortex - which promotes the short term) and the anticipated size of the reward (modelled in the accumbens).  Impulsiveness in ADHD is reflected in abnormal dopamine processing.  Addictive drugs bias the dopamine network towards impulsiveness.  
  • Is lowered by certain gene variants which induce: less dopamine in the synapse, fewer receptors, lower responsiveness of receptors; associated with (as tiny effects in hugely varying social scenarios): sensation seeking, risk taking, attentional problems, extroversion; where:
    
  • The receptor D4's gene shows high variability.  The D47R form is relatively unresponsive to dopamine.  
  • Dopamine is degraded by COMT.  The COMT gene includes a variant which is highly efficient reducing dopamine signalling but with complicating gene/environment interactions.  
  • Dopamine is removed from the synapse by a reuptake transporter DAT. 
    
  receptors.  During extreme fear the amygdala drives the hippocampus is a part of the medial temporal lobe of the brain involved in the temporary storage or coding of long-term episodic memory.  It includes the dentate gyrus.  Memory formation in the cells of the hippocampus uses the MAP kinase signalling network which is impacted by sleep deprivation.  The hippocampus dependent memory system is directly affected by cholinergic changes throughout the wake-sleep cycle.  Increased acetylcholine during REM sleep promotes information attained during wakefulness to be stored in the hippocampus by suppressing previous excitatory connections while facilitating encoding without interference from previously stored information.  During slow-wave sleep low levels of acetylcholine cause the release of the suppression and allow for spontaneous recovery of hippocampal neurons resulting in memory consolidation.  It was initially associated with memory formation by McGill University's Dr. Brenda Milner, via studies of 'HM' Henry Molaison, whose medial temporal lobes had been surgically destroyed leaving him unable to create new explicit memories.  The size of neurons' dendritic trees expands and contracts over a female rat's ovulatory cycle, with the peak in size and cognitive skills at the estrogen high point.  Adult neurogenesis occurs in the hippocampus (3% of neurons are replaced each month) where the new neurons integrate into preexisting circuits.  It is enhanced by learning, exercise, estrogen, antidepressants, environmental enrichment, and brain injury and inhibited by various stressors explains Sapolsky.  Prolonged stress makes the hippocampus atrophy.  He notes the new neurons are essential for integrating new information into preexisting schemas -- learning that two things you thought were the same are actually different.  Specific cells within the hippocampus and its gateway, the entorhinal cortex, are compromised by Alzheimer's disease.  It directly signals area 25. 
  into fear learning.  It outputs directly to subcortical reflexive motor pathways when speed is required.  Its central nucleus is a relatively ancient evolved part of the amygdala which processes 'innate' fears.  It projects to the BNST to raise the heart rate and blood pressure in preparation for fight and flight. 
  projects to the BNST is the bed nucleus of the stria terminalis.  It receives 'innate fear' signals from the central amygdala.  It projects to: Parts of the hypothalamus that initiate the hormonal stress response, Midbrain and brain-stem networks that activate the sympathetic nervous system and inhibit the parasympathetic.  Winning in competition induces the addition of testosterone receptors increasing the sensitivity of the BNST to the hormone.  That will lead to reduced fear and increased confidence.  .  It signals, is an emergent capability which is used by cooperating agents to support coordination & rival agents to support control and dominance.  In eukaryotic cells signalling is used extensively.  A signal interacts with the exposed region of a receptor molecule inducing it to change shape to an activated form.  Chains of enzymes interact with the activated receptor relaying, amplifying and responding to the signal to change the state of the cell.  Many of the signalling pathways pass through the nuclear membrane and interact with the DNA to change its state.  Enzymes sensitive to the changes induced in the DNA then start to operate generating actions including sending further signals.  Cell signalling is reviewed by Helmreich.  Signalling is a fundamental aspect of CAS theory and is discussed from the abstract CAS perspective in signals and sensors.  In AWF the eukaryotic signalling architecture has been abstracted in a codelet based implementation.  To be credible signals must be hard to fake.  To be effective they must be easily detected by the target recipient.  To be efficient they are low cost to produce and destroy. 
  the locus ceruleus and its projections determine the brain's global orientation concerning events in the external world and within the viscera.  It is signalled by the amygdala.  Such a hypothesis of central noradrenergic neuron function has been generated by observations of locus ceruleus unit discharge in untreated, awake, behaviorally responsive rats and monkeys.  These studies reveal the locus ceruleus units to be highly responsive to a variety of non-noxious sensory stimuli and that the responsiveness of these units varies as a function of the higher animal's level of behavioral vigilance.  Increased neuronal activity in the locus ceruleus is associated with unexpected sensory events in the subject's external environment, while decreased noradrenergic activity is associated with mediating tonic vegetative behaviors.  Sapolsky argues that arousal spread through the locus ceruleus to many brain regions, particularly the cortex, increases the intensity of what is sensed. 
  .  It directly signals area 25 is the Subcallosal Cingulate Cortex, an area of the ACC, which Kandel explains, is a region where thought, motor control and drive come together.  It is rich in neurons generating serotonin transporters.  It is directly involved in a signalling network with: amydala, hypothalamus, hippocampus, insula cortex; that integrates thinking and emotion to plan and respond effectively.  Kandel notes whenever area 25 becomes hyperactive, the components of this circuit associated with emotion are disconnected from the thinking brain resulting in a loss of personal identity.  .  The amygdala:
  
• Promotes aggression.  Stimulating the amygdala promotes rage.  It converts anger is an emotion which protects a person who has been cheated by a supposed friend.  When the exploitation of the altruism is discovered, Steven Pinker explains, the result is a drive for moralistic aggression to hurt the cheater.  Anger is mostly experienced as a rapid wave that then quickly dissipates.  When it is repressed, for example by a strong moral sense (superego), it can sustain, inducing long term stress. 
  into aggression and when impaired it impacts the ability to detect angry facial expressions.  
• Participates in disgust is a universal human emotion.  Pinker notes it has its own facial expression and is codified in food taboos.  The mind must be associated with the proximate environment and parents minimize the risk for their omnivorous children by teaching them what foods to eat and what to avoid.  The children's minds are initially receptive to trying all foods but their brains subsequently lock in on the foods they have experienced.  These parental choices are affected by schematic influence on what has been beneficial.  Adolescent's brain developments undermine these constraints enabling intergroup transfers.  Disgust is modulated by the insula cortex which projects signals to the amygdala.  Adult humans merge moral and physical disgust enabling metaphorical out grouping. 
  
• Perceives fear is an emotion which prepares the body for time sensitive action: Blood is sent to the muscles from the gut and skin, Adrenalin is released stimulating: Fuel to be released from the liver, Blood is encouraged to clot, and Face is wide-eyed and fearful.  The short-term high priority goal, experienced as a sense of urgency, is to flee, fight or deflect the danger.  There are both 'innate' - really high priority learning - which are mediated by the central amygdala and learned fears which are mediated by the BLA which learns to fear a stimulus and then signals the central amygdala.  Tara Brach notes we experience fear as a painfully constricted throat, chest and belly, and racing heart.  The mind can build stories of the future which include fearful situations making us anxious about current ideas and actions that we associate with the potential future scenario.  And it can associate traumatic events from early childhood with our being at fault.  Consequent assumptions of our being unworthy can result in shame and fear of losing friendships.  The mechanism for human fear was significantly evolved to protect us in the African savanna.  This does not align perfectly with our needs in current environments: U.S. Grant was unusually un-afraid of the noise or risk of guns and trusted his horses' judgment, which mostly benefited his agency as a modern soldier. 
  promoting stimuli, focusing our attention on these.  In PTSD is post-traumatic stress disorder, an induced level of stress that is so troubling to the brain that it avoids processing it, change that is necessary if the stress is to be dissipated by the normal brain processes.  The hippocampus loses volume.  The damage to the hippocampus results in: flashbacks, becoming emotionally numb and withdrawn from other people, irritability, jumpiness, being more aggressive, having trouble sleeping and avoidance of the sensory experiences associated with the initial event.  The amygdala responds to overwhelming trauma by repeatedly grabbing attention to encourage response to the emergency, increases in volume and is hyperactive and anxious.  As a result it remains in a heightened state, resulting in fear of recall and further stress.  PTSD is often accompanied by depression and substance abuse.  It is now being realized that PTSD can be introduced into patients by traumatic treatment regimens such as ICU procedures.  Traumatic head injuries, seen in athletes and soldiers can be reflected in PTSD and can subsequently become associated with prion based dementia.  Some people are genetically predisposed to PTSD, with identical twins responding similarly.  Another risk factor for PTSD is childhood trauma which can induce epi-genetic changes to stress processing.  PTSD can be managed with CBT, and it also responds to propranolol while recalling the traumatic event, where the drug undermines the memory reconsolidation process. 
  sufferers the Amygdala overreacts to mildly fearful stimuli and is slow to calm down and the amygdala expands in size refers to lasting changes to the brain that occur throughout the life span of the organism.  Many aspects of the brain can be altered into adulthood.  Almost anything in the nervous system can change in response to sustained stimulus.  And in a different environment the changes will often reverse.  The changes include:
  • The strength of dendritic input alters due to genetic, neural and hormonal signals
  • Hebb notes that memories require strengthening of preexisting synapses.  Glutamate responsive neurons' post synaptic dendritic spines have two types of receptor: non-NMDA and NMDA.  NMDA channels are responsible for this strengthening mechanism.  LTP then occurs to prolong the increase in excitability of the synapse. 
    
  • The LTP operation results in calcium diffusion which triggers new spine formation in adjacent parts of the dendrite.  Eventually that can stimulate dentrite growth enabling more neurons to connect. 
    
  • Short term stress promotes hippocampal LTP.  
  • Sustained stress promotes:
    
  • Hippocampal & frontal cortex  LTD & suppresses LTP.  Subsequent reductions in NCAM then reduce dendrite and synapse density. 
    
  • Amygdala LTP and suppresses LTD boosting fear conditioning.  It increases BDNF levels and expands dendrites in the BLA. 
    
  • Depression and anxiety reduce hippocampal dendrite and spine number by reducing BDNF. 
    
  • The axon's conditions for
    
  • Initiating an action potential. 
    
  • Progesterone boosts GABA-ergic neurons response to GABA decreasing the excitability of other neurons over a period of hours. 
    
  • Duration of a neuron's refractory period.  Testosterone shortens the refractory period of amygdala and amygdala target neurons over a period of hours. 
    
  • Synaptic connections being constantly removed and recreated
  • Synapses being created or destroyed.  Stimulation generates additional dendritic spines which become associated with a nearby axon terminal and within weeks a synapse forms.  The synapse then contributes calcium diffusion through LTP triggering more spine formation.  When dendritic spines recede synapses disappear. 
    
  • Cortical maps change to reflect alterations in the inputs and outputs from the body. 
    
  • Birth of brain cells in many areas of adult brains: the hippocampus (where 3% are replaced each month) and olfactory bulb and lesser amounts in the cortex. 
    
  • Restructuring after brain damage including axonal plasticity.  Distant rerouting of axons is observed but no mechanism has been identified yet. 
    
  • Vision is plastic in predators, where the eyes are moved during final development.  Dehaene argues for neuronal recycling supporting reading.  
  over a period of months.  Fear is processed by the lateral nucleus is the basolateral amygdala, a relatively recently evolved part of the amygdala which learns stimuli to fear and then signals the central amygdala.  It recieves inputs from all sensory networks.  Some are fast pathways that allow the BLA to detect and respond when the sensory cortex is unaware.  But it is far less accurate than the cortex.  The BLA's learning involves increased excitability of synapses coupling the BLA and central amygdala.  This is due to gene driven: Increased levels of growth factors promoting new connections, more receptors for excitatory neurotransmitters in dendritic spines.  The BLA also responds to signals from the frontal cortex that a stimulus no longer appears frightening.  This subset of BLA cells respond inhibiting the associating subset.  Stress and glucocorticoids increase levels of CRH and BDNF encouraging the building of new dendrites and synapses. 
  which serves as the input from various senses, and the central nucleus is a relatively ancient evolved part of the amygdala which processes 'innate' fears.  It projects to the BNST to raise the heart rate and blood pressure in preparation for fight and flight. 
  which outputs to the brain stem includes: medulla, raphe, pons, substantia nigra, ventral tegmental area, pituitary, superior colliculi, cerebellum, thalamus (LGN), basal ganglia including caudate nucleus and striatum; amygdala, hypothalamus, nucleus accumbens; (central grey - freezing, lateral hypothalamus is essential to many instinctive operations of the body.  It can be viewed as the executor of emotion: happiness, sadness, aggression, eroticism and mating, relaying the amygdala's responses to low level sensory signals.  It has many small sub-regions whose main functions are to regulate hunger, thirst, temperature, sexual behavior, parenting, heart rate, blood pressure, sleep cycles, and similar body operations.  Kandel notes it includes a nucleus containing two distinct populations of neurons: one that regulates aggression and one that regulates sex and mating.  At the intersection neurons are active in both.  Depending on the intensity of the stimulus applied to these neurons mating (weak) or aggression (danger) is activated.  This probably contributes to sexual rage and is why some couples derive extra pleasure from sexual experiences following an argument.  The hypothalamus's (paraventricular nucleus) is closely connected to the pituitary which secrets hormones into the bloodstream ( => acth -> adrenal cortex => cortisol (+)->  amygdala & (-)-> hippocampus).  It directly signals area 25. 
  - blood pressure, activates paraventricular hypothalamus is essential to many instinctive operations of the body.  It can be viewed as the executor of emotion: happiness, sadness, aggression, eroticism and mating, relaying the amygdala's responses to low level sensory signals.  It has many small sub-regions whose main functions are to regulate hunger, thirst, temperature, sexual behavior, parenting, heart rate, blood pressure, sleep cycles, and similar body operations.  Kandel notes it includes a nucleus containing two distinct populations of neurons: one that regulates aggression and one that regulates sex and mating.  At the intersection neurons are active in both.  Depending on the intensity of the stimulus applied to these neurons mating (weak) or aggression (danger) is activated.  This probably contributes to sexual rage and is why some couples derive extra pleasure from sexual experiences following an argument.  The hypothalamus's (paraventricular nucleus) is closely connected to the pituitary which secrets hormones into the bloodstream ( => acth -> adrenal cortex => cortisol (+)->  amygdala & (-)-> hippocampus).  It directly signals area 25. 
  => crf -> hormone are signalling molecules: ACTH, TRH, Melanocyte stimulating hormone, Testosterone, Oxytocin, Vasopressin, Insulin, Growth hormone, Estrogen, Progesterone, Angiotensin II, Asprosin, EPO, Irisin, Leptin, FGF21 hormone, Prostaglandins, TSH, Thyroxine, Glococorticoids: Cortisol; that are transported by the circulatory system to interact with target organs having appropriate receptors.  The levels of hormones can fluctuate massively, as in pregnancy. 
  adjustments). 
  
• Has lots of receptors is NR3C1 a receptor deployed in several forms, to which cortisol and other glucocorticoids bind.  It regulates transcription of genes controlling development, metabolism and immune response.  The unbound receptor resides in the cytosol.  Gene/environment interactions have been identified:
  • One variant of the gene for the MR receptor in the presence of childhood abuse produces an amydala that is hyperactive to threat.  
  • The GR receptor's activity is modified by FKBP5.  Once FKBP5 variant in the presence of childhood abuse is associated with: aggression, hostility, PTSD, hyperreactivity of the amygdala to threat. 
    
  for and is highly sensitive to glucocorticoids are corticosteroids which bind the glucocorticoid receptor.  They decrease excitability of prefrontal cortical neurons.  They have adverse effects in fetal/infant development having organizational effects on fetal brain construction and decreasing levels of: growth factors, neurons, synapses; resulting in an adult brain that is more sensitive to environmental triggers of depression and anxiety.  Glucocorticoids affect gene control structures and induce epi-genetic changes.  They have been found associated with high sodium chloride consumption (May 2017). 
  .  Stress is a multi-faceted condition reflecting high cortisol levels.  Dr. Robert Sapolsky's studies of baboons indicate that stress helps build readiness for fight or flight.  As these actions occur the levels of cortisol return to the baseline rate.  A stressor is anything that disrupts the regular homeostatic balance.  The stress response is the array of neural and endocrine changes that occur to respond effectively to the crisis and reestablish homeostasis. 
  
  • The short term response to the stressor
    
  • activates the amygdala which: Stimulates the brain stem resulting in inhibition of the parasympathetic nervous system and activation of the sympathetic nervous system with the hormones epinephrine and norepinephrine deployed around the body, Activates the PVN which generates a cascade resulting in glucocorticoid secretion to: get energy to the muscles with increased blood pressure for a powerful response.  The brain's acuity and cognition are stimulated.  The immune system is stimulated with beta-endorphin and repair activities curtail.  In order for the body to destroy bacteria in wounds, pro-inflammatory cytokines increase blood flow to the area.  The induced inflammation signals the brain to activate the insula and through it the ACC.  But when the stressor is
    
  • long term: loneliness, debt; and no action is necessary, or possible, long term damage ensues.  Damage from such stress may only occur in specific situations: Nuclear families coping with parents moving in.  Sustained stress provides an evolved amplifier of a position of dominance and status.  It is a strategy in female aggression used to limit reproductive competition.  Sustained stress:
    
  • Stops the frontal cortex from ensuring we do the harder thing, instead substituting amplification of the individual's propensity for risk-taking and impairing risk assessment! 
    
  • Activates the integration between the thalamus and amygdala. 
    
  • Acts differently on the amygdala in comparison to the frontal cortex and hippocampus: Stress strengthens the integration between the Amygdala and the hippocampus, making the hippocampus fearful. 
    
  • BLA & BNST respond with increased BDNF levels and expanded dendrites persistently increasing anxiety and fear conditioning. 
    
  • Makes it easier to learn a fear association and to consolidate it into long-term memory.  Sustained stress makes it harder to unlearn fear by making the prefrontal cortex inhibit the BLA from learning to break the fear association and weakening the prefrontal cortex's hold over the amygdala.  And glucocorticoids decrease activation of the medial prefrontal cortex during processing of emotional faces.  Accuracy of assessing emotions from faces suffers.  A terrified rat generating lots of glucocorticoids will cause dendrites in the hippocampus to atrophy but when it generates the same amount from excitement of running on a wheel the dendrites expand.  The activation of the amygdala seems to determine how the hippocampus responds. 
    
  • Depletes the nucleus accumbens of dopamine biasing rats toward social subordination and biasing humans toward depression. 
    
  • Disrupts working memory by amplifying norepinephrine signalling in the prefrontal cortex and amygdala to prefrontal cortex signalling until they become destructive.  It also desynchronizes activation in different frontal lobe regions impacting shifting of attention.  
  • Increases the risk of autoimmune disease (Jan 2017) 
  • During depression, stress inhibits dopamine signalling.  
  • Strategies for stress reduction include: Mindfulness. 
    
  inhibits the GABA is gamma-Aminobutyric acid which is:
  • An inhibitory neurotransmitter in the central nervous system of mammals.  It binds to pre- and postsynaptic neuron receptors that induce the opening of potassium and chloride ion channels, or G-protein receptor transformations. 
    
  interneurons in the basolateral amygdala (BLA is the basolateral amygdala, a relatively recently evolved part of the amygdala which learns stimuli to fear and then signals the central amygdala.  It recieves inputs from all sensory networks.  Some are fast pathways that allow the BLA to detect and respond when the sensory cortex is unaware.  But it is far less accurate than the cortex.  The BLA's learning involves increased excitability of synapses coupling the BLA and central amygdala.  This is due to gene driven: Increased levels of growth factors promoting new connections, more receptors for excitatory neurotransmitters in dendritic spines.  The BLA also responds to signals from the frontal cortex that a stimulus no longer appears frightening.  This subset of BLA cells respond inhibiting the associating subset.  Stress and glucocorticoids increase levels of CRH and BDNF encouraging the building of new dendrites and synapses. 
  ) allowing the excitatory glutamate releasing neurons to excite more. 
  
• Is sensitive to unsettling/uncertain social situations where it promotes anxiety is manifested in the amygdala mediating inhibition of dopamine rewards.  Anxiety disorders are now seen as a related cluster, including PTSD, panic attacks, and phobias.  Major anxiety, is typically episodic, correlated with increased activity in the amygdala, results in elevated glucocorticoids and reduces hippocampal dendrite & spine density.  Some estrogen receptor variants are associated with anxiety in women.  Women are four times more likely to suffer from anxiety.  Louann Brizendine concludes this helps prepare mothers, so they are ready to protect their children.  Michael Pollan concludes anxiety is fear of the future.  Sufferers of mild autism often develop anxiety disorders.  Treatments for anxiety differ.  50 to 70% of people with generalized anxiety respond to drugs increasing serotonin concentrations, where there is relief from symptoms: worry, guilt; linked to depression, which are treated with SSRIs (Prozac).  Cognitive anxiety (extreme for worries and anxious thoughts) is also helped by yoga.  But many fear-related disorders respond better to psychotherapy: psychoanalysis, and intensive CBT.  Tara Brach notes that genuine freedom from fear is enabled by taking refuge. 
  and makes us distracted.  It is also interested in uncertain but potentially painful situations.  The amygdala contributes to social and emotional decision making where the BLA is the basolateral amygdala, a relatively recently evolved part of the amygdala which learns stimuli to fear and then signals the central amygdala.  It recieves inputs from all sensory networks.  Some are fast pathways that allow the BLA to detect and respond when the sensory cortex is unaware.  But it is far less accurate than the cortex.  The BLA's learning involves increased excitability of synapses coupling the BLA and central amygdala.  This is due to gene driven: Increased levels of growth factors promoting new connections, more receptors for excitatory neurotransmitters in dendritic spines.  The BLA also responds to signals from the frontal cortex that a stimulus no longer appears frightening.  This subset of BLA cells respond inhibiting the associating subset.  Stress and glucocorticoids increase levels of CRH and BDNF encouraging the building of new dendrites and synapses. 
  supports rejecting an unacceptable offer, as allowed in the Ultimatum Game is an economic game involving two players: One makes an offer about how to split a pot of money.  If the offer is rejected neither party gets any money.  The other player can accept or reject the offer.  Rationality implies that any offer should be accepted by the recipient.  Instead recipients are keenly aware of being unfairly treated.  The longer the amygdala responds to the offer the more likely it is to be rejected.  The rejection is mentally costly and must be encouraged by a dopaminergic reward, fueled by the amygdala and insula.  When the offer is rejected the first player feels dissed, subordinated - especially if the result is shared with others, undermining status & reputation.  Sapolsky notes that:
  
  • People with damaged amygdalae are unusually generous because the BLA normally injects learned implicit distrust and vigilance into social decision making.  
  • People given testosterone before the game become more generous.  Sapolsky notes the effect demands fancy neuroendocrine wiring. 
    
  • People from small-scale, non-Western cultures were less trusting and punished more.  Joseph Henrich found three variables predicted how the play executed: Market integration, Community size, Religion; where large communities need ways to make strangers trustworthy.  Communities that trade are also more likely to act fairly and punish unfairness.  Sapolsky asserts that market interactions represent an impoverishment of human reciprocity with the total transaction having to be judged and occur in an instant.  Small-scale cultures are more practiced at the nuanced judgements about their long term neighbors. 
    
  • Chimps can be trained to play the game.  Max Planck Institute's Michael Tomasello found no evidence of chimp requirements for fairness.  But De Waal & Brosnan found chimps will be fair but only if they see a downside in being unfair.  Primates seem to reflect the same hypocritical strategies underneath any reciprocal altruism that humans display. 
    
  , by injecting implicit mistrust and vigilance, generating an anger driven rejection that is used as punishment.  The amygdala is very rapidly excited by subliminal signals from the thalamus has all the main inputs to the cortex passing through it.  It is massively supplied with return innervations from the cortical regions it routes too.  It does not stand on the route of the main exits from the cortex.  The parafascicular nucleus of the rat thalamus contains relatively high levels of D5 dopamine receptors.  For human vision the primary system connects to the neocortex via, a small part of the thalamus, the LGN.   of outgroup skin color.  The amygdala subsequently tips social emotions are emotions that are induced in response to other people's signals, are implemented by specific brain regions including: Prefrontal cortex, Insula cortex, Anterior cingulate cortex, Amygdala; receive lots of projections from interoceptive networks.  Sapolsky asserts in the moments just before we prioritize a consequential act the process is less rational and autonomous than we assume.  There are many significant signals from the prior seconds to minutes that effect social emotions:
  
  • Our brains respond subliminally to skin color very quickly: Amygdala activates, Fusiform face area activates; prior to the conscious stream activating the anterior cingulate and DLPFC which then inhibit the amygdala. 
    
  • Social dominance is culture independent and accurately subliminally assessed after a 40-millisecond exposure.  Stable status relations activate the ventromedial prefrontal cortex and DLPFC, while a dynamic situation also activates the amygdala.  
  • People who are subliminally judged attractive by the medial orbitofrontal cortex are considered kinder, smarter and more honest.  They are given more breaks. 
    
  • Faces and eyes in particular are most important subliminal cues.  They are monitored by the fusiform.  People respond more appropriately under the subliminal influence of eyes. 
    
  • Olfactory sensors send more direct projections to the limbic network than other sensory networks.  Pheromones signal fear activating the amygdala. 
    
  • Observing pain responses in others results in empathy even among young children. 
    
  • Words are important emotional signals providing unconscious priming of social responses.  Kahneman & Tversky demonstrated how the phrase '95% survival rate' is found to be a more acceptable choice than '5% death rate'.  Sapolsky notes that prosocial word priming fosters cooperation with antisocial word priming doing the opposite.  
  • Cultural objects such as visible: flags, team badges; subliminally modify in-group outgroup decisions. 
    
  • The presence of women in a situation alters the responses of men: Increased risk-taking, more focus on luxuries, increased aggression; in circumstances where conflict is already encouraged but not when status is achieved prosocially.  
  • Physical environment shapes behavior as demonstrated by Philip Zimbardo and leveraged in broken windows policing.  
  • Bodily adjustments to sensory structures introduce adaptive complexity, with the brain being influenced to become more sensitive and alter the sensor networks to make some more sensitive.  But these adaptations also vary culturally.  Collectivist cultures focus on a visual scene's surrounding contextual information while people from individualistic cultures focus on the focal object!  
    
  against outgroups unless restrained by the frontal lobe of the cerebral cortex is at the front of the brain.  It includes the: prefrontal cortex, motor cortex.  Sapolsky asserts it makes you do the harder thing when it's the right thing to do.  The frontal cortex supports working memory to sustain focus on a task.  It also coordinates the strategic actions necessary to achieve success.  It provides impulse control, regulation of emotion, and willpower.  The prefrontal cortex maintains focus by deprioritizing currently irrelevant streams of information.  The frontal cortex tracks rules.  Over a lifetime, that builds into a costly activity.  Once it tires, responses become less prosocial.  But practice shifts operation of tasks to the cerebellum.  The frontal cortex signals the tegmentum and accumbens with the conclusions of its expectancy/discrepancy calculations.  The frontal lobe provides executive function, considering bits of information, assessing patterns and then prioritizing the strategies.  The frontal lobe is the most recent part of the brain to evolve and involves a disproportionate percentage of primate-unique genes in its development and operation.  It does not complete development until the mid-20s.  It includes spindle neurons.  It is easily damaged.  Sapolsky (Nauta) notes that its ventromedial prefrontal cortex is a quasi-member of the limbic system. 
  or influenced by subliminal priming to prioritize inclusion.  The fast path from the thalamus rapidly but inaccurately signals its identified a weapon. 
  
• Sees suffering of others as increasingly salient, Douglas Hofstadter controlled the amount of attention a Workspace object in Copycat would receive from codelets via its salience.  The more descriptions, analogous to geons, an object has and the more highly activated the nodes involved therein, the more important the object is.  Modulating this tendency is any relative lack of connections from the object to the rest of the objects in the Workspace.  Salience is a dynamic number that takes into account both these factors.  In Smiley the instantaneous salience of a Workspace's objects is calculated by itsalience.  In the brain salience is modeled by the salience networks. 
  with loving-kindness meditation practice, Goleman & Davidson
  Daniel Goleman and Richard Davidson describe a scientific investigation of meditation's impact on the brain.  They introduce the book by describing their experiences with meditation, science and the research establishment, their friendship, how meditation is now used in two distinct ways: deep - leading to altered traits & wide - that can reach the multitudes; which the book reviews as it critiques the claims and research used to back them up. 
  
  Goleman and Davidson describe meeting as Harvard psychology graduate students, interested in consciousness, and how minds work.  They rebel against the behavioral orthodoxy, visit Asia and discover the Eastern tradition of exploring and altering the mind. 
  
  Goleman had travelled to Sri Lanka to understand an Asian model of the mind, which he presented to the undergraduates at Harvard.  Goleman and Davidson developed it into a shared vision of consciousness.  It took over twenty years for scientific theory and experimental data to catch up and align with this model.  Much of the prior experimental data had to be abandoned. 
  
  They introduce meditation's impact on the amygdala responding to pain and stress. 
  
  They look at the changes in:
  

  • Stress
    
  • Compassion
    
  • Attention
    
  • Self-awareness; and the potential for use of mediation in psychiatry. 

  And they warn of the occurrence of dark nights. 
  They detail how scientists were able to study the brains of Tibetan meditation masters, starting with Mingyur Rinpoche, and detect meditation altering traits. 
  Finally they discuss the potential benefits of meditation and strategies to distribute it broadly to a busy America. 
  
  
  explain. 
  
• Promotes male, but not female, sexual motivation when it is an uncertain potential pleasure is the outcome of the dopamine reward system, argues UCSF professor Robert Lustig.  He, like the early Christians, contrasts [addiction oriented] pleasure with serotonin driven happiness & contentment. 
  . 
  
• Responds to the longing for uncertain potential pleasures and fear that the reward will not be worth it if it happens.  The amygdala turns off during orgasm, in women, is likely an adaptation to ensure the most fit partner's sperm are the ones that reach and fertilize her egg.  Women have more orgasm's with their most symmetric partners.  Use of contraception and romantic passion did not increase the number of orgasms.  The orgasm also increases the attachment between the partners. 
  . 
  
• Uses but is not directly involved in vision.  
• Amyloidosis is the accumulation of badly folded proteins.  The miss-folding makes them insoluble and so they deposit in the organs and tissues of the body.  The kidney provides multiple vital functions.  It: Produces renin which supports negative feedback, Removes excess organic molecules from the blood, Regulates electrolytes in the blood, Maintains pH homeostasis, Regulates fluid balance, Regulates blood pressure, monitors blood oxygen concentration and signals erythropoiesis with EPO, Reabsorbs water, glucose (SGLT2) and amino acids.  Kidney function is monitored with the GFR.  Kidneys can fail acutely or chronically.  Kidneys are affected by a variety of cancers including: advanced kidney cancer, von Hippel Landau; some of which are induced by PFAS.    Multiple myeloma, type 2 diabetes, TB and drug treatments for MDR TB place a strain on the kidneys and can induce failure.   and heart are most often affected.  Often the problem is that two protein, a relatively long chain (polymer) of peptides.  Shorter chains of peptides are termed polypeptides.   subunits fail to bind together.  Once the protein becomes insoluble it becomes inaccessible to the proteases that would otherwise break it down.  Sometimes prions is a protein with the unusual property of having two highly stable configurations.  DNA generally encodes only one of the stable configurations of the prion.  The other form once present converts the rest of the local prion to its configuration which is very stable.  The generation of prions and their configuration shifts are used by neurons to represent long term state. 
  are viewed as participating in amyloidosis.  However in at least some neurons, specialized eukaryotic cells include channels which control flows of sodium and potassium ions across the massively extended cell membrane supporting an electro-chemical wave which is then converted into an outgoing chemical signal transmission from synapses which target nearby neuron or muscle cell receptors.  Neurons are supported by glial cells.  Neurons include a:
  • Receptive element - dendrites
    
  • Transmitting element - axon and synaptic terminals.  The axon may be myelinated, focusing the signals through synaptic transmission, or unmyelinated - where crosstalk is leveraged. 
  • Highly variable DNA schema using transposons. 
    
  prion re-folding appears to provide long term state transitions for memory.  
• ANA is the American nurses association. 
  
• Anal cancer is very rare.  The cancer is the out-of-control growth of cells, which have stopped obeying their cooperative schematic planning and signalling infrastructure.  It results from compounded: oncogene, tumor suppressor, DNA caretaker; mutations in the DNA.  In 2010 one third of Americans are likely to die of cancer.  Cell division rates did not predict likelihood of cancer.  Viral infections are associated.  Radiation and carcinogen exposure are associated.  Lifestyle impacts the likelihood of cancer occurring: Drinking alcohol to excess, lack of exercise, Obesity, Smoking, More sun than your evolved melanin protection level; all significantly increase the risk of cancer occurring (Jul 2016). 
  typically develops in the squamous cells of the anus.  It has been associated with HPV is human papillomavirus which causes cancer of the cervix in women and is also associated with anal cancer. 
  .  It is distinct from colon cancer is a major hereditary cancer also called colorectal cancer.  It:
  
  • Follows a slow, many yearlong, progression from a benign polyp to a localized cancer to an invasive one.  Two bacteria: Bacteroides fragilis, Escherichia coli variant; from the gut microbiome have been implicated in the early stages of tumor induction (Feb 2018).  It
    
  • Is often associated with Ras mutations and the high risk allele TCF7L2.  30 to 50% of colon cancers have KRAS mutations.  Intensive medical surveillance and removal of polyps can be lifesaving for those at high risk.  Types of colon cancer include the single gene mutation hereditary: FAP, HNPCC; 
  • Is linked to obesity. 
    
  .  
• Anchor and adjust is a behavior broadly adopted by human
  Plans are interpreted and implemented by agents.  This page discusses the properties of agents in a complex adaptive system (CAS). 
  It then presents examples of agents in different CAS.  The examples include a computer program where modeling and actions are performed by software agents.  These software agents are aggregates. 
  The participation of agents in flows is introduced and some implications of this are outlined. 
  
  agents to inductively
  The agents in complex adaptive systems (CAS) must model their environment to respond effectively to it.  Evolution's schematic operators and Samuel modeling together support the indirect recording of past successes and their strategic use by the current agent to learn how to succeed in the proximate environment. 
  
  model the operation of a
  This page introduces the complex adaptive system (CAS) theory frame.  The theory provides an organizing framework that is used by 'life.'  It can be used to evaluate and rank models that claim to describe our perceived reality.  It catalogs the laws and strategies which underpin the operation of systems that are based on the interaction of emergent agents.  It highlights the constraints that shape CAS and so predicts their form.  A proposal that does not conform is wrong. 
  
  John Holland's framework for representing complexity is outlined.  Links to other key aspects of CAS theory discussed at the site are presented. 
  
  CAS network.  Using patterns of past flow rates, the agents select a model that seems to match and anchor to that.  When the actual operation diverges from the anchor model, the agents continue to leverage the model, but make adjustments to account for the differences.  If a characteristic of the network, such as increased demand, has changed the model and adjustments will generate more divergence.  In a network with buffer pools and
  Carlo Rovelli resolves the paradox of time. 
  Rovelli initially explains that low level physics does not include time:
  

  • A present that is common throughout the universe does not exist
    
  • Events are only partially ordered.  The present is localized
  • The difference between past and future is not foundational.  It occurs because of state that through our blurring appears particular to us
  • Time passes at different speeds dependent on where we are and how fast we travel
    
  • Time's rhythms are due to the gravitational field
    
  • Our quantized physics shows neither space nor time, just processes transforming physical variables. 
    
  • Fundamentally there is no time.  The basic equations evolve together with events, not things 

  Then he explains how in a physical world without time its perception can emerge:
  

  • Our familiar time emerges
    
  • Our interaction with the world is partial, blurred, quantum indeterminate
    
  • The ignorance determines the existence of thermal time and entropy that quantifies our uncertainty
    
  • Directionality of time is real but perspectival.  The entropy of the world in relation to us increases with our thermal time.  The growth of entropy distinguishes past from future: resulting in traces and memories
    
  • Each human is a unified being because: we reflect the world, we formed an image of a unified entity by interacting with our kind, and because of the perspective of memory
    
  • The variable time: is one of the variables of the gravitational field.  With our scale we don't register quantum fluctuations, making space-time appear determined.  At our speed we don't perceive differences in time of different clocks, so we experience a single time: universal, uniform, ordered; which is helpful to our decisions

  
  
  time delays, the anchor and adjust strategy ensures both overshooting and undershooting. 
  
• Androgen deprivation therapy lowers the levels of male sex hormones are signalling molecules: ACTH, TRH, Melanocyte stimulating hormone, Testosterone, Oxytocin, Vasopressin, Insulin, Growth hormone, Estrogen, Progesterone, Angiotensin II, Asprosin, EPO, Irisin, Leptin, FGF21 hormone, Prostaglandins, TSH, Thyroxine, Glococorticoids: Cortisol; that are transported by the circulatory system to interact with target organs having appropriate receptors.  The levels of hormones can fluctuate massively, as in pregnancy. 
  .  These hormones stimulate the growth of prostrate cancer is cancer of the prostate gland.  Genomics detected several common DNA variants associated with increased risk of prostate cancer.  Dr. Francis Collins explains that a cluster of these risk variants lies in a stretch of 1 million DNA base pairs on chromosome 8.  The cluster contains seven or more risk variants, each of which can raise the risk of prostate cancer by 10 to 30%.  The high risk variants occur more frequently in African-American men than European or Asians.  African-Americans die from prostate cancer at more than twice the rate of Europeans.  Research in mice may explain a link between obesity and prostate cancer (Jan 2018).  The average diagnosis is at age 66.  Worldwide in 2012 there were 1.1 million cases from which 307,000 died.  A common life-saving (Feb 2017) treatment is androgen deprivation therapy, but it has worrying side effects.  Various classically defined types of cancer can occur.  The most common is adenocarcinoma associated with the epithelial gland cells that generate seminal fluid.  Epithelial cell differentiation potency makes these significant cancer agents.  Other very rare types of cancer that can start in the prostate are:
  • Sarcomas
  • Small cell carcinomas
  • Neuroendocrine tumors
  • Transitional cell carcinomas
  cells.  But the treatment: Bicalutamide, Lupron; is associated with increased rates of: Depression is a debilitating episodic state of extreme sadness, typically beginning in late teens or early twenties. This is accompanied by a lack of energy and emotion, which is facilitated by genetic predisposition - for example genes coding for relatively low serotonin levels, estrogen sensitive CREB-1 gene which increases women's incidence of depression at puberty; and an accumulation of traumatic events.  There is a significant risk of suicide: depression is involved in 50% of the 43,000 suicides in the US, and 15% of people with depression commit suicide.  Depression is the primary cause of disability with about 20 million Americans impacted by depression at any time.  There is evidence of shifts in the sleep/wake cycle in affected individuals (Dec 2015).  The affected person will experience a pathological sense of loss of control, prolonged sadness with feelings of hopelessness, helplessness & worthlessness, irritability, sleep disturbances, loss of appetite, and inability to experience pleasure.  Michael Pollan concludes depression is fear of the past.  It affects 12% of men and 20% of women.  It appears to be associated with androgen deprivation therapy treatment for prostate cancer (Apr 2016).  Chronic stress depletes the nucleus accumbens of dopamine, biasing humans towards depression.  Depression easily leads to following unhealthy pathways: drinking, overeating; which increase the risk of heart disease.   It has been associated with an aging related B12 deficiency (Sep 2016).  During depression, stress mediates inhibition of dopamine signalling.  Both depression and stress activate the adrenal glands' release of cortisol, which will, over the long term, impact the PFC.  There is an association between depression and additional brain regions: Enlarged & more active amygdala, Hippocampal dendrite and spine number reductions & in longer bouts hippocampal volume reductions and memory problems, Dorsal raphe nucleus linked to loneliness, Defective functioning of the hypothalamus undermining appetite and sex drive, Abnormalities of the ACC.  Mayberg notes ACC area 25: serotonin transporters are particularly active in depressed people and lower the serotonin in area 25 impacting the emotion circuit it hubs, inducing bodily sensations that patients can't place or consciously do anything about; and right anterior insula: which normally generates emotions from internal feelings instead feel dead inside; are critical in depression.  Childhood adversity can increase depression risk by linking recollections of uncontrollable situations to overgeneralizations that life will always be terrible and uncontrollable.  Sufferers of mild autism often develop depression.  Treatments include: CBT which works well for cases with below average activity of the right anterior insula (mild and moderate depression), UMHS depression management, deep-brain stimulation of the anterior insula to slow firing of area 25.  Drug treatments are required for cases with above average activity of the right anterior insula.  As of 2010 drug treatments: SSRIs (Prozac), MAO, monoamine reuptake inhibitors; take weeks to facilitate a response & many patients do not respond to the first drug applied, often prolonging the agony.  By 2018, Kandel notes, Ketamine is being tested as a short term treatment, as it acts much faster, reversing the effect of cortisol in stimulating glutamate signalling, and because it reverses the atrophy induced by chronic stress.   Genomic predictions of which treatment will be effective have not been possible because: Not all clinical depressions are the same, a standard definition of drug response is difficult; (Apr 2016), Dementia is a classification of memory impairment, constrained feelings and enfeebled or extinct intellect.  The most common form for people under 60 is FTD.  Dementia has multiple causes including: vascular disease (inducing VCI) including strokes, head trauma, syphilis and mercury poisoning for treating syphilis, alcoholism, B12 deficiency (Sep 2016), privation, Androgen deprivation therapy (Oct 2016), stress, Parkinson's disease, Alzheimer's disease, and prion infections such as CJD and kuru.  The condition is typically chronic and treatment long term (Laguna Honda ward) and is predicted by Stanley Prusiner to become a major burden on the health system.  It may be possible to constrain the development some forms of dementia by: physical activity, hypertension management, and ongoing cognitive training.  Dementia appears to develop faster in women than men.   (Oct 2016) including Alzheimer's disease is a dementia which correlates with deposition of amyloid plaques in the neurons.  As of 2015 there are 5 million Alzheimer's patients in the USA.  It was originally defined as starting in middle age which is rare, so it was a rare dementia.  But in 1980s it was redefined as any dementia without another known cause. Early indications include mood and behavioral changes (MBI) and declarative memory and thinking problems (MCI).  Specific cells within the hippocampal circuitry and its gateway, the entorhinal cortex, are damaged.  The amygdala, cerebelum and other areas supporting implicit memory are not impacted during the early stages of the disease.  Grid cell destruction results in a sense of being lost.  The default mode network is disrupted.  Variants include: late-onset sporadic; with risk factors - ApoE4 for late onset Alzheimer's, presenilin, androgen deprivation therapy (Dec 2015), type 2 diabetes.  There are multiple theories of the mechanism of Alzheimer's during aging: Allen Roses argues that it is due to gene alleles that limit the capacity of mitochondria to support neuron operation, Neurons of sporadic Alzheimer's sufferers show greater APP gene diversity due to somatic recombination; It may be initiated by: stress induced HHV-6a, HHV7 herpes activation (Jun 2018) and or an increasingly leaky blood-brain barrier; and a subsequent innate immune response to the infections (May 2016).  The Alzheimer's pathway follows:
  • Plaques form.  These are seen in fMRIs 10 to 15 years prior to detecting memory and thinking changes.  APP deployed in the cell membrane is cut into three parts.  The external part becomes amyloid-beta peptide which aggregates into Amyloid plaques, external to the neurons, if too much is generated or it is not removed fast enough. 
    
  • Solanezumab aimed to inhibit plaque formation but clinical trials failed (Nov 2016). 
    
  • Encouraging the garbage collection of amyloid and tau with gamma rhythms stimulation retards Alzheimer's in mice studies (Mar 2019)
    
  • BACE inhibitors block an enzyme needed to form amyloid. 
    
  • Mutation driven misfolded Tau proteins can form tangles within the cytoplasm of neurons.  The Tau tangles kill nerve cells.  LMTX is a drug treatment targeted at these tangles. 
    
  • The brain becomes inflamed resulting in the killing of many more nerve cells.  The hippocampus disintegrates and the brain loses critical functions and memory loss becomes noticeable. 
    
  (Dec 2015).  
• Androgens are a class of steroid hormones including testosterone is a hormone secreted by the testes, ovaries, and adrenal glands, in response to stimulation from the hypothalamic/pituitary/testicular cascade, that makes humans more willing to do what it takes to attain and maintain status, according to Sapolsky.  That means players of the Ultimatum Game, if previously given testosterone can become more generous.  High testosterone in a fetus masculinizes the brain.  Males generate 10 times the amount.  It is the trigger for sexual desire in males and females, stimulating the hypothalamus.  Testosterone's effect is highly socially contextual so it may encourage acts of kindness or aggression (when challenged).  The level of testosterone does not predict which individuals will be aggressive in: Birds, Fish, Mammals including primates.  Genes impact the potency of testosterone by altering the enzymes that: Construct it, Convert it to estrogen, code the androgen receptor.   This androgen receptor includes a variable polyglutamine repeat which alters the sensitivity to the testosterone signal.  The more potent form is associated with boys showing more dramatic 'masculinization' of the cortex.  But the detected genetic influences are small.  Testosterone decreases activity in the prefrontal cortex and its functional coupling to the amygdala while increasing the coupling between the amygdala & the thalamus.  Testosterone shortens the refactory period of amygdaloid & amygdaloid target neurons.  This results in impulsive risk taking and more focus on unfamiliar faces and distrust of them.  Testosterone increases activity in the ventral tegmentum projecting dopamine to enhance place preference.  Winners of fights become more willing to fight in part due to testosterone increasing confidence and optimism and reducing fear and anxiety.  And winning at: Chess, Athletics, Stock trades; induces the BNST to add testosterone receptors increasing its sensitivity to the hormone.  People become overconfident and overly optimistic. 
  , androstenedione and dihydrotestosterone.  They are precursors of estrogens is a generic term for a number of related steroid hormones each of which works differently.  Estrogen:
  • Is generated in the ovaries.  It supports the generation of oxytocin, and so is associated with attachment, nurturing and other affiliative behaviors. 
    
  • Supports verbal memory.  Removal of ovaries without immediate estrogen replacement therapy degrades verbal memory performance.  The HT reduces age-related shrinkage of the PFC, parietal cortex, and temporal lobe in women, and made them less depressed and angry. 
    
  • Supports mitochondrial operation in the blood vessels of the brain. 
    
  • Contributes to maternal aggression but it can reduce aggression and enhance empathy, depending on brain state.  There are two different estrogen receptor types which mediate these conflicting effects.  The level of each type of receptor is independently regulated.  Different receptor variants are associated with:
  • Higher rates of anxiety among women
  • Higher rates of antisocial behavior and conduct disorder in men
  • Is essential for vaginal lubrication 
  • Facilitates the elimination of cholesterol
    
  • Has anti-inflammatory and anti-oxidative properties improving response to stress
    
  . 
  
• Anemia is a decrease in the number of red blood cells or the amount of hemoglobin in the blood.  There are various types: Fanconia anemia is a recessive disease where the bone marrow fails to produce red and white cells.  PGD has been used to select for embryos that do not have the Fanconi mutation and are a transplantation match for a suffering sibling, and that would result in a baby whose umbilical cord can be used to generate stem cell bone marrow for transplant to a sibling already born with the anemia. 
  , Iron-deficiency anemia is anemia caused by lack of iron.  It is generally caused by loss of blood, insufficient dietary iron, poor absorption of iron. 
  , Pernicious anemia is an autoimmune disease with a deficiency in red blood cells due to a lack of intrinsic factor limiting absorbtion of vitamin B12.  The cells in the stomach that make intrinsic factor are damaged by the autoimmune attack by antibodies to intrinsic factor. 
  , Sickle-cell anemia is a recessive single gene disease where the sufferer's hemoglobin causes the red blood cells to distort.  It is a side effect of the evolved protection from malaria provided by sickle cell trait.  Potential treatments include gene therapy and drugs that block the sickling of red blood cells.  Carrier screening was undermined by there being no effective prenatal test limiting the benefit of the information and because the white doctors were not trusted by their black patients.  In the future iPS cells could have the problem mutations replaced with ex vivo gene therapy. 
  ;
  
• Anesthesia is the temporary removal of sensation.  It can be local, regional renders a large area of the body insensitive by blocking transmission of nerve impulses between a part of the body and the spinal chord. 
  or general induces a deep sleep that suppresses breathing and vigilance and often requires a breathing tube.  This is far more risky than sedation.  Researchers are actively looking at the impacts on children under three years old including SmartTots since:
  • Studies of children have found an association between learning problems and multiple exposures to anesthesia early in life. 
    
  • Experiments in young monkeys have shown that commonly used anesthetics and sedatives can kill brain cells, diminish learning and memory and cause behavior problems. 
    
  . 
  
• Anesthesiologist is a physician who has completed an accredited residency is the apprenticeship of a medical or nursing graduate with a practitioner (attending), usually performed at a teaching hospital: Brigham & Women's, Cottage Health System, El Camino Hospital, Johns Hopkins, LSU Health Sciences Center, Rush University Medical Center, Stanford University Medical Center; skilled in the specialized techniques required for consistent success in diagnosis and treatment, or treatment execution, of medical conditions.  A first year resident is also called an intern.  Christensen, Grossman & Huang note the difficulty of presenting all the necessary case types to a resident during the limited period of the apprenticeship.  The difficulty of matching graduates with desired residency slots intrigued Al Roth who helped mitigate the problem with efficient market tools deployed by NRMP.  Docphin provides web access to categorized research information used during residency. 
  program in anesthesiology is a four year accredited residency including a one year medical or surgical internship, and three years of anesthesiology training.  This includes specialized testing in anesthesia as well as tests of physiology, pathophysiology, pharmacology and other medical sciences.  There is a board exam at the completion of residency to obtain certification as an anesthesiologist.  Practices as an anesthesiology specialist.   and is trained in anesthesia is the temporary removal of sensation.  It can be local, regional or general. 
  and perioperative medicine is the care of a patient prior to and after surgery. 
  . 
  
• Anesthesiology is a four year accredited residency is the apprenticeship of a medical or nursing graduate with a practitioner (attending), usually performed at a teaching hospital: Brigham & Women's, Cottage Health System, El Camino Hospital, Johns Hopkins, LSU Health Sciences Center, Rush University Medical Center, Stanford University Medical Center; skilled in the specialized techniques required for consistent success in diagnosis and treatment, or treatment execution, of medical conditions.  A first year resident is also called an intern.  Christensen, Grossman & Huang note the difficulty of presenting all the necessary case types to a resident during the limited period of the apprenticeship.  The difficulty of matching graduates with desired residency slots intrigued Al Roth who helped mitigate the problem with efficient market tools deployed by NRMP.  Docphin provides web access to categorized research information used during residency. 
  including a one year medical or surgical internship, and three years of anesthesiology training.  This includes specialized testing in anesthesia is the temporary removal of sensation.  It can be local, regional or general. 
  as well as tests of physiology, pathophysiology, pharmacology and other medical sciences.  There is a board exam at the completion of residency to obtain certification as an anesthesiologist is a physician who has completed an accredited residency program in anesthesiology and is trained in anesthesia and perioperative medicine. 
  .  Practices as an anesthesiology specialist.  
• Anesthetist is used to describe anesthesia is the temporary removal of sensation.  It can be local, regional or general. 
  providers without the qualification of physician.  Often these are CRNA is a certified registered nurses trained in anesthesia.  s. 
  
• Anger is an emotion are low level fast unconscious agents distributed across the brain and body which associate, via the amygdala and rich club hubs, important environmental signals with encoded high speed sensors, and distributed programs of action to model: predict, prioritize guidance signals, select and respond effectively, coherently and rapidly to the initial signal.  The majority of emotion centered brain regions interface to the midbrain through the hypothalamus.  The cerebellum and basal ganglia support the integration of emotion and motor functions, rewarding rhythmic movement.  The most accessible signs of emotions are the hard to control and universal facial expressions.  Emotions provide prioritization for conscious access given that an animal has only one body, but possibly many cells, with which to achieve its highest level goals.  Because of this, base emotions clash with group goals and are disparaged by the powerful.  Pinker notes a set of group selected emotions which he classes as: other-condemning, other-praising, other-suffering and self-conscious emotions.  Evolutionary psychology argues evolution shaped human emotions during the long period of hunter-gatherer existence in the African savanna.  Human emotions are universal and include: Anger, Appreciation of natural beauty, Contempt, Disgust, Embarrassment, Fear, Gratitude, Grief, Guilt, Happiness, Honor, Jealousy, Liking, Love, Moral awe, Rage, Romantic love, Lust for revenge, Passion, Sadness, Self-control, Shame, Sympathy, Surprise; and the sham emotions and distrust induced by reciprocal altruism. 
  which protects a person who has been cheated by a supposed friend.  When the exploitation of the altruism benefits another organism at a cost to the behaver.  It is differentiated from kin altruism, by Williams and Trivers, since it can apply between unrelated individuals.  It can be induced by natural selection when there is mutual survival benefit in group activities and cheating can be detected and discouraged.  Humans, leveraging the cognitive niche, can particularly easily, build an evolved amplifier, through sharing information at little cost and significant benefit.  But African savanna hunters similarly gain from sharing large game meat with other un-related altruistic group members since the meat would otherwise spoil before it could be eaten. 
  is discovered, Steven Pinker
  Computational theory of the mind and evolutionary psychology provide Steven Pinker with a framework on which to develop his psychological arguments about the mind and its relationship to the brain.  Humans captured a cognitive niche by natural selection 'building out' specialized aspects of their bodies and brains resulting in a system of mental organs we call the mind. 
  
  He garnishes and defends the framework with findings from psychology regarding: The visual system - an example of natural selections solutions to the sensory challenges of inverse modeling of our environment; Intensions - where he highlights the challenges of hunter-gatherers - making sense of the objects they perceive and predicting what they imply and natural selections powerful solutions; Emotions - which Pinker argues are essential to human prioritizing and decision making; Relationships - natural selection's strategies for coping with the most dangerous competitors, other people.  He helps us understand marriage, friendships and war. 
  
  These conclusions allow him to understand the development and maintenance of higher callings: Art, Music, Literature, Humor, Religion, & Philosophy; and develop a position on the meaning of life. 
  
  Complex adaptive system (CAS) modeling allows RSS to frame Pinker's arguments within humanity's current situation, induced by powerful evolved amplifiers: Globalization, Cliodynamics, The green revolution and resource bottlenecks; melding his powerful predictions of the drivers of human behavior with system wide constraints.  The implications are discussed. 
  
  
  explains, the result is a drive for moralistic provides rules for identifying right from wrong.  It develops in stages with children using play to work out rules of appropriate behavior.  Kohlberg's 1950s experiments using children led him to conclude moral judgement is a cognitive process that develops in three stages.  Sapolsky raises issues with the framework: Its a model, It does not apply to other cultures, Intuition & emotion are as significant as cognition, Moral reasoning doesn't predict moral actions; and notes the capacity of the frontal cortex to regulate emotions and behavior is far more predictive.  The marshmallow test, performed on three to six year olds, actually predicted their subsequent SAT scores at high school, social success and lack of aggression, and forty years on more PFC activation during a frontal task and a lower BMI!  Jonathan Haidt argues people's moral decisions are rationalizations rather than using reasoning. 
  aggression to hurt the cheater.  Anger is mostly experienced as a rapid wave that then quickly dissipates.  When it is repressed in Freud's structural model, is the mind's unconscious defense mechanism to shift its desires and impulses towards pleasurable instincts by excluding other: distressing memories, thoughts, feelings; from consciousness.  Freud's free-association method revealed his patients' subconscious operation and inconsistencies: professed love associated with actual hate, indignant morality concealing perverse desires, nonconformity concealing guilt; where they were keeping these things hidden, that are present in the adaptive unconscious.  , for example by a strong moral sense is psychologist Jonathan Haidt's classification of primary themes that are drivers of human moral decision making.  Anthropologists have identified the themes across cultures.  Haidt concludes people don't engage in moral reasoning, but moral rationalization.  As Steven Pinker explains in The Moral Instinct, once the moral decision switch is active these themes will gain precedence.  They include:
  • Harm
  • Fairness
  • Community
  • Authority
  • Purity; but what acts are associated with each theme is culturally learned.  For example smoking can be taught to be viewed as a fun pleasure or associated with harm and so morally reprehensible.  
  (superego includes:
  • Id - which he felt seeks pleasure and avoids pain and includes the instinctual unconscious
    
  • Repression - is a defensive mechanism for keeping socially unacceptable desires: children's sexual and aggressive needs; traumatic memories and painful emotions from entering consciousness
    
  • Ego - is concerned with perception, reasoning, planning of actions, and includes:
  • Consciousness
    
  • Adaptive (preconscious) unconscious
    
  • Superego - is a specialized motivational flow of long-term strategies associated with altruism, normative behavior, and group interests.  The ethical & moral aspects of the mind including: conscience; There is intrapsychic conflict.  The mind overall benefits from adaptations that enable strategic tradeoffs. 
  ), it can sustain, inducing long term stress is a multi-faceted condition reflecting high cortisol levels.  Dr. Robert Sapolsky's studies of baboons indicate that stress helps build readiness for fight or flight.  As these actions occur the levels of cortisol return to the baseline rate.  A stressor is anything that disrupts the regular homeostatic balance.  The stress response is the array of neural and endocrine changes that occur to respond effectively to the crisis and reestablish homeostasis. 
  
  • The short term response to the stressor
    
  • activates the amygdala which: Stimulates the brain stem resulting in inhibition of the parasympathetic nervous system and activation of the sympathetic nervous system with the hormones epinephrine and norepinephrine deployed around the body, Activates the PVN which generates a cascade resulting in glucocorticoid secretion to: get energy to the muscles with increased blood pressure for a powerful response.  The brain's acuity and cognition are stimulated.  The immune system is stimulated with beta-endorphin and repair activities curtail.  In order for the body to destroy bacteria in wounds, pro-inflammatory cytokines increase blood flow to the area.  The induced inflammation signals the brain to activate the insula and through it the ACC.  But when the stressor is
    
  • long term: loneliness, debt; and no action is necessary, or possible, long term damage ensues.  Damage from such stress may only occur in specific situations: Nuclear families coping with parents moving in.  Sustained stress provides an evolved amplifier of a position of dominance and status.  It is a strategy in female aggression used to limit reproductive competition.  Sustained stress:
    
  • Stops the frontal cortex from ensuring we do the harder thing, instead substituting amplification of the individual's propensity for risk-taking and impairing risk assessment! 
    
  • Activates the integration between the thalamus and amygdala. 
    
  • Acts differently on the amygdala in comparison to the frontal cortex and hippocampus: Stress strengthens the integration between the Amygdala and the hippocampus, making the hippocampus fearful. 
    
  • BLA & BNST respond with increased BDNF levels and expanded dendrites persistently increasing anxiety and fear conditioning. 
    
  • Makes it easier to learn a fear association and to consolidate it into long-term memory.  Sustained stress makes it harder to unlearn fear by making the prefrontal cortex inhibit the BLA from learning to break the fear association and weakening the prefrontal cortex's hold over the amygdala.  And glucocorticoids decrease activation of the medial prefrontal cortex during processing of emotional faces.  Accuracy of assessing emotions from faces suffers.  A terrified rat generating lots of glucocorticoids will cause dendrites in the hippocampus to atrophy but when it generates the same amount from excitement of running on a wheel the dendrites expand.  The activation of the amygdala seems to determine how the hippocampus responds. 
    
  • Depletes the nucleus accumbens of dopamine biasing rats toward social subordination and biasing humans toward depression. 
    
  • Disrupts working memory by amplifying norepinephrine signalling in the prefrontal cortex and amygdala to prefrontal cortex signalling until they become destructive.  It also desynchronizes activation in different frontal lobe regions impacting shifting of attention.  
  • Increases the risk of autoimmune disease (Jan 2017) 
  • During depression, stress inhibits dopamine signalling.  
  • Strategies for stress reduction include: Mindfulness. 
    
  . 
  
• Angiogenesis is the formation of new blood vessels from existing vessels.  It is important in growth, development and wound healing.  To become malignant many tumors is the out-of-control growth of cells, which have stopped obeying their cooperative schematic planning and signalling infrastructure.  It results from compounded: oncogene, tumor suppressor, DNA caretaker; mutations in the DNA.  In 2010 one third of Americans are likely to die of cancer.  Cell division rates did not predict likelihood of cancer.  Viral infections are associated.  Radiation and carcinogen exposure are associated.  Lifestyle impacts the likelihood of cancer occurring: Drinking alcohol to excess, lack of exercise, Obesity, Smoking, More sun than your evolved melanin protection level; all significantly increase the risk of cancer occurring (Jul 2016). 
  stimulate angiogenesis. 
  
• Angioplasty involves inserting a catheter is a thin tube that can be inserted into the body.  , inflating a balloon to expand a narrowed artery, and inserting a stent is a small wire cage that can be inserted into an artery to prop it open.  They were introduced as an alternative to bypass surgery in the 1990s.  Stents are expensive.  Medicare payments vary depending on what kind of stent is used and how many, but are generally in the range $10,000 to $17,000 in 2015.   Double blind trials show that stents have no effect on chest pain relief (Nov 2017)
  to keep the area propped open.  Christensen argues angioplasty should be part of a radically lower cost business which should
  US healthcare is ripe for disruption.  Christensen, Grossman and Hwang argue that technologies are emerging which will support low cost business models that will undermine the current network.  Applying complex adaptive system (CAS) theory to these arguments suggests that the current power hierarchy can effectively resist these progressive forces. 
  
  disrupt the solution business of the general hospital. 
• Angiotensin receptor blockers block hormone are signalling molecules: ACTH, TRH, Melanocyte stimulating hormone, Testosterone, Oxytocin, Vasopressin, Insulin, Growth hormone, Estrogen, Progesterone, Angiotensin II, Asprosin, EPO, Irisin, Leptin, FGF21 hormone, Prostaglandins, TSH, Thyroxine, Glococorticoids: Cortisol; that are transported by the circulatory system to interact with target organs having appropriate receptors.  The levels of hormones can fluctuate massively, as in pregnancy. 
  signals, is an emergent capability which is used by cooperating agents to support coordination & rival agents to support control and dominance.  In eukaryotic cells signalling is used extensively.  A signal interacts with the exposed region of a receptor molecule inducing it to change shape to an activated form.  Chains of enzymes interact with the activated receptor relaying, amplifying and responding to the signal to change the state of the cell.  Many of the signalling pathways pass through the nuclear membrane and interact with the DNA to change its state.  Enzymes sensitive to the changes induced in the DNA then start to operate generating actions including sending further signals.  Cell signalling is reviewed by Helmreich.  Signalling is a fundamental aspect of CAS theory and is discussed from the abstract CAS perspective in signals and sensors.  In AWF the eukaryotic signalling architecture has been abstracted in a codelet based implementation.  To be credible signals must be hard to fake.  To be effective they must be easily detected by the target recipient.  To be efficient they are low cost to produce and destroy. 
  (angiotensin II) from causing the contraction of muscles surrounding blood vessels and so stop the blood vessels contracting, lowering blood pressure. 
  
• Animal is a eukaryotic is a relatively large multi-component cell type.  It initially emerged from prokaryotic archaea subsuming eubacteria, from which single and multi-celled plants, multi celled fungi, including single-cell variant yeast, drips, protozoa and metazoa, including humans, are constructed.  A eukaryotic cell contains modules including a nucleus and production functions such as chloroplasts and mitochondria. 
  plant eater, directly or indirectly. 
  
• ANK3 is a gene encoding ankyrin-3 is a linker between integral cell membrane proteins and the spectrin-actin cytoskeleton, found in neurons in both central and peripheral networks.  It is also spliced and then found in other tissues. 
  .  GWAS is genome-wide association study which examines common genetic variants (mostly SNPs) of different individuals to find those common variants that are associated with a trait.  Sample size has been made manageable by the HapMap SNP clustering strategy.  To detect the uncommon variants with GWAS would be exponentially more costly and time consuming.  So it can't be used to detect schizophrenia or autism SNPs which are associated with a significant reduction in reproductive fitness and will thus never become common in the population. 
  suggest ANK3 SNP is single nucleotide polymorphism where single base pairs have changed in two chromosomes of the same type.  There are 10 million common SNPs in the human genome.  There are a limited number of chromosomal types (Haplotypes).  This results in SNPs clustering into packs.  On average 30 to 40 SNPs travel together.  Knowing one or two SNPs in a local neighborhood predicts the others that are likely to be present. 
  s are involved in bipolar disorder also termed manic-depression is an episodic developmental disorder beginning in late adolescence, which can stimulate great creativity during the manic phase and suicide in the depressive phase.  Vincent van Gough suffered from depression for much of his adult life, and killed himself at thirty seven.  He produced three hundred of his greatest art works, using color to convey mood, while struggling with psychotic depression and mania in the last two years of his life.  Only the first manic phase requires a significant positive or negative stressful situation.  Type I bipolar includes more manic situations which may include psychosis.  Type II does not include psychosis.  Some people suffer 'mixed state' where mania and depression occur at the same time.  Sleep deprivation activates the amygdala and can induce mania in some people with bipolar disorder.  It affects 3 million Americans.  The amygdala is more active in people with bipolar disorder.  Franz Kallman found identical twins are likely (70% chance) to share the disorder.  Swedish researchers studying thousands of families in 2009 showed a strong hereditary link between bipolar disorder and schizophrenia, which was corroborated in 2012.  Genetic analysis of 2.3 million different regions of DNA of 9,747 people with bipolar disorder and 14,278 comparable people without, found five regions that appear connected with bipolar disorder.  Gene ADCY2, was identified, supports production of an enzyme facilitating neural signalling, and correlates with observed impairment of communication in certain brain regions in bipolar disorder.  GWAS implicate ANK3 and CACNA1C SNPs in bipolar disorder.  And de Novo mutations increase the risk.  Lithium limits the extremes of the mood swings in some patients but has side effects.  Anti-psychotic medications are prescribed.  . 
  
• Ankyrin-3 is a linker between integral cell membrane proteins and the spectrin-actin cytoskeleton, found in neurons, specialized eukaryotic cells include channels which control flows of sodium and potassium ions across the massively extended cell membrane supporting an electro-chemical wave which is then converted into an outgoing chemical signal transmission from synapses which target nearby neuron or muscle cell receptors.  Neurons are supported by glial cells.  Neurons include a:
  • Receptive element - dendrites
    
  • Transmitting element - axon and synaptic terminals.  The axon may be myelinated, focusing the signals through synaptic transmission, or unmyelinated - where crosstalk is leveraged. 
  • Highly variable DNA schema using transposons. 
    
  in both central and peripheral networks.  It is also spliced and then found in other tissues. 
  
• Anorexia nervosa is an eating disorder include anorexia, bulimia & obesity. 
  .  As of 2015, 50 percent of hospitalized anorexic patients who are discharged at a normal rate relapse within a year.  It has the highest mortality of any mental illness.  It involves brain circuits involved in habitual behavior.  The initial weightloss acts as a reward with compliments relieving anxiety is manifested in the amygdala mediating inhibition of dopamine rewards.  Anxiety disorders are now seen as a related cluster, including PTSD, panic attacks, and phobias.  Major anxiety, is typically episodic, correlated with increased activity in the amygdala, results in elevated glucocorticoids and reduces hippocampal dendrite & spine density.  Some estrogen receptor variants are associated with anxiety in women.  Women are four times more likely to suffer from anxiety.  Louann Brizendine concludes this helps prepare mothers, so they are ready to protect their children.  Michael Pollan concludes anxiety is fear of the future.  Sufferers of mild autism often develop anxiety disorders.  Treatments for anxiety differ.  50 to 70% of people with generalized anxiety respond to drugs increasing serotonin concentrations, where there is relief from symptoms: worry, guilt; linked to depression, which are treated with SSRIs (Prozac).  Cognitive anxiety (extreme for worries and anxious thoughts) is also helped by yoga.  But many fear-related disorders respond better to psychotherapy: psychoanalysis, and intensive CBT.  Tara Brach notes that genuine freedom from fear is enabled by taking refuge. 
  and increasing self-esteem.  Diet gets paired with weight loss (the reward) in the ventral striatum is a region within the basal ganglia.   It is a target of the tegmentostriatal dopamine pathway.  It has been captured by brain imaging assigning values to subliminal symbols experimentally associated with winning (highly valued) and losing (low valuation) money.  During adolescence, prior to the deployment of the prefrontal cortex, the ventral striatum helps balance/control emotional decision making. 
  and eventually dieting becomes the reward as the dorsal striatum is a region within the basal ganglia.   It has been associated with spatial and motor functions and habitual behavior.  It degenerates in Parkinson's disease.  It is the target of the nigrostriatal dopamine pathway's projections. 
  gets involved in the patient's decision making integrates situational context, state and signals to prioritize among strategies and respond in a timely manner.  It occurs in all animals, including us and our organizations: 
  
  • Individual human decision making includes conscious and unconscious aspects.  Situational context is highly influential: supplying meaning to our general mechanisms, & for robots too.  Emotions are important in providing a balanced judgement.  The adaptive unconscious interprets percepts quickly supporting 'fast' decision making.  Conscious decision making, supported by the: DLPFC, vmPFC and limbic system; can use slower autonomy.  The amygdala, during unsettling or uncertain social situations, signals the decision making regions of the frontal lobe, including the orbitofrontal cortex.  The BLA supports rejecting unacceptable offers.  Moral decisions are influenced by a moral decision switch.  Sleeping before making an important decision is useful in obtaining the support of the unconscious in developing a preference.  Word framing demonstrates the limitations of our fast intuitive decision making processes.  And prior positive associations detected by the hippocampus, can be reactivated with the support of the striatum linking it to the memory of a reward, inducing a bias into our choices.  Prior to the development of the PFC, the ventral striatum supports adolescent decision making.  Neurons involved in decision making in the association areas of the cortex are active for much longer than neurons participating in the sensory areas of the cortex.  This allows them to link perceptions with a provisional action plan.  Association neurons can track probabilities connected to a choice.  As evidence is accumulated and a threshold is reached a choice is made, making fast thinking highly adaptive.  Diseases including: schizophrenia and anorexia; highlight aspects of human decision making. 
    
  • Organisations often struggle to balance top down and distributed decision making: parliamentry government must use a process, health care is attempting to improve the process: checklists, end-to-end care; and include more participants, but has systemic issues, business leaders struggle with strategy. 
    
  making it a habit allow higher organisms: humans, rats, flies; to perform important behaviors automatically, without involvement of consciousness.  Habits are adaptive, being promoted by the release of dopamine into the PFC and striatum, generating a feeling of pleasure and conditioning us.  As the dopamine detaches from the synaptic receptors in the PFC and striatum the motivation to perform the behavior subsides.  If the dopamine remains at the synapse for an extended period, because it is not removed as occurs when cocaine is present, or when too much dopamine is generated, the habit can become an addiction.  . 
  
• Anosognosia is unawareness of a major deficit, including paralysis. 
  
• Anterior insula is a rich club hub are areas of the brain which are highly connected to other club hubs: Ventral anterior insula, Dorsal anterior cingulate cortex, Posterior orbitofrontal cortex, Parahippocampal gyrus, Temporal pole. 
  within the insula cortex is part of the cerebral cortex folded deep within the lateral sulcus.  It includes: anterior, posterior insula; and is overlaid by the operculum.  Kandel notes the anterior insula is where feelings are calibrated by evaluating and integrating the importance of the stimuli.  It directly signals area 25.  LeDoux showed there are two routes for signals of feelings and emotions to the amygdala: a fast unconscious one and a slow one that involves the anterior insula.  So the insula is assumed to participate in consciousness where it has been linked to emotion, salience & body homeostasis functions:
  
  • Perception,
    
  • Motor control: Hand-&-eye motor movement, Swallowing, Gastric motility, Speech articulation;
    
  • Self-awareness,
    
  • Inter-personal experiences: Disgust at smells, contamination & mutilation which generate visceral responses, that are projected to the amygdala; binding physical and moral aspects of purity (Macbeth effect)
  • Suffering of others can be projected by the insula to the amygdala and made increasingly salient with loving-kindness meditation practice, Goleman & Davidson explain. 
    
  • Homeostatic regulation of the sympathetic network, parasympathetic network, and immune system.  Heart rate and sweat gland activity are monitored.   When the amygdala signals concern, the insula prepares the body for action, increasing blood flow to the muscles etc.
    
  .  It is anatomically subdivided by sulci into gyri.  It is where self-awareness and social experience integrate.  Feelings are subjective models: sad, glad, mad, scared, surprised, and compassionate; of the organism and its proximate environment, including ratings of situations signalled by broadly distributed chemicals and neural circuits.  These feelings become highly salient inputs, evolutionarily associated, to higher level emotions encoded in neural circuits: amygdala, and insula.  Deacon shows James' conception of feeling can build sentience.  Damasio, similarly, asserts feelings reveal to the conscious mind the subjective status of life: good, bad, in between; within a higher organism.  They especially indicate the affective situation within the old interior world of the viscera located in the abdomen, thorax and thick of the skin - so smiling makes one feel happy; but augmented with the reports from the situation of the new interior world of voluntary muscles.  Repeated experiences build intermediate narratives, in the mind, which reduce the salience.  Damasio concludes feelings relate closely and consistently with homeostasis, acting as its mental deputies once organisms developed 'nervous systems' about 600 million years ago, and building on the precursor regulatory devices supplied by evolution to social insects and prokaryotes and leveraging analogous dynamic constraints.  Damasio suggests feelings contribute to the development of culture:
  • As motives for intellectual creation: prompting detection and diagnosis of homeostatic deficiencies, identifying desirable states worthy of creative effort.
    
  • As monitors of the success and failure of cultural instruments and practices
  • As participants in the negotiation of adjustments required by the cultural process over time 
  from the internal state of the body are used to generate emotions are low level fast unconscious agents distributed across the brain and body which associate, via the amygdala and rich club hubs, important environmental signals with encoded high speed sensors, and distributed programs of action to model: predict, prioritize guidance signals, select and respond effectively, coherently and rapidly to the initial signal.  The majority of emotion centered brain regions interface to the midbrain through the hypothalamus.  The cerebellum and basal ganglia support the integration of emotion and motor functions, rewarding rhythmic movement.  The most accessible signs of emotions are the hard to control and universal facial expressions.  Emotions provide prioritization for conscious access given that an animal has only one body, but possibly many cells, with which to achieve its highest level goals.  Because of this, base emotions clash with group goals and are disparaged by the powerful.  Pinker notes a set of group selected emotions which he classes as: other-condemning, other-praising, other-suffering and self-conscious emotions.  Evolutionary psychology argues evolution shaped human emotions during the long period of hunter-gatherer existence in the African savanna.  Human emotions are universal and include: Anger, Appreciation of natural beauty, Contempt, Disgust, Embarrassment, Fear, Gratitude, Grief, Guilt, Happiness, Honor, Jealousy, Liking, Love, Moral awe, Rage, Romantic love, Lust for revenge, Passion, Sadness, Self-control, Shame, Sympathy, Surprise; and the sham emotions and distrust induced by reciprocal altruism. 
  .  It includes a direct projection from the: thalamus has all the main inputs to the cortex passing through it.  It is massively supplied with return innervations from the cortical regions it routes too.  It does not stand on the route of the main exits from the cortex.  The parafascicular nucleus of the rat thalamus contains relatively high levels of D5 dopamine receptors.  For human vision the primary system connects to the neocortex via, a small part of the thalamus, the LGN.  's ventral medial nucleus, central nucleus of the amygdala contains > 12 distinct areas: Central, Lateral.  It receives simple signals from the lower parts of the brain: pain from the PAG; and abstract complex information from the highest areas: Disgust, heart rate, and suffering from the insula cortex, allowing it to orchestrate emotion.  It connects strongly to attention focusing networks.  It sends signals to almost every other part of the brain, including to the decision making circuitry of the frontal lobes.  It has high levels of D(1) dopamine receptors.  During extreme fear the amygdala drives the hippocampus into fear learning.  It outputs directly to subcortical reflexive motor pathways when speed is required.  Its central nucleus projects to the BNST.  It signals the locus ceruleus.  It directly signals area 25.  The amygdala:
  
  • Promotes aggression.  Stimulating the amygdala promotes rage.  It converts anger into aggression and when impaired it impacts the ability to detect angry facial expressions.  
  • Participates in disgust
  • Perceives fear promoting stimuli, focusing our attention on these.  In PTSD sufferers the Amygdala overreacts to mildly fearful stimuli and is slow to calm down and the amygdala expands in size over a period of months.  Fear is processed by the lateral nucleus which serves as the input from various senses, and the central nucleus which outputs to the brain stem (central grey - freezing, lateral hypothalamus - blood pressure, activates paraventricular hypothalamus => crf -> hormone adjustments). 
    
  • Has lots of receptors for and is highly sensitive to glucocorticoids.  Stress inhibits the GABA interneurons in the basolateral amygdala (BLA) allowing the excitatory glutamate releasing neurons to excite more. 
    
  • Is sensitive to unsettling/uncertain social situations where it promotes anxiety and makes us distracted.  It is also interested in uncertain but potentially painful situations.  The amygdala contributes to social and emotional decision making where the BLA supports rejecting an unacceptable offer, as allowed in the Ultimatum Game, by injecting implicit mistrust and vigilance, generating an anger driven rejection that is used as punishment.  The amygdala is very rapidly excited by subliminal signals from the thalamus of outgroup skin color.  The amygdala subsequently tips social emotions against outgroups unless restrained by the frontal lobe or influenced by subliminal priming to prioritize inclusion.  The fast path from the thalamus rapidly but inaccurately signals its identified a weapon. 
    
  • Sees suffering of others as increasingly salient with loving-kindness meditation practice, Goleman & Davidson explain. 
    
  • Promotes male, but not female, sexual motivation when it is an uncertain potential pleasure. 
    
  • Responds to the longing for uncertain potential pleasures and fear that the reward will not be worth it if it happens.  The amygdala turns off during orgasm. 
    
  • Uses but is not directly involved in vision.  
  .  The anterior insula projects into the amygdala contains > 12 distinct areas: Central, Lateral.  It receives simple signals from the lower parts of the brain: pain from the PAG; and abstract complex information from the highest areas: Disgust, heart rate, and suffering from the insula cortex, allowing it to orchestrate emotion.  It connects strongly to attention focusing networks.  It sends signals to almost every other part of the brain, including to the decision making circuitry of the frontal lobes.  It has high levels of D(1) dopamine receptors.  During extreme fear the amygdala drives the hippocampus into fear learning.  It outputs directly to subcortical reflexive motor pathways when speed is required.  Its central nucleus projects to the BNST.  It signals the locus ceruleus.  It directly signals area 25.  The amygdala:
  
  • Promotes aggression.  Stimulating the amygdala promotes rage.  It converts anger into aggression and when impaired it impacts the ability to detect angry facial expressions.  
  • Participates in disgust
  • Perceives fear promoting stimuli, focusing our attention on these.  In PTSD sufferers the Amygdala overreacts to mildly fearful stimuli and is slow to calm down and the amygdala expands in size over a period of months.  Fear is processed by the lateral nucleus which serves as the input from various senses, and the central nucleus which outputs to the brain stem (central grey - freezing, lateral hypothalamus - blood pressure, activates paraventricular hypothalamus => crf -> hormone adjustments). 
    
  • Has lots of receptors for and is highly sensitive to glucocorticoids.  Stress inhibits the GABA interneurons in the basolateral amygdala (BLA) allowing the excitatory glutamate releasing neurons to excite more. 
    
  • Is sensitive to unsettling/uncertain social situations where it promotes anxiety and makes us distracted.  It is also interested in uncertain but potentially painful situations.  The amygdala contributes to social and emotional decision making where the BLA supports rejecting an unacceptable offer, as allowed in the Ultimatum Game, by injecting implicit mistrust and vigilance, generating an anger driven rejection that is used as punishment.  The amygdala is very rapidly excited by subliminal signals from the thalamus of outgroup skin color.  The amygdala subsequently tips social emotions against outgroups unless restrained by the frontal lobe or influenced by subliminal priming to prioritize inclusion.  The fast path from the thalamus rapidly but inaccurately signals its identified a weapon. 
    
  • Sees suffering of others as increasingly salient with loving-kindness meditation practice, Goleman & Davidson explain. 
    
  • Promotes male, but not female, sexual motivation when it is an uncertain potential pleasure. 
    
  • Responds to the longing for uncertain potential pleasures and fear that the reward will not be worth it if it happens.  The amygdala turns off during orgasm. 
    
  • Uses but is not directly involved in vision.  
  .  It includes spindle neurons are also termed von Economo neurons and are:
  • Found only in: Primates, Whales, Dolphins, Elephants;
  • Present in the: Insula, Anterior cingulate - focused on empathy; integrating and repurposing these basic facilities into high level capabilities such as moral disgust. 
    
  • First neurons destroyed by FTD. 
    
  . 
  
• Anti-Kickback Statute of the SSA is the social securities act of 1935 was part of the second New Deal.  It attempted to limit risks of old age, poverty and unemployment.  It is funded through payroll taxes via FICA and SECA into the social security trust funds.  Title IV of the original SSA created what became the AFDC.  The Social Security Administration controls the OASI and DI trust funds.  The funds are administered by the trustees.  The SSA was amended in 1965 to include:
  • Title V is Maternal and child health services. 
    
  • Title XVIII is Medicare.  
  criminally prohibits giving a kickback for a Medicare is a social insurance program that guarantees access to health insurance for Americans aged 65 and over, and younger people with disabilities and end stage renal disease or ALS.  Medicare is currently missing a cap on out-of-pocket costs and direct prescription drug coverage.  It includes:
  
  • Benefits
  • Part A: Hospital inpatient insurance.  As of Dec 2013 Medicare pays for home care in only limited circumstances, such as when a person needs temporary nursing care after a hospitalization.  Part A covers 20 days of inpatient rehabilitation at a SNF after discharge from inpatient care at a hospital. 
    
  • Part B: Medical insurance for non-hospital services including: doctor visits, tests, injectable drugs, ambulances, physical therapy;
    
  • Part C: Medicare Advantage 
  • Part D: indirect prescription drug coverage The MMA prohibits Medicare from directly negotiating drug prices. 
    
  • Eligibility
    
  • All persons 65 years of age or older who are legal residents for at least 5 years.  If they or a spouse have paid Medicare taxes for 10 years the Medicare part A payments are waived.  Medicare is legislated to become the primary health plan. 
    
  • Persons under 65 with disabilities who receive SSDI. 
    
  • Persons with specific medical conditions:
  • Have end stage renal disease or need a kidney transplant. 
    
  • They have ALS. 
    
  • Some beneficiaries are dual eligible. 
    
  • Part A requires the person has been admitted as an inpatient at a hospital.  This is constrained by a rule that they stay for three days after admission.  
    
  • Sign-up
  • Part A has automatic sign-up if the person is drawing social security.  Otherwise the person must sign-up for Part A and Part B. 
    
  • Should sign-up for Part B during the Initial Enrollment Period, of seven months centered around 65th birthday, online or at a social security office.  But if still covered by spouse's insurance or not yet retired then may only join during the 3 month general enrollment period (January to March) each year, with coverage initiated the following July.  Incremental yearly 10% penalties apply for not signing up at 65.  These penalties apply to all subsequent premiums. 
    
  • Premiums
  • Part A premium
  • Part B insurance premium
    
  • Part C & D premiums are set by the commercial insurer.  
  or Medicaid is the state-federal program for the poor.  Originally part of Lyndon Johnson's 1965 Bill, eligibility and services vary by state.  Medicaid currently pays less for care than Medicare, resulting in many care providers refusing to participate in the program.  Less than 10 percent of Medicaid recipients, those in long-term care including nursing homes where 64% are dependent on Medicaid, use one-third of all Medicaid spending which is a problem.  The ACA's Medicaid expansion program, made state optional by the SCOTUS decision, was initially taken up by fifty percent of states.  As of 2016 it covers 70 million Americans at a federal cost of $350 billion a year.  In 2017 it pays for 40% of new US births. 
  service referral links a doctors patient to an additional service as part of a treatment proposal.  The regulations are state based so the mechanism is geography dependent.  Referral services will be key to providers managing their revenue base.  
  .  
• Antibiotics are compounds which kill bacteria, molds, etc.  Sulfur dye stuffs were found to be effective antibiotics.  The first evolved antibiotic discovered was penicillin.  Antibiotics are central to modern health care supporting the processes of: Surgery, Wound management, Infection control works to prevent healthcare-associated infections.  It monitors & supports associated hospital processes: Anti-microbial surfaces, Barrier clothing, Cleaning, Disinfection, Hand washing: North shore; Patient access during epidemics, Sterilization; to contain cross infection.  The CDC provides support: Ebola process; and works closely with the primary biocontainment unit at Emory University Hospital. 
  ; which makes the development of antibiotic resistance results from evolutionary pressure of antibiotics, supported by plasmids and R factors: NDN1; which encode resistance properties for otherwise lethal antibiotics.  World leaders hope cooperation can preserve the power of last resort antibiotics: Carbapenems, Colistin (Oct 2016).  Worrying trends include: C. auris resistance to medical antifungals: itraconazole; as well as azole agricultural fungicides (Apr 2019), CRE (May 2016), C. diff (May 2015), MDR & XDR TB; resulting in increased risk of sepsis and death.  The World Bank estimates full resistance would reduce the global economy in 2050 by between 1.1 and 3.8%. 
  worrying.  Antibiotics are:
• Economically is the study of trade between humans.  Traditional Economics is based on an equilibrium model of the economic system.  Traditional Economics includes: microeconomics, and macroeconomics.  Marx developed an alternative static approach.  Limitations of the equilibrium model have resulted in the development of: Keynes's dynamic General Theory of Employment Interest & Money, and Complexity Economics.  Since trading depends on human behavior, economics has developed behavioral models including: behavioral economics. 
  problematic to develop and sell. 
  
• Congress enacted GAIN is generating antibiotic incentives now act of 2012 which grants manufacturers an extended exclusive period to sell newly approved antibiotics.  It was an attempt by Congress to encourage pharmaceutical companies to invest in antibiotics, which would be likely to be held back from the market, as last resort solutions for antibiotic resistant infections.   to encourage development of new antibiotics.  But it has not developed any market-entry award scheme, which seems necessary to encourage new antibiotic R&D. 
  
• Medicare is a social insurance program that guarantees access to health insurance for Americans aged 65 and over, and younger people with disabilities and end stage renal disease or ALS.  Medicare is currently missing a cap on out-of-pocket costs and direct prescription drug coverage.  It includes:
  
  • Benefits
  • Part A: Hospital inpatient insurance.  As of Dec 2013 Medicare pays for home care in only limited circumstances, such as when a person needs temporary nursing care after a hospitalization.  Part A covers 20 days of inpatient rehabilitation at a SNF after discharge from inpatient care at a hospital. 
    
  • Part B: Medical insurance for non-hospital services including: doctor visits, tests, injectable drugs, ambulances, physical therapy;
    
  • Part C: Medicare Advantage 
  • Part D: indirect prescription drug coverage The MMA prohibits Medicare from directly negotiating drug prices. 
    
  • Eligibility
    
  • All persons 65 years of age or older who are legal residents for at least 5 years.  If they or a spouse have paid Medicare taxes for 10 years the Medicare part A payments are waived.  Medicare is legislated to become the primary health plan. 
    
  • Persons under 65 with disabilities who receive SSDI. 
    
  • Persons with specific medical conditions:
  • Have end stage renal disease or need a kidney transplant. 
    
  • They have ALS. 
    
  • Some beneficiaries are dual eligible. 
    
  • Part A requires the person has been admitted as an inpatient at a hospital.  This is constrained by a rule that they stay for three days after admission.  
    
  • Sign-up
  • Part A has automatic sign-up if the person is drawing social security.  Otherwise the person must sign-up for Part A and Part B. 
    
  • Should sign-up for Part B during the Initial Enrollment Period, of seven months centered around 65th birthday, online or at a social security office.  But if still covered by spouse's insurance or not yet retired then may only join during the 3 month general enrollment period (January to March) each year, with coverage initiated the following July.  Incremental yearly 10% penalties apply for not signing up at 65.  These penalties apply to all subsequent premiums. 
    
  • Premiums
  • Part A premium
  • Part B insurance premium
    
  • Part C & D premiums are set by the commercial insurer.  
  has required hospitals and SNF is skilled nursing facility. 
  s to execute plans to ensure correct use of antibiotics & prevent the spread of drug-resistant infections.  
• C.D.C. is the HHS's center for disease control and prevention based in Atlanta Georgia.  
  is acting to stop the spread of resistant infections and reduce unnecessary use of antibiotics.  
  
• F.D.A. Food and Drug Administration.   has simplified approval standards.  It is working with industry to limit use of antibiotics in livestock. 
  
• BARDA is the biomedical advanced research and development authority, an HHS ASPR office responsible for procurement and development of vaccines, drugs, therapies and diagnostic tools for public health emergencies. 
  is promoting public-private partnerships to support promising research.
  
• Impacting the microbiome, the trillions of bacteria and viruses that live inside higher animals' guts, on their skin etc.  These bacteria and viruses seem to play a role in: immune responses, digesting food, making nutrients, controlling mental health and maintaining a healthy weight.  The signals from the gut microbiota are relayed by major nerve fibers: vagus; to the central nervous system.  The symbiotic relationship must be actively managed.  Human armpits include glands which provide food favoring certain symbionts who build a defensive shield above the skin.  In the human gut: Barriers are setup: Mucus secretions form a physical constraint and provide sites for bacteriophages to anchor and attack pathogenic bacteria; Symbiont tailored nourishment: Plant-heavy food creates opportunities for fibre specialists like Bacteroides thetaiotaomicron; is provided, Selective binding sites are provided, Poisons are deployed against the unwelcome, and Temperature, acidity and oxygenation are managed.    High throughput sequencing allows the characterization of bacterial populations inside guts.  Beginning at birth, as they pass down the birth canal infants are supplied with a microbiome from their mothers.  If they are borne via cesarean they never receive some of the key bacteria: Bifidobaterium infantis which is also dependent on oligosaccharides in breast milk; from their mothers.  A variety of diseases may be caused by changes in the microbiome:
  • Eczema can be related to changes in the skin microbiome. 
    
  • Obesity can be induced by changes to the gut microbiome.  
  • Chronic inflammation
    
  • Allergies
    
  • Type 1 diabetes
    
  of the recipient.  Stool banking is a solution  (Sloan-Kettering stool banking).  
• Associated with obesity is an addictive disorder where the brain is induced to require more eating, often because of limits to the number of fat cells available to report satiation (Jul 2016).  Brain images of drug-addicted people and obese people have found similar changes in the brain.  Obese people's reward network tends to be less responsive to dopamine and have a lower density of dopamine receptors.  Obesity spreads like a virus through a social network with a 171% likelihood that a friend of someone who becomes obese will also become so.  Obesity is associated with: metabolic syndrome including inflammation, cancer (Aug 2016), high cholesterol, hypertension, type-2-diabetes, asthma and heart disease.  It is suspected that this is contributing to the increase in maternal deaths in the US (Sep 2016).  Obesity is a complex condition best viewed as representing many different diseases, which is affected by the: Amount of brown adipose tissue (Oct 2016), Asprosin signalling by white adipose tissue (Nov 2016), Genetic alleles including 25 which guarantee an obese outcome, side effects of some pharmaceuticals for: Psychiatric disorders, Diabetes, Seizure, Hypertension, Auto-immunity; Acute diseases: Hypothyroidism, Cushing's syndrome, Hypothalamus disorders; State of the gut microbiome.  Infections, but not antibiotics, appear associated with childhood obesity (Nov 2016). 
  , although evidence suggests childhood obesity relates to the infections not the antibiotic treatments (Nov 2016). 
  
• Monitored globally by W.H.O. is World Health Organization a United Nations organization.  
  
• Regulated in the US is the United States of America.   by the F.D.A. Food and Drug Administration.   who promote voluntary labeling by industry to discourage livestock fattening (Dec 2013).  
• Customer demands have more effect - Perdue shifts to no antibiotics in premier chickens (Aug 2015). 
  
• Antibiotic resistance results from
  This page reviews the implications of selection, variation and heredity in a complex adaptive system (CAS).  The mechanism and its emergence are discussed. 
  
  evolutionary pressure of antibiotics are compounds which kill bacteria, molds, etc.  Sulfur dye stuffs were found to be effective antibiotics.  The first evolved antibiotic discovered was penicillin.  Antibiotics are central to modern health care supporting the processes of: Surgery, Wound management, Infection control; which makes the development of antibiotic resistance worrying.  Antibiotics are:
  • Economically problematic to develop and sell. 
    
  • Congress enacted GAIN to encourage development of new antibiotics.  But it has not developed any market-entry award scheme, which seems necessary to encourage new antibiotic R&D. 
    
  • Medicare has required hospitals and SNFs to execute plans to ensure correct use of antibiotics & prevent the spread of drug-resistant infections.  
  • C.D.C. is acting to stop the spread of resistant infections and reduce unnecessary use of antibiotics.  
    
  • F.D.A. has simplified approval standards.  It is working with industry to limit use of antibiotics in livestock. 
    
  • BARDA is promoting public-private partnerships to support promising research.
    
  • Impacting the microbiome of the recipient.  Stool banking is a solution  (Sloan-Kettering stool banking).  
  • Associated with obesity, although evidence suggests childhood obesity relates to the infections not the antibiotic treatments (Nov 2016). 
    
  • Monitored globally by W.H.O.
    
  • Regulated in the US by the F.D.A. who promote voluntary labeling by industry to discourage livestock fattening (Dec 2013).  
  • Customer demands have more effect - Perdue shifts to no antibiotics in premier chickens (Aug 2015). 
    
  , supported by plasmids and R factors provide bacteria with a way to transfer parts of their DNA complement with one another.  The effect is to ensure that useful mutations can become rapidly distributed within a population of bacteria.  Because the plasmid reproduces asexually beneficial mutations will result in competition between hosts containing different plasmid variants through clonal interference. 
  : NDN1 is New Delhi metallo-beta-lactamase 1 plasmid which provides bacterial populations globally with total current antibiotic resistance. 
  ; which encode resistance properties for otherwise lethal antibiotics are compounds which kill bacteria, molds, etc.  Sulfur dye stuffs were found to be effective antibiotics.  The first evolved antibiotic discovered was penicillin.  Antibiotics are central to modern health care supporting the processes of: Surgery, Wound management, Infection control; which makes the development of antibiotic resistance worrying.  Antibiotics are:
  • Economically problematic to develop and sell. 
    
  • Congress enacted GAIN to encourage development of new antibiotics.  But it has not developed any market-entry award scheme, which seems necessary to encourage new antibiotic R&D. 
    
  • Medicare has required hospitals and SNFs to execute plans to ensure correct use of antibiotics & prevent the spread of drug-resistant infections.  
  • C.D.C. is acting to stop the spread of resistant infections and reduce unnecessary use of antibiotics.  
    
  • F.D.A. has simplified approval standards.  It is working with industry to limit use of antibiotics in livestock. 
    
  • BARDA is promoting public-private partnerships to support promising research.
    
  • Impacting the microbiome of the recipient.  Stool banking is a solution  (Sloan-Kettering stool banking).  
  • Associated with obesity, although evidence suggests childhood obesity relates to the infections not the antibiotic treatments (Nov 2016). 
    
  • Monitored globally by W.H.O.
    
  • Regulated in the US by the F.D.A. who promote voluntary labeling by industry to discourage livestock fattening (Dec 2013).  
  • Customer demands have more effect - Perdue shifts to no antibiotics in premier chickens (Aug 2015). 
    
  .  World leaders now aims to develop plans and strategies which ensure effective coordination to improve the common good of the in-group.  Pinker notes the evolved pressure of social rivalry associating power with leadership.  Saposky observes the disconnect between power hierarchies and wisdom in apes.  John Adair developed a modern leadership methodology based on the three-circles model. 
  hope cooperation can preserve the power of last resort antibiotics: Carbapenems are a class of beta-lactam antibiotics with a broad spectrum of antibacterial activity.  Some bacteria (such as CRE) have developed resistance due to the development and r-factor distribution of carbapenemases.  This is a huge problem as carbapenems have been used as the last resort antibiotic.   , Colistin is an old antibiotic that is held in reserve in the US to treat especially dangerous infections (CREs) that are resistant to carbapenems.   (Oct 2016).  Worrying trends include: C. auris is a fungus resident in soils, which has developed resistance to medical antifungals: itraconazole; as well as azole agricultural fungicides.  90% of C. auris infections are resistant to an antifungal.  30% are resistant to two of the drugs.  Genome analysis indicates four ancient strains persist.  It has been assisted by the widespread use of fungicides enabling it to opportunistically migrate to niches cleared of its normal competitors.  C. auris was first identified in an ear infection of a Japanese patient in 2009.  But it had subsequently colonized all proximate surfaces and was detected in the air.  It infects the very ill and those with weakened immune systems.  50% of those infected die within 90 days. 
  resistance to medical antifungals: itraconazole is an antifungal medication, classified by the WHO as an essential medicine.  It is a triazole which stops fungal growth by undermining metabolism and cell membrane integrity.  Effectiveness is being undermined by global agricultural deployment of equivalent azole fungicides on crops. 
  ; as well as azole agricultural fungicides (Apr 2019), CRE is carbapenem-resistant Enterobacteriaceae.  When carbapenem fails to treat an infection the patient is in serious trouble.  The CDC estimated CRE accounts for around 9,300 infections and 610 deaths yearly in the US in 2010-15.  However the CDC also reports:
  
  • In July 2010 the state of Florida instigated procedures that reduced the number of patients with CRE from 60% to less than 10% at a problem LTCH.  The improvement was based on
  • Detecting and protecting - Screening, isolating, and grouping patients with CRE to prevent spread to other patients. 
    
  • Reviewing staff operations for 40 hours checking hand hygene, glove and gown use and other practices during care of patients. 
    
  • Iterative communications between the problem facility and local, state and federal public health workers.  
  (May 2016), C. diff usually competes with other bacteria in the human gut microbiome.  But antibiotic treatments provide it with an advantage where it becomes the predominant gut bacteria causing diarrhea, abdominal pain, and toxic megacolon.  Repeated treatments select for infections that are progressively more difficult to treat.  C. difficile infections kill more than 25,000 people a year in the US.  Fecal transplants, especially enabled by stool-banking, reintroduce competitive bacteria that limit the success of C. difficile and cure patients with previously recurrent infections.  But the F.D.A. has not approved such transplants as a treatment and the procedure is not covered by insurance. 
  
  (May 2015), MDR is multidrug-resistant Tuberculosis (Vank's Disease).   It is difficult to treat.  Some of the medicines are intravenous, must be taken for two years (potentially just 9 months - Oct 2017) and can cause deafness, psychosis and kidney failure.  Patients must be hospitalized and their movements restricted to one or two corridors, for months until they stop coughing live bacteria. 
  & XDR is extensively drug-resistant tuberculosis.  It requires very toxic and costly drugs to treat.  Most patients die.   TB, consumption or otherwise TB, is mostly an airborn bacterial lung infection, but it can also infect the brain, kidneys and other parts of the body.  The only vaccine is still the BCG.  The deployment of antibiotics during the 1940s allowed effective treatment: Streptomycin.  In 1963 epidemiologist George Comstock realized why 30% of Alaskan adults were infected with TB - it grows slowly and is transmitted to other people before symptoms occur.  Treatment was expanded to all contacts of a person with symptoms, who tested positive for TB.  This strategy eradicated TB in the West, but was considered impractical in poor countries.  Diagnostic tools for TB are insufficient.  And because TB grows slowly in walled off pockets in the lungs it takes many months of treatment for antibiotics to eradicate the infection.  TB benefits from compromised hosts and has benefited from HIV/AIDS.  TB is also leveraging the plasmids that now carry immunity to all current antibiotics.  In 2016 it is estimated to latently infect two billion people.  9.6 million worldwide became infected in 2014.  1.5 million people will die from TB in 2016.  Deaths from the disease have fallen drastically since 2000.  TB has been halted or reversed in 16 of the 22 countries: India (Sep 2016, Infection base estimate increased Oct 2016), Vietnam, Indonesia; that have the majority of cases.  But it is still the infectious disease causing the most deaths world-wide.  In 2018 W.H.O. asserts there is a $3.5 billion shortfall in funding for TB public health control efforts, a gap that will double by 2023.  Nano scale drug delivery has the potential to push back on TB and is being actively researched (May 2016).   ; resulting in increased risk of sepsis is an infection triggered over-reaction by the immune system which causes general inflammation resulting in a cascade of problems: Blood clots, Leaky blood vessels; impeding blood flow to vital organs which can induce septic shock: Blood pressure drops, multiple organ failure, Heart damage and death.  For every hour without antibiotics the probability of death increases 8%.  Most cases start before people are hospitalized.  People over 65, infants under 1 year, people with chronic diseases such as diabetes, or weakened immune systems and healthy people with incorrectly treated infections are most likely to contract sepsis.  Most often the infections are of: lungs, urinary tract, skin, gut or intestines.  Typically such infections were the result of a previous visit to a clinic or hospital.  Symptoms of sepsis include: chills or fever, extreme pain or discomfort, clammy or sweaty skin, confusion or disorientation, shortness of breath and high heart rate.  Dr. Diane Craig noted that sepsis had become the leading cause of death among hospitalized patients.  Using patient matching on: age, symptoms, degree of illness; from the hospital system EHR, Craig identified the blood-lactate test as the key diagnostic that supported early, aggressive treatment of sepsis.  She argued that whenever a patient had two symptoms of significant infection a lactate test be used along with EGDT treatment for patients with lactate counts as low as 2.5 millimoles/liter.  This reduced sepsis mortality to 40% below the national average.  But only half the hospitals in the US followed Craig's recommendations.  Dr. Robert Pearl concludes this is because of the high risk of killing a patient with EGDT treatment, even though the protocol will reduce overall mortality by half.  Doctors don't want to be responsible for killing patients so they opt not to order the lactate test.  In 2017 sepsis is estimated to cost the US health care system more than $20 billion a year.  The C.D.C. is concerned (Sep 2016) with antibiotic resistance generating more sepsis. 
  and death.  The World Bank was setup as part of the Bretton Woods agreements, as the International Bank for Reconstruction and Development, to repair and reconstruct Europe after the Second World War and as the World Bank continues to provide reconstruction and development resources for projects in developing economies. It includes:
  • International Finance Corporation 
  estimates full resistance would reduce the global economy is a human SuperOrganism complex adaptive system (CAS) which operates and controls trade flows within a rich niche.  Economics models economies.  Robert Gordon has described the evolution of the American economy.  Like other CAS, economic flows are maintained far from equilibrium by: demand, financial flows and constraints, supply infrastructure constraints, political and military constraints; ensuring wealth, legislative control, legal contracts and power have significant leverage through evolved amplifiers. 
  in 2050 by between 1.1 and 3.8%. 
  
• Antibody is a y-shaped blood transported protein, a relatively long chain (polymer) of peptides.  Shorter chains of peptides are termed polypeptides.   generated by the adaptive in evolutionary biology is a trait that increased the number of surviving offspring in an organism's ancestral lineage.  Holland argues: complex adaptive systems (CAS) adapt due to the influence of schematic strings on agents.  Evolution indicates fitness when an organism survives and reproduces.  For his genetic algorithm, Holland separated the adaptive process into credit assignment and rule discovery.  He assigned a strength to each of the rules (alternate hypothesis) used by his artificial agents, by credit assignment - each accepted message being paid for by the recipient, increasing the sender agent's rule's strength (implicit modeling) and reducing the recipient's.  When an agent achieved an explicit goal they obtained a final reward.  Rule discovery used the genetic algorithm to select strong rule schemas from a pair of agents to be included in the next generation, with crossing over and mutation applied, and the resulting schematic strategies used to replace weaker schemas.  The crossing over genetic operator is unlikely to break up a short schematic sequence that provides a building block retained because of its 'fitness';  In Deacon's conception of evolution, an adaptation is the realization of a set of constraints on candidate mechanisms, and so long as these constraints are maintained, other features are arbitrary. 
  immune system has to support and protect an inventory of host cell types, detect and respond to invaders and maintain the symbiont equilibrium within the microbiome.  It detects microbes which have breached the secreted mucus barrier, driving them back and fortifying the barrier.  It culls species within the microbiome that are expanding beyond requirements.  It destroys invaders who make it into the internal transport networks.  As part of its initialization it has immune cells which suppress the main system to allow the microbiome to bootstrap.  The initial microbiome is tailored by the antibodies supplied from the mother's milk while breastfeeding.  The immune system consists of two main parts the older non-adaptive part and the newer adaptive part.  The adaptive part achieves this property by being schematically specified by DNA which is highly variable.  By rapid reproduction the system recombines the DNA variable regions in vast numbers of offspring cells which once they have been shown not to attack the host cell lines are used as templates for interacting with any foreign body (antigen).  When the immune cell's DNA hyper-variable regions are expressed as y-shaped antibody proteins they typically include some receptor like structures which match the surfaces of the typical antigen.  Once the antibody becomes bound to the antigen the immune system cells can destroy the invader. 
  's plasma cells, B lymphocytes are a type of leukocyte.  They appear mainly in the lymphatic network.  Their are various types:
  • B cells which make antibodies that bind to pathogens, and activate the complement system.  When malignant these cells can produce multiple myeloma. 
    
  • Natural killer cells can kill body cells that do not display MHC class 1 molecules, or do display stress markers including MIC-A. 
    
  • T cells including CD4+ helper cells, Cytotoxic T cells, Gamma 5 T cells; 
    
  , to accurately identify and neutralize pathogens such as bacteria and viruses is a relatively small capsule containing genetic material: RNA, DNA; which utilizes the cellular infrastructure of its target host to replicate its genetic material and operational proteins.  David Quammen explains the four key challenges of viruses: Getting from one host to another, penetrating a cell within the host, commandeering the cell's infrastructure, escaping from the cell and organism; Single-stranded RNA viruses: Coronavirus, chickungunya, dengue, Ebola, Hantas, Hendra, Influenzas, Junin, Lassa, Machupo, Marburg, Measles, Mumps, Nipah, Rabies, Retrovirus (HIV), Rhinovirus, yellow fever; are subject to more mutation events than DNA viruses, but limits the size of the genetic string.  Double stranded DNA viruses: baculoviruses, hepadnaviruses, Herpesviruses, iridoviruses, papillomavirses, poxviruses; can leverage relatively far larger genetic payloads.  The relationship with the reservoir host is long-term, a parasitic or symbiotic relationship, developing over millions of years.  But opportunistically, it may spillover into a secondary host, with the virus entering the host cell, leveraging the host infrastructure to replicate its self massively and then exiting the host cell by rupturing it and killing the organism. 
  that exhibit a matching antigen. 
  
• Anticipation compensates for the sluggishness of our consciousness.  Almost all sensory and motor areas contain temporal learning mechanisms that anticipate external events. 
  
• Anticommutator of two elements a and b of a ring or an associative algebra is defined by {a,b} = ab + ba.  It is used in the derivation of the Dirac equation, developed by Paul Dirac using only first derivatives, is a Lagrangian density formula where the photon emission is equated to the contributing: magnitude of the electric charge of the proton, the electromagnetic current of the proton and Dirac spinor of the photon; and to the contributing: magnitude of the electric charge of the proton with contributing: ubar of the proton, Dirac matrix, Dirac spinor of the proton; and the Dirac spinor of the photon.  Dirac took the square root of the relativistic energy-mass equation generating four partial differential equations involving four 4*4 matrices and a new four-component wave function which was soon understood to be a bispinor consisting of two Weyl-like spinors one for electrons and the other for the positron (anti-electron). 
  . 
  
• Antihypertensives are treatments for hypertension is high blood pressure.  It is directly associated with death rate due to pressure induced damage to the left ventricle and in general to cardiovascular diseases.  Treated with antihypertensives: Diuretics, Calcium channel blockers, Angiotensin receptor blockers or Beta blockers.   including: diuretics increase water excretion which results in reduced blood volume and pressure.  Many work by making the kidneys transport more sodium into the urine.  The sodium pulls water from the blood with it.  The reduced fluid level in the blood vessels reduces the pressure on the walls of the arteries.  , ACE inhibitors is angiotensin-converting-enzyme inhibitor.  They help relax blood vessels and are used to treat hypertension and CHF.  , calcium channel blockers make blood vessels expand.  They have four main effects:
  1. Reduce contraction of arteries by blocking calcium gates in vascular smooth muscle. 
     
  2. By blocking calcium gates in cardiac muscle they reduce the force of contraction of the heart. 
     
  3. By slowing the conduction of electrical flows within the heart they slow the heart beat. 
     
  4. By blocking the calcium signal on adrenal cortex cells, they directly reduce aldosterone production reducing blood pressure. 
     
  , beta blockers stop the action of beta-adrenergic signals and hence slow the heart.   and angiotensin antagonists block hormone signals (angiotensin II) from causing the contraction of muscles surrounding blood vessels and so stop the blood vessels contracting, lowering blood pressure. 
  . 
  
• Antisocial punishment is where someone is punished for being overly generous.  People from Greece and Oman, where there is low social capital is the collective quantity of resources such as trust, reciprocity & cooperation according to Sapolsky.  , were particularly likely to do this. 
  
• Anxiety is manifested in the amygdala contains > 12 distinct areas: Central, Lateral.  It receives simple signals from the lower parts of the brain: pain from the PAG; and abstract complex information from the highest areas: Disgust, heart rate, and suffering from the insula cortex, allowing it to orchestrate emotion.  It connects strongly to attention focusing networks.  It sends signals to almost every other part of the brain, including to the decision making circuitry of the frontal lobes.  It has high levels of D(1) dopamine receptors.  During extreme fear the amygdala drives the hippocampus into fear learning.  It outputs directly to subcortical reflexive motor pathways when speed is required.  Its central nucleus projects to the BNST.  It signals the locus ceruleus.  It directly signals area 25.  The amygdala:
  
  • Promotes aggression.  Stimulating the amygdala promotes rage.  It converts anger into aggression and when impaired it impacts the ability to detect angry facial expressions.  
  • Participates in disgust
  • Perceives fear promoting stimuli, focusing our attention on these.  In PTSD sufferers the Amygdala overreacts to mildly fearful stimuli and is slow to calm down and the amygdala expands in size over a period of months.  Fear is processed by the lateral nucleus which serves as the input from various senses, and the central nucleus which outputs to the brain stem (central grey - freezing, lateral hypothalamus - blood pressure, activates paraventricular hypothalamus => crf -> hormone adjustments). 
    
  • Has lots of receptors for and is highly sensitive to glucocorticoids.  Stress inhibits the GABA interneurons in the basolateral amygdala (BLA) allowing the excitatory glutamate releasing neurons to excite more. 
    
  • Is sensitive to unsettling/uncertain social situations where it promotes anxiety and makes us distracted.  It is also interested in uncertain but potentially painful situations.  The amygdala contributes to social and emotional decision making where the BLA supports rejecting an unacceptable offer, as allowed in the Ultimatum Game, by injecting implicit mistrust and vigilance, generating an anger driven rejection that is used as punishment.  The amygdala is very rapidly excited by subliminal signals from the thalamus of outgroup skin color.  The amygdala subsequently tips social emotions against outgroups unless restrained by the frontal lobe or influenced by subliminal priming to prioritize inclusion.  The fast path from the thalamus rapidly but inaccurately signals its identified a weapon. 
    
  • Sees suffering of others as increasingly salient with loving-kindness meditation practice, Goleman & Davidson explain. 
    
  • Promotes male, but not female, sexual motivation when it is an uncertain potential pleasure. 
    
  • Responds to the longing for uncertain potential pleasures and fear that the reward will not be worth it if it happens.  The amygdala turns off during orgasm. 
    
  • Uses but is not directly involved in vision.  
  mediating inhibition of dopamine is a synaptic signal supporting generalized goal-directed behavior & anticipation of reward.  Its significance is that the receptors that detect the signal are of the slow acting type and are used to alter (modulate) the response of fast acting dopaminergic neural circuits in which the receptors are deployed (LTP).  The signal detects significant changes including predictions of models and actual results which differ unexpectedly.  Dopamine is released primarily by neurons of the ventral tegmental area and the substantia nigra.  The dopamine network architecture is designed to signal the possibility of any type of reward: Norm violation punishment, Winning a lottery, & Misfortune of an envied competitor.  Dopamine signalling:
  
  • Rescales continuously to accommodate the range of intensity offered by different stimuli.  So dopamine's responses to any reward habituate.  GABA is released by some tegmental neurons to induce habituation.  This allows addictions to develop. 
    
  • Reflects the anticipation of reward.  It supports establishment of a relationship between a signal, working for a reward and obtaining the reward, but subsequently dopamine is mainly released encouraging the work, right after the signal supporting anticipation of the reward.  Anticipation requires learning and is reflected in hippocampus activity.  That explains context dependent cravings.  And the learning architecture means reliable cues become rewarding.  The accumbens supports willpower.  And dopamine
    
  • Promotes goal-oriented behavior needed to obtain & likely to achieve the reward - through the dopamine projections to the prefrontal cortex.  That makes dopamine central to:
    
  • Motivation.  This binding fails in depression - due to stress and in anxiety - due to signals from the amygdala.  
  • The prefrontal cortex's mesocortically stimulated support for willpower to act to delay rewards.  To sustain work for delayed rewards additional dopamine is released based on the length of the delay and the rewards uncertainty (modelled in the dorsolateral prefrontal cortex - which promotes the long term and the ventromedial prefrontal cortex - which promotes the short term) and the anticipated size of the reward (modelled in the accumbens).  Impulsiveness in ADHD is reflected in abnormal dopamine processing.  Addictive drugs bias the dopamine network towards impulsiveness.  
  • Is lowered by certain gene variants which induce: less dopamine in the synapse, fewer receptors, lower responsiveness of receptors; associated with (as tiny effects in hugely varying social scenarios): sensation seeking, risk taking, attentional problems, extroversion; where:
    
  • The receptor D4's gene shows high variability.  The D47R form is relatively unresponsive to dopamine.  
  • Dopamine is degraded by COMT.  The COMT gene includes a variant which is highly efficient reducing dopamine signalling but with complicating gene/environment interactions.  
  • Dopamine is removed from the synapse by a reuptake transporter DAT. 
    
  rewards.  Anxiety disorders are now seen as a related cluster, including PTSD is post-traumatic stress disorder, an induced level of stress that is so troubling to the brain that it avoids processing it, change that is necessary if the stress is to be dissipated by the normal brain processes.  The hippocampus loses volume.  The damage to the hippocampus results in: flashbacks, becoming emotionally numb and withdrawn from other people, irritability, jumpiness, being more aggressive, having trouble sleeping and avoidance of the sensory experiences associated with the initial event.  The amygdala responds to overwhelming trauma by repeatedly grabbing attention to encourage response to the emergency, increases in volume and is hyperactive and anxious.  As a result it remains in a heightened state, resulting in fear of recall and further stress.  PTSD is often accompanied by depression and substance abuse.  It is now being realized that PTSD can be introduced into patients by traumatic treatment regimens such as ICU procedures.  Traumatic head injuries, seen in athletes and soldiers can be reflected in PTSD and can subsequently become associated with prion based dementia.  Some people are genetically predisposed to PTSD, with identical twins responding similarly.  Another risk factor for PTSD is childhood trauma which can induce epi-genetic changes to stress processing.  PTSD can be managed with CBT, and it also responds to propranolol while recalling the traumatic event, where the drug undermines the memory reconsolidation process. 
  , panic attacks, and phobias are innate fears with a predisposition encoded genetically in the central amygdala that have become learned fears in the BLA and have not been subsequently deprioritized by the frontal cortex. 
  .  Major anxiety, is typically episodic, correlated with increased activity in the amygdala, results in elevated glucocorticoids are corticosteroids which bind the glucocorticoid receptor.  They decrease excitability of prefrontal cortical neurons.  They have adverse effects in fetal/infant development having organizational effects on fetal brain construction and decreasing levels of: growth factors, neurons, synapses; resulting in an adult brain that is more sensitive to environmental triggers of depression and anxiety.  Glucocorticoids affect gene control structures and induce epi-genetic changes.  They have been found associated with high sodium chloride consumption (May 2017). 
  and reduces hippocampal is a part of the medial temporal lobe of the brain involved in the temporary storage or coding of long-term episodic memory.  It includes the dentate gyrus.  Memory formation in the cells of the hippocampus uses the MAP kinase signalling network which is impacted by sleep deprivation.  The hippocampus dependent memory system is directly affected by cholinergic changes throughout the wake-sleep cycle.  Increased acetylcholine during REM sleep promotes information attained during wakefulness to be stored in the hippocampus by suppressing previous excitatory connections while facilitating encoding without interference from previously stored information.  During slow-wave sleep low levels of acetylcholine cause the release of the suppression and allow for spontaneous recovery of hippocampal neurons resulting in memory consolidation.  It was initially associated with memory formation by McGill University's Dr. Brenda Milner, via studies of 'HM' Henry Molaison, whose medial temporal lobes had been surgically destroyed leaving him unable to create new explicit memories.  The size of neurons' dendritic trees expands and contracts over a female rat's ovulatory cycle, with the peak in size and cognitive skills at the estrogen high point.  Adult neurogenesis occurs in the hippocampus (3% of neurons are replaced each month) where the new neurons integrate into preexisting circuits.  It is enhanced by learning, exercise, estrogen, antidepressants, environmental enrichment, and brain injury and inhibited by various stressors explains Sapolsky.  Prolonged stress makes the hippocampus atrophy.  He notes the new neurons are essential for integrating new information into preexisting schemas -- learning that two things you thought were the same are actually different.  Specific cells within the hippocampus and its gateway, the entorhinal cortex, are compromised by Alzheimer's disease.  It directly signals area 25. 
  dendrite & spine density.  Some estrogen is a generic term for a number of related steroid hormones each of which works differently.  Estrogen:
  • Is generated in the ovaries.  It supports the generation of oxytocin, and so is associated with attachment, nurturing and other affiliative behaviors. 
    
  • Supports verbal memory.  Removal of ovaries without immediate estrogen replacement therapy degrades verbal memory performance.  The HT reduces age-related shrinkage of the PFC, parietal cortex, and temporal lobe in women, and made them less depressed and angry. 
    
  • Supports mitochondrial operation in the blood vessels of the brain. 
    
  • Contributes to maternal aggression but it can reduce aggression and enhance empathy, depending on brain state.  There are two different estrogen receptor types which mediate these conflicting effects.  The level of each type of receptor is independently regulated.  Different receptor variants are associated with:
  • Higher rates of anxiety among women
  • Higher rates of antisocial behavior and conduct disorder in men
  • Is essential for vaginal lubrication 
  • Facilitates the elimination of cholesterol
    
  • Has anti-inflammatory and anti-oxidative properties improving response to stress
    
  receptor, in biological cells these proteins are able to span the cell membrane and present an active site which is tailored to interact with a specific signal.  When the receptor pairs with its signal, its overall shape changes resulting in changes in the part internal to the cell which can be relayed by the cells signalling infrastructure.  In neuron synapses one type of receptor (fast) is associated with an ion channel.  The other (slow) is associated with a signalling enzyme chain and modulates the neuron's response. 
  variants are associated with anxiety in women.  Women are four times more likely to suffer from anxiety.  Louann Brizendine concludes this helps prepare mothers, so they are ready to protect their children.  Michael Pollan concludes anxiety is fear is an emotion which prepares the body for time sensitive action: Blood is sent to the muscles from the gut and skin, Adrenalin is released stimulating: Fuel to be released from the liver, Blood is encouraged to clot, and Face is wide-eyed and fearful.  The short-term high priority goal, experienced as a sense of urgency, is to flee, fight or deflect the danger.  There are both 'innate' - really high priority learning - which are mediated by the central amygdala and learned fears which are mediated by the BLA which learns to fear a stimulus and then signals the central amygdala.  Tara Brach notes we experience fear as a painfully constricted throat, chest and belly, and racing heart.  The mind can build stories of the future which include fearful situations making us anxious about current ideas and actions that we associate with the potential future scenario.  And it can associate traumatic events from early childhood with our being at fault.  Consequent assumptions of our being unworthy can result in shame and fear of losing friendships.  The mechanism for human fear was significantly evolved to protect us in the African savanna.  This does not align perfectly with our needs in current environments: U.S. Grant was unusually un-afraid of the noise or risk of guns and trusted his horses' judgment, which mostly benefited his agency as a modern soldier. 
  of the future.  Sufferers of mild autism is a major hereditary mental disorder that starts before age three when it features: a strong preference to be alone, a desire for things to stay the same, and areas of creative ability - they see the ordinary as beautiful and have special talents for: poetry, foreign languages, music, art, and calculations.  They generate less but more original ideas.  It occurs as a spectrum of symptoms, from mild to severe, across the population of sufferers (ASD).  Before age two the circumference of an autistic child's head is larger than typical and regions: amygdala, frontal lobe; develop prematurely, altering activity in other regions.  Autism highlights aspects of the brain's specialized regions and processes for interacting with other people.  Autistic's interests are restricted.  They struggle with social interactions & verbal and nonverbal communications.  Autistics do not attribute minds to other people: attributing mental states to others allows us to predict their behavior; a critical skill for social learning and interaction.  While their visual area MT detects motion, the superior temporal sulcus does not respond to biological motion in autistics, undermining the understanding of intention.  And they gaze at mouths rather than eyes when looking at faces.  The default mode network is disrupted.  Autistic adolescents have unusually large numbers of synapses, because of a failure of synaptic pruning.  Autistics almost never pretend.  They can't explain the difference between an instance of an object and a memory of it.  Mild autism still maintains some pressure to conform socially and often results in depression and anxiety.  Autism occurs in every country and social class.  It lasts a lifetime.  It has genetic and neurological causes.  Identical twins are 90% likely to both have autism if one of them does.  With 50% of genes active in the brain, mutations are likely to impact the development and operation of the brain.  The genes: SHANK3, CDH10; are involved but account for a very small percentage of the risk.  Facial gaze studies indicate a high genetic influence and an opportunity to identify more genes associated with autism (Jul 2017).  Copy number variations: an extra copy of a segment of 25 genes of chromosome 7 increases the risk of ASD, while deletion of the segment causes Williams syndrome; and de novo mutations which drive up the number of autism cases as paternal age has increased in the US.  ASD is associated with a reduced fusiform face area response.  Tests [in development] for autism include: SynapDx's blood test. 
  often develop anxiety disorders.  Treatments for anxiety differ.  50 to 70% of people with generalized anxiety respond to drugs increasing serotonin is a neurotransmitter.  it is:
  • Inversely associated with: human impulsive, cricket, mollusk, crustacean; aggression.  Low levels of serotonin are associated with impulsive aggression ranging from psychological measures of hostility to overt violence and cognitive impulsivity and impulsive suicide. 
    
  • Nearly all synthesized in the Raphe nucleus.  Tryptophan hydroxylase makes serotonin from the amino-acid tryptophan.  Monoamine oxidase degrades serotonin.  The serotonin receptor binds serotonin to initiate cross membrane signalling.  The serotonin transporter actively removes serotonin from synapses.  Serotonin levels can be increased with: exercise, high light levels, consumption of chickpeas and traditional lime boiled corn tortillas.  Reuptake is inhibited by SSRIs.  Variants of the genes coding for these various enzymes alter the strength of their effects. 
    
  • Increasing serotonin signalling does not lessen impulsiveness in normal subjects but did in those prone to impulsivity.  However, such experiments are fraught with complexity:
  • Transient changes induced by drugs may adjust the immediate levels of serotonin but may not demonstrate structural effects. 
    
  • Gene variants likely produce structural changes in the developing brain.  
  • Effects monitored in experiments are often tiny.  
  • Behavioral changes: Violence, Arson, Exhibitionism; seen in different test subjects may be difficult to compare.  
  • Monoamine oxidase has high gene/environment interactions undermining heritability estimates.  Its gene promotor is regulated by stress and glucocorticoids.  So non genetic factors such as childhood adversity and adult provocation appear to be significant.  
  concentrations, where there is relief from symptoms: worry, guilt is an emotion which alerts us to the risk of cheating on a friend.  To be culturally effective the individuals must have respect for the law.  Guilt is associated with activation of the posterior cingulate cortex. 
  ; linked to depression is a debilitating episodic state of extreme sadness, typically beginning in late teens or early twenties. This is accompanied by a lack of energy and emotion, which is facilitated by genetic predisposition - for example genes coding for relatively low serotonin levels, estrogen sensitive CREB-1 gene which increases women's incidence of depression at puberty; and an accumulation of traumatic events.  There is a significant risk of suicide: depression is involved in 50% of the 43,000 suicides in the US, and 15% of people with depression commit suicide.  Depression is the primary cause of disability with about 20 million Americans impacted by depression at any time.  There is evidence of shifts in the sleep/wake cycle in affected individuals (Dec 2015).  The affected person will experience a pathological sense of loss of control, prolonged sadness with feelings of hopelessness, helplessness & worthlessness, irritability, sleep disturbances, loss of appetite, and inability to experience pleasure.  Michael Pollan concludes depression is fear of the past.  It affects 12% of men and 20% of women.  It appears to be associated with androgen deprivation therapy treatment for prostate cancer (Apr 2016).  Chronic stress depletes the nucleus accumbens of dopamine, biasing humans towards depression.  Depression easily leads to following unhealthy pathways: drinking, overeating; which increase the risk of heart disease.   It has been associated with an aging related B12 deficiency (Sep 2016).  During depression, stress mediates inhibition of dopamine signalling.  Both depression and stress activate the adrenal glands' release of cortisol, which will, over the long term, impact the PFC.  There is an association between depression and additional brain regions: Enlarged & more active amygdala, Hippocampal dendrite and spine number reductions & in longer bouts hippocampal volume reductions and memory problems, Dorsal raphe nucleus linked to loneliness, Defective functioning of the hypothalamus undermining appetite and sex drive, Abnormalities of the ACC.  Mayberg notes ACC area 25: serotonin transporters are particularly active in depressed people and lower the serotonin in area 25 impacting the emotion circuit it hubs, inducing bodily sensations that patients can't place or consciously do anything about; and right anterior insula: which normally generates emotions from internal feelings instead feel dead inside; are critical in depression.  Childhood adversity can increase depression risk by linking recollections of uncontrollable situations to overgeneralizations that life will always be terrible and uncontrollable.  Sufferers of mild autism often develop depression.  Treatments include: CBT which works well for cases with below average activity of the right anterior insula (mild and moderate depression), UMHS depression management, deep-brain stimulation of the anterior insula to slow firing of area 25.  Drug treatments are required for cases with above average activity of the right anterior insula.  As of 2010 drug treatments: SSRIs (Prozac), MAO, monoamine reuptake inhibitors; take weeks to facilitate a response & many patients do not respond to the first drug applied, often prolonging the agony.  By 2018, Kandel notes, Ketamine is being tested as a short term treatment, as it acts much faster, reversing the effect of cortisol in stimulating glutamate signalling, and because it reverses the atrophy induced by chronic stress.   Genomic predictions of which treatment will be effective have not been possible because: Not all clinical depressions are the same, a standard definition of drug response is difficult;, which are treated with SSRI is a selective serotonin reuptake inhibitor:
  • Is a class of drugs used to treat anxiety and major depression. 
    
  • These limit reuptake of the modulatory neurotransmitter serotonin into the presynaptic vesicles in effect
    
  • Increases the level of active serotonin.  But boosting serotonin does not help all patients get better.  And SSRIs increase serotonin levels very rapidly, but people's mood and synaptic connection levels do not alter for weeks. 
    
  • Use increases the risk of: Suicide in children & adolescents, Osteoporosis, Bleeding by interacting with warfarin & aspirin, problems for patients with severe pre-existing cardiovascular disease. 
    
  s (Prozac).  Cognitive anxiety (extreme for worries and anxious thoughts) is also helped by yoga.  But many fear-related disorders respond better to psychotherapy is a treatment for psychiatric illnesses, using verbal signals exchanged between the patient and therapist within a supportive relationship.  There are various approaches:
  • Psychoanalysis, intially developed by Josef Breuer, where he applied free association.  Freud adopted the technique.  He applied it to his patients, concluding their problems originated in infancy and early childhood.  He observed:
    
  1. Children have sexual and aggressive behavioral instincts which
     
  2. The children suppress the socially unacceptible thoughts into their unconscious.  The suppressed thoughts can result in illness as the children grow into adults.  Free association can reveal the supressed ideas. 
     
  3. The patient develops a relationship, transference, with the therapist where their early relationships are reenacted.  Freud's analysis of his depressed patients suggested they had been in a hostile relationship.  Freud concluded this anger resulted in feelings of unworthyness and low self-esteem. 
     
  • CBT developed by University of Pennsylvania's Aaron Beck, whose depressed patients were not hostile to others, but consistently rated themselves as losers, having unrealistically high expectations of themselves, and struggled with disappointment. 
    
  : psychoanalysis, and intensive CBT is cognitive behavioral therapy.  It was originally designed to treat depression. Depressed patients demonstrated problems with how they perceived themselves in the world (cognitive style).  Aaron Beck proposed to identify their negative beliefs and then replace them with more positive thoughts.  CBT leverages cognitive and behavioral principles to cope with behaviors, induced by prior conditioning, which cannot be managed directly with rational thoughts.  Instead it assumes that one's relationship with maladaptive thinking and emotional bindings can be changed through antecedent strategies.  CBT is problem focused and action oriented.  Errors in thinking like: overgeneralizing, magnifying negatives, minimizing positives and catastrophizing are replaced with more realistic and effective thoughts.  CBT has been extended with prolonged exposure therapy and virtual reality exposure therapy, which have been used to treat PTSD, where the BLA learns the signals are no longer dangerous. 
  .  Tara Brach
  Tara Brach was worried from a young age that there was something terribly wrong with her: she like many others felt unworthy.  She responded by developing Radical Acceptance.  Brach then explains the steps in applying it: pause, greet what happens next with unconditional friendliness; allowing us to:
  

  • Initially attend to the sensations of our body, 
  • Accept the wanting self and discover its source of boundless love.  
  • Welcome fear with a widening attention, accept the pain of death and become free.  
  • Use adversity as a gateway to limitless compassion for ourselves and others.  
  • Focus on our basic goodness to counter Western culture turning anger, at being betrayed, towards ourselves.  Extend observing this goodness in everyone.  This enables the use of loving-kindness.  
  • Leverage friendships to understand more about our shared nature and strengthen Radical Acceptance.  
  • Realize our Buddha nature. 
    

  
  Complex adaptive system (CAS) theory describes the emergence of the dualistic self and the tree of life linked by the genetic code and machinery.  It provides an analog of the Buddhist presence. 
  
  
  notes that genuine freedom from fear is enabled by taking refuge is a Buddhist practice used to develop a mental model of safety and belonging.  Tara Brach explains there are three fundamental refuges: the Buddha, the dharma, and the sangha.  Each person can approach the refuges in a way that is sincere for them:
  • Buddha refuge can represent the way Siddhartha Gautama coped with his fears of the terrible Mara: meeting it with his full attention, and observing and welcoming it, rather than responding to the feelings emotionally.   And the devotional can seek safety in the living spirit of the Buddha's awakened heart and mind.  
  • Dharma refuge depends on realizing that everything in nature must change.  Buddhists can call upon the practices and teachings; they have developed over centuries, which highlight this truth.  And they can take refuge in these skills.  Lovingkindness mediation can be particularly helpful practices in fearful situations.  
  • Sangha refuge is the community of monks and nuns that are also practicing and taking refuge. 
    
  . 
  
• APC is an antigen presenting cell that activates the immune response, such as a dendritic cell is an APC that is critical to inflammatory state activation and control of the innate and adaptive immune systems and induction of tolerance during the system's steady-state.  Regulatory dendritic cells present environmental antigens to regulatory T-cells to induce immune tolerance.  It is possible to push abundant immature white blood cells to transform into dendritic cells in-vitro.  . 
  
• Aperture problem is the ambiguity introduced by sampling through a narrow peephole.  It is impossible to resolve direction of motion of a item sampled through the peephole for example. 
  
• Apicomplexa are a group of parasitic is a long term relationship between the parasite and its host where the resources of the host are utilized by the parasite without reciprocity.  Often parasites include schematic adaptations allowing the parasite to use the hosts modeling and control systems to divert resources to them or improve their chance of reproduction: Toxoplasma gondii.   alveolates are eukaryotes which include flattened vesicles in the outer cortical region. 
  , obligate endoparasites, which are distinguished in developing a unique organelle used to penetrate host cells within which the apicomplexa live. 
  
• Aplysia, a giant Californian marine snail has a limited neural network and large neurons, specialized eukaryotic cells include channels which control flows of sodium and potassium ions across the massively extended cell membrane supporting an electro-chemical wave which is then converted into an outgoing chemical signal transmission from synapses which target nearby neuron or muscle cell receptors.  Neurons are supported by glial cells.  Neurons include a:
  • Receptive element - dendrites
    
  • Transmitting element - axon and synaptic terminals.  The axon may be myelinated, focusing the signals through synaptic transmission, or unmyelinated - where crosstalk is leveraged. 
  • Highly variable DNA schema using transposons. 
    
  .  Eric Kandel used it as an experimental system for studying neurons and was able to explain how long term memory is recorded by the Aplysia neurons. 
  
• APM is alternative payment model, Medicare is a social insurance program that guarantees access to health insurance for Americans aged 65 and over, and younger people with disabilities and end stage renal disease or ALS.  Medicare is currently missing a cap on out-of-pocket costs and direct prescription drug coverage.  It includes:
  
  • Benefits
  • Part A: Hospital inpatient insurance.  As of Dec 2013 Medicare pays for home care in only limited circumstances, such as when a person needs temporary nursing care after a hospitalization.  Part A covers 20 days of inpatient rehabilitation at a SNF after discharge from inpatient care at a hospital. 
    
  • Part B: Medical insurance for non-hospital services including: doctor visits, tests, injectable drugs, ambulances, physical therapy;
    
  • Part C: Medicare Advantage 
  • Part D: indirect prescription drug coverage The MMA prohibits Medicare from directly negotiating drug prices. 
    
  • Eligibility
    
  • All persons 65 years of age or older who are legal residents for at least 5 years.  If they or a spouse have paid Medicare taxes for 10 years the Medicare part A payments are waived.  Medicare is legislated to become the primary health plan. 
    
  • Persons under 65 with disabilities who receive SSDI. 
    
  • Persons with specific medical conditions:
  • Have end stage renal disease or need a kidney transplant. 
    
  • They have ALS. 
    
  • Some beneficiaries are dual eligible. 
    
  • Part A requires the person has been admitted as an inpatient at a hospital.  This is constrained by a rule that they stay for three days after admission.  
    
  • Sign-up
  • Part A has automatic sign-up if the person is drawing social security.  Otherwise the person must sign-up for Part A and Part B. 
    
  • Should sign-up for Part B during the Initial Enrollment Period, of seven months centered around 65th birthday, online or at a social security office.  But if still covered by spouse's insurance or not yet retired then may only join during the 3 month general enrollment period (January to March) each year, with coverage initiated the following July.  Incremental yearly 10% penalties apply for not signing up at 65.  These penalties apply to all subsequent premiums. 
    
  • Premiums
  • Part A premium
  • Part B insurance premium
    
  • Part C & D premiums are set by the commercial insurer.  
  's risk based payments to organizations set up as ACO is an Accountable Care Organization. These are accredited bundles of companies which together try to offer Dartmouth-Hitchcock like business models (Dec 2015, Sep 2016) focused on wellness, improving the provision of primary care to a large group of Medicare patients, and rewarding doctors for preventing problems.  Advocate health illustrates the idea.  Robert Pearl notes that the transition is difficult: hospitals that find their efficiency improving should reduce the number of doctors they utilize.  But any doctors that are pushed out of the ACO will likely take their patients with them, undermining the revenues that support the FFV business.  The ACA regulates qualification to be a Medicare ACO.  Individual organizations within a Medicare shared savings ACO continue to submit their own claims and are paid by Medicare for FFS.  But the ACO is eligible for shared savings.  Within the shared savings program the CMS innovation center has setup advanced payment ACOs.  As an alternative to shared savings, in a Pioneer ACO, over time 50% of the FFS payments flow directly to the ACO as a bundled payment.  CMS has established quality measures for ACOs for Medicare.  The CMS program's purpose is to reward providers for reducing total cost of care for patients through prevention, disease management, and coordination. 
  
  • CMS initiated its Physician Group Practice Demonstration in 2005.  By 2008 the congressional budget office reported on Bonus-eligible organizations. 
    
  • CMS defines ACOs as organizations that "create incentives for health care providers to work together to treat an individual patient across care settings - including doctors' offices, hospitals and long-term care facilities."
  • CMS has developed APMs which include ACOs, and advanced APMs where the ACOs must be risk bearing. 
    
  • CMMI accepts providers' proposals to test various payment systems including shared savings and partial capitation.  
  • Private market ACOs have formed including: Providence Health & Services, Blue Shield California, Anthem Blue Cross, United Health Care, BCBS Minnesota, BCBS Illinois, Humana, CIGNA, Main Health Management Coalition, BCBS Massachusetts, Aetna.  
  s.  It includes track 1 ACOs which are not risk bearing.  APMs have to report various measures to CMS is the centers for Medicare and Medicaid services.  . 
  
• APOE is Apolipoprotein are lipoproteins without the lipid bound.  They allow lipids to form into water-soluble complexes and can thus act as lipid transfer carriers, and are also found operating as enzyme cofactors and receptor ligands.   E which is essential for normal catabolism of triglyceride-rich lipoproteins.  It is used by the liver is an emergent cellular system providing metabolic: Dietary compound metabolism and signalling: After gorging on sugar-rich foods the liver releases FGF21 hormone to dampen further eating activity; Detoxification, Regulation of glucose through glycogen storage (asprosin signalling from white adipose tissue); clotting, immune, exocrine and endocrine functions.  It is supplied with oxygen-rich blood via the hepatic artery and blood rich in semi-processed foodstuffs from the intestines & spleen via the hepatic portal vein.  It is constructed from: Hepatocytes which swim in the blood to process it, BECs, Stromal cells, Hepatic stellate cells, Kupffer cells, and blood vessels.  The embryonic endoderm cells invade the mesoderm to form the liver bud.  Subsequently the liver bud vascularizes and is colonized by hematopoietic cells.  The liver operates on a daily cycle (Aug 2018) allowing it time to recover from the stress of processing toxic substances.  In a healthy adult liver cells do not divide significantly.  But in a damaged liver, the liver cells shift back to a neonatal state to re-enter the cell cycle and rebuild the liver.  There are over 100 disorders of the liver.  Obesity and diabetes are associated with increased prevalence of these liver disorders worldwide. 
  , macrophages, and central nervous system where astrocytes use it to transport cholesterol to neurons, specialized eukaryotic cells include channels which control flows of sodium and potassium ions across the massively extended cell membrane supporting an electro-chemical wave which is then converted into an outgoing chemical signal transmission from synapses which target nearby neuron or muscle cell receptors.  Neurons are supported by glial cells.  Neurons include a:
  • Receptive element - dendrites
    
  • Transmitting element - axon and synaptic terminals.  The axon may be myelinated, focusing the signals through synaptic transmission, or unmyelinated - where crosstalk is leveraged. 
  • Highly variable DNA schema using transposons. 
    
  via APOE receptors. 
  
• ApoE4 is a gene variant which produces the E4 variant of APOE is Apolipoprotein E which is essential for normal catabolism of triglyceride-rich lipoproteins.  It is used by the liver, macrophages, and central nervous system where astrocytes use it to transport cholesterol to neurons via APOE receptors. 
  .  It is a risk-factor for late-onset sporadic Alzheimer's disease is a dementia which correlates with deposition of amyloid plaques in the neurons.  As of 2015 there are 5 million Alzheimer's patients in the USA.  It was originally defined as starting in middle age which is rare, so it was a rare dementia.  But in 1980s it was redefined as any dementia without another known cause. Early indications include mood and behavioral changes (MBI) and declarative memory and thinking problems (MCI).  Specific cells within the hippocampal circuitry and its gateway, the entorhinal cortex, are damaged.  The amygdala, cerebelum and other areas supporting implicit memory are not impacted during the early stages of the disease.  Grid cell destruction results in a sense of being lost.  The default mode network is disrupted.  Variants include: late-onset sporadic; with risk factors - ApoE4 for late onset Alzheimer's, presenilin, androgen deprivation therapy (Dec 2015), type 2 diabetes.  There are multiple theories of the mechanism of Alzheimer's during aging: Allen Roses argues that it is due to gene alleles that limit the capacity of mitochondria to support neuron operation, Neurons of sporadic Alzheimer's sufferers show greater APP gene diversity due to somatic recombination; It may be initiated by: stress induced HHV-6a, HHV7 herpes activation (Jun 2018) and or an increasingly leaky blood-brain barrier; and a subsequent innate immune response to the infections (May 2016).  The Alzheimer's pathway follows:
  • Plaques form.  These are seen in fMRIs 10 to 15 years prior to detecting memory and thinking changes.  APP deployed in the cell membrane is cut into three parts.  The external part becomes amyloid-beta peptide which aggregates into Amyloid plaques, external to the neurons, if too much is generated or it is not removed fast enough. 
    
  • Solanezumab aimed to inhibit plaque formation but clinical trials failed (Nov 2016). 
    
  • Encouraging the garbage collection of amyloid and tau with gamma rhythms stimulation retards Alzheimer's in mice studies (Mar 2019)
    
  • BACE inhibitors block an enzyme needed to form amyloid. 
    
  • Mutation driven misfolded Tau proteins can form tangles within the cytoplasm of neurons.  The Tau tangles kill nerve cells.  LMTX is a drug treatment targeted at these tangles. 
    
  • The brain becomes inflamed resulting in the killing of many more nerve cells.  The hippocampus disintegrates and the brain loses critical functions and memory loss becomes noticeable. 
    
  .  Being homozygote for E4 does not imply getting Alzheimer's but does increase the risk 20 fold.  ApoE2 may reduce the risk of Alzheimer's.  It appears that ApoE4 differentially affects women.  Apoe4 is known to be broken down into fragments which impare mitochondrial operation.  It also promotes amyloid plaque buildup.  Therapies are being developed based on small molecules which reshape ApoE4 to be more like ApoE3 reducing the breakdown.   
  
• Apolipoproteins are lipoproteins without the lipid bound.  They allow lipids to form into water-soluble complexes and can thus act as lipid transfer carriers, and are also found operating as enzyme cofactors and receptor ligands.  
• Apoptosis, programmed cell death is a signal, is an emergent capability which is used by cooperating agents to support coordination & rival agents to support control and dominance.  In eukaryotic cells signalling is used extensively.  A signal interacts with the exposed region of a receptor molecule inducing it to change shape to an activated form.  Chains of enzymes interact with the activated receptor relaying, amplifying and responding to the signal to change the state of the cell.  Many of the signalling pathways pass through the nuclear membrane and interact with the DNA to change its state.  Enzymes sensitive to the changes induced in the DNA then start to operate generating actions including sending further signals.  Cell signalling is reviewed by Helmreich.  Signalling is a fundamental aspect of CAS theory and is discussed from the abstract CAS perspective in signals and sensors.  In AWF the eukaryotic signalling architecture has been abstracted in a codelet based implementation.  To be credible signals must be hard to fake.  To be effective they must be easily detected by the target recipient.  To be efficient they are low cost to produce and destroy. 
  initiated DNA (DNA), a polymer composed of a chain of deoxy ribose sugars with purine or pyrimidine side chains.  DNA naturally forms into helical pairs with the side chains stacked in the center of the helix.  It is a natural form of schematic string.  The purines and pyrimidines couple so that AT and GC pairs make up the stackable items.  A code of triplets of base pairs (enabling 64 separate items to be named) has evolved which now redundantly represents each of the 20 amino-acids that are deployed into proteins, along with triplets representing the termination sequence.  Chemical modifications and histone binding (chromatin) allow cells to represent state directly on the DNA schema.  To cope with inconsistencies in the cell wide state second messenger and evolved amplification strategies are used.   controlled process which results in eukaryotic is a relatively large multi-component cell type.  It initially emerged from prokaryotic archaea subsuming eubacteria, from which single and multi-celled plants, multi celled fungi, including single-cell variant yeast, drips, protozoa and metazoa, including humans, are constructed.  A eukaryotic cell contains modules including a nucleus and production functions such as chloroplasts and mitochondria. 
  cells self-destructing.  
• APP is Amyloid Precursor Protein.  It is encoded by the gene presenilin is a gene which encodes the APP.  John Hardy of UCL followed a family with a history of Alzheimer's disease who inherited the gene with a mutation that supported amyloidosis.  . 
  
• Appreciation of natural beauty is an emotion are low level fast unconscious agents distributed across the brain and body which associate, via the amygdala and rich club hubs, important environmental signals with encoded high speed sensors, and distributed programs of action to model: predict, prioritize guidance signals, select and respond effectively, coherently and rapidly to the initial signal.  The majority of emotion centered brain regions interface to the midbrain through the hypothalamus.  The cerebellum and basal ganglia support the integration of emotion and motor functions, rewarding rhythmic movement.  The most accessible signs of emotions are the hard to control and universal facial expressions.  Emotions provide prioritization for conscious access given that an animal has only one body, but possibly many cells, with which to achieve its highest level goals.  Because of this, base emotions clash with group goals and are disparaged by the powerful.  Pinker notes a set of group selected emotions which he classes as: other-condemning, other-praising, other-suffering and self-conscious emotions.  Evolutionary psychology argues evolution shaped human emotions during the long period of hunter-gatherer existence in the African savanna.  Human emotions are universal and include: Anger, Appreciation of natural beauty, Contempt, Disgust, Embarrassment, Fear, Gratitude, Grief, Guilt, Happiness, Honor, Jealousy, Liking, Love, Moral awe, Rage, Romantic love, Lust for revenge, Passion, Sadness, Self-control, Shame, Sympathy, Surprise; and the sham emotions and distrust induced by reciprocal altruism. 
  which derives from the benefit to hunter-gatherers is a lifestyle organized around a band of relatives, evolved in humans focused on capturing the cognitive niche in the African savanna.  It is of great significance in shaping our minds: behaviors, emotions, creativity, intelligence; and developing survival strategies including use of fire and language, according to evolutionary psychologists.  It was practiced by all humans, for most of Homo sapiens existence, until the emergence of farming, and still is by some isolated bands: Ju/'hoansi, New Guinea: Gebusi, Mae Enga; & Borneo head hunters, Maasai & Zulu warriors from Africa, Amazonians: Waorani, Jivaro; Brazilian and Venezuelan Yanomamo.  Since the band moves on when it has depleted the resources in an area of land, the soil remains vibrant, but the large animals were typically placed in a position of stress from which they did not recover. 
  of recognizing and seeking out the African savanna is the environment where hunter-gatherers primarily evolved.  Its grassland supported large herbivores that could be hunted easily across the plains.  Clumps of Acacia trees: with short trunks, and broad bows; & rocks supported places to hide from large carnivores.  Streams, especially important in times of drought, and paths add to the signals enabling orientation. 
  setting in which humans evolved.  
• Arden Syntax is an HL7 standard.  It is a grammar for representing medical conditions and recommendations.  
• Area 25 is the Subcallosal Cingulate Cortex, an area of the ACC is either the
  
  • Anterior cingulate cortex which:
  • Includes the subgenual ACC and the paragenual ACC, and Brodmann areas 24, 25, 32 and 33. 
    
  • The gyrus of the ACC has two functional components, which both operate abnormally in mood disorders: depression, anxiety & bipolar.  The
    
  • Rostral/ventral part is involved in emotional processes and autonomic functions.  It connects to the hippocampus, amygdala, orbital prefrontal cortex, anterior insula, nucleus accumbens.  It is overactive during regular or bipolar depression. 
    
  • Caudal part is involved in cognition and the control of behavior.  It connects with the dorsal PFC, secondary motor cortex, and posterior cingulate cortex
    
  • Is a central focus of empathy supporting people relating to other's pain.  This is dependent on oxytocin. 
    
  • In non-human mammals it processes interoceptive signals.  The ACC focuses the internal signals into high level 'gut intuitions.'  Pain catches the ACC's attention. 
    
  • Performs discrepancy detection from the outcome that was predicted - at a high level.  The ACC cares about the meaning of what is predicted. 
    
  • If the ACC has been convinced that a pain killer placebo has inhibited pain signals, the ACC will stay silent about actual pain that is signalled from interoceptive networks.  
  • The ACC will signal: physical pain, emotional pain, metaphorical pain, anxiety, disgust, embarrassment, social exclusion especially in adolescence; as one and the same.  The ACC's abnormalities being associated with major depression. 
    
  • Has a bridging role between the empathetic and self-interested pain monitor.  Sapolsky notes the ACC is essential for learning fear and conditioned avoidance by observation alone through an intermediate step of shared representation of self.  He concludes "At its core the ACC is about self-interest, with caring about the other person in pain as an add-on." 
    
  • American College of Cardiology
    
  , which Kandel explains, is a region where thought, motor control and drive come together.  It is rich in neurons, specialized eukaryotic cells include channels which control flows of sodium and potassium ions across the massively extended cell membrane supporting an electro-chemical wave which is then converted into an outgoing chemical signal transmission from synapses which target nearby neuron or muscle cell receptors.  Neurons are supported by glial cells.  Neurons include a:
  • Receptive element - dendrites
    
  • Transmitting element - axon and synaptic terminals.  The axon may be myelinated, focusing the signals through synaptic transmission, or unmyelinated - where crosstalk is leveraged. 
  • Highly variable DNA schema using transposons. 
    
  generating serotonin is a neurotransmitter.  it is:
  • Inversely associated with: human impulsive, cricket, mollusk, crustacean; aggression.  Low levels of serotonin are associated with impulsive aggression ranging from psychological measures of hostility to overt violence and cognitive impulsivity and impulsive suicide. 
    
  • Nearly all synthesized in the Raphe nucleus.  Tryptophan hydroxylase makes serotonin from the amino-acid tryptophan.  Monoamine oxidase degrades serotonin.  The serotonin receptor binds serotonin to initiate cross membrane signalling.  The serotonin transporter actively removes serotonin from synapses.  Serotonin levels can be increased with: exercise, high light levels, consumption of chickpeas and traditional lime boiled corn tortillas.  Reuptake is inhibited by SSRIs.  Variants of the genes coding for these various enzymes alter the strength of their effects. 
    
  • Increasing serotonin signalling does not lessen impulsiveness in normal subjects but did in those prone to impulsivity.  However, such experiments are fraught with complexity:
  • Transient changes induced by drugs may adjust the immediate levels of serotonin but may not demonstrate structural effects. 
    
  • Gene variants likely produce structural changes in the developing brain.  
  • Effects monitored in experiments are often tiny.  
  • Behavioral changes: Violence, Arson, Exhibitionism; seen in different test subjects may be difficult to compare.  
  • Monoamine oxidase has high gene/environment interactions undermining heritability estimates.  Its gene promotor is regulated by stress and glucocorticoids.  So non genetic factors such as childhood adversity and adult provocation appear to be significant.  
  transporters.  It is directly involved in a signalling, is an emergent capability which is used by cooperating agents to support coordination & rival agents to support control and dominance.  In eukaryotic cells signalling is used extensively.  A signal interacts with the exposed region of a receptor molecule inducing it to change shape to an activated form.  Chains of enzymes interact with the activated receptor relaying, amplifying and responding to the signal to change the state of the cell.  Many of the signalling pathways pass through the nuclear membrane and interact with the DNA to change its state.  Enzymes sensitive to the changes induced in the DNA then start to operate generating actions including sending further signals.  Cell signalling is reviewed by Helmreich.  Signalling is a fundamental aspect of CAS theory and is discussed from the abstract CAS perspective in signals and sensors.  In AWF the eukaryotic signalling architecture has been abstracted in a codelet based implementation.  To be credible signals must be hard to fake.  To be effective they must be easily detected by the target recipient.  To be efficient they are low cost to produce and destroy. 
  
  This page discusses the effect of the network on the agents participating in a complex adaptive system (CAS).  Small world and scale free networks are considered. 
  
  network with: amydala contains > 12 distinct areas: Central, Lateral.  It receives simple signals from the lower parts of the brain: pain from the PAG; and abstract complex information from the highest areas: Disgust, heart rate, and suffering from the insula cortex, allowing it to orchestrate emotion.  It connects strongly to attention focusing networks.  It sends signals to almost every other part of the brain, including to the decision making circuitry of the frontal lobes.  It has high levels of D(1) dopamine receptors.  During extreme fear the amygdala drives the hippocampus into fear learning.  It outputs directly to subcortical reflexive motor pathways when speed is required.  Its central nucleus projects to the BNST.  It signals the locus ceruleus.  It directly signals area 25.  The amygdala:
  
  • Promotes aggression.  Stimulating the amygdala promotes rage.  It converts anger into aggression and when impaired it impacts the ability to detect angry facial expressions.  
  • Participates in disgust
  • Perceives fear promoting stimuli, focusing our attention on these.  In PTSD sufferers the Amygdala overreacts to mildly fearful stimuli and is slow to calm down and the amygdala expands in size over a period of months.  Fear is processed by the lateral nucleus which serves as the input from various senses, and the central nucleus which outputs to the brain stem (central grey - freezing, lateral hypothalamus - blood pressure, activates paraventricular hypothalamus => crf -> hormone adjustments). 
    
  • Has lots of receptors for and is highly sensitive to glucocorticoids.  Stress inhibits the GABA interneurons in the basolateral amygdala (BLA) allowing the excitatory glutamate releasing neurons to excite more. 
    
  • Is sensitive to unsettling/uncertain social situations where it promotes anxiety and makes us distracted.  It is also interested in uncertain but potentially painful situations.  The amygdala contributes to social and emotional decision making where the BLA supports rejecting an unacceptable offer, as allowed in the Ultimatum Game, by injecting implicit mistrust and vigilance, generating an anger driven rejection that is used as punishment.  The amygdala is very rapidly excited by subliminal signals from the thalamus of outgroup skin color.  The amygdala subsequently tips social emotions against outgroups unless restrained by the frontal lobe or influenced by subliminal priming to prioritize inclusion.  The fast path from the thalamus rapidly but inaccurately signals its identified a weapon. 
    
  • Sees suffering of others as increasingly salient with loving-kindness meditation practice, Goleman & Davidson explain. 
    
  • Promotes male, but not female, sexual motivation when it is an uncertain potential pleasure. 
    
  • Responds to the longing for uncertain potential pleasures and fear that the reward will not be worth it if it happens.  The amygdala turns off during orgasm. 
    
  • Uses but is not directly involved in vision.  
  , hypothalamus is essential to many instinctive operations of the body.  It can be viewed as the executor of emotion: happiness, sadness, aggression, eroticism and mating, relaying the amygdala's responses to low level sensory signals.  It has many small sub-regions whose main functions are to regulate hunger, thirst, temperature, sexual behavior, parenting, heart rate, blood pressure, sleep cycles, and similar body operations.  Kandel notes it includes a nucleus containing two distinct populations of neurons: one that regulates aggression and one that regulates sex and mating.  At the intersection neurons are active in both.  Depending on the intensity of the stimulus applied to these neurons mating (weak) or aggression (danger) is activated.  This probably contributes to sexual rage and is why some couples derive extra pleasure from sexual experiences following an argument.  The hypothalamus's (paraventricular nucleus) is closely connected to the pituitary which secrets hormones into the bloodstream ( => acth -> adrenal cortex => cortisol (+)->  amygdala & (-)-> hippocampus).  It directly signals area 25. 
  , hippocampus is a part of the medial temporal lobe of the brain involved in the temporary storage or coding of long-term episodic memory.  It includes the dentate gyrus.  Memory formation in the cells of the hippocampus uses the MAP kinase signalling network which is impacted by sleep deprivation.  The hippocampus dependent memory system is directly affected by cholinergic changes throughout the wake-sleep cycle.  Increased acetylcholine during REM sleep promotes information attained during wakefulness to be stored in the hippocampus by suppressing previous excitatory connections while facilitating encoding without interference from previously stored information.  During slow-wave sleep low levels of acetylcholine cause the release of the suppression and allow for spontaneous recovery of hippocampal neurons resulting in memory consolidation.  It was initially associated with memory formation by McGill University's Dr. Brenda Milner, via studies of 'HM' Henry Molaison, whose medial temporal lobes had been surgically destroyed leaving him unable to create new explicit memories.  The size of neurons' dendritic trees expands and contracts over a female rat's ovulatory cycle, with the peak in size and cognitive skills at the estrogen high point.  Adult neurogenesis occurs in the hippocampus (3% of neurons are replaced each month) where the new neurons integrate into preexisting circuits.  It is enhanced by learning, exercise, estrogen, antidepressants, environmental enrichment, and brain injury and inhibited by various stressors explains Sapolsky.  Prolonged stress makes the hippocampus atrophy.  He notes the new neurons are essential for integrating new information into preexisting schemas -- learning that two things you thought were the same are actually different.  Specific cells within the hippocampus and its gateway, the entorhinal cortex, are compromised by Alzheimer's disease.  It directly signals area 25. 
  , insula cortex is part of the cerebral cortex folded deep within the lateral sulcus.  It includes: anterior, posterior insula; and is overlaid by the operculum.  Kandel notes the anterior insula is where feelings are calibrated by evaluating and integrating the importance of the stimuli.  It directly signals area 25.  LeDoux showed there are two routes for signals of feelings and emotions to the amygdala: a fast unconscious one and a slow one that involves the anterior insula.  So the insula is assumed to participate in consciousness where it has been linked to emotion, salience & body homeostasis functions:
  
  • Perception,
    
  • Motor control: Hand-&-eye motor movement, Swallowing, Gastric motility, Speech articulation;
    
  • Self-awareness,
    
  • Inter-personal experiences: Disgust at smells, contamination & mutilation which generate visceral responses, that are projected to the amygdala; binding physical and moral aspects of purity (Macbeth effect)
  • Suffering of others can be projected by the insula to the amygdala and made increasingly salient with loving-kindness meditation practice, Goleman & Davidson explain. 
    
  • Homeostatic regulation of the sympathetic network, parasympathetic network, and immune system.  Heart rate and sweat gland activity are monitored.   When the amygdala signals concern, the insula prepares the body for action, increasing blood flow to the muscles etc.
    
  ; that integrates thinking and emotion are low level fast unconscious agents distributed across the brain and body which associate, via the amygdala and rich club hubs, important environmental signals with encoded high speed sensors, and distributed programs of action to model: predict, prioritize guidance signals, select and respond effectively, coherently and rapidly to the initial signal.  The majority of emotion centered brain regions interface to the midbrain through the hypothalamus.  The cerebellum and basal ganglia support the integration of emotion and motor functions, rewarding rhythmic movement.  The most accessible signs of emotions are the hard to control and universal facial expressions.  Emotions provide prioritization for conscious access given that an animal has only one body, but possibly many cells, with which to achieve its highest level goals.  Because of this, base emotions clash with group goals and are disparaged by the powerful.  Pinker notes a set of group selected emotions which he classes as: other-condemning, other-praising, other-suffering and self-conscious emotions.  Evolutionary psychology argues evolution shaped human emotions during the long period of hunter-gatherer existence in the African savanna.  Human emotions are universal and include: Anger, Appreciation of natural beauty, Contempt, Disgust, Embarrassment, Fear, Gratitude, Grief, Guilt, Happiness, Honor, Jealousy, Liking, Love, Moral awe, Rage, Romantic love, Lust for revenge, Passion, Sadness, Self-control, Shame, Sympathy, Surprise; and the sham emotions and distrust induced by reciprocal altruism. 
  to plan and respond effectively.  Kandel notes whenever area 25 becomes hyperactive, the components of this circuit associated with emotion are disconnected from the thinking brain resulting in a loss of personal identity. 
• Area MT is the middle temporal motion area MT (V5 is visual cortex area 5 also called area MT.  ) located in the occipital lobe of the cerebral cortex includes the primary visual cortex area V1.  It performs early stages of visual analysis supporting recognition of shapes, colors and objects.  .  It contains many neurons, specialized eukaryotic cells include channels which control flows of sodium and potassium ions across the massively extended cell membrane supporting an electro-chemical wave which is then converted into an outgoing chemical signal transmission from synapses which target nearby neuron or muscle cell receptors.  Neurons are supported by glial cells.  Neurons include a:
  • Receptive element - dendrites
    
  • Transmitting element - axon and synaptic terminals.  The axon may be myelinated, focusing the signals through synaptic transmission, or unmyelinated - where crosstalk is leveraged. 
  • Highly variable DNA schema using transposons. 
    
  detecting motion.  Each neuron suffers from aperture problems is the ambiguity introduced by sampling through a narrow peephole.  It is impossible to resolve direction of motion of a item sampled through the peephole for example. 
  but consciousness resolves the ambiguity with a most likely current Bayesian is an iterative form of statistics invented by Thomas Bayes.  It uses a 'prior' statistic to represent the prior situation and then performs a calculation that integrates the probability of new events occurring into a 'posterior' probability.  This posterior becomes the prior for the next iteration with the application of the Bayesian identity xpost = xprior*y/(xprior*y + z(1-xprior)).  The magic in Bayesian statistics is in accurately generating the prior xprior and the current event probabilities y and z.  R. A. Fischer was so skeptical of the legitimacy of the prior that he advocated an alternative statistical framework and experimental process.   sampling.  The resolution takes
  Carlo Rovelli resolves the paradox of time. 
  Rovelli initially explains that low level physics does not include time:
  

  • A present that is common throughout the universe does not exist
    
  • Events are only partially ordered.  The present is localized
  • The difference between past and future is not foundational.  It occurs because of state that through our blurring appears particular to us
  • Time passes at different speeds dependent on where we are and how fast we travel
    
  • Time's rhythms are due to the gravitational field
    
  • Our quantized physics shows neither space nor time, just processes transforming physical variables. 
    
  • Fundamentally there is no time.  The basic equations evolve together with events, not things 

  Then he explains how in a physical world without time its perception can emerge:
  

  • Our familiar time emerges
    
  • Our interaction with the world is partial, blurred, quantum indeterminate
    
  • The ignorance determines the existence of thermal time and entropy that quantifies our uncertainty
    
  • Directionality of time is real but perspectival.  The entropy of the world in relation to us increases with our thermal time.  The growth of entropy distinguishes past from future: resulting in traces and memories
    
  • Each human is a unified being because: we reflect the world, we formed an image of a unified entity by interacting with our kind, and because of the perspective of memory
    
  • The variable time: is one of the variables of the gravitational field.  With our scale we don't register quantum fluctuations, making space-time appear determined.  At our speed we don't perceive differences in time of different clocks, so we experience a single time: universal, uniform, ordered; which is helpful to our decisions

  
  
  time.  Neuronal recordings show the inference may take a tenth of a second.  In the meantime MT neurons see only local motion.  Subsequently they encode the global direction.  Subjective consciousness sees only the end result.  The global resolution requires consciousness vanishing under anesthesia is the temporary removal of sensation.  It can be local, regional or general. 
  .  Consciousness enables the iterative exchange of modeling results resulting in eventual agreement.  
  
• Arms race, in a war where both sides use the strategy of development and use of advanced weapon systems to gain an advantage, each advance induces the other side to respond with its own
  This page introduces a series of asymmetries which encourage different strategic approaches.   
  The differences found in business, sexual selection, gamete structure, as well as in chess encourage escalations in the interactions. 
  And yet the systems including these asymmetries can be quite stable. 
  
  asymmetric advances.  Neither side will necessarily gain the upper hand in which case the weapon systems themselves advance rapidly with little direct benefit for the combatants.  
• Aromatase inhibitors limit the synthesis of estrogen by aromatase.  Breast is a variety of different cancerous conditions of the breast tissue.  World wide it is the leading type of cancer in women and is 100 times more common in women than men.  260,000 new cases of breast cancer will occur in the US in 2018 causing 41,000 deaths.  The varieties include: Hormone sensitive tumors that test negative for her2 (the most common type affecting three quarters of breast cancers in the US, BRCA1/2 positive, ductal carcinomas including DCIS, lobular carcinomas including LCIS.  Receptor presence on the cancer cells is used as a classification: Her2+/-, estrogen (ER)+/-, progesterone (PR)+/-.  Metastasis classes the cancer as stage 4.  Genetic risk factors include: BRCA, p53, PTEN, STK11, CHEK2, ATM, GATA3, BRIP1 and PALB2.  Treatments include: Tamoxifen, Raloxifene; where worrying racial disparities have been found (Dec 2013).  International studies indicate early stage breast cancer typed by a genomic test: Oncotype DX, MammaPrint; can be treated without chemotherapy (Aug 2016, Jun 2018) and ovarian cancer is a relatively uncommon disease but is often fatal.  It has been associated with use of talcum powder (May 2016).  s grow more stimulated by estrogen. 
  
• ARRA is the American Recovery and Reinvestment Act of 2009.  It included health care provisions:
• COBRA payments
• Funds to help states with Medicaid is the state-federal program for the poor.  Originally part of Lyndon Johnson's 1965 Bill, eligibility and services vary by state.  Medicaid currently pays less for care than Medicare, resulting in many care providers refusing to participate in the program.  Less than 10 percent of Medicaid recipients, those in long-term care including nursing homes where 64% are dependent on Medicaid, use one-third of all Medicaid spending which is a problem.  The ACA's Medicaid expansion program, made state optional by the SCOTUS decision, was initially taken up by fifty percent of states.  As of 2016 it covers 70 million Americans at a federal cost of $350 billion a year.  In 2017 it pays for 40% of new US births. 
  . 
  
• $20 billion to modernize health care IT systems.  
  
• $10 billion for health care research
• ART is an ARV is antiretroviral treatments for H.I.V. infection, such as abacavir. 
  therapy for H.I.V is human immunodeficiency virus, an RNA retrovirus which causes AIDS.  It infects T-lymphocytes helper cells slowly destroying the host's immune system.  The main pandemic form of HIV is HIV-1 M which has been traced back to a spillover to Cameroon/Congolese forest Chimpanzees of SIVs that weakly infected proximate humans and then was amplified by social conditions in expanding towns: Ouesso, Brazzaville, Leopoldville; down river from these forests during the 1900 - 1920s.  Additional amplification occurred through public health programs: Trypanosomiasis, STDs; which cross-infected subpopulations of Leopoldville/Kinshasa around the same time.  UNESCO organized Haitian support for the DRC in the 1960s vectored HIV-1 M back to Haiti where the blood plasma trade provided an evolved amplifier for HIV-1 M infected plasma to flow into the US healthcare supply chain through Miami.  Some HIV's enter the lymphocytes by leveraging the T cells CCR5 protein.  The HIV X4 variant leverages CXCR4. 
  .  ART is a cocktail of drugs, such as the three in HAART is highly active ARV therapy using a combination of at least three drugs that supress HIV replication. 
  , which prevents the virus is a relatively small capsule containing genetic material: RNA, DNA; which utilizes the cellular infrastructure of its target host to replicate its genetic material and operational proteins.  David Quammen explains the four key challenges of viruses: Getting from one host to another, penetrating a cell within the host, commandeering the cell's infrastructure, escaping from the cell and organism; Single-stranded RNA viruses: Coronavirus, chickungunya, dengue, Ebola, Hantas, Hendra, Influenzas, Junin, Lassa, Machupo, Marburg, Measles, Mumps, Nipah, Rabies, Retrovirus (HIV), Rhinovirus, yellow fever; are subject to more mutation events than DNA viruses, but limits the size of the genetic string.  Double stranded DNA viruses: baculoviruses, hepadnaviruses, Herpesviruses, iridoviruses, papillomavirses, poxviruses; can leverage relatively far larger genetic payloads.  The relationship with the reservoir host is long-term, a parasitic or symbiotic relationship, developing over millions of years.  But opportunistically, it may spillover into a secondary host, with the virus entering the host cell, leveraging the host infrastructure to replicate its self massively and then exiting the host cell by rupturing it and killing the organism. 
  from replicating leaving it dormant so AIDS is acquired auto-immune deficiency syndrome, a pandemic disease caused by the HIV.  It also amplifies the threat of tuberculosis.   Initially deadly, infecting and destroying the T-lymphocytes of the immune system, it can now be treated with HAART to become a chronic disease.  And with an understanding of HIV's mode of entry into the T-cells, through its binding to CCR5 and CD4 encoded transmembrane proteins, AIDS may be susceptible to treatment with recombinant DNA to alter the CCR5 binding site, or with drugs that bind to the CCR5 cell surface protein preventing binding by the virus.  Future optimization of drug delivery may leverage nanoscale research (May 2016). 
  does not develop. 
  
• Artemisinin is a highly effective anti-malarial.  It was initially identified by Tu Youyou in China, where it was extracted from sweet wormwood.  Berkeley professor Jay Keasling subsequently programmed yeast to make artemisinin.  Sanofi started to manufacture the yeast engineered artemisinin in 2014. 
  
• ARV is antiretroviral treatments for H.I.V. is human immunodeficiency virus, an RNA retrovirus which causes AIDS.  It infects T-lymphocytes helper cells slowly destroying the host's immune system.  The main pandemic form of HIV is HIV-1 M which has been traced back to a spillover to Cameroon/Congolese forest Chimpanzees of SIVs that weakly infected proximate humans and then was amplified by social conditions in expanding towns: Ouesso, Brazzaville, Leopoldville; down river from these forests during the 1900 - 1920s.  Additional amplification occurred through public health programs: Trypanosomiasis, STDs; which cross-infected subpopulations of Leopoldville/Kinshasa around the same time.  UNESCO organized Haitian support for the DRC in the 1960s vectored HIV-1 M back to Haiti where the blood plasma trade provided an evolved amplifier for HIV-1 M infected plasma to flow into the US healthcare supply chain through Miami.  Some HIV's enter the lymphocytes by leveraging the T cells CCR5 protein.  The HIV X4 variant leverages CXCR4. 
  infection, such as abacavir is a nucleoside reverse transcriptase inhibitor, an ARV medication, branded as Ziagen, which is used in the prevention and constraint of AIDS.  It is a WHO essential medicine.  Its use is problematic in about 6% of the patient base.  Pharmacogenomics allows these patients to be identified and treated with an alternative ARV. 
  . 
  
• ASC is either:
  
• An ambulatory surgery center providing same day surgical care, or
  
• The accredited standards committee responsible for standard X.12. 
  
• ASC X12N is the insurance (N) subcommittee of the X12 EDI and XML ASC is either:
  
  • An ambulatory surgery center providing same day surgical care, or
    
  • The accredited standards committee responsible for standard X.12. 
    
  accredited by ANSI. 
  
• ASCA is the Administrative Simplification Compliance Act of 2002.  Public Law 107-105 implemented as regulation 42 CFR 424.32.  It alters the SSA is the social securities act of 1935 was part of the second New Deal.  It attempted to limit risks of old age, poverty and unemployment.  It is funded through payroll taxes via FICA and SECA into the social security trust funds.  Title IV of the original SSA created what became the AFDC.  The Social Security Administration controls the OASI and DI trust funds.  The funds are administered by the trustees.  The SSA was amended in 1965 to include:
  • Title V is Maternal and child health services. 
    
  • Title XVIII is Medicare.  
  to make electronic claims submission a mandatory requirement for some classes of health care providers, health plans and health care clearing houses.  
• ASD is autism is a major hereditary mental disorder that starts before age three when it features: a strong preference to be alone, a desire for things to stay the same, and areas of creative ability - they see the ordinary as beautiful and have special talents for: poetry, foreign languages, music, art, and calculations.  They generate less but more original ideas.  It occurs as a spectrum of symptoms, from mild to severe, across the population of sufferers (ASD).  Before age two the circumference of an autistic child's head is larger than typical and regions: amygdala, frontal lobe; develop prematurely, altering activity in other regions.  Autism highlights aspects of the brain's specialized regions and processes for interacting with other people.  Autistic's interests are restricted.  They struggle with social interactions & verbal and nonverbal communications.  Autistics do not attribute minds to other people: attributing mental states to others allows us to predict their behavior; a critical skill for social learning and interaction.  While their visual area MT detects motion, the superior temporal sulcus does not respond to biological motion in autistics, undermining the understanding of intention.  And they gaze at mouths rather than eyes when looking at faces.  The default mode network is disrupted.  Autistic adolescents have unusually large numbers of synapses, because of a failure of synaptic pruning.  Autistics almost never pretend.  They can't explain the difference between an instance of an object and a memory of it.  Mild autism still maintains some pressure to conform socially and often results in depression and anxiety.  Autism occurs in every country and social class.  It lasts a lifetime.  It has genetic and neurological causes.  Identical twins are 90% likely to both have autism if one of them does.  With 50% of genes active in the brain, mutations are likely to impact the development and operation of the brain.  The genes: SHANK3, CDH10; are involved but account for a very small percentage of the risk.  Facial gaze studies indicate a high genetic influence and an opportunity to identify more genes associated with autism (Jul 2017).  Copy number variations: an extra copy of a segment of 25 genes of chromosome 7 increases the risk of ASD, while deletion of the segment causes Williams syndrome; and de novo mutations which drive up the number of autism cases as paternal age has increased in the US.  ASD is associated with a reduced fusiform face area response.  Tests [in development] for autism include: SynapDx's blood test. 
  spectrum disorder.  All these disorders are characterized by difficulty connecting with others.  People who suffer from ASD show a reduced fusiform is a region of the brain which supports advanced mechanisms of shape recognition and implements the early stages of reading.  Subliminal priming with words did not depend on the shape of the word.  The fusiform gyrus was able to process the abstract identity of a word without caring if it was upper or lower case.   While high up in the cortex it can operate below the level of conscious experience.  It contributes to social emotions with:
  
  • Its face area being more activated by faces with in-group skin color.  
  • It activating when shown pictures of cars in automobile aficionados. 
    
  • It activating when shown pictures of birds in birdwatchers; since it really recognizes examples of items from an individual's emotionally salient categories. 
    
  response to faces.  ASD is linked to gene variants affecting oxytocin is a peptide hormone which makes humans more prosocial to and socially competent in their in-group and more antisocial to everyone else.  The effects are contingent; changing during stress and in the presence of a threatening out-group.  Oxytocin makes people look at eyes longer, encouraging improved accuracy at perceiving emotions.  It enhances activity in the TPJ supporting modeling of other people's thinking.  Dogs and their owners secrete oxytocin increasing the amount of eye contact between them.  It is associated with pair bonding.  Brizendine explains that oxytocin and dopamine production are stimulated by ovarian estrogen at the onset of puberty, encouraging girls to connect and bond with their girlfriends, reducing stress, and exclude the out-group.  It is central to female mammals wanting to nurse, nursing, and remembering their child.  Its effects are context dependent and so is the regulation of the genes that control oxytocin.  Variants of a gene CD38 which facilitates oxytocin secretion from neurons are associated with differing levels of activation of the fusiform face area when looking at faces.  Sapolsky describes an oxytocin receptor gene variant that is associated with children showing: Extreme aggression, A callous unemotional style; foreshadowing adult psychopathy.  And another receptor gene variant is associated with childhood social disconnection and unstable adult relationships.  Gene/environment interactions complicate the interpretation of the presence of particular gene variants.  Hypothalamic neurons send projections to: ventral tegmentum which also becomes more receptive during child birth, nucleus accumbens, hippocampus, amygdala where it inhibits the central amygdala suppressing fear & anxiety consistently in men while still allowing women to respond to threats to their infants, frontal cortex, olfactory network where it helps new rat mums to learn the smell of their offspring; where oxytocin prepares the brain for in-group bonding, out-grouping, birth and maternal behavior.  Outside the brain hypothalamic neurons in females send oxytocin to the posterior pituitary where it enters the blood stream stimulating uterine contraction during labor & supporting milk production for weaning.  Disorders associated with oxytocin abnormalities include ASD. 
  and vasopressin developed by duplication and subsequent mutation of the vasotocin gene, along with oxytocin, during the initial formation of mammals.   It acts as a hormone regulating water retention in the kidneys.  It supports paternal behavior stimulated by a female giving birth.  Sex releases vasopressin in the nucleus accumbens of male prairie voles.  And prairie voles have more receptors in the accumbens than other voles supporting their pair bonding.  This situation is similar in bonobos relative to chimps where it encourages social bonding - but not monogamy.  Vasopressin is made in hypothalamic neurons which project to the posterior pituitary for release as a hormone.  It is also a neuropeptide transmitting from hypothalamic projections to the ventral tegmentum, nucleus accumbens, hippocampus, amygdala, and frontal cortex.  And it is made & secreted in other areas of the brain.  Vasopressin enhances aggression in paternal prairie vole males.  But the aggression is then maintained by social learning. 
  , to nongenetic mechanisms that silence the oxytocin receptor gene and to lower levels of the receptor, in biological cells these proteins are able to span the cell membrane and present an active site which is tailored to interact with a specific signal.  When the receptor pairs with its signal, its overall shape changes resulting in changes in the part internal to the cell which can be relayed by the cells signalling infrastructure.  In neuron synapses one type of receptor (fast) is associated with an ion channel.  The other (slow) is associated with a signalling enzyme chain and modulates the neuron's response. 
  itself. 
  
• Asexual reproduction, uses the current germ-line, a master copy of the schematic structures is maintained for reproduction of offspring.  There will also be somatic copies which are modified by the operational agents so that they can represent their current state.   DNA (DNA), a polymer composed of a chain of deoxy ribose sugars with purine or pyrimidine side chains.  DNA naturally forms into helical pairs with the side chains stacked in the center of the helix.  It is a natural form of schematic string.  The purines and pyrimidines couple so that AT and GC pairs make up the stackable items.  A code of triplets of base pairs (enabling 64 separate items to be named) has evolved which now redundantly represents each of the 20 amino-acids that are deployed into proteins, along with triplets representing the termination sequence.  Chemical modifications and histone binding (chromatin) allow cells to represent state directly on the DNA schema.  To cope with inconsistencies in the cell wide state second messenger and evolved amplification strategies are used.  , without any sexual sharing and recombination process enforces the mixing of current germ-line DNA of a male and a female organism, with a recombination process, to ensure the generation of new schematic recipes and phenotypes in their shared offspring.  Matt Ridley argues that the cost of sexual reproduction is justified by the protection from parasites that long-lived organisms gain. 
  , to generate new clones of the original
  This page reviews the implications of reproduction initially generating a single initialized child cell.  For multi-cellular organisms this 'cell' must contain all the germ-line schematic structures including for organelles and multi-generational epi-genetic state.  Any microbiome is subsequently integrated during the innovative deployment of this creative event.  Organisms with skeletal infrastructure cannot complete the process of creation of an associated adult mind, until the proximate environment has been sampled during development.  The mechanism and resulting strategic options are discussed. 
  
  organism.  
• ASHG is the American Society of Human Genetics. 
  
• Aspirin (acetylsalicylic acid) is a pain emerged as a mental experience, Damasio asserts, constructed by the mind using mapping structures and events provided by nervous systems.  But feeling pain is supported by older biological functions that support homeostasis.  These capabilities reflect the organism's underlying emotive processes that respond to wounds: antibacterial and analgesic chemical deployment, flinching and evading actions; that occur in organisms without nervous systems.  Later in evolution, after organisms with nervous systems were able to map non-neural events, the components of this complex response were 'imageable'.  Today, a wound induced by an internal disease is reported by old, unmyelinated C nerve fibers.  A wound created by an external cut is signalled by evolutionarily recent myelinated fibers that result in a sharp well-localized report, that initially flows to the dorsal root ganglia, then to the spinal cord, where the signals are mixed within the dorsal and ventral horns, and then are transmitted to the brain stem nuclei, thalamus and cerebral cortex.  The pain of a cut is located, but it is also felt through an emotive response that stops us in our tracks.  Pain amplifies the aggression response of people by interoceptive signalling of brain regions providing social emotions including the PAG projecting to the amygdala; making aggressive people more so and less aggressive people less so.  Fear of pain is a significant contributor to female anxiety.  Pain is the main reason people visit the ED in the US.  Pain is mediated by the thalamus and nucleus accumbens, unless undermined by sleep deprivation. 
  , fever and inflammation medicine.  It is a platelet aggregation inhibitor block the formation of clots and inhibit thrombosis.  Clots are usually initiated by the aggregation of platelets.  Clots can be a risk factor in heart attack.  The inhibitors include: Low dose aspirin, Clopidogrel;
  .  While its NNT is number needed to treat.  Austin Frakt and Aaron Carroll explain in the NYT Upshot that it is a number that describes how many people must be treated for one to gain a benefit.  For aspirin protection from heart attack it is about 2000.  That means 2000 people taking aspirin for two years will result in 1 person not having a heart attack, while 3.6 will have a heart attack anyway, 1995.4 will never have heart attacks any way.  But we don't know who the one person is and aspirin are cheap and don't have many side effects.  The NNT for catching influenza is between 37 and 77.  Since millions can catch flu, and thousands of those die the payoff of flu vaccination is huge. 
  is 2000 for cardiovascular disease refers to:
  
  • Conditions where narrowed and blocked blood vessels result in angina, hypertension, CHD and heart attacks and hemorrhagic/ischemic strokes.  Mutations of the gene PCSK9 have been implicated in cardiovascular disease.  Rare families with dominant inheritence of the mutations have an overactive protein, very high levels of blood cholesterol and cardiac disease. Other rare PCSK9 mutations result in an 88% reduced risk from heart disease.  Inflammation is associated with cardiovascular disease (Aug 2017). 
    
  prophylaxis, it is so cheap that this strategy is still important.  It has been found beneficial in limiting esophageal cancer is a rare cancer (less than 200,000 cases per year in the US) that typically starts in the cells that line the esophagus: flat cell squamous cell carcinoma, and mucus secreting cell adenocarcinoma.  It is associated with: Failure of TAD borders,  Obesity (adenocarcinoma Aug 2016), Alcohol consumption and smoking (Jul 2016).  It appears to be inhibited by exercise (May 2016), helicobacter pylori and aspirin (ACS's Eric Jacobs argues Sep 2015). 
  . 
  
• Asprosin is a protein based hormone are signalling molecules: ACTH, TRH, Melanocyte stimulating hormone, Testosterone, Oxytocin, Vasopressin, Insulin, Growth hormone, Estrogen, Progesterone, Angiotensin II, Asprosin, EPO, Irisin, Leptin, FGF21 hormone, Prostaglandins, TSH, Thyroxine, Glococorticoids: Cortisol; that are transported by the circulatory system to interact with target organs having appropriate receptors.  The levels of hormones can fluctuate massively, as in pregnancy. 
  produced in white adipose tissue that signals, is an emergent capability which is used by cooperating agents to support coordination & rival agents to support control and dominance.  In eukaryotic cells signalling is used extensively.  A signal interacts with the exposed region of a receptor molecule inducing it to change shape to an activated form.  Chains of enzymes interact with the activated receptor relaying, amplifying and responding to the signal to change the state of the cell.  Many of the signalling pathways pass through the nuclear membrane and interact with the DNA to change its state.  Enzymes sensitive to the changes induced in the DNA then start to operate generating actions including sending further signals.  Cell signalling is reviewed by Helmreich.  Signalling is a fundamental aspect of CAS theory and is discussed from the abstract CAS perspective in signals and sensors.  In AWF the eukaryotic signalling architecture has been abstracted in a codelet based implementation.  To be credible signals must be hard to fake.  To be effective they must be easily detected by the target recipient.  To be efficient they are low cost to produce and destroy. 
  the brain and liver is an emergent cellular system providing metabolic: Dietary compound metabolism and signalling: After gorging on sugar-rich foods the liver releases FGF21 hormone to dampen further eating activity; Detoxification, Regulation of glucose through glycogen storage (asprosin signalling from white adipose tissue); clotting, immune, exocrine and endocrine functions.  It is supplied with oxygen-rich blood via the hepatic artery and blood rich in semi-processed foodstuffs from the intestines & spleen via the hepatic portal vein.  It is constructed from: Hepatocytes which swim in the blood to process it, BECs, Stromal cells, Hepatic stellate cells, Kupffer cells, and blood vessels.  The embryonic endoderm cells invade the mesoderm to form the liver bud.  Subsequently the liver bud vascularizes and is colonized by hematopoietic cells.  The liver operates on a daily cycle (Aug 2018) allowing it time to recover from the stress of processing toxic substances.  In a healthy adult liver cells do not divide significantly.  But in a damaged liver, the liver cells shift back to a neonatal state to re-enter the cell cycle and rebuild the liver.  There are over 100 disorders of the liver.  Obesity and diabetes are associated with increased prevalence of these liver disorders worldwide. 
  to release glucose into the blood stream.  It is encoded by the FBN1 is a gene which encodes fibrillin and in white adipose tissue the hormone asprosin. 
  gene.  cAMP, a nucleotide base is the side chain purine (A or G) or pyrimidine (T or C).  A is a natural pair for T.  G pairs naturally with C.  These bases have multiple uses in cells including energy transfer, second messenger signalling as well as genetic data storage, transcription and translation.  Deacon argues that the multiple uses are significant to the emergence of evolution. 
  is the second messenger in the signalling network. 
  
• Assertion is a hypothesis which can be tested and found to be true or false.  In the adaptive web framework's (AWF)
  This page describes the Adaptive Web framework (AWF) test system and the agent programming framework (Smiley) that supports its operation. 
  Example test system statements are included.  To begin a test a test statement is loaded into Smiley while Smiley executes on the Perl interpreter. 
  Part of Smiley's Perl code focused on setting up the infrastructure is included bellow. 
  The setup includes:
  

  • Loading the 'Meta file' specification,
    
  • Initializing the Slipnet, and Workspaces and loading them
    
  • So that the Coderack can be called. 

  The Coderack, which is the focus of a separate page of the Perl frame then schedules and runs the codelets that are invoked by the test statement structures. 
  
  Smiley assertion statements are used to define the test that will be applied by the application's codelets.  The statements must include
  Plans emerge in complex adaptive systems (CAS) to provide the instructions that agents use to perform actions.  The component architecture and structure of the plans is reviewed. 
  
  schematic strings which can
  This page describes the adaptive web framework (AWF) Smiley agent progamming infrastructure's codelet based Copycat grouping operation. 
  The requirements needed for a group to complete are described. 
  The association of group completion with a Slipnet defined operon is described.  Either actions or signals result from the association. 
  How a generated signal is transported to the nucleus of the cell and matched with an operon is described. 
  A match with an operon can result in deployment of a schematic string to the original Workspace.  But eventually the deployed string will be destroyed. 
  Smiley infrastructure amplification of the group completion operation is introduced.  This includes facilities to inhibit crowding out of offspring. 
  A test file awfart04 is included. 
  The group codelet and supporting functions are included. 
  
  group complete and become associated with codelets.  Smileys own codelets:
  This page describes the Copycat Coderack. 
  The details of the codelet architecture are described. 
  The specialized use of the Coderack by the adaptive web framework's (AWF) Smiley is discussed. 
  The codelet scheduling mechanism is discussed. 
  A variety of Smiley extensions to the Coderack are reviewed. 
  The Coderack infrastructure functions are included. 
  
  Coderack generated
  This page looks at how Smiley processes the statement, such as a test request, to ensure that each part of the statement is composed of groups. 
  Smiley does this through the operation of a part codelet which indirectly sponsors the modeling of the parts of the statement. 
  The modeling itself is performed by model codelets. 
  The part codelet synchronizes with the completion of the modeling. 
  The part evaluator's signal along with the associated operons and subgroup schematic sequences are included. 
  The group models' Slipnet associations are included. 
  The codelets and supporting functions are included. 
  
  part and
  This page looks at how Smiley processes the statement, such as a test request, to ensure that the statement contains all required parts. 
  Smiley does this through the operation of a statement codelet which indirectly sponsors the modeling of the whole statement. 
  The modeling itself is performed by model codelets.  The group models' Slipnet associations are included.  The codelets and supporting functions are included. 
  
  statement enforces the syntax of the assertion.  The specific form of the statements is defined in the application's Meta file is loaded by the adaptive web framework's (AWF) Smiley.  It defines the application system's basic rules, its keywords and their properties and the form of the assertion or implementation statement the application uses. 
  .  Statement codelets also support the operation of the application's
  Walter Shewhart's iterative development process is found in many complex adaptive systems (CAS).  The mechanism is reviewed and its value in coping with random events is explained. 
  
  Shewhart cycle. 
  
• Assisted living is an alternative to parents joining their children's nuclear family or entering a SNF is skilled nursing facility. 
  , or Greenhouse Nursinghome Greenhouse nursing homes offer personal service and private rooms.  This reduces the opportunities for cross infections reducing cost of errors. 
  
  • Most nursing homes are designed like hospitals.  They are designed around the nursing station.  They are institutions and aim to limit risk and serve the patient's childrens' interest in the safety of their parents.  But they actually undermine will to live. 
    
  • Greenhouses are smaller and designed around the kitchen.  They allow knives.  Patients keep their own shoes - even though they may increase the likelihood of falling.  Patients bring in their own furniture.  Greenhouse nursing home developers had to educate the regulators and health officials about the goal of improved purpose of life rather than patients being destroyed by 'safety' (really boredom, loneliness and helplessness).  
  .  Atul Gawande's
  Gawande uses his personal experience, analytic skills and lots of stories of innovators to demonstrate better ways of coping with aging and death.  He introduces the lack of focus on aging and death in traditional medicine.  And goes on to show how technology has amplified this stress point.  He illustrates the traditional possibility of the independent self, living fully while aging with the support of the extended family.  Central planning responded to the technological and societal changes with poorly designed infrastructure and funding.  But Gawande then contrasts the power of bottom up innovations created by experts responding to their own family situations and belief systems. 
  
  Gawande then explores in depth the challenges that unfold currently as we age and become infirm.  He notes that the world is following the US path.  As such it will have to understand the dilemma of integrating medical treatment and hospice strategies.  He notes that all parties involved need courage to cope. 
  
  He proposes medicine must aim to assure well being.  At that point all doctors will practice palliative care. 
  
  Complex adaptive system (CAS) models of agency, death, evolution, cooperation and adaptations to new technologies are discussed. 
  
  
  Being Mortal describes the situation.  Federal Medicaid is the state-federal program for the poor.  Originally part of Lyndon Johnson's 1965 Bill, eligibility and services vary by state.  Medicaid currently pays less for care than Medicare, resulting in many care providers refusing to participate in the program.  Less than 10 percent of Medicaid recipients, those in long-term care including nursing homes where 64% are dependent on Medicaid, use one-third of all Medicaid spending which is a problem.  The ACA's Medicaid expansion program, made state optional by the SCOTUS decision, was initially taken up by fifty percent of states.  As of 2016 it covers 70 million Americans at a federal cost of $350 billion a year.  In 2017 it pays for 40% of new US births. 
  does not directly cover assisted living.  State Medicaid adds coverage through a federal waiver.  Congressional legislation covering assisted living is limited.  Assisted living providers are represented by the National Center for Assisted Living. 
  
• Asthma is inflammation of the airways resulting in their narrowing, swelling and generating additional mucus is used to cover tissues that are exposed.  It is made from mucins.  Mucous membranes may secrete mucus to generate a robust barrier. 
  which inhibits breathing.  Its prevalence doubled in the US between 1980 and 2000.  Asthma is the most common chronic disease in childhood, the most common reason for being away from school and the most common reason for hospitalization.  10 to 13% of children's asthma cases are due to obesity is an addictive disorder where the brain is induced to require more eating, often because of limits to the number of fat cells available to report satiation (Jul 2016).  Brain images of drug-addicted people and obese people have found similar changes in the brain.  Obese people's reward network tends to be less responsive to dopamine and have a lower density of dopamine receptors.  Obesity spreads like a virus through a social network with a 171% likelihood that a friend of someone who becomes obese will also become so.  Obesity is associated with: metabolic syndrome including inflammation, cancer (Aug 2016), high cholesterol, hypertension, type-2-diabetes, asthma and heart disease.  It is suspected that this is contributing to the increase in maternal deaths in the US (Sep 2016).  Obesity is a complex condition best viewed as representing many different diseases, which is affected by the: Amount of brown adipose tissue (Oct 2016), Asprosin signalling by white adipose tissue (Nov 2016), Genetic alleles including 25 which guarantee an obese outcome, side effects of some pharmaceuticals for: Psychiatric disorders, Diabetes, Seizure, Hypertension, Auto-immunity; Acute diseases: Hypothyroidism, Cushing's syndrome, Hypothalamus disorders; State of the gut microbiome.  Infections, but not antibiotics, appear associated with childhood obesity (Nov 2016). 
  .  Among obese children 23 to 27% of asthma cases are due to obesity.  Diagnosis: Propeller Health; Treatments include: Xolair;
  
• This page introduces a series of asymmetries which encourage different strategic approaches.   
  The differences found in business, sexual selection, gamete structure, as well as in chess encourage escalations in the interactions. 
  And yet the systems including these asymmetries can be quite stable. 
  
  Asymmetry.
  
• Atezolizumab is a MAB as a terminator in medication names indicates the drug is a monoclonal antibody biologic.   of lgG1 targeting the apoptosis, programmed cell death is a signal initiated DNA controlled process which results in eukaryotic cells self-destructing.   ligand PD-L1.  It is marketed as Tecentriq.  It blocks PD-L1's interaction with PD-1 is programmed cell death protein 1 (CD279) is encoded by the PDCD1 gene.  It is a cell surface receptor that belongs to the immunoglobulin superfamily. It is expressed on T-cells and pro-B cells.  It acts as an immune checkpoint preventing the activation of T-cells to help self-tolerance and reduce autoimmunity.  When it fails people can suffer from: Lupus, Crohn's disease, Rheumatoid arthritis.  PD-1 inhibitor drugs activate the immune system to attack tumors.   PD-1 inhibitors are being approved for Melanoma and squamous-cell form of lung cancer.   and B7.1.  PD-L1 expression reduces the activation of cytotoxic T-cells (immune checkpoint inhibition release the immune system's checkpoints: PD-1, CTLA-4; on attacking host cells: by 1) stopping T-cell division and 2) reducing their life spans.  They are used in immuno-oncology where, in 2016: They are approved for treatment of: Advanced melanoma, HL, lung, kidney, liver cancer; They have a general success rate of 20 - 40% and higher for melanoma.   Checkpoint inhibitors work best for tumors that have many mutations: melanomas, lung and bladder cancers.  They are enhanced by adjunct treatments that kill tumor cells generating debris to stimulate the immune system.  The drugs include: ipilimumab (CTLA-4 inhbition), nivolumab, pembrolizumab, atezolizumab (PD-1 inhibitors);  They are costly and often have high copayments.  They cause auto-immune side effects including inflammation, rheumatoid arthritis and damage to glands: Adrenal, Thyroid, Pituitary.  Powerful steroids such as prednisone can help reduce the inflammation.  Damaged glands require sustained hormone treatment.  Checkpoint inhibitor research is funded by the CRI.  ). 
  
• Atherosclerosis is the thickening of an artery wall due to invasion and accumulation of leukocytes are produced by hematopoietic stem cells in the bone marrow and are a major part of the adaptive immune system.  Five types have been identified:
  1. Basophils,
     
  2. Eosinophils,
     
  3. Lymphocytes,
     
  4. Monocytes,
     
  5. Neutrophyls.  
  .  It is associated with lack of sleep facilitates salient memory formation and removal of non-salient memories.  The five different stages of the nightly sleep cycles support different aspects of memory formation.  The sleep stages follow Pre-sleep and include: Stage one characterized by light sleep and lasting 10 minutes, Stage two where theta waves and sleep spindles occur, Stage three and Stage four together represent deep slow-wave sleep (SWS) with delta waves, Stage five is REM sleep; sleep cycles last between 90-110 minutes each and as the night progresses SWS times reduce and REM times increase.   Sleep includes the operation of synapse synthesis and maintenance through DNA based activity including membrane trafficking, synaptic vesicle recycling, myelin structural protein formation and cholesterol and protein synthesis.  Sleep also controls inflammation (Jan 2019)  Sleep deprivation undermines the thalamus & nucleus accumbens management of pain. 
  .  Sleep reduces inflammation (Jan 2019). 
  
• ATM is automated teller machine, supporting consumers by reducing the
  Carlo Rovelli resolves the paradox of time. 
  Rovelli initially explains that low level physics does not include time:
  

  • A present that is common throughout the universe does not exist
    
  • Events are only partially ordered.  The present is localized
  • The difference between past and future is not foundational.  It occurs because of state that through our blurring appears particular to us
  • Time passes at different speeds dependent on where we are and how fast we travel
    
  • Time's rhythms are due to the gravitational field
    
  • Our quantized physics shows neither space nor time, just processes transforming physical variables. 
    
  • Fundamentally there is no time.  The basic equations evolve together with events, not things 

  Then he explains how in a physical world without time its perception can emerge:
  

  • Our familiar time emerges
    
  • Our interaction with the world is partial, blurred, quantum indeterminate
    
  • The ignorance determines the existence of thermal time and entropy that quantifies our uncertainty
    
  • Directionality of time is real but perspectival.  The entropy of the world in relation to us increases with our thermal time.  The growth of entropy distinguishes past from future: resulting in traces and memories
    
  • Each human is a unified being because: we reflect the world, we formed an image of a unified entity by interacting with our kind, and because of the perspective of memory
    
  • The variable time: is one of the variables of the gravitational field.  With our scale we don't register quantum fluctuations, making space-time appear determined.  At our speed we don't perceive differences in time of different clocks, so we experience a single time: universal, uniform, ordered; which is helpful to our decisions

  
  
  time for banking teller transactions and extending access to 24/7.   
• Atopic dermatitis, is also called eczema is atopic dermatitis. 
  is a long lasting inflammation of the skin.  It can be successfully treated with dupilumab is a monoclonal antibody which blocks two immune system pathways: interleukin 4 and interleukin 13; that are over produced in atopic dermatitis, by binding to the alpha subunit of the interleukin-4 receptor.  It was developed by Regeneron and marketed as Dupixent.  .  
• ATPase is adenosine triphosphatase, an enzyme, a protein with a structure which allows it to operate as a chemical catalyst and a control switch. 
  class that breaks the high energy bond from ATP to generate ADP, phosphate, and energy used to drive other reactions away from equilibrium.  
• ATR is either:
  
• A serine/threonine-specific kinase is an enzyme which catalyzes the addition of a phosphate group to a side chain of a specific protein.  When paired with a phosphatase that targets the same protein and side chain it gives the cell a schematically controlled switching capability.  , that binds to single-strand DNA (DNA), a polymer composed of a chain of deoxy ribose sugars with purine or pyrimidine side chains.  DNA naturally forms into helical pairs with the side chains stacked in the center of the helix.  It is a natural form of schematic string.  The purines and pyrimidines couple so that AT and GC pairs make up the stackable items.  A code of triplets of base pairs (enabling 64 separate items to be named) has evolved which now redundantly represents each of the 20 amino-acids that are deployed into proteins, along with triplets representing the termination sequence.  Chemical modifications and histone binding (chromatin) allow cells to represent state directly on the DNA schema.  To cope with inconsistencies in the cell wide state second messenger and evolved amplification strategies are used.   breaks coated with RPA is replication protein A, which binds to single-stranded DNA in eukaryotic cells. 
  , with partner ATRIP, sensing DNA damage and activating the DNA damage checkpoint, through a signalling, is an emergent capability which is used by cooperating agents to support coordination & rival agents to support control and dominance.  In eukaryotic cells signalling is used extensively.  A signal interacts with the exposed region of a receptor molecule inducing it to change shape to an activated form.  Chains of enzymes interact with the activated receptor relaying, amplifying and responding to the signal to change the state of the cell.  Many of the signalling pathways pass through the nuclear membrane and interact with the DNA to change its state.  Enzymes sensitive to the changes induced in the DNA then start to operate generating actions including sending f