Maintenance of health involves a synchronized network of catabolic and anabolic signals among organs/tissues/cells that requires differential bioenergetics from mitochondria and glycolysis . We defined biological circadian rhythms as Yin  and Yang (tumorigenic) arms of acute inflammation (effective immunity) involving immune and non-immune systems. Role of pathogens in altering immunity and inducing diseases and cancer has been documented for over a century. However, in 1955s decision makers in cancer/medical establishment allowed public (current baby boomers) to consume million doses of virus-contaminated polio vaccines. The risk of cancer incidence and mortality sharply rose from 5% (rate of hereditary/genetic or innate disease) in 1900s, to its current scary status of 33% or 50% among women and men, respectively. Despite better hygiene, modern detection technologies and discovery of antibiotics, baby boomers and subsequent 2–3 generations are sicker than previous generations at same age. American health status ranks last among other developed nations while America invests highest amount of resources for healthcare. In this perspective we present evidence that cancer is an induced disease of twentieth century, facilitated by a great deception of cancer/medical establishment for huge corporate profits. Unlike popularized opinions that cancer is 100, 200 or 1000 diseases, we demonstrate that cancer is only one disease; the severe disturbances in biorhythms  or loss of balance in Yin and Yang of effective immunity. Cancer projects that are promoted and funded by decision makers are reductionist approaches, wrong and unethical and resulted in loss of millions of precious lives and financial toxicity to society. Public vaccination with pathogen-specific vaccines  weakens, not promotes, immunity. Results of irresponsible projects on cancer sciences or vaccines are increased population of drug-dependent sick society. Outcome failure rates of claimed ‘targeted’ drugs, ‘precision’ or ‘personalized’ medicine are 90% (± 5) for solid tumors. We demonstrate that aging, frequent exposures to environmental hazards, infections and pathogen-specific vaccines and ingredients are ‘antigen overload’ for immune system, skewing the Yin and Yang response profiles and leading to induction of ‘mild’, ‘moderate’ or ‘severe’ immune disorders. Induction of decoy or pattern recognition receptors , such as IRAK-M or IL-1dRs (‘designer’ molecules) and associated genomic instability and over-expression of growth promoting factors  could lead to immune tolerance, facilitating cancer cells to hijack anabolic machinery of immunity (Yang) for their increased growth requirements. Expression of constituent embryonic factors would negatively regulate differentiation of tumor cells through epithelial–mesenchymal-transition and create “dual negative feedback loop” that influence tissue metabolism under hypoxic conditions. It is further hypothesized that induction of tolerance creates ‘dark energy’ and increased entropy and temperature in cancer microenvironment allowing disorderly cancer proliferation and mitosis along with increased glucose metabolism via Crabtree and Pasteur Effects, under mitophagy and ribophagy, conditions that are toxic to host survival. Effective translational medicine into treatment requires systematic and logical studies of complex interactions of tumor cells with host environment that dictate clinical outcomes. Promoting effective immunity  are fundamental steps in correcting host differential bioenergetics and controlling cancer growth, preventing or delaying onset of diseases and maintaining public health. The author urges independent professionals and policy makers to take a closer look at cancer dilemma and stop the ‘scientific/medical ponzi schemes’ of a powerful group that control a drug-dependent sick society before all hopes for promoting public health evaporate. The world will not be destroyed by those who do evil, but by those who watch and do nothing. Albert Einstein.Maintenance of human health is the result of an amazingly harmonious, synchronized and autonomous neurophysiological status of body. Health of an adult depends on the reciprocal interactions of positive and negative biological feedback control mechanisms  between and among the immune-vascular-metabolic-genomic-hormonal-neuronal (sympathetic and parasympathetic) pathways that constitute effective immunity  for preventing diseases including cancer. As early as the nineteenth century, Paul Ehrlich using the newly invented microscope made fundamental observations that cancer cells are destroyed by immune/inflammatory cells . Furtherl-histidine, recombinant DNA, embryonic serum), which are ‘antigen overload’ for the immune system to clear. In the last few decades, public has additionally been exposed to a wide range of environmental hazards  and other immune disruptors whose cumulative effects adversely influence immunity  or other tissues with different cell compositions .As detailed elsewhere  and Yang (tumorigenic) of inflammation, associated with loss of differential bioenergetics (anabolic vs catabolic) in tissues. Evidence is presented that over the last six decades, decision makers in cancer establishment has gradually weakened and manipulated the autonomic biological circadian rhythms, the Yin and Yang of effective immunity, by introducing the public to various pathogen-specific vaccines and ingredients, in addition to exposures to exposures to a wide range of environmental hazards and low level carcinogens that made young and old in America sick and drug-dependent.Analyses of related data suggest that nearly all diseases, to varying degrees, are the results of altered effective immunity or loss of biological circadian rhythms (on–off switches) that adversely influence tissue bioenergetics (mitochondria), the principal generator of energy and electricity (proton pumping) in organ systems , 35–90.Vascular and lymphatic channels disorders.Tissue necrosis.Tissue growth.It is also noteworthy that the special or shared biological/medical features of full-blown diseases that often determine the outcomes of nearly all age-associated chronic conditions fall into the following three major categories, as interdependent defects in immune surveillance (biorhythms) associated with varying degrees of loss of bioenergetics in affected tissues , 39:VascManifestations of organ-specific diseases that are known as distinct pathological and clinical complications such as polyps, pre-cancer, cancer metastasis and angiogenesis, or neurodegenerative and autoimmune diseases, diabetes and cardiovascular complications, are generally the outcomes of cumulative damages in the immune-responsive tissues  or immune-privileged tissues  and/or insulin-dependent  and insulin-independent tissues  for glucose transport and metabolism –8.Overview and integration of data on diverse experimental models of chronic illnesses or cancer research and clinical studies suggest that all diseases share features of one or more defects in innate  and/or adoptive (extrinsic or induced) pathways including cellular  activities that contribute to the complex signal communications of altered immunity and manifest in different tissues as different diseases –8, 34–80As detailed elsewhere –8, 35–40In an acute inflammation, autonomic crosstalk between innate and adaptive immune cells and non-immune pathways has a 2-fold mission with differential energy requirements from mitochondria and cytosol as outlined below , 35–40.Yin events are involved in encountering/sensing (recognizing), processing or digesting and eliminating the intrinsic or extrinsic foreign elements  and the injured host tissue. Yin  events require burst of energy (ATP hydrolysis) from mitochondrial oxidative phosphorylation (OxPhos) for activation of innate and adoptive immune cells , as well as activation of non-immune systems  for generation of required toxins, oxidants and apoptotic factors. Pathogen-specific induction of danger molecules and expression of specific pro-inflammatory mediators and receptor molecules  as well as, secretory lysosomal activities, membrane fusion, exocytosis, ion fluxes and vascular hyperpermeability responses facilitate the destruction of foreign elements and injured host tissue. Yin events require genomic activation of specific tumoricidal factors (above examples) –8, 35–39Following the release of oxidants toxins and utilization of high energy from mitochondrial OxPhos during destruction of foreign entity and the injured/infected target tissue, the activated cells simultaneously signal for polarization of immune cells  that would automatically shut-down mitochondria, allowing regeneration of TCA cycle intermediates  and numerous other important mitochondrial activities  that are required for mitochondrial function. Yang  events involve polarization of immune cells and non-immune pathways for expression of growth promoting mediators and decoy receptors  to neutralize and remove the toxicities that are generated during Yin and to repair, reconstruct or remodel the target host tissue and terminate inflammation. Switching from oxidative phosphorylation in mitochondria, under hypoxic conditions and low energy utilization from glycolytic pathways are fundamental events that require differential bioenergetics (high-low energy switches from mitochondria to cytosol) for maintenance of effective immunity. The Yang processes are required not only for revival and repair mechanisms of injured tissue, but for mitochondrial recovery and biosynthesis of TCA cycle intermediates to generate efficient energy. Therefore, Yang events are naturally anabolic (low energy) and possess regenerative (growth) features of effective immunity, and function under low oxygen tension (hypoxia) for wound healing purposes.Simply described, in an acute inflammation, apoptotic arm or Yin responses are catabolic processes requiring high energy consumption from mitochondrial OxPhos to express death signals, oxidants, enzymes and receptor molecules for destruction of both the enemy and the injured/infected host cells. In contrast, the wound healing or Yang responses are anabolic processes and require simultaneous polarization of immune and non-immune cells for generation of growth promoting factors to counteract and neutralize the toxicity of injured tissue. Yang responses follow mitochondrial shutdown and switch to cytosolic low energy utilization from glycolysis (Warburg effect) to resolve inflammation.The major outcomes of an acute inflammation are lymphocyte-derived clonal expansion, increased synthesis of pathogen-, or allergen-specific antibodies and plasma and memory T and B cells that would prepare the body to defend and unleash appropriate responses such as antigen-specific antibody release when tissue is exposed to the same hazardous agents –7, 35–40The author’s original definitions of biphasic roles of Yin  and Yang (tumorigenic) of effective immunity  present The body is a dynamic and energy consuming system involving highly complex interactions between and among multi-organs whose function continually evolves, from conception, placentation, embryonic and fetal growth, after birth, puberty and adulthood and aging or disease processes. The anabolic  and catabolic  arms of effective immunity follow highly organized biological circadian rhythms (biorhythms) requiring on–off switches of immune and non-immune responses that constitute the human health. Insufficient circadian rhythms  are perhaps the result of one or more mutations or deficiencies in the circadian clock genes that influence the amazingly synchronized and interdependent features of biological oscillators in Yin–Yang or ‘effective acquisition time’ of immunity , 7, 39.The earliest features in fetus growth are vasculogenesis and organogenesis, events that are completed and functional after birth , 39. In Majority of the required fetus constituent growth factors, receptors and enzymes  also share features of wound healing, tolerance or tumorigenic (Yang) arm of effective immunity after birth.Features of rapid aging and maturation in prenatal-embryonic tissues and postnatal development of childhood cancers  have been reported , 73–76. Growth requirements of embryo-fetus development are orderly processes  occurring under protected environment of placenta during embryonic development involving expression of constituent receptors, projected from trophoblasts that anchor embryo and during fetus growth under limited oxygen tension (hypoxic condition). Angiogenesis and organogenesis, including development of lymphoid organs and generation of naïve pluriepotent stem cells or mesenchymal stem cells (MSC) require growth factors and metabolism, primarily using glycolysis for energy requirements. The energy production for growth involves constituent growth pathways such as expression of pyruvate kinases, aspartyl-asparginyl β-hydroxylases (ASPH or HAAH), mTOR/PI3Ks, insulin and insulin-like growth factor (IGF) , 69–76. 2 and completion of organs development. It is proposed that independent life of individual after birth requires the following major biological changes, adaptations and reprogramming , metabolism of essential branched amino acids  for biosynthesis of structural proteins and ribosomal recycling activities or perhaps chromatin remodeling-related events. It was proposed that biosynthesis of structural proteins after birth are required for maintaining architectural integrities and boundaries among and between cells and tissues . Fully functional mitochondria have the capability for production of high energy (burst of ATPase hydrolysis) that are required by Yin events  at moment notice to combat foreign elements , 82–119.Exposure of newborn to outside environment and independent living demand establishment of fully functional biological circadian rhythms or the catabolic and anabolic responses in tissues. How the effective immunity and signal transduction between and among immune and non-immune pathways are completed after birth are among crucial knowledge gaps that deserve systematic, insightful and integrated understanding. It is likely that completion of many organs  functionality and reprogramming of tissues, cellular and subcellular components  are not fully activated during orderly fetus growth. The molecular/cellular and subcellular adaptation and reprogramming could occur simultaneously after birth and at the interface between host and environment. The fact that during the first few months after birth, newborn limited immunity depends on mother’s immunity supports the above suggestions.After birth, the complex establishment of effective immunity  and mitochondrial-related cellular functions are likely to take a few months to be completed. It is possible that the majority of components that contribute to catabolic pathways are genetically (innately) present as constituent elements but they are not functional or not expressed until after birth. Potential examples of such constituent pathways are structurally naïve immune and none immune cells, sympathetic and parasympathetic neuronal systems, inactive/inhibited apoptotic factors and components of double membrane in mitochondria. Examples of constituent components that are likely to be functional after birth include immature or naïve lymphocytes, oxidases, pro-inflammatory cytokines, toxins, pyruvate-shuttle, pyruvate carrier proteins, TCA cycle proteins/enzymes, metabolic pathways of essential amino acids  and biosynthesis of structural proteins for cell–cell contact inhibition and vasculature tight junctions, components of epigenetic modifications, hypo- or hypermethylated genomic materials.After birth and during infancy the most pronounced biological changes and reprogramming relate to newborn’s exposure and adaptation to atmospheric Ong Figs. , 2.ComplIt is noteworthy that biological development and reprogramming and responding to environmental conditions continue through puberty for hormonal regulations and reproductive cycles and adulthood; many of which processes decline or change during aging process (senescence).+/H+ exchanger, Ca2+/ATPase) alter, to varying degrees, from the time of fetus growth, after birth, during reproductive period and adulthood, in aging or disease processes .Continued proton pumping and generation of electricity across the membrane, are crucial for establishing pH gradients and differential acidity among extra-, and intra-cellular membrane components and cytoplasm for numerous routine biological activities  as well as, numerous biosynthetic pathways in mitochondria. It is likely that the extent of proton pumping provided through vascular or cellular membrane by ATPases or exchangers , as well as, aging process, could temporarily or permanently disturb the effective membrane potential or pH gradient (proton pumping) across the extracellular or intracellular membranes that would skew signal transductions and auto-regulatory processes of cellular biorhythms , 179–185Innocuous substances and occasional exposures to a wide range of foreign elements are ordinarily and differentially ignored by tissues that are immune-responsive or immune-privileged . The immune-privileged tissues  are highly sensitive toward oxidative damage. These tissues possess special anatomical or molecular features to minimize response to oxidative damage –40, 89. Oxidative stress and alterations of Yin and Yang properties of effective immunity often differentially facilitate growth promotion (anabolism) or growth arrest (catabolism) in different tissues. The processes are natural/inherent properties of immunity (biorhythms) to resolve inflammation. Potential adverse influence of extensive oxidative stress in immune-responsive tissues includes epithelial–mesenchymal transition (EMT), changes in extra- and intra-cellular membrane matrix  further affecting cellular hydrophobicity or hydrophilicity, protein foldings and cellular function. Extensive oxidative stress is the results of exaggerated expression and co-expression of growth and apoptotic factors that result in immunological chaos (immune tsunami) that could damage the tissue integrity at multiple levels of biological, mechanical, physical and bioenergetics. Serious damages in immune-responsive tissues lead to changes in bioenergetics and metabolism and proton pumping in the direction of initiation of tissue growth, neoplasia, precancer-polyps, invasive cancer growth and angiogenesis. In immune-privileged tissues, exaggerated expression of tumoricidal mediators (catabolic or apoptotic factors) causes necrosis and local immune responsiveness in tissues in the direction of neurodegenerative and autoimmune diseases .Glucose toxicity-induced changes in immune response dynamics could additionally and adversely influence tissues that are insulin-dependent  or insulin-independent  for glucose transport, metabolism or growth as contributing factors in the induction of tolerance and initiation of chronic diseases such as diabetes and cardiovascular complications, hypertension, stroke, as well as increased risk of carcinogenesis .l-histidine, embryo serum) to varying degrees, could induce polarization of immune cells  and direct expression of wound healing factors, decoy or pattern recognition receptors  ( and enhance the vulnerability of host tissue toward loss of balance between apoptosis and wound healing processes, increased memory B or T cells, clonal expansion and increased hypersensitivity of humoral or cellular responses toward new or old stimuli , additionally contributing to the mitochondrial and ribosomal dysfunction  , 89, 109ation)] , under oxidative stress represents extended wound healing processes. Continued activities of Yang (tumorigenic) are associated with mitochondrial dysfunction (mitophagy) causing damages to tissue recycling processes and ribosomal activities (autophagy) that are features of skewed immune responses or immune suppression Figs. , 2, 3.In immune-responsive tissues, enzymes or other factors that modulate senescence negatively regulate differentiation of tumor cells (mitosis) through epithelial–mesenchymal-transition (EMT) often involving polarization, unscheduled or immature synthesis and activation of immune cells, or expression of factors and receptors , selective membrane catalysis of sulfimine or changes in H bonds with protein structures that create “dual negative feedback loop” and further influence tissue metabolism, fibrosis or cancer.During EMT, polarized immune cells are capable of expression of a panel of growth-promoting factors and decoy receptor molecules that are immune suppressive and signal for mitochondrial shutdown, inhibiting pro-inflammatory responses, leading to tolerance in favor of tumorigenesis and enhanced activities of cytosolic glycolysis.Stimuli-induced activation and polarization of immune cells are accompanied by activation of several other metabolic pathways and expression of factors  with potential different bioenergetics requirements that could influence cellular function. For example, changes in PKM1 and PEP in red blood cells, whose principal energy source is from glycolysis could lead to altered hemoglobin metabolism, anemia, hemophilia, hemolysis, cardiovascular complications, jaundice (bilirubin) and blood-related diseases including cancers  or severity of Guillian–Barre syndrome  for maintenance of health. In 2016, we proposed a working model for differential bioenergetics requirements of Yin and Yang pathways from fetus orderly growth, after birth and all the way to adulthood, aging process and development of chronic diseases and cancer . The folIn summary, disturbance of the well orchestrated crosstalk in effective immunity by frequent exposures to immune disruptors and aging processes cause minor or major degrees of retardation in immune response dynamics that could increase the risks of initiation and progression of a wide range of ‘mild’, ‘moderate’ or ‘severe’ immune disorders in susceptible tissues. Low level circulating histamine was proposed as a blueprint in the induction of tolerance leading to diverse immune disorders and alterations of acid–base balance and tissue bioenergetics , 39. Can2+, ascorbate, myo-inositol), enzymatic processes , protein biosynthesis and other physiological pathways, and physical, mechanical or locomotion and architectural integrity of cells/tissues/organs  have limited respiration in the presence of high glucose concentration. The phenomenon is known as Crabtree Effect. Under such conditions, cancer cells are able to trigger the competitive inhibition of oxidative phosphorylation (respiration) for using phosphate groups  and ADP, through glycolysis for their enhanced growth requirements, conditions that are toxic to normal cells. An excellent publication by Hammad et al. . TNFRs also have proliferative capabilities for growth of fibroblasts or thymocytes and induction of expression of mitochondrial or cytoplasmic superoxide dismutases (SODs) to terminate acute inflammation (Yang) during wound healing , 209–211Staphylococcus aureus). For example, LPS-induced expression of TLRs leads to activation of immature DCs and differentiation and migration of appropriate phenotypes from peripheral tissues to lymphoid organs to activate naïve T cells (T0) and upregulate expression of major histocompatibility complexes (MHC I and II) and co-stimulatory surface molecules. The actions are followed by expression of other pro-inflammatory cytokines and chemokines for destruction of microbial . The actions require high energy production from OxPhos in mitochondria. Stimuli-induced expression of TLRs is associated with induction of IL-1R that form a group of superfamily regulatory proteins with shared and special features for signaling to intracellular domains to induce expression of other cytokines at extra-, and intra-cellular levels and for recruiting adaptor molecule response such as myeloid differentiation (MY 88 gene) and formation of receptor-adaptor complex domains for proper immune responses  failed patients , 39, 43.Policy makers who appropriate funding for cancer research and therapy have no clue on how to assess worthiness of the tremendously expensive projects that are highly promoted by members of the cancer establishment. Such projects are considered ‘molecular false flags’, based on false foundations that destroy the precious lives of patients and drain resources to create huge corporate profits for the establishment Fig.  5, 7, 1, 237–241“If the government is put in charge of Sub Sahara, in 5 years there will be a shortage of sands”.Milton Friedman best described the situation S-nitrosoglutathione-GSNO) induces IRAK-M in LPS-activated monocytes in the presence of TNF-α are also interesting and support our definitions of tumoricidal and tumorigenic arms acute inflammation  or neurodegenerative and autoimmune diseases are features of altered immunity involving polarization of immune cells and skewed expression of pro-inflammatory mediators, receptors or surface molecules . In the case of diabetes mellitus, insulin-insensitivity are reported to increase the risk of several cancers, while it reduces risks of other cancers , 202–2072+ under impaired ER and T cell-dependent plasma membrane influx of Ca+2 and other ion channels   , 253. Hyhangers] , 250–260hangers] –207, 221hangers] , 202–207Therefore, it is logical to consider that PI3K/AKT/mTOR activities play crucial and interdependent roles in contributing to the induction of tolerance, growth and metabolism of tissues that would influence innate/intrinsic pathways under hypoxic conditions and mitochondrial dysfunction.Effective immunity requires elaborate and precise communication with a variety of hormones  that are induced or secreted from tissues and organs  for routine maintenance of health throughout life , 202–207As noted above, continued proton pumping and generation of electricity are required for numerous routine cellular activities such as transport of ion/solute and metabolites, lysosomal digestion and protein recycling, degradation of pathogens’ structural proteins-lipids-genes for immune recognition, activation and cellular proliferation. Proper functioning of mitochondria as energy power plant is crucial for proton pumping during routine metabolism or fighting against harmful elements (intrinsic and extrinsic). Mitochondrial function depends on presence and function of essential basic building blocks  to generate energy and maintain crosstalk between cytoplasm and mitochondria, at moment notice for production of high energy and oxidants to fight pathogens (Yin) and also during downtime (Yang) for biosynthesis of intermediates of TCA cycle and preservation of energy.Loss of synchronized network of Yin and Yang of effective immunity is intimately entangled with energy drain and electronic charges of important proteins for integrity of intra-, extra-cellular membrane structures. It is suggested that the altered (increased) entropy or temperature creates ‘dark energy’ around cancer masses and drain energy from neighboring normal tissues. The differential bioenergetics that are required for maintenance of circadian rhythms in health could be shifted/switched under oxidative stress, during the induction of tolerance and mitochondrial shutdown in exchange for increased glycolysis, enhanced growth of cancer cells and associated increase in entropy and temperature. The shifts in energy distribution and enhanced entropy around cancerous cells (‘dark energy’) could alter energy requiring events of protein electrical charges  for proper cellular functions. It is further suggested that impaired electrical charges could adversely influence protein folding that would alter a number of cellular activities . Cumulatively, altered energy-requiring biological activities could limit energy utilization in normal neighboring cells, a potential factor in symptom of fatigue observed in cancer patients. Enhanced ‘dark energy’ and entropy create asymmetry that could force the normal cells from oscillating at required energy (loss of biorhythms) for cell survival Fig.   that is responsible for fighting and destroying cancerous cells or any other intrinsic and extrinsic hazardous materials. Under immune suppression cancerous cells slowly or aggressively take over the machinery of host for its enhanced and lawless growth, under hypoxic conditions and mitochondrial dysfunction. The energy for abnormal growth of cancerous cells is supplied by increased glucose uptake and altered tissue metabolism via glycolysis and Crabtree and Pasteur Effects that create ‘dark energy’ and entropy, conditions that are toxic to normal cells. Induction of ‘dark energy’ is characteristics of disorderly growth and proliferation of cancer cells that drain the energy of neighboring normal cells, potentially contributing to the observed fatigues in patients.It was hypothesized that mitochondria and Yin and Yang of effective immunity and biological reprogramming develop after birth when newborn is exposed to atmospheric pressure and environmental conditions. Longevity and unresolved inflammation were defined as alterations in immune and non-immune response dynamics. Tardiness of immunity  leads to induction of ‘mild’, ‘moderate’ or ‘severe’ immune disorders, conditions that are associated with altered mitochondrial function. Insufficient circadian rhythms  were suggested to be the results of one or more mutations or deficiencies in the circadian clock genes that influence the synchronized communications among biological oscillators (positive and negative rhythms) or ‘effective acquisition time’ of immunity. Lawless growth of cancer cells is peculiarly comparable to the orderly (one way) growth of fetus that involve activation of trophoblasts factors and constituent receptors that are required for fetus orderly growth under hypoxic conditions Fig. .The current reductionist approaches to cancer science and therapy are conducting numerous out-of-focus and fuzzy projects projects on identification of one or combination of mutated genes or expression products using expensive and specific technologies as bases for drug development. The outcome failure rates of such reductionist, fraud and chaotic projects are 90% ± 5) that destroyed the precious lives of millions, but generated huge corporate profits for the cancer/medical establishment   that des, 39, 43.What are the early changes in complex network of immune responses that lead to genetic instability, loss of biorhythms, mitochondrial dysfunction and altered metabolism that lead to immune tolerance toward multistep carcinogenesis and angiogenesis.How to develop universal vaccines and prophylactic agents that promote body’s natural immunity for maintaining the autonomous, sympathetic and parasympathetic or Yin and Yang, biological circadian rhythms that are required for improving public health and preventing majority of chronic diseases or cancer.After investing several trillions of dollars of taxpayers’ and private organizations funding for cancer research and treatment, the decision makers have yet to seriously consider the need for understanding the following scientific common senses and logics:i.Time-course kinetics of immune response dynamics are fundamental and essential first steps in understanding details of host interactions with stimuli . The extent of damage that specific immune disruptors impose on bioenergetics and architectural integrity and function of affected tissues during developmental phases of multistep disease processes are among important topics that deserve detailed studies. Identification of shared or special features of early events during host–pathogen interactions that alter immune response profiles are among important knowledge gaps that require detailed studies.ii.Potential reversibility of early stages of inflammation-induced immune dysfunction including alterations in cellular chromosomal/genetic material that would lead to cellular growth promotion and genesis of hyperplasia, neoplasia/pre-cancer or cancer-malignancy deserve detailed studies.iii.The quality (nature) and quantity of initial acute immune responses (strong or weak) and the generation of histamine and other pro-, or post-inflammatory mediators could influence subsequent responses such as the extent of rejection or penetration of antigen in subepithelial tissue, vascular hyperpermeability and tissue integrity during Yin and Yang activities and clearance of antigen.iv.It is important to understand the influence of mitochondrial dysfunction and energy shifts during increased glycolytic pathways that result in adaptation of cancer cell growth and immune tolerance. Induction of tolerance could change mitochondrial-dependent activities of cMyc, Alt/PTEN or p53 and related pathways and alter apoptosis (Yin) events leading to proliferation and entropy or ‘dark energy’ in cancer mass.v.Understanding the thermodynamics and biological communications of high energy-consuming and voltage-dependent pathways in apoptosis  that are involved in destroying defective cancer cells are important topics that are not fully understood.vi.Stimuli-induced redox-sensitive mitochondrial transition pore (MTP) that opens to the cytoplasm, followed by depolarization, electron flux in the electron transport chain (ETC) during production of electron donors (NADH and FADH2) that would increase the level of reactive oxygen species (ROS) are crucial topics that require better systematic studies.Future research directions require focusing on systematic and logical studies that are outlined in the following overall topics , 72, 175Minor or major heterogeneities in intrinsic biology and genetic makeup of individuals often lead to heterogeneities in response profiles toward different biological insults (immune disruptors). These confounding factors present unique challenges and opportunities to overcome in future research. However, the outcomes are expected to be rewarding as the truth in science has always advanced us to extraordinary achievements in many biomedical fields. Solving cancer problem is not an exception if the business of cancer did not overwhelm the search for scientific facts and logics.For over six decades the reductionist approaches of decision makers in cancer science popularized the notion that cancer is too many diseases ; cancer is too complex to solve; that they have made ‘extraordinary advances’ and need more money to further progress on the war against cancer. The decision makers now make up other stories that they need to aggregate and share data and require more resources and time to solve cancer mystery. The truth about claims of ‘targeted’ therapy based on identification of endless defective molecular entities is that such mindless and chaotic approaches failed patients at the rate of 90% (±5), costing the loss of millions of precious lives and financial toxicity to the society. All relevant data are available in various medical and basic science disciplines. Integration of quality data on how cancer is initiated has been practically ignored and its systematic investigations are not allowed when competent professionals propose more logical and cost-effective studies to help understand cancer biology and how to prevent or treat it. As author presented in the last couple of decades, analyses of data from her accidental discoveries on experimental models of ocular inflammatory diseases and extension of relevant data on multidisciplinary fields of medical and immunological sciences suggest that cancer is only one disease. Disorderly growth of cancer cells is the results of loss of autonomic and synchronized balance in tumoricidal (Yin) and tumorigenic (Yang) properties of immunity to arrest cancer cells. Loss of differential bioenergetics in Yin  and Yang  pathways often leads to ‘mild’, ‘moderate’ or ‘severe’ immune disorders or cancer.we may be intelligent, but if not able to think and love well being of others, we use the intelligence against humanity’ [?].After all ‘The goal of this comprehensive perspective was to extend the design of a roadmap as comprehensive as possible, by analyzing relevant data on major biological features at different stages of life. In the process of integrating and connecting the informational dots, important knowledge gaps that are worthy of future investigation were revealed. Integrating and disseminating relevant information are important for broadening the scope of intellectual understanding on the complex dynamics of effective immunity that lead to effective promotion and maintenance of health.


Dirofilaria immitis. Praziquantel is routinely used to treat feline tapeworm infections. The safety of a fluralaner plus moxidectin combination topical solution  was assessed when administered concurrently with a commercially available praziquantel topical solution . The highest dose rates in clinical use were tested.Fluralaner provides efficacy against feline ectoparasites following topical administration. Moxidectin is routinely used to treat gastrointestinal nematode infections and prevent heartworm disease caused by Concurrent topical administration of a fluralaner plus moxidectin and a praziquantel product did not result in adverse findings. One out of ten cats receiving praziquantel only (control group), and two out of ten cats receiving fluralaner plus moxidectin and praziquantel (treatment group) had dandruff-like flakes in their coat at the application site. Two out of the ten control cats and three cats out of the ten treatment group cats had very small amounts of unidentified material (minute crusts or crumbs) at the application site which was only visible during close inspection.The concurrent treatment of cats with fluralaner plus moxidectin and praziquantel at the maximum dose in clinical use was well tolerated. Ctenocephalides felis) and tick (Ixodes ricinus) killing activity for 12 weeks [Toxocara cati and Ancylostoma tubaeforma) and prevents heartworm disease caused by Dirofilaria immitis [Fluralaner is active against ectoparasite infestations in cats. Following a single topical application, fluralaner provides immediate and persistent flea  [Praziquantel is active against tapeworm in cats (cularis) .Cats may concurrently be infested with ectoparasites such as ticks or fleas as well as gastrointestinal helminths. Therefore, veterinarians may choose to administer an anticestodal agent such as praziquantel concurrently with fluralaner plus moxidectin topical solution. Fluralaner plus moxidectin  and praziquantel  are topical formulations, providing efficacy after systemic absorption.A previous study showed that fluralaner is well tolerated in cats when administered concurrently with an endectoparasiticide combination product containing emodepside and praziquantel . The stuTwenty healthy domestic breed cats  were included in the study. This study was conducted in 2017 in Queensland, Australia, under the Australian Pesticides and Veterinary Medicines Authority (APVMA) General Permit PER7250 covering a defined range of Small Scale Trials.Twenty cats were allocated to two study groups (control group and treatment group) using a randomized block method, ranked by sex then body weight Table . Cats inPhysical examinations were performed by a veterinarian on study days -7, -1, 14 and 28. Parameters assessed included appearance, body condition, musculoskeletal system and locomotion, palpable lymph nodes, skin and hair, abnormalities at the application site, palpation of the abdomen and pulse, auscultation of the heart, heart rate, auscultation of respiratory tract, respiratory rate, rectal temperature, sensory system including ears, eyes and pupils, oral cavity including mucous membranes and capillary refill time; any other abnormalities were recorded. General health observations were performed twice daily throughout the study and body weights were recorded weekly.In addition, clinical assessments for abnormalities in behavior, locomotion, body orifices, pulse, eyes, mucous membranes, respiration, coat and skin (including application site) were carried out by a veterinarian for all study cats prior to treatment on day 0, during the first hour following treatment, and at 2, 4, 8, 12, 24, 36, 48 and 72 hours and at 4, 5, 6 and 7 days after treatment.The concurrent application of fluralaner plus moxidectin and praziquantel (treatment group) did not result in findings considered to be related to the concurrent application of both products. All cats remained in good general health throughout the study.One cat in the control group and two cats in the treatment group had dandruff-like flakes in their coat at the application site for up to three weeks after application. Two cats in the control group and three cats in the treatment group had very small amounts of unidentified material (minute crusts or crumbs) at the application site, which were only visible during close inspection of the application site, for up to two weeks after application. The skin was normal in all cases. One cat in the control group developed an over-grooming lesion within 12 hours of the praziquantel administration, which resolved by the end of the study. Findings at the application site occurred to a similar extent in control and treatment group cats, and are consistent with possible local reactions specified on the products’ labels . All casCases of mild epiphora and sniffling, and suspected overgrooming lesion at the abdomen were observed but are considered incidental and not related to the application of praziquantel and/or fluralaner-moxidectin. All cases were mild and did not require concomitant medication.Body weights remained stable throughout the study in all cats Table .Whilst generated on a limited number of cats, the study results do not indicate a safety risk associated with the concurrent use of fluralaner-moxidectin and praziquantel at the maximum dose rates recommended for clinical use.Concurrent topical application of fluralaner plus moxidectin and praziquantel at the maximum recommended dose rates is well tolerated by cats.


OBJECTIVES/SPECIFIC AIMS: To improve translational research, we have developed a program called Duke Multidisciplinary Education and Research in Translational Sciences (Duke MERITS). Duke MERITS will facilitate cross-disciplinary collaboration among faculty involved in foundational, clinical and/or health care research and in turn also prepare them to train the next generation of translational researchers. METHODS/STUDY POPULATION: The program aims are (1) to define metrics and outcomes measures so faculty can track their progress and identify impact of their collaborative research in translational sciences; (2) to offer a multi-modal faculty development series to promote team science, improve didactic teaching, and incorporate innovative resources to promote interdisciplinary approach to translational research; (3) to provide module-based hands-on-training sessions in bench to bedside research and training in translational grant writing to facilitate the development of multidisciplinary research collaborations. The present study describes results from Aim 1 and includes (a) development of baseline outcome assessment tools necessary to gauge the impact of our programs on both the participating faculty and the research culture within Duke University, (b) impact of a specific course offering in Translational Medicine. In order to achieve this, we conducted multiple focus group sessions with faculty self-identified as junior-, mid-, or advanced-career, a mixed group at any career level and included a group of graduate students and postdoctoral trainees to study the impact of a graduate level course in Translational Aspects of Pathobiology. The activities during these translational science focus groups were designed to define what successful translational science is, to determine what resources support translational Science at Duke, and to decide what resources we need in order to enhance Duke’s position as a leader in research and scientific education. RESULTS/ANTICIPATED RESULTS: We identified that translational science is changing standards while incorporating leadership, teamwork, collaborations, and movement primarily focusing on the overall goal of improving all aspects of health. Participants categorized their field of study and the fields of their coparticipants most frequently as basic discovery and a combination of intervention and health services. The most frequently identified pros/benefits of performing translational science at Duke include industry connections, collaborations with other departments resulting in disciplines being bridged, improving patient care, and access to resources as well as money. The most frequently identified cons/barriers of performing translational science includes the expensiveness, silos, and lack of resources willing to absorb risks. DISCUSSION/SIGNIFICANCE OF IMPACT: The identification of these defined factors from the focus groups has allowed us to issue a comprehensive, sliding Likert scale-based anonymous survey from the secure RedCap system and is being rolled out throughout Duke University, including schools of medicine, nursing, Trinity, biomedical engineering. We envision that Duke MERITS education program will facilitate interprofessional efforts, which we define as a team science approach to identify the clinical “roadblock” and then seek an innovative approach or technology to help overcome this “roadblock”? It can facilitate institutional and departmental recognition in faculty career development. The common goal is to gain fundamental new insights that will result in significant improvement of the existing “standard of care” and meet the challenges of dwindling extramural support.


Triple-negative breast cancer (TNBC) is the most deadly form of breast cancer (BC) today. TNBC treatment is fraught with challenges because of the extensive interpatient heterogeneity in clinical behavior and scarcity of stratifying biomarkers and actionable targets. Women of African ancestry face a disproportionate burden resulting from this disease, which affects them earlier and more aggressively and has a higher propensity to spread and resist conventional treatments. A much higher proportion of Nigerian patients with BC have TNBC compared with patients with BC in the United States and Europe.This article spotlights Nigeria as an example of a nation wherein genetic and nongenetic spheres of influence intersect to affect the prevalence of this disease, the scale of its challenge, and its toll.Studies have illuminated the inherently different tumor biology of Nigerian TNBCs, which show distinct genetic variants and gene expression patterns compared with European or European-American TNBCs. Parallels are apparent between TNBC phenotypes among African Americans and Nigerians, implicating the common thread of shared genetic ancestry between these populations. Reproductive, lifestyle, socioeconomic, and cultural factors also shape TNBC outcomes in Nigeria, as do resource constraints in Nigerian health care and research sectors.Increasing our understanding of how these factors contribute to poorer outcomes among Nigerian women may uncover valuable insights and strategies in alleviating the TNBC burden in many countries of the world and help reduce the racial disparity in BC-related outcomes here in the United States. Importantly, this review also highlights collaborative global and local initiatives that converge expertise and resources to advance research on effective management of TNBC in diverse populations. Despite these treatments, TNBCs run a high risk of progression, especially within the first 5 years after diagnosis.3 Rampant interpatient and intratumor heterogeneity render management of this disease complex and warrant deeper dissection of the molecular landscape of TNBC.4 Nongenetic factors such as health care facilities, resource constraints in patients’ countries, and lifestyle, epidemiologic, and cultural factors all collude and contribute to the burden that TNBC imposes on patients and families, as the disease takes away years from life and life from years. Thus, enhancing our understanding of tumor biology and modifiable factors that influence clinical outcomes, identifying better biomarkers for patient stratification, and developing newer, more effective targeted therapies are critical for improving TNBC management globally.Triple-negative breast cancer (TNBC) accounts for 20% (approximately 0.17 million) of breast cancer (BC) cases worldwide but remains the most deadly subgroup of BCs.5 Among patients with TNBC, AAs are more likely to experience rapid disease progression and shorter survival times than EAs. Furthermore, TNBC is significantly more prevalent and presents with higher grade and earlier onset among West African (WA) women compared with AA women.6 Thus, clearer understanding of the interplay between genetic and nongenetic causes of higher TNBC prevalence in WA women, who share a common ancestry with AAs because of the trans-Atlantic colonial slave trade, may allow us to design better strategies  to ameliorate global TNBC burden and racial disparity in BC outcomes in the United States. Essentially, this review aims to dissect the complex landscape of Nigerian TNBC to understand drivers of the disproportionate burden of TNBC in WA women and racial disparity in outcomes in the United States and to highlight concerted global and local initiatives and collaborative interventions across multiple stakeholders that aim to drive sustainable change and reduce the devastating footprint of this disease.Several studies have suggested that biogeographic ancestry might be a key driver of aggressive BC. Women of African ancestry are disproportionately affected by TNBC, with poorer clinical outcomes compared with patients with BC of other ethnicities. In the United States, African American (AA) women are two to three times more likely to be diagnosed with TNBC compared with European Americans (EAs).“The roots of education are bitter, but the fruit is sweet.” —Aristotle7 Mortality rates have been reported to be much lower among East African compared with WA patients with BC, suggesting that WA ancestry may explain, at least in part, poorer clinical outcomes between AA and EA patients.8 Nigeria, the largest and most populous developing country in Africa, exemplifies the current dismal state of BC in WA. There are more than 27,000 new cases of BC annually in Nigeria; roughly 70% to 80% of these patients present with locally advanced or metastatic BC, and nine of 10 of these women die within the first 5 years.9 The mean age at presentation for Nigerian patients with BC is approximately 43 years, with 74% identified as premenopausal and 12% younger than age 30 years.10 A large percentage of Nigerian BC cases are often classified as TNBC, although it has been suggested that many of these cases are false negatives, resulting from suboptimal tissue fixation and pathology practices.12 Over the next few sections, we discuss contributions of genetic and nongenetic factors to the etiology and prognosis of TNBC in Nigeria and explore how this knowledge could inform clinicians about strategies to more effectively overcome the disease.Ancestry genotyping studies show that the AA population predominantly harbors West or West-Central African ancestry, presumably because of the colonial slave trade.“We can’t choose where we come from, but we can choose where we go from there.” —Steven Chbosky14 Mutations in tumor suppressor genes such as BRCA1 have also been implicated in the higher TNBC incidence rate in Nigeria.16 Furthermore, studies have uncovered multiple biomarkers that are generally overexpressed in Nigerian and WA patients with BC and are associated with TNBC status and aggressive clinicopathologic characteristics , tend to believe that early BC detection leads to better survival rates, and are more likely to practice BSE compared with those with a lower level of education.44 Studies have also revealed that most Nigerian health care providers lack sufficient knowledge of BC risk factors and the procedure for BSE.4,49 A majority of Nigerian women obtain their BC information from television (31%), clinics (31%), and health professionals as well as from their elders, friends, and neighbors among rural women according to one study; thus, disparities in socioeconomic status may underlie differences in awareness and stage at presentation between semiurban and rural Nigerian communities.52 These studies highlight a need for continuing medical and health education programs to improve awareness among the Nigerian adult population and health care professionals of early detection to improve outcomes. Several nonprofit organizations or nongovernmental societies and community outreach programs have been established in Nigeria to improve BC awareness to eventually reduce societal, financial, emotional, and health burdens resulting from TNBC.A clinical study conducted at the University College Hospital in Ibadan, Nigeria, found that approximately 85% of Nigerian patients with BC presented at an advanced stage.53 Another study found that 17.5% of Nigerian patients with BC initially consulted with traditional healers for treatment, which was associated with a more than 3-month delay until presentation.54 Also, in some African cultures, people believe that BC is caused by social misconduct, such as oral or nipple contact, or a woman wearing unclean garments.55 Fear of being divorced by her husband or of being ostracized by the community, fear of disfigurement by surgery, fear of pain or embarrassment during medical examinations , fear of ineffective treatment, lack of confidence in physicians, belief that surgery accelerates metastasis, fear of death, and other factors, including lack of family support, may also deter a woman from seeking medical help immediately.55 Thus, to reduce the TNBC burden in Nigeria, there is a critical unmet need to develop a more nuanced understanding of the wider social context of the human lives it affects and develop focused interventions to address all exacerbating factors.Cultural traditions and spiritual beliefs in Nigeria can influence a patient’s decision to seek timely medical treatment. Some Nigerian women believe that unless the swelling or lump in the breast is painful, it is unlikely to be malignant, and they do not need medical attention.43 Cosmetic products frequently used among African women, such as hair relaxers and skin lighteners, may also be contributing to increased risk for TNBC among Nigerian women, because these contain dangerous carcinogens and/or hormonally active compounds.43 Their potential influence on TNBC risk in Nigeria merits further study.Infectious agents or environmental estrogens such as insecticides and dichlorodiphenyltrichloroethane, used for preventing insect-borne diseases like malaria, are postulated to elevate risk for developing hormonal-related diseases, because they can alter hormone levels.“Access to healthcare shouldn’t depend on your postcode.” —Richard Di NataleThe resource-constrained Nigerian health care system, lack of education and empowerment, poverty, shortage of well-trained health care personnel, and inadequate research infrastructure, as compared with other countries in the world such as the United States, have had significant adverse impacts on TNBC outcomes among the Nigerian population.43 In addition to aforementioned cultural and awareness-related factors, the delay in seeking medical attention may also be attributed to prohibitive cost of treatment, lack of transportation or access to radiology and chemotherapy facilities, and hospital overcrowding.60 In Nigeria, out-of-pocket expenditure for health care was an alarming 95.7% in 2014 according to the WHO. WHO reported that Nigeria allocates only $67 per person for health care, and financial constraints were the primary reason for patients with BC discontinuing treatments. Quality of health care also leaves much to be desired, and inappropriate surgeries and biopsy management lead to late-stage presentation.61 Palliative care is often the only option for patients diagnosed in advanced stages; however, pain medications are often limited or unavailable, especially in rural areas.62A study conducted in a Nigerian teaching hospital in southwestern Nigeria found that the average duration between onset of BC symptoms and presentation was approximately 11.2 months, and approximately 39% of women presented with fungating tumors.9 Nigeria houses seven radiotherapy laboratories; however, only 15% of the reported 4 million Nigerians needing radiotherapy have access to these facilities.64 Furthermore, lack of trained personnel to properly operate radiotherapy equipment results in poor maintenance and equipment malfunction.9 The majority of the radiology equipment at cancer treatment centers is considered nonfunctional because of a lack of qualified personnel who can properly handle the equipment.65 The frequent breakdown of radiotherapy equipment may be attributed to equipment procurement without consultation or advice from end users, unreliable electricity, high cost of operation, bottlenecks in securing spare parts, absence of maintenance contracts with suppliers, and lack of quick response from foreign engineers when equipment malfunctions.9 In addition, mammography facilities are scarce in Africa, and they inadequately detect cancer in women with dense breasts.66 Mammography screening may not detect all tumors in women at the premenopausal age, when the bulkiness of the breast is often an interference in Nigerian women.67 Furthermore, public hospitals are often overcrowded, lack human resources, and require long waiting periods, which stalls screening, diagnosis, and treatment of patients.68 Also, lack of follow-up and poor patient recordkeeping in clinics interfere with determination of specific factors influencing survival patterns for refinement of treatment plans.39Inferior health care infrastructure, especially paucity of facilities for BC detection and treatment, majorly underlies late presentation and poor clinical outcomes among Nigerian patients with TNBC. Nigeria is one of the least developed countries with regard to oncology services, resources, and radiation therapy facilities.69 compared histologic parameters in pathology reports from a teaching hospital in Nigeria with the cancer data set of the Royal College of Pathologists in the United Kingdom to verify compliance and concordance. Almost half of the Nigerian BC cases examined were discordant with the Royal College of Pathologists, and roughly half of the cases were either undergraded or overgraded. Poor fixation and exclusion of mitotic count were underlying factors for discordant grading. Thus, proper training and education of Nigerian pathologists are critical to improving accuracy in BC diagnosis and reporting. Templates or proformas have been suggested for use by African pathologists to guide accurate reporting.Subpar pathology practices are prevalent in many centers in Nigeria and often result in inaccurate diagnoses and consequently inappropriate treatment. Incorrect immunohistochemistry results attributable to poor tissue collection or processing, delayed fixation or overfixation, poor-quality reagents, incorrect laboratory techniques, and lack of quality assurance practices are often prime suspects. Records about cause of death are often not notifiable or centrally maintained. Although Nigeria is one of the few African countries that have published guidelines, created by the Nigeria Breast Pathology Working Group in 2010, on standardized pathology reporting, these guidelines have not been adequately circulated or implemented in medical centers. Daramola et al71 The number of physicians per 100,000 people in Nigeria is currently 18.8, which is much lower than the numbers per 100,000 people in most Western nations, including the United States, where there are approximately 148 physicians per 100,000 people.72 Nigeria currently ranks seventh highest among 57 countries in the world facing a health care shortage crisis, according to the Federal Ministry of Health. Adebayo et al72 reported that there are 33.% and 29.3% gaps in the supply of doctors and nurses, respectively, in Nigeria.72 The shortage of pathologists in Nigeria is also extreme, with only 6% of practicing specialist physicians certified as pathologists.73 Furthermore, Nigeria possesses fewer than 40 trained radiation oncologists to provide radiology services and meet the needs of the growing population of patients with cancer.65 The paucity of practicing clinicians in African countries can be attributed to a significant reduction (6% to 18%) in medical school teaching staff, who have opted to emigrate over the past 5 years (phenomenon known as brain drain).74 Many trainees often leave countries in sub-Saharan Africa for developing countries because of inadequate infrastructure to practice, poor working conditions, and low remuneration.73 Implementing strategies to attract more African health care personnel, such as raising salaries and improving working conditions, will be crucial to ensuring adequate patient coverage. Fortunately, Nigeria possesses a number of highly skilled, motivated, and overseas-trained clinicians who can serve as conduits for revamping health care and conquering challenges of TNBC management.The severe shortage of competent health care providers, including oncologists, radiologists, surgeons, and pathologists, has also contributed to the poor BC-related outcomes in Nigeria. The number of physicians per 100,000 people in Africa is presently 12, which is much lower than the 387 physicians per 100,000 people in Europe.75 There is also a significant shortage of cancer registries and trained cancer registry personnel. In 2006, only 11% of the African population was covered by a cancer registry.76 Nigeria has many population-based cancer registries, such as the Ibadan Cancer Registry located in South West Nigeria and the Abuja Cancer Registry located in North Central Nigeria.77 Both ensure high-quality cancer data; however, together they cover only 2.5% of the Nigerian population. In addition, the scarcity of data on cancer statistics and trends may be a result of government prioritization of funding of research on communicable diseases, rather than cancer research, infrastructure, or treatment. Furthermore, cancer advocates and trained community health care workers responsible for educating the public and policymakers on cancer are unable to meet the needs of the nation.Research provides the evidence base on which cancer prevention, control, and treatment strategies are built. The numbers of cancer researchers, including epidemiologists, statisticians, scientists, public health experts, health economists, and behavioral scientists, in Africa are limited. Although Nigeria is among the top countries in Africa for publishing research articles on BC, cutting-edge research is still lacking.“United we conquer, divided we fall.” —AesopThe increased global awareness of the alarming worldwide BC burden has sparked the launch of several global and local initiatives targeting BC and TNBC globally and in Nigeria Appendix . HoweverThis review spotlights TNBC in Nigeria, where the disease has reached crisis levels. Insights generated from underlying drivers of this high prevalence would affect our understanding of the etiology and biology of TNBC globally; guide research to improve clinical management of TNBC, especially in women of African ancestry; and help design evidence-based, patient-centered, holistic, and efficacious policy frameworks and health awareness programs that factor in resource constraints while targeting key risk factors and cultural issues that may be exacerbating the burden of TNBC in certain nations or ethnic groups. The stark gap in adequate cancer care between Nigeria and the United States and strategies to reduce this gap are shown in “Success is a staircase, not a doorway.” —Dottie Walters


An increasing number of studies is applying advanced neuroimaging techniques in order to elucidate the pathophysiological processes and to identify quantitative outcomes to be used in clinical trials. Diffusion tensor imaging (DTI) is a non-invasive method to detect white matter alterations involving the upper motor neuron and extra-motor white matter tracts. According to this background, the aim of this review is to highlight the key role of MRI and especially DTI, summarizing cross-sectional and longitudinal results of different approaches applied in MND. Current literature suggests that DTI is a promising tool in order to define anatomical “signatures” of the different phenotypes of MND and to track in vivo the progressive spread of pathological proteins aggregates.Motor neuron disease (MND) is a fatal progressive neurodegenerative disorder characterized by the breakdown of the motor system. The clinical spectrum of MND encompasses different phenotypes classified according to the relative involvement of the upper or lower motor neurons (LMN) and the presence of genetic or cognitive alterations, with clear prognostic implications. However, the pathophysiological differences of these phenotypes remain largely unknown. Recently, magnetic resonance imaging (MRI) has been recognized as a helpful  Although neurodegeneration primarily affects the gray matter (GM), pathological alterations in the white matter (WM) have also been reported (Motor neuron disease (MND) is a group of fatal neurodegenerative diseases characterized by progressive damage of the upper motor neurons (UMN) in the cortex and/or lower motor neurons (LMN) in the brainstem and spinal cord. Depending on the relative involvement of UMN and LMN, MND can be classified in a wide range of clinical phenotypes , characterized by different clinical presentation and progression rate. Advanced brain imaging techniques, such as magnetic resonance imaging (MRI), have been developed over the last decades in order to detect reported , involvireported .The present review aims to discuss the current state of the art of MRI within different phenotypes of MND, focusing on WM microstructural alterations, underlining the role of MRI as a tool to understand disease pathophysiology and to provide potential biomarkers for diagnosis and prognostic stratification. Moreover, we also highlight emerging techniques, such as graph analysis, that will likely provide further insights in disease pathogenesis and might help in monitoring disease progression.a priori hypothesis and might be influenced by inter-subject anatomical variability (Diffusion tensor imaging (DTI) is the most common MRI technique that allows to investigate WM microstructural changes. DTI is based on the random diffusion of water molecules in the fiber bundles, also known as Brownian motion . DTI anaiability . The mosiability . To reduiability . In addiiability . CurrentThe weakness of DTI is the lack of specificity in voxels presenting multiple fiber populations (termed “crossing fibers”) . In ordeSeveral studies have consistently demonstrated decreased FA and increased MD, RD, and AD along the entire CST in ALS patients relative to healthy controls –18. SeveC9orf72 repeat expansion carriers (the most common genetic mutation)  , 29. Parpatients , 31.C9orf72 mutation, demonstrating the spreading of diffusivity alterations from anterior to posterior WM regions over a 6-month period  the number of streamlines is calculated for each tract and inserted into a matrix; (5) for each structural connection, the level of microstructural integrity is measured extracting the mean FA, MD, RD, and AD values; (6) finally, all the values are inserted into four different matrices. From the analysis of these matrices, it is possible to provide information concerning the topological organization of network architecture . FA is Section Editor of NeuroImage: Clinical; has received speaker honoraria from Biogen Idec and Novartis; and receives or has received research supports from the Italian Ministry of Health, AriSLA , and the European Research Council. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Here we conducted a literature review on functional neuroimaging, with focus on three general challenges in big data tasks: data collection and sharing, data infrastructure construction, and data analysis methods. The review covers a wide range of literature types including perspectives, database descriptions, methodology developments, and technical details. We show how each of the challenges was proposed and addressed, and how these solutions formed the three core foundations for the functional neuroimaging as a big data science and helped to build the current data-rich and data-driven community. Furthermore, based on our review of recent literature on the upcoming challenges and opportunities toward future scientific discoveries, we envisioned that the functional neuroimaging community needs to advance from the current foundations to better data integration infrastructure, methodology development toward improved learning capability, and multi-discipline translational research framework for this new era of big data.The field of functional  Science, Akil et al. e.g., MRI and behavioral data) and microscopic  connectomes to achieve the goal of deciphering the “neural choreography” of the brain at multiple scales spatiotemporally. From the machine learning perspective under a big data premise, traditional methods for functional neuroimaging analysis, which have been proven successful in multiple applications including functional network analysis and functional dynamics modeling e.g., via parallel computing Functional neuroimaging techniques, including functional magnetic resonance imaging (fMRI) acquired both during task (tfMRI) and resting-state (rsfMRI), electroencephalography (EEG), magnetoencephalography (MEG), and other modalities, provide powerful tools to study human brain and serve as methodological foundations for quantative cognitive neuroscience e.g., memory and motor controls). In addition to these large data sharing efforts, which usually consist of healthy individuals and people with common diseases, more heterogeneous small datasets produced by individual groups are equally important to the community In the past decades we have seen a rapid growth in both the quantity and quality of the neuroimaging data on various scales, thanks to a series of collaborative projects on brain science with huge amount of functional neuroimaging data collected i.e., more subjects) of new functional neuroimaging databases, there have also been community efforts to improve the quality of the images acquired, which include but not limited to: (1) higher image resolution  to support more precise localization and temporal characterization of brain function; (2) more imaging modalities; (3) more imaging sessions; and (4) specific target populations and/or specific cognition processes to identify new functional biomarkers It should also be noted that along with the growing size , discovery-oriented neuroimaging analysis framework comes from Shifting toward the big data perspective of functional neuroimaging on the basis of both higher image quality https://spark.apache.org) for large-scale distributed computing of the neuroimaging data. Also based on Spark, distributed Singular Value Decomposition (SVD) As the growth of neuroimaging dataset size quickly outnumbered the computational capacity of a single workstation, the need for parallel, computationally scalable framework becomes an important topic. The Thunder library Led by the international projects and collaborative efforts, we have seen the advancement of functional neuroimaging as a big data science. At the same time, also in the past decade we have experienced a tremendous paradigm shift in the field of scientific research as a whole, toward data-intensive, discovery-oriented approaches, as envisioned in the book “The Fourth Paradigm” e.g., functional connectivity and gray matter volume), other imaging modalities such as EEG, MEG, or functional near-infrared spectroscopy (fNIRS) should also be considered. Ashar et al. One major challenge of neuroimaging recently recognized by the field lies in its (relative) lack of impact on the clinical practice and public health While registration to common template has been a standard practice for MRI-based studies (which is the similar case for EEG), establishing a common ground for neuroimaging studies across different populations, scales, and imaging modalities is still a tremendous challenge. The Allen Brain Atlas showed a promising architecture for characterizing and localizing mouse brain on different scales, integrating MRI, serial two-photon (STP) tomography e.g., time frames). Various preliminary attempts have been made to apply RNN to functional neuroimaging data, including functional network identification In the book that Goodfellow et al. laid the foundation of deep learning e.g., in clinical practice and drug discovery) and on the difficulty in fully leveraging the ever-growing amount of data. We then conducted focused review on the recent progress in both methodologies  and research frameworks (in data integration and multi-type data collection) to address these concerns. We envision that in the new era of big data, the field of functional neuroimaging could be greatly enhanced by the tools and concepts in the new paradigm of scientific discovery, with promises of better understanding the brain functional architecture and more useful discoveries from the imaging data.In this work, we reviewed studies and efforts on the advancement of functional neuroimaging as a big data science in the past decade. The field has been rapidly growing in data quantity, infrastructure, and analytical methods. At the same time, there are also growing concerns on the translational limitation of functional neuroimaging (The authors have declared no competing interests.


Previous studies have suggested that both bipolar disorder and atopy are associated with an increased risk of stroke. However, the role of atopic diseases/diathesis in the risk of stroke among patients with bipolar disorder remains unclear.Using Taiwan’s National Health Insurance Research Database, we selected 55,593 patients with bipolar disorder between 2002 and 2008, divided them into patients with atopic diseases/diathesis  and patients without atopic diseases/diathesis , and observed them until the end of 2011. Patients who experienced a stroke during the follow-up period were identified.Patients with bipolar disorder and atopic diseases/diathesis had an elevated risk of ischemic stroke  compared with patients with only bipolar disorder; a dose-dependent relationship was observed between the number of allergic comorbidities and the risk of ischemic stroke .The role of atopic diseases in the risk of hemorrhagic stroke among patients with bipolar disorder was nonsignificant .Patients with bipolar disorder and atopic diseases/diathesis are more prone to ischemic stroke later in life than are those without atopic diseases/diathesis. Further study is required to investigate the underlying mechanism linking atopy, bipolar disorder, and stroke. The high prevalence of stroke-related risk factors, including hypertension, dyslipidemia, and diabetes mellitus, among patients with bipolar disorder has gained much attention in the public health and psychiatric fields with respect to its subsequent cerebrovascular diseases . MountinBecause bipolar disorder is a multisystemic disorder affecting cardiovascular status and immunological function , 6, 7, pUsing a longitudinal study design and a large sample extracted from Taiwan’s National Health Insurance Research Database (NHIRD), we investigated the impact of atopic comorbidity on the risk of stroke among patients with bipolar disorder. We hypothesized that patients with bipolar disorder and atopic comorbidity have an increased risk of stroke later in life compared with patients with only bipolar disorder.http://www.nhi.gov.tw/). The NHIRD is administered by the National Health Research Institute and provides comprehensive patient information such as demographic data, clinical visit dates, and disease diagnoses. The identities of all patients included in the NHIRD are withheld to ensure privacy. The diagnostic codes used were based on the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM). The NHIRD has been used extensively in many epidemiologic studies in Taiwan  to Level 5 [least urbanized area]) was assessed in our study .t test was used for continuous variables and Pearson’s X2 test for nominal variables when appropriate. Two Cox regression models were used to investigate the hazard ratios (HRs) and 95% CIs of ischemic stroke and hemorrhagic stroke. The primary model was applied to investigate the presence or absence of atopic diseases/diathesis as a categorical variable with the risks of ischemic stroke and hemorrhagic stroke; the secondary model used the number of atopic comorbidities as a categorical variable to assess the risks of ischemic stroke and hemorrhagic stroke. The 2 models were adjusted according to demographic factors and medical comorbidities. A 2-tailed p value of less than 0.05 was considered statistically significant. All data processing and statistical analyses were performed using Statistical Package for Social Science (SPSS) Version 17 (SPSS Inc.) and Statistical Analysis Software (SAS) Version 9.1 .For between-group comparisons, the independent In total, 55,593 patients with bipolar disorder between 2002 and 2008 were identified and divided into 2 subgroups according to the presence  or absence  of atopic diseases/diathesis . Most paThe Cox regression analysis with adjustments for demographic factors and medical comorbidities revealed that, compared with patients with bipolar disorder and without atopic diseases/diathesis, patients with bipolar disorder and atopic diseases/diathesis had an increased likelihood of ischemic stroke ; a dose-dependent relationship was observed between the number of allergic comorbidities and the risk of ischemic stroke  . In addiStratified by sex and age group, the Cox regression models also revealed that both male  and female  patients with bipolar disorder and atopic diseases/diathesis were prone to ischemic stroke during the follow-up period, and 3 age groups  of patients with bipolar disorder and atopic diseases/diathesis had an increased risk of ischemic stroke .Allergic diseases had no significant role in the risk of hemorrhagic stroke  among patients with bipolar disorder, whereas hypertension  was associated with an elevated risk of hemorrhagic stroke .This is the first study to investigate the impact of atopic comorbidities to the risk of stroke among patients with bipolar disorder. The findings support our hypothesis that after adjustment for demographic factors and stroke-related medical comorbidities, patients with bipolar disorder and atopic diseases/diathesis have an increased risk of ischemic stroke later in life; a dose-dependent relationship exists between the number of atopic comorbidities and the likelihood of ischemic stroke.Previous studies have reported a frequent comorbid association between bipolar disorder and atopic diseases. Jerrell et al. revealed that more than one-fifth of patients with bipolar disorder had comorbid atopic diseases and atopic diathesis . In a saAn atopy-related immunological disturbance may explain the association between bipolar disorder and ischemic stroke. Previous studies have suggested that the proinflammatory cytokines related to recurrent atopic responses, including interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF)-α, play a critical role in the pathophysiology of stroke-related risk factors (atherosclerosis and hypertension) and ischemic stroke –34. In aIn accordance with previous findings that bipolar disorder and atopic diseases were unassociated with hemorrhagic stroke, our study discovered no evidence of an association between atopic diseases/diathesis and hemorrhagic stroke among patients with bipolar disorder , 46. HowThis study had several limitations. First, the incidence of stroke and the prevalence of bipolar disorder and atopic diseases may have been underestimated because only patients who sought medical assistance were examined in our study. However, all patients in our study received diagnoses from board-certified physicians, yielding a high diagnostic validity. Second, we did not investigate the effects of medications for bipolar disorder and atopic diseases on the risk of stroke because of the prohibitive complexity posed by medication use during such a long follow-up period. Third, we were unable to examine the influence of factors not included in the NHIRD patient information, such as age at onset of bipolar disorder, the subtypes of bipolar disorder, family history, personal lifestyle, obesity, and environmental factors.In conclusion, after adjusting for demographic factors and stroke-related medical comorbidities, we determined that patients with bipolar disorder and atopic diseases/diathesis have an increased likelihood of ischemic stroke later in life compared with patients with only bipolar disorder. In addition, we observed a dose-dependent relationship between the number of atopic comorbidities and the risk of ischemic stroke among patients with bipolar disorder. In the clinical practice, we suggest that clinicians should pay more attention to the likelihood of metabolic and cerebrocardiovascular diseases among patients with bipolar disorder, especially those with atopic diseases. A high-quality and integrated care with detection and follow-up of cerebrocardiovascular risk factors such as smoking, hypertension, obesity or unhealthy life styles should be necessary in patients with bipolar disorder and atopic diseases. Further study is required to investigate the underlying mechanism linking bipolar disorder, atopic diseases/diathesis, and ischemic stroke, and to elucidate whether prompt intervention in atopic diseases may reduce the risk of ischemic stroke among patients with bipolar disorder.S1 Data(XLSX)Click here for additional data file.


In this data article, we present the 2004–2014 average European seafood production volume by production sector, country, and species. The production data originates from the Food and Agriculture Organisation of the United Nations (FAO) and covers three production sectors: Marine fisheries, marine aquaculture, and freshwater production. We present the main ecological characteristics of each species produced or harvested. These species characteristics were retrieved from various published sources and include biological sensitivity to harvesting and temperature ranges for the most important species. These indices were weighted by each species production volume in order to produce maps of European country’s color-coded by their overall temperature range, maximum temperature, and biological sensitivity within each production sector. Specifications tableValue of the data•Species-specific temperature range and extremes can allow for further studies, for example, what if scenarios.•Species-specific biological sensitivity allows for comparisons between on-going studies on fish production and coastal communities vulnerability to climate change in Europe and elsewhere.•The data can be used to provide an indicator of the vulnerability of each European country’s seafood production to climate change based on the country’s production volume and the main species produced or harvested. The main species stand for at least 90% of the production volume in each sector.•The data provides scientists, policy-makers, and industry actors with a recent overview of the seafood production of the most important species in the European Region and the European Economic Area. It allows comparisons of seafood production vulnerability to climate change of between countries and sectors: Marine fisheries, marine aquaculture, and freshwater production.12www.climefish.eu).We define seafood as farmed and captured fish, shellfish and seaweed products from marine and freshwater ecosystems that directly or indirectly (as feed) are meant for human consumption (EU-2020 project ClimeFish Description of Actions http://www.fao.org/fishery/statistics/software/fishstatj/en) and averaged over a period of 11 years (2004–2014). Data are presented as an 11-year (2004–2014) average in tons for each species, within each production sector  for each country , Turkey and the Faroe Islands. Data from the Channel Islands, the Isle of Man, and Gibraltar were included in the UK production statistics; data from Monaco were included in the French production and data from San Marino were included in the Italian production. Production volume data were extracted from the FAO database using the custom-made interface FishStatJ ( country . ProductThe maps created for


Like catarrhines, some platyrrhines show exposed and reddish skin, raising the possibility that reddish signals have evolved convergently. This variation in skin exposure and color combined with sex‐linked polymorphic color vision in platyrrhines presents a unique, and yet underexplored, opportunity to investigate the relative importance of chromatic versus achromatic signals, the influence of color perception on signal evolution, and to understand primate communication broadly. By coding the facial skin exposure and color of 96 platyrrhines, 28 catarrhines, 7 strepsirrhines, 1 tarsiiform, and 13 nonprimates, and by simulating the ancestral character states for these traits, we provide the first analysis of the distribution and evolution of facial skin exposure and color in platyrrhini. We highlight ways in which studying the presence and use of color signals by platyrrhines and other primates will enhance our understanding of the evolution of color signals, and the forces shaping color vision. IntriguCacajao calvus]) to a complete absence of exposed skin (e.g. moustached tamarins [Saguinus mystax]). The increased surface area of exposed skin in African and Asian monkeys has been hypothesized to enhance communication based on skin color signals.In addition to color variation, the extent of exposed skin among the monkeys of the Americas ranges from the most extensive seen in the order  completely exposed skin ; (b)The ancestral character states for skin exposure (continuous trait) were simulated using the Maximum Likelihood method. We tested three models of evolution: Brownian Motion (BM), Ornstein‐Uhlenbeck (OU), and Early Burst (EB), before selecting the best‐fitting model (OU). Skin exposure evolution was plotted using the phytools contMap function in R.Saguinus, and among the Atelidae family, with interesting variation within the genus Cacajao. There is also considerable exposed skin within the genera Cebus and Sapajus, and the callitrichids, including some but not all species of Callithrix, some Saguinus, and all examined members of the genus Leontopithecus  seem to have experienced re‐covering of the face in hair. Faces covered by hair are reconstructed as ancestral for strepsirrhines, although at least one genus (including nine species) Propithecus, has exposed facial skin.Our results indicate that exposure of facial skin is an evolutionarily plastic trait, with shifts from relatively hairy to relatively exposed skin and vice versa being relatively common among platyrrhines Figure . The lass Figure . InteresChiropotes albinasus), and for at least four species  the facial skin is predominantly red  white‐nosed saki  contrast to body pelage Figure . In some4OPN1LW opsin gene.OPN1LW polymorphism, all males and homozygous females have dichromatic (red‐green colorblind) vision, while a subset of females are heterozygous and have trichromatic color vision. This variation has important consequences for the perception of natural stimuli, including socially relevant scenes.Characteristics of the color vision system are of critical importance to perception and interpretation of visual signals.With few exceptions5Studying skin chroma and luminance variation in platyrrhines, alongside other understudied taxa , will add to the wealth of information now available for catarrhines and enable us to answer new questions about the variation and evolution of primate color signals. For example, this framework will promote tests of potential convergence in the evolution of color signals among distantly related species, and improve our ability to assess the socio‐sexual, ecological, and perceptual variables that shape the emergence, persistence, and form of different traits. Research questions could include the role of skin signals in male–male competition, mate choice, color signals as potential condition indicators, and the heritability of color traits, and their relationship to fitness. We suggest that studies in these areas should aim to: (a) document skin signal variation, (b) understand the genetic and physiological mechanisms involved in the production of skin color, (c) understand the relationship to behavior and/or biologically important traits such as ovulation, and (d) test these signals experimentally back to live animal receivers. The impressive array of work done on catarrhine primates, for which numerous viable methods have been developed Table , provideOPN1LW opsins of platyrrhine primates with reddish, exposed faces, along with closely related species without red faces or patches, the hypothesis that red and visible facial skin is associated with increased diversity of opsin alleles in platyrrhines can be tested. It is of particular interest to note that among monkeys in the Americas, females may have a private color channel due to the sex‐linked nature of color vision variation in platyrrhines. A private channel is a signaling channel that only a subset of potential receivers can see. This has been suggested, for example, for bird UV signaling, which is visible to other birds, but not visible to mammalian predators.We hypothesize that luminance and/or chromatic variation is involved in socio‐sexual communication for at least some species of platyrrhine primates. Specifically, we predict that color variation of facial or genital skin plays a role in communication for species with exposed faces and genitals. If socio‐sexual communication among females along the red‐green channel is important, then those taxa are predicted to have greater numbers of opsin alleles and higher instances of trichromacy. By genotyping the Alouatta sp.), whose routine trichromacy has evolved independently from that of catarrhines, and monochromatic owl monkeys (Aotus sp.) may provide unique test cases that generate new insight into primates color vision evolution.In studies of the evolution of platyrrhine color vision, we urge a more holistic approach that integrates the role of natural selection in foraging and predator detection strategies with pressures linked to sexual selection and socio‐sexual communication. For example, species that are less reliant on cryptically colored foods, for which dichromacy is advantageous,Challenges to studying skin color signals in platyrrhines include: (a) difficulties in measuring coloration of small, highly arboreal primates; (b) finding appropriate populations for testing attention to signals through experimental image and/or model presentation; and (c) collecting biological samples with appropriate sampling of wild populations to assess opsin gene diversity within and between species. Sampling wild populations is crucial, as captive populations can have low sample sizes and decreased genetic heterozygosity, yet this is increasingly difficult given shrinking primate populations across Central and South America and Mexico. Possible solutions for each of these issues include: (a) innovating methods in color‐calibrated digital photographyFinally, although we have focused on skin color and intraspecific communication, we would be remiss if we failed to highlight the potential of interspecific pelage and skin color variation to contribute to key evolutionary processes. For example, species boundaries may be enhanced via conspicuous character displacement among callitrichid and titi monkey lineages that have radiated widely in short time periods.Figure S1 Ancestral state reconstruction of skin exposure visualized on an alternate phylogeny of the Order PrimatesClick here for additional data file.Figure S2 Ancestral state reconstruction of skin exposure visualized on a Bayesian inference of primate phylogeny reconstructed by the 10kTrees Project.Click here for additional data file.Figure S3 Ancestral state reconstruction of skin color visualized on a Bayesian inference of primate phylogeny reconstructed by the 10kTrees Project.Click here for additional data file.Figure S4 Ancestral state reconstruction of skin color visualized on an alternate phylogeny of the Order PrimatesClick here for additional data file.Table S1 Additional sources of images for platyrrhine skin assessment. Most coding was done by consulting a current encyclopedia of living primate species.Click here for additional data file.


Evidence-based reproductive care reduces morbidity and mortality for women and their children, decreases health disparities and saves money. Community health centres (CHCs) are a key point of access to reproductive and primary care services for women who are publicly insured, uninsured or unable to pay for care. Women of reproductive age (15–44 years) comprise just of a quarter (26%) of the total CHC patient population, with higher than average proportions of women of colour, women with lower income and educational status and social challenges (e.g. housing). Such factors are associated with poorer reproductive health outcomes across contraceptive, preventive and pregnancy-related services. The Affordable Care Act (ACA) prioritised reproductive health as an essential component of women’s preventive services to counter these barriers and increase women’s access to care. In 2012, the United States Supreme Court ruled ACA implementation through Medicaid expansion as optional, creating a natural experiment to measure the ACA’s impact on women’s reproductive care delivery and health outcomes.This paper describes a 5-year, mixed-methods study comparing women’s contraceptive, preventive, prenatal and postpartum care before and after ACA implementation and between Medicaid expansion and non-expansion states. Quantitative assessment will leverage electronic health record data from the ADVANCE Clinical Research Network, a network of over 130 CHCs in 24 states, to describe care and identify patient, practice and state-level factors associated with provision of recommended evidence-based care. Qualitative assessment will include patient, provider and practice level interviews to understand perceptions and utilisation of reproductive healthcare in CHC settings.To our knowledge, this will be the first study using patient level electronic health record data from multiple states to assess the impact of ACA implementation in conjunction with other practice and policy level factors such as Title X funding or 1115 Medicaid waivers. Findings will be relevant to policy and practice, informing efforts to enhance the provision of timely, evidence-based reproductive care, improve health outcomes and reduce disparities among women. Patient, provider and practice-level interviews will serve to contextualise our findings and develop subsequent studies and interventions to support women’s healthcare provision in CHC settings. Use of electronic health record and community-level data from the ADVANCE Clinical Research Network will enable broader, more inclusive assessment of policy impacts on women’s healthcare at the patient, provider and practice levels.Patients in ADVANCE are evenly divided between 24 Medicaid expansion and non-expansion states; our study will provide the most comprehensive and in-depth assessment of state and local policy impacts on women’s healthcare in community health centre settings to date.Patient, provider and community health centre leader interviews will provide a practical context to our quantitative findings and inform subsequent studies and interventions.critical gap” in women’s preventive services  will continue to be a complex interplay of human behavior, social mores, technology, and science. The demand for research to explore these nuanced relationships and better understand the needs of women and families will only increase with the removal of traditional barriers to health care access” [Moreover, alongside ACA implementation, complex state policies, social and political environments, and clinic factors will continue to shape the availability and utilisation of reproductive health services in CHCs , 80, 81. access” . AcknowlFindings will be relevant to policy and practice, informing efforts to enhance the provision of timely, evidence-based reproductive care, improve health outcomes, and reduce disparities among low-income and vulnerable populations of women. Patient, provider and practice level interviews will serve to contextualise our findings and develop subsequent studies and interventions to support women’s healthcare provision in CHC settings.


The purpose of this symposium is twofold: (1) To present innovative research linking social relationships, isolation, and well-being among older adults, and (2) To highlight new and emerging scholars in the Behavioral and Social Sciences section of GSA. The papers in this symposium examine the repercussions of numerous relationships for well-being in later life. Huo and colleagues examine the impacts of contact with close and not-close social partners on physical activity, highlighting differences by gender. Polenick and colleagues focus on perhaps the closest of relationships in later life: marriage, analyzing longitudinal associations between discordant chronic conditions and depressive symptoms among older couples. Upenieks takes an intergenerational perspective, examining the embeddedness of adult children in older adults’ networks in the context of both depression onset and chronically high depressive symptomology. This paper also highlights the consequences of well-being for older adults’ social isolation, and not merely the reverse. Hladek and colleagues explore the subjective side of isolation among older adults with chronic disease, noting links between loneliness and self-efficacy that may have clinical and interventional significance. Lastly, Meinertz and Gilligan explore potential gaps in service provision that may increase rural older adults’ risk of isolation and abuse. Taken together, these five papers underscore the importance of various social relationships for older adults’ well-being, and suggest implications for how best to promote healthy aging. As discussant, Thomas will assess the strengths and limitations of these papers, and consider the contributions these studies – and new scholars – can make to the field.