1 5224 202 PRIORITIZED RESEARCH FOR THE PREVENTION, TREATMENT, AND REVERSAL OF CHRONIC DISEASE: RECOMMENDATIONS FROM THE LIFESTYLE MEDICINE RESEARCH SUMMIT. DECLINING LIFE EXPECTANCY AND INCREASING ALL-CAUSE MORTALITY IN THE UNITED STATES HAVE BEEN ASSOCIATED WITH UNHEALTHY BEHAVIORS, SOCIOECOLOGICAL FACTORS, AND PREVENTABLE DISEASE. A GROWING BODY OF BASIC SCIENCE, CLINICAL RESEARCH, AND POPULATION HEALTH EVIDENCE POINTS TO THE BENEFITS OF HEALTHY BEHAVIORS, ENVIRONMENTS AND POLICIES TO MAINTAIN HEALTH AND PREVENT, TREAT, AND REVERSE THE ROOT CAUSES OF COMMON CHRONIC DISEASES. SIMILARLY, INNOVATIONS IN RESEARCH METHODOLOGIES, STANDARDS OF EVIDENCE, EMERGENCE OF UNIQUE STUDY COHORTS, AND BREAKTHROUGHS IN DATA ANALYTICS AND MODELING CREATE NEW POSSIBILITIES FOR PRODUCING BIOMEDICAL KNOWLEDGE AND CLINICAL TRANSLATION. TO UNDERSTAND THESE ADVANCES AND INFORM FUTURE DIRECTIONS RESEARCH, THE LIFESTYLE MEDICINE RESEARCH SUMMIT WAS CONVENED AT THE UNIVERSITY OF PITTSBURGH ON DECEMBER 4-5, 2019. THE SUMMIT'S GOAL WAS TO REVIEW CURRENT STATUS AND DEFINE RESEARCH PRIORITIES IN THE SIX CORE AREAS OF LIFESTYLE MEDICINE: PLANT-PREDOMINANT NUTRITION, PHYSICAL ACTIVITY, SLEEP, STRESS, ADDICTIVE BEHAVIORS, AND POSITIVE PSYCHOLOGY/SOCIAL CONNECTION. FORTY INVITED SUBJECT MATTER EXPERTS (1) REVIEWED EXISTING KNOWLEDGE AND GAPS RELATING LIFESTYLE BEHAVIORS TO COMMON CHRONIC DISEASES, SUCH AS CARDIOVASCULAR DISEASE, DIABETES, MANY CANCERS, INFLAMMATORY- AND IMMUNE-RELATED DISORDERS AND OTHER CONDITIONS; AND (2) DISCUSSED THE POTENTIAL FOR APPLYING CUTTING-EDGE MOLECULAR, CELLULAR, EPIGENETIC AND EMERGING SCIENCE KNOWLEDGE AND COMPUTATIONAL METHODOLOGIES, RESEARCH DESIGNS, AND STUDY COHORTS TO ACCELERATE CLINICAL APPLICATIONS ACROSS ALL SIX DOMAINS OF LIFESTYLE MEDICINE. NOTABLY, FEDERAL HEALTH AGENCIES, SUCH AS THE DEPARTMENT OF DEFENSE AND VETERANS ADMINISTRATION HAVE BEGUN TO ADOPT "WHOLE-PERSON HEALTH AND PERFORMANCE" MODELS THAT ADDRESS THESE LIFESTYLE AND ENVIRONMENTAL ROOT CAUSES OF CHRONIC DISEASE AND ASSOCIATED MORBIDITY, MORTALITY, AND COST. RECOMMENDATIONS STRONGLY SUPPORT LEVERAGING EMERGING RESEARCH METHODOLOGIES, SYSTEMS BIOLOGY, AND COMPUTATIONAL MODELING IN ORDER TO ACCELERATE EFFECTIVE CLINICAL AND POPULATION SOLUTIONS TO IMPROVE HEALTH AND REDUCE SOCIETAL COSTS. NEW AND ALTERNATIVE HIERARCHIES OF EVIDENCE ARE ALSO BE NEEDED IN ORDER TO ASSESS THE QUALITY OF EVIDENCE AND DEVELOP EVIDENCE-BASED GUIDELINES ON LIFESTYLE MEDICINE. CHILDREN AND UNDERSERVED POPULATIONS WERE IDENTIFIED AS PRIORITIZED GROUPS TO STUDY. THE COVID-19 PANDEMIC, WHICH DISPROPORTIONATELY IMPACTS PEOPLE WITH CHRONIC DISEASES THAT ARE AMENABLE TO EFFECTIVE LIFESTYLE MEDICINE INTERVENTIONS, MAKES THE SUMMIT'S FINDINGS AND RECOMMENDATIONS FOR FUTURE RESEARCH PARTICULARLY TIMELY AND RELEVANT. 2020 2 1737 52 EARLY DETECTION OF ACCELERATED AGING AND CELLULAR DECLINE (AACD): A CONSENSUS STATEMENT. THE CELLULAR HALLMARKS OF ACCELERATED AGING AND THEIR CLINICAL EXPRESSION MAY BE GROUPED USING THE TERMS 'ACCELERATED AGING AND CELLULAR DECLINE' (AACD) AND/OR 'AGE-ASSOCIATED CELLULAR DECLINE'. THIS CONSTRUCT IS DESIGNED TO CAPTURE THE BIOLOGICAL BACKGROUND PREDISPOSING THE DEVELOPMENT OF AGE-RELATED CONDITIONS. BY CLASSIFYING RISK FACTORS, EARLY INDICATORS, AND CLINICAL DIFFERENTIATORS OF AACD THROUGH EXPERT CONSENSUS, THIS STUDY AIMED TO IDENTIFY THE SIGNS, SYMPTOMS, AND MARKERS INDICATIVE OF AACD. IN DOING SO, THIS WORK PAVES THE WAY FOR FUTURE IMPLEMENTATION OF THE AACD CONCEPT IN THE CLINICAL AND RESEARCH SETTINGS. AN INTERDISCIPLINARY PANEL OF EXPERTS WITH CLINICAL AND RESEARCH EXPERTISE WAS SELECTED TO PARTICIPATE IN A VIRTUAL WORKSHOP TO DISCUSS AACD. A MODIFIED NOMINAL GROUP TECHNIQUE WAS USED TO ESTABLISH CONSENSUS AMONG THE GROUP. AN EXTENDED GROUP OF INTERNATIONAL EXPERTS CRITICALLY REVIEWED AN EARLY DRAFT OF THE MANUSCRIPT, AND THEIR FEEDBACK WAS THEN INCORPORATED INTO THE MODEL. EXPERTS IDENTIFIED 13 FACTORS PREDISPOSING TO OR CLINICALLY MANIFESTING AACD. AMONG THESE, CHRONIC DISEASES, OBESITY, AND UNFAVORABLE GENETIC BACKGROUND WERE CONSIDERED AS THE MOST IMPORTANT. THERE WAS A CONSENSUS THAT A GRADUAL AND NONSPECIFIC DEVELOPMENT OFTEN CHARACTERIZES AACD, MAKING ITS CLINICAL DETECTION POTENTIALLY CHALLENGING. IN ADDITION, SIGNS AND SYMPTOMS MIGHT HAVE MULTIFACTORIAL CAUSES AND OVERLAPPING ORIGINS, SUCH AS GENETIC AND EPIGENETIC PREDISPOSITIONS. AS A RESULT, AN INITIAL CHECKLIST WAS OUTLINED, LISTING CLINICAL FACTORS OF SPECIAL RELEVANCE (E.G., FATIGUE, LOW QUALITY OF SLEEP, AND LOW MOOD) TO REPRESENT EARLY MANIFESTATIONS OF THE ORGANISM'S EXHAUSTION, WHICH ARE ALSO FREQUENTLY NEGLECTED IN THE CLINICAL SETTING. DIFFERENTIATING AACD FROM OTHER CONDITIONS IS ESSENTIAL. THE USE OF A COMBINATION OF BIOMARKERS WAS PROPOSED AS A VIABLE METHOD IN A TWO-STEP PROCESS OF DIFFERENTIATION: 1) IDENTIFICATION OF EARLY AACD CLINICAL INDICATORS, FOLLOWED BY 2) SYMPTOM AND BIOMARKER CONFIRMATION WITH A FOCUS ON SYSTEM DOMAINS (TO BE POTENTIALLY TARGETED BY FUTURE SPECIFIC INTERVENTIONS). ALTHOUGH THE AACD CONSTRUCT IS NOT YET READY FOR ROUTINE USE IN CLINICAL PRACTICE, ITS OPERATIONALIZATION MAY SUPPORT THE EARLY IDENTIFICATION OF AGE-RELATED CONDITIONS (WHEN THIS MIGHT STILL BE AMENABLE TO REVERSION) AND ALSO ENCOURAGE PREVENTATIVE INTERVENTIONS. FURTHER INVESTIGATION IS NEEDED TO ESTABLISH SPECIFIC BIOMARKERS THAT CONFIRM INDEPENDENT RISK FACTORS FOR AACD AND PROVIDE A MORE DEFINITIVE STRUCTURE TO THE CONCEPT OF AACD (AND AGE-ASSOCIATED CELLULAR DECLINE). 2021 3 734 52 CANCER HEALTHCARE DISPARITIES AMONG AFRICAN AMERICANS IN THE UNITED STATES. A NEED EXISTS TO EXAMINE RACIAL DISPARITIES IN THE HEALTHCARE ARENA AND THE IMPACT ON PATIENTS WITH CANCER. DESPITE ONGOING EFFORTS TO INCREASE EQUITY IN PRIMARY HEALTHCARE ACCESS, RACIAL AND SOCIOECONOMIC DISPARITIES PERSIST, THUS CONTRIBUTING TO DISPROPORTIONATE TREATMENT OUTCOMES AND SURVIVORSHIP AMONG MINORITY AND LOW-INCOME PATIENTS. SUCH DISPARITIES HAVE BEEN REVEALED IN TREATMENT COHORTS OF PATIENTS WITH MULTIPLE FORMS OF CANCER, INCLUDING BREAST, CERVICAL, OVARIAN, ENDOMETRIAL, PROSTATE, LUNG, COLORECTAL, GASTROINTESTINAL, AND HEPATOCELLULAR, AND HAVE BEEN ATTRIBUTED TO A RANGE OF CO-OCCURRING BEHAVIORAL, SOCIAL DETERMINANTS OF HEALTH, UNDERLYING GENETIC FACTORS, AS WELL AS ACCESS TO EDUCATIONAL OPPORTUNITIES THAT LIMIT THE QUALITY OF INFORMED HEALTHCARE. THESE VARIOUS INTERRELATED FACTORS WIDEN CANCER HEALTHCARE DISPARITIES SYNERGISTICALLY THROUGHOUT UNDERSERVED COMMUNITIES, AND THEIR INFLUENCE HAS BEEN AMPLIFIED BY THE CORONAVIRUS DISEASE 2019 (COVID-19) PANDEMIC. FUNDAMENTALLY, A LACK OF BASIC AND CLINICAL RESEARCH EXISTS THAT FAILS TO ADEQUATELY REFLECT DIVERSITY AND MINORITY INVOLVEMENT IN DRUG DEVELOPMENT. ALTHOUGH OVERCOMING THE OBSTACLES RESPONSIBLE FOR CHRONIC TREATMENT DISPARITIES IS A FORMIDABLE TASK, PROMISING MEANS OF ACHIEVING MORE UNIFORM QUALITY HEALTHCARE ARE BECOMING MORE CLEARLY ELUCIDATED. TO REDUCE DISEASE PROGRESSION, INCREASE OVERALL SURVIVAL, AND IMPROVE THE HEALTH OF VULNERABLE POPULATIONS, IT IS NECESSARY TO IDENTIFY AND FULLY DISCLOSE ENVIRONMENTAL, BIOLOGICAL, AND ANCESTRAL FACTORS THAT IMPACT THE RISK FOR CANCER; HEAL HISTORICAL FRACTURES WITHIN COMMUNITIES; AND INCREASE PARTICIPATION OF RACIAL AND ETHNIC MINORITIES IN SCREENING EFFORTS AND RESEARCH STUDIES. THIS REQUIRES DEVELOPING A SYSTEM OF JUSTICE AND TRUST BASED ON SPECIFIC, SOLUTION-ORIENTED GRASSROOTS COMMUNITY EFFORTS WORKING IN TANDEM WITH MEDICAL AND PHARMACEUTICAL LEADERS. BY FULLY EXPLORING AND PINPOINTING THE UNDERLYING CAUSES OF HEALTHCARE DISPARITIES, IT SHOULD BE POSSIBLE TO DEFINE STRATEGIES AND INTERVENTIONS MOST LIKELY TO TRANSFORM CANCER CARE. THE ULTIMATE GOAL IS UNDERSTANDING INDIVIDUAL, CULTURAL, AND BIOLOGICAL VULNERABILITIES, INCLUDING ENVIRONMENTAL AND EPIGENETIC LIABILITIES, TO OPTIMIZE CANCER PREVENTION, DIAGNOSIS, AND TREATMENT. 2022 4 4344 41 MINIREVIEW: TRANSLATIONAL ANIMAL MODELS OF HUMAN MENOPAUSE: CHALLENGES AND EMERGING OPPORTUNITIES. INCREASING IMPORTANCE IS PLACED ON THE TRANSLATIONAL VALIDITY OF ANIMAL MODELS OF HUMAN MENOPAUSE TO DISCERN RISK VS. BENEFIT FOR PREDICTION OF OUTCOMES AFTER THERAPEUTIC INTERVENTIONS AND TO DEVELOP NEW THERAPEUTIC STRATEGIES TO PROMOTE HEALTH. BASIC DISCOVERY RESEARCH CONDUCTED OVER MANY DECADES HAS BUILT AN EXTENSIVE BODY OF KNOWLEDGE REGARDING REPRODUCTIVE SENESCENCE ACROSS MAMMALIAN SPECIES UPON WHICH TO ADVANCE ANIMAL MODELS OF HUMAN MENOPAUSE. MODIFICATIONS TO EXISTING ANIMAL MODELS COULD RAPIDLY ADDRESS TRANSLATIONAL GAPS RELEVANT TO CLINICAL ISSUES IN HUMAN MENOPAUSAL HEALTH, WHICH INCLUDE THE IMPACT OF 1) CHRONIC OVARIAN HORMONE DEPRIVATION AND HORMONE THERAPY, 2) CLINICALLY RELEVANT HORMONE THERAPY REGIMENS (CYCLIC VS. CONTINUOUS COMBINED), 3) CLINICALLY RELEVANT HORMONE THERAPY FORMULATIONS, AND 4) WINDOWS OF OPPORTUNITY AND OPTIMAL DURATION OF INTERVENTIONS. MODIFICATIONS IN EXISTING ANIMAL MODELS TO MORE ACCURATELY REPRESENT HUMAN MENOPAUSE AND CLINICAL INTERVENTIONS COULD RAPIDLY PROVIDE PRECLINICAL TRANSLATIONAL DATA TO PREDICT OUTCOMES REGARDING UNRESOLVED CLINICAL ISSUES RELEVANT TO WOMEN'S MENOPAUSAL HEALTH. DEVELOPMENT OF THE NEXT GENERATION OF ANIMAL MODELS OF HUMAN MENOPAUSE COULD LEVERAGE ADVANCES IN IDENTIFYING GENOTYPIC VARIATIONS IN ESTROGEN AND PROGESTERONE RECEPTORS TO DEVELOP PERSONALIZED MENOPAUSAL CARE AND TO PREDICT OUTCOMES OF INTERVENTIONS FOR PROTECTION AGAINST OR VULNERABILITY TO DISEASE. KEY TO THE SUCCESS OF THESE MODELS IS THE CLOSE COUPLING BETWEEN THE TRANSLATIONAL TARGET AND THE RANGE OF PREDICTIVE VALIDITY. PRECLINICAL TRANSLATIONAL ANIMAL MODELS OF HUMAN MENOPAUSE NEED TO KEEP PACE WITH CHANGES IN CLINICAL PRACTICE. WITH FOCUS ON PREDICTIVE VALIDITY AND STRATEGIC USE OF ADVANCES IN GENETIC AND EPIGENETIC SCIENCE, NEW ANIMAL MODELS OF HUMAN MENOPAUSE HAVE THE OPPORTUNITY TO SET NEW DIRECTIONS FOR MENOPAUSAL CLINICAL CARE FOR WOMEN WORLDWIDE. 2012 5 3011 28 GENETICS AND EPIGENETICS IN THE FIBROGENIC EVOLUTION OF CHRONIC LIVER DISEASES. RECENT YEARS HAVE SEEN UNPRECEDENTED PROGRESS IN THE IDENTIFICATION AND CHARACTERIZATION OF GENETIC INFORMATION RELATED TO CHRONIC LIVER DISEASES (CLDS). HOWEVER, DESPITE THE CONCEPTUAL BENEFIT IN EARLY RECOGNITION OF AT-RISK POPULATIONS AMENABLE TO PRE-EMPTIVE TREATMENT AND/OR SURVEILLANCE STRATEGIES, RECENT GENOMIC RESEARCH IN THE FIELD HAS PLACED FOCUS ON UNRAVELLING THE GENETIC ARCHITECTURE OF DISEASE SUSCEPTIBILITY, WHILE DATA ON GENETIC MARKERS ANTICIPATING AN ACCELERATED FIBROGENESIS IN AN INDIVIDUAL ARE STILL LIMITED. LIKEWISE, SEQUENCE VARIATION ASSIGNING RAPID FIBROGENIC EVOLUTION COMMON TO CLDS IRRESPECTIVE OF ETIOLOGY ARE POORLY DEFINED ASIDE FROM PNPLA3 (ADIPONUTRIN) AS A PROMINENT EXCEPTION. THE EMERGING FIELD OF EPIGENETICS IN HEPATOLOGY HAS MOSTLY BEEN STUDIED UNDER THE PERSPECTIVE OF GENE REGULATION, LESS SO AS A HERITABLE ALTERATION IN GENE ACTIVITY. IN THIS ARTICLE WE WILL CRITICALLY DISCUSS RECENT FINDINGS IN GENOMIC HEPATOLOGY WITH SPECIAL FOCUS ON THE (EPI)GENETIC CONTRIBUTION TO THE FIBROGENIC EVOLUTION OF CLDS. 2011 6 618 40 BIOBEHAVIORAL MECHANISMS ASSOCIATED WITH NONHEALING WOUNDS AND PSYCHONEUROLOGIC SYMPTOMS (PAIN, COGNITIVE DYSFUNCTION, FATIGUE, DEPRESSION, AND ANXIETY) IN OLDER INDIVIDUALS WITH CHRONIC VENOUS LEG ULCERS. THE PREVALENCE AND INCIDENCE OF CHRONIC VENOUS LEG ULCERS (CVLUS) ARE INCREASING WORLDWIDE, AS ARE THE ASSOCIATED FINANCIAL COSTS. ALTHOUGH IT HAS LONG BEEN KNOWN THAT THEIR UNDERLYING ETIOLOGY IS VENOUS INSUFFICIENCY, THE MOLECULAR ASPECTS OF HEALING VERSUS NONHEALING, AS WELL AS THE PSYCHONEUROLOGIC SYMPTOMS (PNS; PAIN, COGNITIVE DYSFUNCTION, FATIGUE, DEPRESSION, AND ANXIETY) ASSOCIATED WITH CVLUS REMAIN UNDERSTUDIED. IN THIS BIOBEHAVIORALLY FOCUSED REVIEW, WE AIM TO ELUCIDATE THE COMPLEX MECHANISMS THAT LINK THE BIOLOGICAL AND MOLECULAR ASPECTS OF CLVUS WITH THEIR PNS. INNOVATIONS IN "OMICS" RESEARCH HAVE INCREASED OUR UNDERSTANDING OF IMPORTANT WOUND MICROENVIRONMENTAL FACTORS (E.G., INFLAMMATION, MICROBIAL PATHOGENIC BIOFILM, EPIGENETIC PROCESSES) THAT MAY ADVERSELY ALTER THE WOUND BED'S MOLECULAR MILIEU SO THAT MICROBES EVADE IMMUNE DETECTION. ALTHOUGH THESE MOLECULAR FACTORS ARE NOT SINGULARLY RESPONSIBLE FOR WOUND HEALING, THEY ARE MAJOR COMPONENTS OF WOUND DEVELOPMENT, NONHEALING, AND PNS THAT, UNTIL NOW, HAVE NOT BEEN AMENABLE TO SYSTEMATIC STUDY, ESPECIALLY OVER TIME. FURTHER, THIS REVIEW EXPLORES OUR CURRENT UNDERSTANDING OF THE MOLECULAR MECHANISMS BY WHICH THE IMMUNE ACTIVATION THAT CONTRIBUTES TO THE DEVELOPMENT AND PERSISTENCE OF CVLUS ALSO LEADS TO THE DEVELOPMENT, PERSISTENCE, AND SEVERITY OF WOUND-RELATED PNS. WE ALSO MAKE RECOMMENDATIONS FOR FUTURE RESEARCH THAT WILL EXPAND THE FIELD OF BIOBEHAVIORAL WOUND SCIENCE. BIOBEHAVIORAL RESEARCH THAT FOCUSES ON THE INTERRELATED MECHANISMS OF PNS WILL LEAD TO SYMPTOM-MANAGEMENT INTERVENTIONS THAT IMPROVE QUALITY OF LIFE FOR THE POPULATION BURDENED BY CVLUS. 2019 7 644 28 BIOPHARMACEUTICAL MONOTARGETING VERSUS 'UNIVERSAL TARGETING' OF LATE-ONSET ALZHEIMER'S DISEASE USING MIXTURES OF PLEIOTROPIC NATURAL COMPOUNDS. A FIVE-YEAR CLOSE READING OF THE SCIENTIFIC LITERATURE ON LATE-ONSET ALZHEIMER'S DISEASE (AD) HAS PROMPTED THE INVENTION OF A NOVEL THERAPEUTIC METHOD THAT BIOMECHANISTICALLY TARGETS THE TARGETABLE DISEASE-PROCESS TARGETS OF AD WITH ONE OR ANOTHER MIXTURE OF NON-TOXIC PLEIOTROPIC NATURAL COMPOUNDS. THE FEATURED MIXTURE HEREIN IS COMPRISED OF CURCUMIN, RESVERATROL, AND EGCG. THE MIXTURE'S TARGETS INCLUDE CENTRAL PATHOLOGICAL ELEMENTS OF AD (INCLUDING AMYLOID, TAU, SYNAPTIC DYSFUNCTION, OXIDATIVE STRESS, MITOCHONDRIAL DYSFUNCTION, AND ABERRANT NEUROINFLAMMATION), MODIFIABLE RISK FACTORS, COMORBIDITIES, AND EPIGENETIC ELEMENTS. THE FEATURED MIXTURE AND OTHER SUCH MIXTURES ARE SUITABLE FOR LONG-TERM USE, AND MAY BE APPLIED TO ANY STAGE OF AD, INCLUDING PRIMARY AND SECONDARY PREVENTION. SUCH MIXTURES ALSO WOULD BE AMENABLE FOR USE AS PRE-TREATMENT, CO-TREATMENT, AND POST-TREATMENT APPLICATIONS WITH CERTAIN BIOPHARMACEUTICAL AGENTS. THE TARGETING FOCUS HERE IS THE MAJOR CREDIBLE HYPOTHESES OF AD. THE FOCUS OF FUTURE SUCH ARTICLES WILL INCLUDE OTHER AD-RELATED TARGETS, MODIFIABLE RISK FACTORS AND COMORBIDITIES, APOE4, EPIGENETIC FACTORS, BIOAVAILABILITY, DOSE RESPONSE, AND IMPLICATIONS FOR CLINICAL TESTING. THE "UNIVERSAL TARGETING" METHOD DESCRIBED HEREIN-THAT IS, "TARGETING THE TARGETABLE TARGETS" OF AD USING CERTAIN MIXTURES OF NATURAL COMPOUNDS-IS REPROGRAMMABLE AND THUS IS APPLICABLE TO OTHER CHRONIC NEUROLOGICAL CONDITIONS, INCLUDING PARKINSON'S DISEASE, VASCULAR DEMENTIA, ISCHEMIC-STROKE PREVENTION AND RECOVERY, AND SPORTS-RELATED HEAD INJURIES AND SEQUELAE LEADING TO CHRONIC TRAUMATIC ENCEPHALOPATHY. 2019 8 4663 39 NEW HORIZONS: NOVEL APPROACHES TO ENHANCE HEALTHSPAN THROUGH TARGETING CELLULAR SENESCENCE AND RELATED AGING MECHANISMS. THE ELDERLY POPULATION IS INCREASING FASTER THAN OTHER SEGMENTS OF THE POPULATION THROUGHOUT THE WORLD. AGE IS THE LEADING PREDICTOR FOR MOST CHRONIC DISEASES AND DISORDERS, MULTIMORBIDITY, GERIATRIC SYNDROMES, AND IMPAIRED ABILITY TO RECOVER FROM ACCIDENTS OR ILLNESSES. ENHANCING THE DURATION OF HEALTH AND INDEPENDENCE, TERMED HEALTHSPAN, WOULD BE MORE DESIRABLE THAN EXTENDING LIFESPAN MERELY BY PROLONGING THE PERIOD OF MORBIDITY TOWARD THE END OF LIFE. THE GEROSCIENCE HYPOTHESIS POSITS THAT HEALTHSPAN CAN BE EXTENDED BY TARGETING FUNDAMENTAL AGING MECHANISMS, RATHER THAN ATTEMPTING TO ADDRESS EACH AGE-RELATED DISEASE ONE AT A TIME, ONLY SO THE AFFLICTED INDIVIDUAL SURVIVES DISABLED AND DIES SHORTLY AFTERWARD OF ANOTHER AGE-RELATED DISEASE. THESE FUNDAMENTAL AGING MECHANISMS INCLUDE, AMONG OTHERS, CHRONIC INFLAMMATION, FIBROSIS, STEM CELL/ PROGENITOR DYSFUNCTION, DNA DAMAGE, EPIGENETIC CHANGES, METABOLIC SHIFTS, DESTRUCTIVE METABOLITE GENERATION, MITOCHONDRIAL DYSFUNCTION, MISFOLDED OR AGGREGATED PROTEIN ACCUMULATION, AND CELLULAR SENESCENCE. THESE PROCESSES APPEAR TO BE TIGHTLY INTERLINKED, AS TARGETING ANY ONE APPEARS TO AFFECT MANY OF THE REST, UNDERLYING OUR UNITARY THEORY OF FUNDAMENTAL AGING MECHANISMS. INTERVENTIONS TARGETING MANY FUNDAMENTAL AGING PROCESSES ARE BEING DEVELOPED, INCLUDING DIETARY MANIPULATIONS, METFORMIN, MTOR (MECHANISTIC TARGET OF RAPAMYCIN) INHIBITORS, AND SENOLYTICS, WHICH ARE IN EARLY HUMAN TRIALS. THESE INTERVENTIONS COULD LEAD TO GREATER HEALTHSPAN BENEFITS THAN TREATING AGE-RELATED DISEASES ONE AT A TIME. TO ILLUSTRATE THESE POINTS, WE FOCUS ON CELLULAR SENESCENCE AND THERAPIES IN DEVELOPMENT TO TARGET SENESCENT CELLS. COMBINING INTERVENTIONS TARGETING AGING MECHANISMS WITH DISEASE-SPECIFIC DRUGS COULD RESULT IN MORE THAN ADDITIVE BENEFITS FOR CURRENTLY DIFFICULT-TO-TREAT OR INTRACTABLE DISEASES. MORE RESEARCH ATTENTION NEEDS TO BE DEVOTED TO TARGETING FUNDAMENTAL AGING PROCESSES. 2021 9 6319 28 THE ROAD LESS TAKEN: LESS APPRECIATED PATHWAYS FOR MANIPULATING CD8(+) T CELL EXHAUSTION. EXHAUSTED CD8(+) T (TEX) CELLS ARE A DISTINCT CELL POPULATION THAT ARISE DURING PERSISTENT ANTIGEN EXPOSURE IN THE CONTEXT OF CHRONIC INFECTIONS AND CANCERS. ALTHOUGH CHARACTERIZED BY PROGRESSIVE LOSS OF EFFECTOR FUNCTIONS, HIGH AND SUSTAINED INHIBITORY RECEPTOR EXPRESSION AND DISTINCT TRANSCRIPTIONAL AND EPIGENETIC PROGRAMS, TEX CELLS ARE HETEROGENEOUS. AMONG THESE, A SELF-RENEWING TCF-1(+) TEX POPULATION, HAVING UNIQUE CHARACTERISTICS AND THE ABILITY TO RESPOND TO IMMUNE-CHECKPOINT BLOCKADE, GIVES RISE TO TCF-1(-) TERMINALLY TEX CELLS. THESE TCF-1(+) CELLS HAVE STEM CELL-LIKE PROPERTIES SIMILAR TO MEMORY T CELL POPULATIONS, BUT THE SIGNALS THAT REGULATE THE DEVELOPMENTAL PATHWAYS AND RELATIONSHIPS AMONG EXHAUSTED CELL POPULATIONS ARE STILL UNCLEAR. HERE, WE REVIEW OUR CURRENT UNDERSTANDING OF TEX CELL BIOLOGY, AND DISCUSS SOME LESS APPRECIATED MOLECULES AND PATHWAYS AFFECTING T CELL EXHAUSTION. WE HIGHLIGHT TWO CO-STIMULATORY RECEPTORS, CD226 AND CD137, AND THEIR ROLE IN INDUCING OR RESTRAINING T CELL EXHAUSTION, AS WELL AS SIGNALING PATHWAYS THAT MAY BE AMENABLE TO PHARMACOLOGICAL INHIBITION WITH A FOCUS ON PHOSPHOINOSITIDE-3 KINASE AND IL-2 PARTIAL AGONISTS. FINALLY, WE DISCUSS NOVEL METHODS THAT MAY INCREASE TCF-1(+) POPULATIONS AND THEREFORE IMPROVE IMMUNOTHERAPY RESPONSIVENESS. UNDERSTANDING FEATURES OF AND PATHWAYS TO EXHAUSTION HAS IMPORTANT IMPLICATIONS FOR THE SUCCESS OF IMMUNOTHERAPY, INCLUDING CHECKPOINT BLOCKADE AND ADOPTIVE T-CELL TRANSFER THERAPIES. 2022 10 5254 37 PROGRAMMING OF RESPIRATORY HEALTH IN CHILDHOOD: INFLUENCE OF OUTDOOR AIR POLLUTION. PURPOSE OF REVIEW: THIS OVERVIEW HIGHLIGHTS RECENT EXPERIMENTAL AND EPIDEMIOLOGICAL EVIDENCE FOR THE PROGRAMMING EFFECTS OF OUTDOOR AIR POLLUTION EXPOSURES DURING EARLY DEVELOPMENT ON LUNG FUNCTION AND CHRONIC RESPIRATORY DISORDERS, SUCH AS ASTHMA AND RELATED ALLERGIC DISORDERS. RECENT FINDINGS: AIR POLLUTANTS MAY IMPACT ANATOMY AND/OR PHYSIOLOGICAL FUNCTIONING OF THE LUNG AND INTERRELATED SYSTEMS. PROGRAMMING EFFECTS MAY RESULT FROM POLLUTANT-INDUCED SHIFTS IN A NUMBER OF MOLECULAR, CELLULAR, AND PHYSIOLOGICAL STATES AND THEIR INTERACTING SYSTEMS. SPECIFIC KEY REGULATORY SYSTEMS SUSCEPTIBLE TO PROGRAMMING MAY INFLUENCE LUNG DEVELOPMENT AND VULNERABILITY TO RESPIRATORY DISEASES, INCLUDING BOTH CENTRAL AND PERIPHERAL COMPONENTS OF NEUROENDOCRINE PATHWAYS AND AUTONOMIC NERVOUS SYSTEM (ANS) FUNCTIONING WHICH, IN TURN, INFLUENCE THE IMMUNE SYSTEM. STARTING IN UTERO, ENVIRONMENTAL FACTORS, INCLUDING AIR POLLUTANTS, MAY PERMANENTLY ORGANIZE THESE SYSTEMS TOWARD TRAJECTORIES OF ENHANCED PEDIATRIC (E.G., ASTHMA, ALLERGY) AS WELL AS ADULT DISEASE RISK (E.G., CHRONIC OBSTRUCTIVE PULMONARY DISEASE). EVIDENCE SUPPORTS A CENTRAL ROLE OF OXIDATIVE STRESS IN THE TOXIC EFFECTS OF AIR POLLUTION. ADDITIONAL RESEARCH SUGGESTS XENOBIOTIC METABOLISM AND SUBCELLULAR COMPONENTS, SUCH AS MITOCHONDRIA ARE TARGETS OF AMBIENT AIR POLLUTION AND PLAY A ROLE IN ASTHMA AND ALLERGY PROGRAMMING. MECHANISMS OPERATING AT THE LEVEL OF THE PLACENTA ARE BEING ELUCIDATED. EPIGENETIC MECHANISMS MAY BE AT THE ROOTS OF ADAPTIVE DEVELOPMENTAL PROGRAMMING. SUMMARY: OPTIMAL COORDINATED FUNCTIONING OF MANY COMPLEX PROCESSES AND THEIR NETWORKS OF INTERACTION ARE NECESSARY FOR NORMAL LUNG DEVELOPMENT AND THE MAINTENANCE OF RESPIRATORY HEALTH. OUTDOOR AIR POLLUTION MAY PLAY AN IMPORTANT ROLE IN EARLY PROGRAMMING OF RESPIRATORY HEALTH AND IS POTENTIALLY AMENABLE TO INTERVENTION. 2013 11 6252 39 THE MICROBIOME AND CANCER: IMPLICATIONS FOR ONCOLOGY NURSING SCIENCE. BACKGROUND: APPROXIMATELY 1.6 MILLION AMERICANS WERE DIAGNOSED WITH CANCER IN 2014. TO COMBAT THEIR DISEASE, MANY INDIVIDUALS RECEIVED EITHER CURATIVE OR PALLIATIVE TREATMENTS THAT PRODUCED UNDESIRED SYMPTOMS. THESE SYMPTOMS, WHICH OFTEN CAUSE SIGNIFICANT DISTRESS FOR INDIVIDUALS COPING WITH CANCER, MAY SHARE BIOLOGIC UNDERPINNINGS SUCH AS EPIGENETIC CHANGES AND IMMUNE DYSREGULATION. ALTERATIONS IN THE NORMAL FLORA OF THE GUT MAY ALSO INFLUENCE CANCER SYMPTOMS. OBJECTIVE: THE AIM OF THIS REVIEW IS TO DESCRIBE THE EMERGING ROLE FOR THE GUT MICROBIOME IN CANCER RESEARCH, ESPECIALLY THE POTENTIAL RELATIONSHIP BETWEEN THE GUT MICROBIOME AND CANCER SYMPTOMS. METHODS: EXTANT LITERATURE WAS REVIEWED AND SYNTHESIZED. RESULTS: THE MAJORITY OF STUDIES LINKING THE GUT MICROBIOTA AND CANCER ARE ANIMAL MODELS AND FOCUS ON THE RELATIONSHIP BETWEEN DYSBIOSIS AND COLORECTAL CANCER. EMERGING EVIDENCE SUPPORTS THAT THE "GUT-BRAIN" CONNECTION IS A PLAUSIBLE MECHANISM FOR "PSYCHONEUROLOGICAL" CANCER SYMPTOMS SUCH AS DEPRESSION, PAIN, AND FATIGUE. CONCLUSIONS: THERE IS COMPELLING EVIDENCE THAT THE GUT MICROBIOTA AFFECTS CANCER VIA SEVERAL MECHANISMS, INCLUDING MICROBIAL DIVERSITY AND NUMBER, METABOLISM, AND/OR IMMUNE INITIATION. HOWEVER, MORE RESEARCH IS NECESSARY TO ELUCIDATE THESE MECHANISMS, PARTICULARLY AMONG A VARIETY OF CANCERS AND CANCER-RELATED SYMPTOMS. IMPLICATIONS FOR PRACTICE: A BETTER UNDERSTANDING OF THE ROLE OF THE GUT MICROBIOTA IN CANCER SYMPTOMS MAY LEAD TO THE DEVELOPMENT OF TARGETED INDIVIDUALIZED INTERVENTIONS AFFECTING THE GUT MICROBIOTA THAT PREVENT OR AMELIORATE DYSBIOSIS, THEREBY REDUCING SYMPTOMS. THESE INTERVENTIONS MAY EMPHASIZE SELF-CARE MANAGEMENT STRATEGIES ESSENTIAL FOR WELLNESS, SUCH AS DIET, NUTRITION, AND STRESS REDUCTION. 2016 12 707 39 BY WHAT MOLECULAR MECHANISMS DO SOCIAL DETERMINANTS IMPACT CARDIOMETABOLIC RISK? WHILE IT IS WELL KNOWN FROM NUMEROUS EPIDEMIOLOGIC INVESTIGATIONS THAT SOCIAL DETERMINANTS (SOCIOECONOMIC, ENVIRONMENTAL, AND PSYCHOSOCIAL FACTORS EXPOSED TO OVER THE LIFE-COURSE) CAN DRAMATICALLY IMPACT CARDIOVASCULAR HEALTH, THE MOLECULAR MECHANISMS BY WHICH SOCIAL DETERMINANTS LEAD TO POOR CARDIOMETABOLIC OUTCOMES ARE NOT WELL UNDERSTOOD. THIS REVIEW COMPREHENSIVELY SUMMARIZES A VARIETY OF CURRENT TOPICS SURROUNDING THE BIOLOGICAL EFFECTS OF ADVERSE SOCIAL DETERMINANTS (I.E., THE BIOLOGY OF ADVERSITY), LINKING TRANSLATIONAL AND LABORATORY STUDIES WITH EPIDEMIOLOGIC FINDINGS. WITH A STRONG FOCUS ON THE BIOLOGICAL EFFECTS OF CHRONIC STRESS, WE HIGHLIGHT AN ARRAY OF STUDIES ON MOLECULAR AND IMMUNOLOGICAL SIGNALING IN THE CONTEXT OF SOCIAL DETERMINANTS OF HEALTH (SDOH). THE MAIN TOPICS COVERED INCLUDE BIOMARKERS OF SYMPATHETIC NERVOUS SYSTEM AND HYPOTHALAMIC-PITUITARY-ADRENAL AXIS ACTIVATION, AND THE ROLE OF INFLAMMATION IN THE BIOLOGY OF ADVERSITY FOCUSING ON GLUCOCORTICOID RESISTANCE AND KEY INFLAMMATORY CYTOKINES LINKED TO PSYCHOSOCIAL AND ENVIRONMENTAL STRESSORS (PSES). WE THEN FURTHER DISCUSS THE EFFECT OF SDOH ON IMMUNE CELL DISTRIBUTION AND CHARACTERIZATION BY SUBSET, RECEPTOR EXPRESSION, AND FUNCTION. LASTLY, WE DESCRIBE EPIGENETIC REGULATION OF THE CHRONIC STRESS RESPONSE AND EFFECTS OF SDOH ON TELOMERE LENGTH AND AGING. ULTIMATELY, WE HIGHLIGHT CRITICAL KNOWLEDGE GAPS FOR FUTURE RESEARCH AS WE STRIVE TO DEVELOP MORE TARGETED INTERVENTIONS THAT ACCOUNT FOR SDOH TO IMPROVE CARDIOMETABOLIC HEALTH FOR AT-RISK, VULNERABLE POPULATIONS. 2023 13 103 36 A REHABILOMICS FRAMEWORK FOR PERSONALIZED AND TRANSLATIONAL REHABILITATION RESEARCH AND CARE FOR INDIVIDUALS WITH DISABILITIES: PERSPECTIVES AND CONSIDERATIONS FOR SPINAL CORD INJURY. DESPITE MANY PEOPLE HAVING SIMILAR CLINICAL PRESENTATION, DEMOGRAPHIC FACTORS, AND CLINICAL CARE, OUTCOME CAN DIFFER FOR THOSE SUSTAINING SIGNIFICANT INJURY SUCH AS SPINAL CORD INJURY (SCI) AND TRAUMATIC BRAIN INJURY (TBI). IN ADDITION TO TRADITIONAL DEMOGRAPHIC, SOCIAL, AND CLINICAL FACTORS, VARIABILITY ALSO MAY BE ATTRIBUTABLE TO INNATE (INCLUDING GENETIC, TRANSCRIPTOMIC PROTEOMIC, EPIGENETIC) BIOLOGICAL VARIATION THAT INDIVIDUALS BRING TO RECOVERY AND THEIR UNIQUE RESPONSE TO THEIR CARE AND ENVIRONMENT. TECHNOLOGIES COLLECTIVELY CALLED "-OMICS" ENABLE SIMULTANEOUS MEASUREMENT OF AN ENORMOUS NUMBER OF BIOMOLECULES THAT CAN CAPTURE MANY POTENTIAL BIOLOGICAL CONTRIBUTORS TO HETEROGENEITY OF INJURY/DISEASE COURSE AND OUTCOME. DUE TO THE NATURE OF INJURY AND COMPLEX DISEASE, AND ITS ASSOCIATIONS WITH IMPAIRMENT, DISABILITY, AND RECOVERY, REHABILITATION DOES NOT LEND ITSELF TO A SINGULAR "PROTOCOLIZED" PLAN OF THERAPY. YET, BY NATURE AND BY NECESSITY, REHABILITATION MEDICINE OPERATES AS A FUNCTIONAL MODEL OF "PERSONALIZED CARE". THUS, THE CHALLENGE FOR SUCCESSFUL PROGRAMS OF TRANSLATIONAL REHABILITATION CARE AND RESEARCH IS TO IDENTIFY VIABLE APPROACHES TO EXAMINE BROAD POPULATIONS, WITH VARIED IMPAIRMENTS AND FUNCTIONAL LIMITATIONS, AND TO IDENTIFY EFFECTIVE TREATMENT RESPONSES THAT INCORPORATE PERSONALIZED PROTOCOLS TO OPTIMIZE FUNCTIONAL RECOVERY. THE REHABILOMICS FRAMEWORK IS A TRANSLATIONAL MODEL THAT PROVIDES AN "-OMICS" OVERLAY TO THE SCIENTIFIC STUDY OF REHABILITATION PROCESSES AND MULTIDIMENSIONAL OUTCOMES. REHABILOMICS RESEARCH PROVIDES NOVEL OPPORTUNITIES TO EVALUATE THE NEUROBIOLOGY OF COMPLEX INJURY OR CHRONIC DISEASE AND CAN BE USED TO EXAMINE METHODS AND TREATMENTS FOR PERSON-CENTERED CARE AMONG POPULATIONS WITH DISABILITIES. EXEMPLARS FOR APPLICATION IN SCI AND OTHER NEUROREHABILITATION POPULATIONS ARE DISCUSSED. 2014 14 3630 50 INCLUSION OF SOCIAL AND STRUCTURAL DETERMINANTS OF HEALTH TO ADVANCE UNDERSTANDING OF THEIR INFLUENCE ON THE BIOLOGY OF CHRONIC DISEASE. SOCIAL DETERMINANTS OF HEALTH (SDOH) CONSIDER SOCIAL, POLITICAL, AND ECONOMIC FACTORS THAT CONTRIBUTE TO HEALTH DISPARITIES IN PATIENTS AND POPULATIONS. THE MOST COMMON HEALTH-RELATED SDOH EXPOSURES ARE FOOD AND HOUSING INSECURITY, FINANCIAL INSTABILITY, TRANSPORTATION NEEDS, LOW LEVELS OF EDUCATION, AND PSYCHOSOCIAL STRESS. THESE DOMAINS DESCRIBE RISKS THAT CAN IMPACT HEALTH OUTCOMES MORE THAN HEALTH CARE. EPIDEMIOLOGIC AND TRANSLATIONAL RESEARCH DEMONSTRATES THAT SDOH FACTORS REPRESENT EXPOSURES THAT PREDICT HARM AND IMPACT THE HEALTH OF INDIVIDUALS. INTERNATIONAL AND NATIONAL GUIDELINES URGE HEALTH PROFESSIONALS TO ADDRESS SDOH IN CLINICAL PRACTICE AND PUBLIC HEALTH. THE FURTHER IMPLEMENTATION OF THESE RECOMMENDATIONS INTO BASIC AND TRANSLATIONAL RESEARCH, HOWEVER, IS LAGGING. HEREIN, WE CONSIDER A PRECISION HEALTH FRAMEWORK TO DESCRIBE HOW SDOH CONTRIBUTES TO THE EXPOSOME AND EXACERBATES PHYSIOLOGIC PATHWAYS THAT LEAD TO CHRONIC DISEASE. SDOH FACTORS ARE ASSOCIATED WITH VARIOUS FORMS OF STRESSORS THAT IMPACT PHYSIOLOGICAL PROCESSES THROUGH EPIGENETIC, INFLAMMATORY, AND REDOX REGULATION. MANY SDOH EXPOSURES MAY ADD TO OR POTENTIATE THE PATHOLOGIC EFFECTS OF ADDITIONAL ENVIRONMENTAL EXPOSURES. THIS OVERVIEW AIMS TO INFORM BASIC LIFE SCIENCE AND TRANSLATIONAL RESEARCHERS ABOUT SDOH EXPOSURES THAT CAN CONFOUND ASSOCIATIONS BETWEEN CLASSIC BIOMEDICAL DETERMINANTS OF DISEASE AND HEALTH OUTCOMES. TO ADVANCE THE STUDY OF TOXICOLOGY THROUGH EITHER QUALITATIVE OR QUANTITATIVE ASSESSMENT OF EXPOSURES TO CHEMICAL AND BIOLOGICAL SUBSTANCES, A MORE COMPLETE ENVIRONMENTAL EVALUATION SHOULD INCLUDE SDOH EXPOSURES. WE DISCUSS COMMON APPROACHES TO MEASURE SDOH FACTORS AT INDIVIDUAL AND POPULATION LEVELS AND REVIEW THE ASSOCIATIONS BETWEEN SDOH RISK FACTORS AND PHYSIOLOGIC MECHANISMS THAT INFLUENCE CHRONIC DISEASE. WE PROVIDE CLINICAL AND POLICY-BASED MOTIVATION TO ENCOURAGE RESEARCHERS TO CONSIDER THE IMPACT OF SDOH EXPOSURES ON STUDY RESULTS AND DATA INTERPRETATION. WITH VALID MEASURES OF SDOH FACTORS INCORPORATED INTO STUDY DESIGN AND ANALYSES, FUTURE TOXICOLOGICAL RESEARCH MAY CONTRIBUTE TO AN EVIDENCE BASE THAT CAN BETTER INFORM PREVENTION AND TREATMENT OPTIONS, TO IMPROVE EQUITABLE CLINICAL CARE AND POPULATION HEALTH. (C) 2022 WILEY PERIODICALS LLC. 2022 15 4985 41 PATHWAYS TO AGING: THE MITOCHONDRION AT THE INTERSECTION OF BIOLOGICAL AND PSYCHOSOCIAL SCIENCES. COMPELLING EVIDENCE SUGGESTS THAT BOTH BIOLOGICAL AND PSYCHOSOCIAL FACTORS IMPACT THE PROCESS OF AGING. HOWEVER, OUR UNDERSTANDING OF THE DYNAMIC INTERPLAY AMONG BIOLOGICAL AND PSYCHOSOCIAL FACTORS ACROSS THE LIFE COURSE IS STILL FRAGMENTARY. FOR EXAMPLE, IT NEEDS TO BE ESTABLISHED HOW THE INTERACTION OF INDIVIDUAL FACTORS (E.G., GENETIC AND EPIGENETIC ENDOWMENT AND PERSONALITY), BEHAVIORAL FACTORS (E.G., PHYSICAL ACTIVITY, DIET, AND STRESS MANAGEMENT), AND PSYCHOSOCIAL EXPERIENCES (E.G., SOCIAL SUPPORT, WELL-BEING, SOCIOECONOMIC STATUS, AND MARRIAGE) IN PERINATAL, CHILDHOOD, AND ADULTHOOD INFLUENCE HEALTH ACROSS THE AGING CONTINUUM. THIS PAPER AIMS TO OUTLINE POTENTIAL INTERSECTION POINTS SERVING AS AN INTERFACE BETWEEN BIOLOGICAL AND PSYCHOSOCIAL FACTORS, WITH AN EMPHASIS ON THE MITOCHONDRION. MITOCHONDRIA ARE CELLULAR ORGANELLES WHICH PLAY A CRITICAL ROLE IN CELLULAR SENESCENCE. BOTH CHRONIC EXPOSURE TO PSYCHOSOCIAL STRESS AND GENETIC-BASED MITOCHONDRIAL DYSFUNCTION HAVE STRIKINGLY SIMILAR BIOLOGICAL CONSEQUENCES; BOTH PREDISPOSE INDIVIDUALS TO ADVERSE AGE-RELATED HEALTH DISORDERS AND EARLY MORTALITY. EXPLORING THE INTERACTIVE NATURE OF THE FACTORS RESULTING IN PATHWAYS TO NORMAL HEALTHY AGING, AS WELL AS THOSE LEADING TO MORBIDITY AND EARLY MORTALITY, WILL CONTINUE TO ENHANCE OUR ABILITY TO TRANSLATE RESEARCH INTO EFFECTIVE PRACTICES THAT CAN BE IMPLEMENTED THROUGHOUT THE LIFE COURSE TO OPTIMISE THE AGING PROCESS. 2011 16 380 41 AN EPIGENETIC PERSPECTIVE ON LIFESTYLE MEDICINE FOR DEPRESSION: IMPLICATIONS FOR PRIMARY CARE PRACTICE. DEPRESSION IS THE MOST COMMON PRESENTING MENTAL HEALTH DISORDER IN PRIMARY CARE. IT IS ALSO A MAJOR CONTRIBUTOR TO SOMATIC COMPLAINTS, WORSENING OF CHRONIC MEDICAL CONDITIONS, POOR QUALITY OF LIFE, AND SUICIDE. CURRENT PHARMACOLOGIC AND PSYCHOTHERAPEUTIC APPROACHES AVERT LESS THAN HALF OF DEPRESSION'S CUMULATIVE BURDEN ON SOCIETY. HOWEVER, THERE IS A GROWING BODY OF RESEARCH DESCRIBING BOTH HOW MALADAPTIVE LIFESTYLE CHOICES CONTRIBUTE TO THE DEVELOPMENT AND WORSENING OF DEPRESSION AND HOW LIFESTYLE-ORIENTED MEDICAL INTERVENTIONS CAN REDUCE THE INCIDENCE AND SEVERITY OF DEPRESSION. THIS RESEARCH, LARGELY DERIVED FROM AN EMERGING FIELD CALLED EPIGENETICS, ELUCIDATES THE INTERACTIONS BETWEEN OUR LIFESTYLE CHOICES AND THOSE EPIGENETIC FACTORS WHICH MEDIATE OUR TENDENCIES TOWARD EITHER HEALTH, OR THE ONSET, IF NOT WORSENING OF DISEASE. THE PRESENT REVIEW HIGHLIGHTS HOW LIFESTYLE CHOICES INVOLVING DIET, PHYSICAL ACTIVITY, SLEEP, SOCIAL RELATIONSHIPS, AND STRESS INFLUENCE EPIGENETIC PROCESSES POSITIVELY OR NEGATIVELY, AND THEREBY PLAY A SIGNIFICANT ROLE IN DETERMINING WHETHER ONE DOES OR DOES NOT SUFFER FROM DEPRESSION. THE AUTHORS PROPOSE THAT MEDICAL TRAINING PROGRAMS CONSIDER AND ADOPT LIFESTYLE MEDICINE ORIENTED INSTRUCTIONAL INITIATIVES THAT WILL ENABLE TOMORROW'S PRIMARY CARE PROVIDERS TO MORE EFFECTIVELY IDENTIFY AND THERAPEUTICALLY INTERVENE IN THE MALADAPTIVE CHOICES CONTRIBUTING TO THEIR PATIENTS' DEPRESSION. 2022 17 6412 41 THE SPECTRUM OF FUNDAMENTAL BASIC SCIENCE DISCOVERIES CONTRIBUTING TO ORGANISMAL AGING. AGING RESEARCH HAS UNDERGONE UNPRECEDENTED ADVANCES AT AN ACCELERATING RATE IN RECENT YEARS, LEADING TO EXCITEMENT IN THE FIELD AS WELL AS OPPORTUNITIES FOR IMAGINATION AND INNOVATION. NOVEL INSIGHTS INDICATE THAT, RATHER THAN RESULTING FROM A PREPROGRAMMED SERIES OF EVENTS, THE AGING PROCESS IS PREDOMINANTLY DRIVEN BY FUNDAMENTAL NON-ADAPTIVE MECHANISMS THAT ARE INTERCONNECTED, LINKED, AND OVERLAP. TO VARYING DEGREES, THESE MECHANISMS ALSO MANIFEST WITH AGING IN BONE WHERE THEY CAUSE SKELETAL FRAGILITY. BECAUSE THESE MECHANISMS OF AGING CAN BE MANIPULATED, IT MIGHT BE POSSIBLE TO SLOW, DELAY, OR ALLEVIATE MULTIPLE AGE-RELATED DISEASES AND THEIR COMPLICATIONS BY TARGETING CONSERVED GENETIC SIGNALING PATHWAYS, CONTROLLED FUNCTIONAL NETWORKS, AND BASIC BIOCHEMICAL PROCESSES. INDEED, FINDINGS IN VARIOUS MAMMALIAN SPECIES SUGGEST THAT TARGETING FUNDAMENTAL AGING MECHANISMS (EG, VIA EITHER LOSS-OF-FUNCTION OR GAIN-OF-FUNCTION MUTATIONS OR ADMINISTRATION OF PHARMACOLOGICAL THERAPIES) CAN EXTEND HEALTHSPAN; IE, THE HEALTHY PERIOD OF LIFE FREE OF CHRONIC DISEASES. IN THIS REVIEW, WE SUMMARIZE THE EVIDENCE SUPPORTING THE ROLE OF THE SPECTRUM OF FUNDAMENTAL BASIC SCIENCE DISCOVERIES CONTRIBUTING TO ORGANISMAL AGING, WITH EMPHASIS ON MAMMALIAN STUDIES AND IN PARTICULAR AGING MECHANISMS IN BONE THAT DRIVE SKELETAL FRAGILITY. THESE MECHANISMS OR AGING HALLMARKS INCLUDE: GENOMIC INSTABILITY, TELOMERE ATTRITION, EPIGENETIC ALTERATIONS, LOSS OF PROTEOSTASIS, DEREGULATED NUTRIENT SENSING, MITOCHONDRIAL DYSFUNCTION, CELLULAR SENESCENCE, STEM CELL EXHAUSTION, AND ALTERED INTERCELLULAR COMMUNICATION. BECAUSE THESE MECHANISMS ARE LINKED, INTERVENTIONS THAT AMELIORATE ONE HALLMARK CAN IN THEORY AMELIORATE OTHERS. IN THE FIELD OF BONE AND MINERAL RESEARCH, CURRENT CHALLENGES INCLUDE DEFINING THE RELATIVE CONTRIBUTIONS OF EACH AGING HALLMARK TO THE NATURAL SKELETAL AGING PROCESS, BETTER UNDERSTANDING THE COMPLEX INTERCONNECTIONS AMONG THE HALLMARKS, AND IDENTIFYING THE MOST EFFECTIVE THERAPEUTIC STRATEGIES TO SAFELY TARGET MULTIPLE HALLMARKS. BASED ON THEIR INTERCONNECTIONS, IT MAY BE FEASIBLE TO SIMULTANEOUSLY INTERFERE WITH SEVERAL FUNDAMENTAL AGING MECHANISMS TO ALLEVIATE A WIDE SPECTRUM OF AGE-RELATED CHRONIC DISEASES, INCLUDING OSTEOPOROSIS. (C) 2018 AMERICAN SOCIETY FOR BONE AND MINERAL RESEARCH. 2018 18 264 39 ADVANCING ASTHMA CARE: THE GLASS IS ONLY HALF FULL! OVER THE PAST 20 YEARS, THERE HAS BEEN A CONCERTED EFFORT IN THE UNITED STATES TO REDUCE MORBIDITY RELATED TO CHRONIC DISEASE, INCLUDING ASTHMA. ATTENTION WAS INITIALLY DIRECTED TOWARD ASTHMA IN RESPONSE TO THE RECOGNITION THAT ASTHMA MORTALITY WAS INCREASING AND THAT THE BURDEN OF DISEASE WAS SIGNIFICANT. THESE EFFORTS TO ADDRESS ASTHMA MORTALITY LED TO MANY NEW INITIATIVES TO DEVELOP CLINICAL PRACTICE GUIDELINES, IMPLEMENT THE ASTHMA GUIDELINES INTO CLINICAL PRACTICE, CONDUCT RESEARCH TO FILL THE GAPS IN THE GUIDELINES, AND CONTINUOUSLY REVISE THE ASTHMA GUIDELINES AS MORE INFORMATION BECAME AVAILABLE. AN ASSESSMENT OF OUR PROGRESS SHOWS SIGNIFICANT ACCOMPLISHMENTS IN RELATION TO REDUCING ASTHMA MORTALITY AND HOSPITALIZATIONS. CONSEQUENTLY, WE ARE NOW AT A CROSSROADS IN ASTHMA CARE. ALTHOUGH WE HAVE RECOGNIZED SOME REMARKABLE ACCOMPLISHMENTS IN REDUCING ASTHMA MORTALITY AND MORBIDITY, THE AVAILABILITY OF NEW TOOLS TO MONITOR DISEASE ACTIVITY, INCLUDING BIOMARKERS AND EPIGENETIC MARKERS, ALONG WITH INFORMATION TECHNOLOGY SYSTEMS TO MONITOR ASTHMA CONTROL HOLD SOME PROMISE IN IDENTIFYING GAPS IN DISEASE MANAGEMENT. THESE ADVANCES SHOULD PROMPT THE EVOLUTION OF NEW STRATEGIES AND NEW TREATMENTS TO FURTHER REDUCE DISEASE BURDEN. IT NOW BECOMES IMPERATIVE TO CONTINUE A FOCUS ON WAYS TO FURTHER REDUCE THE BURDEN OF ASTHMA AND PREVENT ITS ONSET. 2011 19 3910 30 LIFE COURSE OF ASTHMA. ASTHMA IS A HETEROGENEOUS CHRONIC AIRWAY DISEASE THAT CAN VARY OVER A LIFETIME. ALTHOUGH BROAD CATEGORIES OF ASTHMA BY SEVERITY AND TYPE HAVE BEEN CONSTRUCTED, THERE REMAINS A TREMENDOUS OPPORTUNITY TO DISCOVER AN APPROACH TO MANAGING ASTHMA WITH ADDITIONAL FACTORS IN MIND. MANY IN THE FIELD HAVE SUGGESTED AND ARE PURSUING A NOVEL PARADIGM SHIFT IN HOW ASTHMA MIGHT BE BETTER MANAGED, CONSIDERING THE LIFE COURSE OF EXPOSURES, MANAGEMENT PRIORITIES, AND PREDICTED TRAJECTORY OF LUNG FUNCTION GROWTH. THIS APPROACH WILL REQUIRE A MORE HOLISTIC VIEW OF PRENATAL, POSTNATAL, ADOLESCENCE, HORMONAL AND GENDER ASPECTS, AND THE AGING PROCESS. IN ADDITION, THE ENVIRONMENT, EXTERNALLY AND INTERNALLY, INCLUDING IN ONE'S GENETIC CODE AND EPIGENETIC CHANGES, ARE FACTORS THAT AFFECT HOW ASTHMA PROGRESSES OR BECOMES MORE STABLE IN INDIVIDUALS. THIS CHAPTER FOCUSES ON THE VARIOUS INFLUENCES THAT MAY, TO DIFFERING DEGREES, AFFECT PEOPLE WITH ASTHMA, WHICH CAN DEVELOP AT ANY TIME IN THEIR LIVES. SHIFTING THE PARADIGM OF THOUGHT AND STRATEGIES FOR CARE AND ADVOCATING FOR PUBLIC POLICIES AND HEALTH DELIVERY THAT FOCUS ON THIS PHILOSOPHY IS PARAMOUNT TO ADVANCE ASTHMA CARE FOR ALL. 2023 20 5689 29 SILENCING HEPATITIS B VIRUS COVALENTLY CLOSED CIRCULAR DNA: THE POTENTIAL OF AN EPIGENETIC THERAPY APPROACH. GLOBAL PROPHYLACTIC VACCINATION PROGRAMMES HAVE HELPED TO CURB NEW HEPATITIS B VIRUS (HBV) INFECTIONS. HOWEVER, IT IS ESTIMATED THAT NEARLY 300 MILLION PEOPLE ARE CHRONICALLY INFECTED AND HAVE A HIGH RISK OF DEVELOPING HEPATOCELLULAR CARCINOMA. AS SUCH, HBV REMAINS A SERIOUS HEALTH PRIORITY AND THE DEVELOPMENT OF NOVEL CURATIVE THERAPEUTICS IS URGENTLY NEEDED. CHRONIC HBV INFECTION HAS BEEN ATTRIBUTED TO THE PERSISTENCE OF THE COVALENTLY CLOSED CIRCULAR DNA (CCCDNA) WHICH ESTABLISHES ITSELF AS A MINICHROMOSOME IN THE NUCLEUS OF HEPATOCYTES. AS THE VIRAL TRANSCRIPTION INTERMEDIATE, THE CCCDNA IS RESPONSIBLE FOR PRODUCING NEW VIRIONS AND PERPETUATING INFECTION. HBV IS DEPENDENT ON VARIOUS HOST FACTORS FOR CCCDNA FORMATION AND THE MINICHROMOSOME IS AMENABLE TO EPIGENETIC MODIFICATIONS. TWO HBV PROTEINS, X (HBX) AND CORE (HBC) PROMOTE VIRAL REPLICATION BY MODULATING THE CCCDNA EPIGENOME AND REGULATING HOST CELL RESPONSES. THIS INCLUDES VIRAL AND HOST GENE EXPRESSION, CHROMATIN REMODELING, DNA METHYLATION, THE ANTIVIRAL IMMUNE RESPONSE, APOPTOSIS, AND UBIQUITINATION. ELIMINATION OF THE CCCDNA MINICHROMOSOME WOULD RESULT IN A STERILIZING CURE; HOWEVER, THIS MAY BE DIFFICULT TO ACHIEVE. EPIGENETIC THERAPIES COULD PERMANENTLY SILENCE THE CCCDNA MINICHROMOSOME AND PROMOTE A FUNCTIONAL CURE. THIS REVIEW EXPLORES THE CCCDNA EPIGENOME, HOW HOST AND VIRAL FACTORS INFLUENCE TRANSCRIPTION, AND THE RECENT EPIGENETIC THERAPIES AND EPIGENOME ENGINEERING APPROACHES THAT HAVE BEEN DESCRIBED. 2021