1 847 93 CHILDHOOD MALTREATMENT AND HEADACHE DISORDERS. CHILDHOOD MALTREATMENT IS SUBSTANTIATED IN 12 % OF CHILDREN, BUT NEARLY 50 % ADULTS RECALL HAVING BEEN NEGLECTED OR ABUSED AS CHILDREN. MALTREATMENT, ESPECIALLY EMOTIONAL ABUSE, IS ASSOCIATED WITH MIGRAINE. DYSREGULATION OF THE HPA AXIS, AUTONOMIC, IMMUNE, AND METABOLIC SYSTEMS APPEARS TO BE A CONSEQUENCE OF MALTREATMENT, AND IS ALSO REPORTED IN MIGRAINE. AREAS OF THE BRAIN STRUCTURALLY AND FUNCTIONALLY AFFECTED BY CHILDHOOD ABUSE AND BY MIGRAINE ARE ALSO SIMILAR, AND INCLUDE THE LIMBIC SYSTEM STRUCTURES, WHICH CONNECT TO PAIN REGIONS IN THE BRAINSTEM. PUTATIVE MECHANISMS BY WHICH EARLY LIFE STRESS INCREASES THE LIKELIHOOD OF DEVELOPING MIGRAINE INCLUDE GENE X ENVIRONMENT INTERACTIONS, IN ADDITION TO EPIGENETIC MODIFICATIONS VIA DNA METHYLATION. THESE MODIFICATIONS ARE STABLE AND MAY BE TRANSFERRED ACROSS GENERATIONS, BUT THEY MAY ALSO BE REVERSED BY SOME MEDICATIONS COMMONLY USED IN MIGRAINE, INCLUDING VALPROIC ACID AND TOPIRAMATE. 2016 2 5164 32 PRECLINICAL AND CLINICAL EVIDENCE OF DNA METHYLATION CHANGES IN RESPONSE TO TRAUMA AND CHRONIC STRESS. EXPOSURE TO CHRONIC STRESS, EITHER REPEATED SEVERE ACUTE OR MODERATE SUSTAINED STRESS, IS ONE OF THE STRONGEST RISK FACTORS FOR THE DEVELOPMENT OF PSYCHOPATHOLOGIES SUCH AS POST-TRAUMATIC STRESS DISORDER AND DEPRESSION. CHRONIC STRESS IS LINKED WITH SEVERAL LASTING BIOLOGICAL CONSEQUENCES, PARTICULARLY TO THE STRESS ENDOCRINE SYSTEM BUT ALSO AFFECTING INTERMEDIATE PHENOTYPES SUCH AS BRAIN STRUCTURE AND FUNCTION, IMMUNE FUNCTION, AND BEHAVIOR. ALTHOUGH GENETIC PREDISPOSITION CONFERS A PROPORTION OF THE RISK, THE MOST RELEVANT MOLECULAR MECHANISMS DETERMINING THOSE SUSCEPTIBLE AND RESILIENT TO THE EFFECTS OF STRESS AND TRAUMA MAY BE EPIGENETIC. EPIGENETICS REFERS TO THE MECHANISMS THAT REGULATE GENOMIC INFORMATION BY DYNAMICALLY CHANGING THE PATTERNS OF TRANSCRIPTION AND TRANSLATION OF GENES. MOUNTING EVIDENCE FROM PRECLINICAL RODENT AND CLINICAL POPULATION STUDIES STRONGLY SUPPORT THAT EPIGENETIC MODIFICATIONS CAN OCCUR IN RESPONSE TO TRAUMATIC AND CHRONIC STRESS. HERE, WE DISCUSS THIS LITERATURE EXAMINING STRESS-INDUCED EPIGENETIC CHANGES IN PRECLINICAL MODELS AND CLINICAL COHORTS OF STRESS AND TRAUMA OCCURRING EARLY IN LIFE OR IN ADULTHOOD. WE HIGHLIGHT THAT A COMPLEX RELATIONSHIP BETWEEN THE TIMING OF ENVIRONMENTAL STRESSORS AND GENETIC PREDISPOSITIONS LIKELY MEDIATE THE RESPONSE TO CHRONIC STRESS OVER TIME, AND THAT A BETTER UNDERSTANDING OF EPIGENETIC CHANGES IS NEEDED BY FURTHER INVESTIGATIONS IN LONGITUDINAL AND POSTMORTEM BRAIN CLINICAL COHORTS. 2017 3 1364 35 DEVELOPMENTAL NEUROENDOCRINOLOGY OF EARLY-LIFE STRESS: IMPACT ON CHILD DEVELOPMENT AND BEHAVIOR. OUR INTERNAL BALANCE, OR HOMEOSTASIS, IS THREATENED OR PERCEIVED AS THREATENED BY STRESSFUL STIMULI, THE STRESSORS. THE STRESS SYSTEM IS A HIGHLY CONSERVED SYSTEM THAT ADJUSTS HOMEOSTASIS TO THE RESTING STATE. THROUGH THE CONCURRENT ACTIVATION OF THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS AND THE LOCUS COERULEUS/NOREPINEPHRINE-AUTONOMIC NERVOUS SYSTEMS, THE STRESS SYSTEM PROVIDES THE APPROPRIATE PHYSICAL AND BEHAVIORAL RESPONSES, COLLECTIVELY TERMED AS "STRESS RESPONSE", TO RESTORE HOMEOSTASIS. IF THE STRESS RESPONSE IS PROLONGED, EXCESSIVE OR EVEN INADEQUATE, SEVERAL ACUTE OR CHRONIC STRESS-RELATED PATHOLOGIC CONDITIONS MAY DEVELOP IN CHILDHOOD, ADOLESCENCE AND ADULT LIFE. ON THE OTHER HAND, EARLY-LIFE EXPOSURE TO STRESSORS HAS BEEN RECOGNIZED AS A MAJOR CONTRIBUTING FACTOR UNDERLYING THE PATHOGENESIS OF NON-COMMUNICABLE DISORDERS, INCLUDING NEURODEVELOPMENTAL DISORDERS. ACCUMULATING EVIDENCE SUGGESTS THAT EARLY-LIFE STRESS HAS BEEN ASSOCIATED WITH AN INCREASED RISK FOR ATTENTION DEFICIT HYPERACTIVITY DISORDER AND AUTISM SPECTRUM DISORDER IN THE OFFSPRING, ALTHOUGH FINDINGS ARE STILL CONTROVERSIAL. NEVERTHELESS, AT THE MOLECULAR LEVEL, EARLY-LIFE STRESSORS ALTER THE CHEMICAL STRUCTURE OF CYTOSINES LOCAT- ED IN THE REGULATORY REGIONS OF GENES, MOSTLY THROUGH THE ADDITION OF METHYL GROUPS. THESE EPIGENETIC MODIFICATIONS RESULT IN THE SUPPRESSION OF GENE EXPRESSION WITHOUT CHANGING THE DNA SEQUENCE. IN ADDITION TO DNA METHYLATION, SEVERAL LINES OF EVIDENCE SUPPORT THE ROLE OF NON-CODING RNAS IN THE EVOLVING FIELD OF EPIGENETICS. IN THIS REVIEW ARTICLE, WE PRESENT THE ANATOMICAL AND FUNCTIONAL COMPO- NENTS OF THE STRESS SYSTEM, DISCUSS THE PROPER, IN TERMS OF QUALITY AND QUANTITY, STRESS RESPONSE, AND PROVIDE AN UPDATE ON THE IMPACT OF EARLY-LIFE STRESS ON CHILD DEVELOPMENT AND BEHAVIOR. 2023 4 2917 29 GENE-ENVIRONMENT INTERACTIONS IN COMMON MENTAL DISORDERS: AN UPDATE AND STRATEGY FOR A GENOME-WIDE SEARCH. A DECADE OF RESEARCH HAS DEMONSTRATED THE EXPLANATORY POTENTIAL OF INTERPLAY BETWEEN GENETIC VARIANTS AND ENVIRONMENTAL FACTORS IN THE DEVELOPMENT OF COMMON MENTAL DISORDERS. INITIAL FINDINGS HAVE UNDERGONE TESTS OF REPLICABILITY AND SPECIFICITY. SOME GENE-ENVIRONMENT INTERACTIONS HAVE BEEN CONFIRMED, SOME HAVE NOT REPLICATED AND YET OTHER TURNED OUT TO BE MORE SPECIFIC THAN INITIALLY THOUGHT. SPECIFIC AND COMPLEMENTARY ROLES OF GENETIC FACTORS HAVE BEEN DELINEATED: A COMMON FUNCTIONAL LENGTH POLYMORPHISM IN THE SEROTONIN TRANSPORTER GENE (5-HTTLPR) MODERATED THE EFFECT OF CHILDHOOD MALTREATMENT ON CHRONIC DEPRESSION IN ADULTHOOD, BUT DID NOT SUBSTANTIALLY INFLUENCE THE EFFECTS OF ADULT STRESSFUL LIFE EVENTS ON THE ONSET OF NEW DEPRESSIVE EPISODES; IN CONTRAST, A COMMON FUNCTIONAL POLYMORPHISM IN THE BRAIN-DERIVED NEUROTROPHIC FACTOR GENE (BDNF) MODERATED THE EFFECT OF STRESSFUL LIFE EVENTS IN ADULTHOOD IN TRIGGERING NEW DEPRESSIVE EPISODES, BUT DID NOT INFLUENCE THE EFFECTS OF CHILDHOOD MALTREATMENT. MOLECULAR MECHANISMS UNDERLYING GENE-ENVIRONMENT INTERACTIONS ARE BEING UNCOVERED, INCLUDING DNA METHYLATION AND OTHER EPIGENETIC MODIFICATIONS. NEW GENE-ENVIRONMENT INTERACTIONS CONTINUE TO BE REPORTED, STILL LARGELY FROM HYPOTHESIS-DRIVEN RESEARCH. STATISTICAL AND BIOLOGICAL PRIORITIZATION STRATEGIES ARE PROPOSED TO FACILITATE A SYSTEMATIC DISCOVERY OF NOVEL GENE-ENVIRONMENT INTERACTIONS IN GENOME-WIDE ANALYSES. 2014 5 5316 28 PSYCHOLOGICAL STRESS IN EARLY LIFE AS A PREDISPOSING FACTOR FOR THE DEVELOPMENT OF CHRONIC PAIN: CLINICAL AND PRECLINICAL EVIDENCE AND NEUROBIOLOGICAL MECHANISMS. A WEALTH OF RESEARCH OVER THE PAST 2 DECADES HAS EXPANDED OUR UNDERSTANDING OF THE IMPACT OF EARLY-LIFE ADVERSITY ON PHYSIOLOGICAL FUNCTION AND, CONSEQUENTLY, HEALTH AND WELLBEING IN LATER LIFE. EARLY-LIFE ADVERSITY INCREASES THE RISK OF DEVELOPING A NUMBER OF DISORDERS, SUCH AS CHRONIC PAIN, FIBROMYALGIA, AND IRRITABLE BOWEL SYNDROME. ALTHOUGH MUCH OF THE RESEARCH HAS EXAMINED THE IMPACT OF PHYSICAL MALTREATMENT, AN INCREASING NUMBER OF STUDIES HAVE BEEN PUBLISHED OVER THE PAST FEW YEARS EXAMINING THE EFFECT OF CHILDHOOD PSYCHOLOGICAL STRESS AND TRAUMA ON THE DEVELOPMENT OF VARIOUS TYPES OF CHRONIC PAIN CONDITIONS. WE REVIEW THE CLINICAL AND PRECLINICAL DATA EXAMINING THE LINK AMONG EARLY-LIFE PSYCHOLOGICAL STRESS, ALTERED NOCICEPTIVE BEHAVIOR, AND CHRONIC PAIN IN LATER LIFE. EVIDENCE SUPPORTING A ROLE FOR CERTAIN KEY NEUROBIOLOGICAL SUBSTRATES, INCLUDING THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS; MONOAMINERGIC, OPIOIDERGIC, ENDOCANNABINOID AND IMMUNE SYSTEMS; AND EPIGENETIC MECHANISMS IN THE ASSOCIATION BETWEEN EARLY-LIFE PSYCHOLOGICAL STRESS AND CHRONIC PAIN, IS PROVIDED. GREATER UNDERSTANDING OF THE IMPACT OF EARLY-LIFE STRESS MAY INFORM THE DEVELOPMENT OF PERSONALIZED TREATMENTS FOR CHRONIC PAIN IN LATER LIFE AND STRATEGIES TO PREVENT ITS ONSET IN SUSCEPTIBLE INDIVIDUALS. (C) 2016 WILEY PERIODICALS, INC. 2017 6 5810 17 STRESS & SLEEP: A RELATIONSHIP LASTING A LIFETIME. STRESS IS AN ADAPTATIVE RESPONSE AIMED AT RESTORING BODY HOMEOSTASIS. THE CLASSICAL NEUROENDOCRINE STRESS RESPONSE INVOLVING THE ACTIVATION OF THE HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS MODULATES MANY PHYSIOLOGICAL ASPECTS, SUCH AS THE WAKE-SLEEP CYCLE. IN THE PRESENT REVIEW, WE WILL FIRST REPORT A SERIES OF HUMAN AND RODENT STUDIES SHOWING THAT EACH ACTOR OF THE HPA AXIS HAS THE POTENTIAL TO INTERFERE WITH SLEEP HOMEOSTASIS AND, THEN, WE WILL HIGHLIGHT HOW ACUTE OR CHRONIC STRESS DIFFERENTLY MODULATES THE WAKE-SLEEP CYCLE. MOREOVER, WE WILL PRESENT NEW AND INTERESTING STUDIES DEALING WITH THE RELATIONSHIP BETWEEN SLEEP AND STRESS ON A DIFFERENT (LONGER) TIME SCALE. PARTICULARLY, WE WILL DISCUSS HOW THE EXPOSURE TO PERINATAL STRESS, PROBABLY THROUGH EPIGENETIC MODULATIONS, IS SUFFICIENT TO CAUSE PERSISTENT SLEEP DERANGEMENTS DURING ADULT LIFE. IN LIGHT OF THIS EVIDENCE, THE MAIN MESSAGE OF THE PRESENT REVIEW IS THAT THE COMPLEX RELATIONSHIP BETWEEN SLEEP AND STRESS CHANGES DRAMATICALLY ON THE BASIS OF THE TIME SCALE CONSIDERED AND, CONSEQUENTLY, "TIME" SHOULD BE CONSIDERED AS A CRITICAL FACTOR WHEN FACING THIS TOPIC. 2020 7 6228 27 THE LINKS BETWEEN STRESS AND DEPRESSION: PSYCHONEUROENDOCRINOLOGICAL, GENETIC, AND ENVIRONMENTAL INTERACTIONS. THE ROLE OF STRESS IN THE ORIGIN AND DEVELOPMENT OF DEPRESSION MAY BE CONCEIVED AS THE RESULT OF MULTIPLE CONVERGING FACTORS, INCLUDING THE CHRONIC EFFECT OF ENVIRONMENTAL STRESSORS AND THE LONG-LASTING EFFECTS OF STRESSFUL EXPERIENCES DURING CHILDHOOD, ALL OF WHICH MAY INDUCE PERSISTENT HYPERACTIVITY OF THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS. THESE CHANGES, INCLUDING INCREASED AVAILABILITY OF CORTICOTROPIN-RELEASING FACTOR AND CORTISOL, ARE ALSO ASSOCIATED WITH HYPERACTIVITY OF THE AMYGDALA, HYPOACTIVITY OF THE HIPPOCAMPUS, AND DECREASED SEROTONERGIC NEUROTRANSMISSION, WHICH TOGETHER RESULT IN INCREASED VULNERABILITY TO STRESS. THE ROLE OF OTHER MONOAMINERGIC NEUROTRANSMITTERS, GENETIC POLYMORPHISMS, EPIGENETIC MECHANISMS, INFLAMMATORY PROCESSES, AND ALTERED COGNITIVE PROCESSING HAS ALSO BEEN CONSIDERED IN THE DEVELOPMENT OF A COMPREHENSIVE MODEL OF THE INTERACTIONS BETWEEN DIFFERENT FACTORS OF VULNERABILITY. FURTHER UNDERSTANDING OF THE UNDERLYING MECHANISMS THAT LINK THESE FACTORS MAY CONTRIBUTE SIGNIFICANTLY TO THE DEVELOPMENT OF MORE EFFECTIVE TREATMENTS AND PREVENTIVE STRATEGIES IN THE INTERFACE BETWEEN STRESS AND MOOD DISORDERS. 2016 8 291 27 AGING AND STRESS: PAST HYPOTHESES, PRESENT APPROACHES AND PERSPECTIVES. BRAIN AGING HAS BEEN SUGGESTED TO BE CONDITIONED BY AN EXCESSIVE GLUCOCORTIOID SECRETION LEADING TO DAMAGES ON BRAIN AREAS INVOLVED NOT ONLY IN COGNITIVE AND EMOTIONAL PROCESSES BUT ALSO IN THE CONTROL OF THE ACTIVITY OF THE HYPOTHALAMIC-PITUITARY ADRENAL AXIS. THIS REVIEW DESCRIBES SOME OF THE HYPOTHESIS THAT TRY TO EXPLAIN THE RELATION BETWEEN THE DYSREGULATION OF THE STRESS RESPONSE AND BRAIN AGING, FOCUSING ON CORTICOSTERONE BUT ALSO ON NEUROTRANSMISSION IN THE HIPPOCAMPUS, THE PREFRONTAL CORTEX AND THE AMYGDALA. MOREOVER, DIFFERENT MOLECULAR FACTORS CAN ACCOUNT FOR AN ENHANCED VULNERABILITY OF THE AGED BRAIN TO STRESS EXPOSURE, SPECIALLY FOR RESILIENCE. AMONG THEM, GOOD CANDIDATES COULD BE THOSE MECHANISMS DETERMINING THE LEVELS OF CORTICOSTERONE IN THE BRAIN, SEVERAL MOLECULES DOWNSTREAM GLUCOCORTICOID RECEPTOR ACTIVATION (IE: HEAT SHOCK PROTEINS, BAG-1) OR EVEN THE EPIGENETIC PROGRAMMING OF THE HPA AXIS IN EARLY STAGES. IN CONCLUSION, GENETIC AND ENVIRONMENTAL FACTORS (EARLY LIFE STRESS, CHRONIC STRESS DURING ADULTHOOD) CAN PRODUCE AN ENHANCED VULNERABILITY AND A REDUCED RESILIENCE OF THE BRAIN TO SUBSEQUENT STRESS EXPOSURES OR TO METABOLIC CHALLENGES LEADING, IN TURN, TO AN UNSUCCESSFUL AGING OF THE BRAIN. HOWEVER, RESULTS OBTAINED WITH THE USE OF THE ENVIRONMENTAL ENRICHMENT MODEL IN ANIMALS, ADDED TO SEVERAL RESULTS IN HUMANS ALSO DESCRIBED IN THIS REVIEW SUGGEST THAT POSITIVE ENVIRONMENTAL FACTORS (COGNITIVE-DEMANDING TASKS OR PHYSICAL EXERCISE) CAN HELP TO MAINTAIN NEURONAL PLASTICITY DURING AGING AND TO PROTECT THE BRAIN AGAINST THE DAMAGING EFFECTS OF STRESS EXPOSURE. 2011 9 120 28 A SYSTEMATIC REVIEW OF CHILDHOOD MALTREATMENT AND DNA METHYLATION: CANDIDATE GENE AND EPIGENOME-WIDE APPROACHES. CHILDHOOD MALTREATMENT IS A MAJOR RISK FACTOR FOR CHRONIC AND SEVERE MENTAL AND PHYSICAL HEALTH PROBLEMS ACROSS THE LIFESPAN. INCREASING EVIDENCE SUPPORTS THE HYPOTHESIS THAT MALTREATMENT IS ASSOCIATED WITH EPIGENETIC CHANGES THAT MAY SUBSEQUENTLY SERVE AS MECHANISMS OF DISEASE. THE CURRENT REVIEW USES A SYSTEMATIC APPROACH TO IDENTIFY AND SUMMARIZE THE LITERATURE RELATED TO CHILDHOOD MALTREATMENT AND ALTERATIONS IN DNA METHYLATION IN HUMANS. A TOTAL OF 100 EMPIRICAL ARTICLES WERE IDENTIFIED IN OUR SYSTEMATIC REVIEW OF RESEARCH PUBLISHED PRIOR TO OR DURING MARCH 2020, INCLUDING STUDIES THAT FOCUSED ON CANDIDATE GENES AND STUDIES THAT LEVERAGED EPIGENOME-WIDE DATA IN BOTH CHILDREN AND ADULTS. THEMES ARISING FROM THE LITERATURE, INCLUDING CONSISTENT AND INCONSISTENT PATTERNS OF RESULTS, ARE PRESENTED. SEVERAL DIRECTIONS FOR FUTURE RESEARCH, INCLUDING IMPORTANT METHODOLOGICAL CONSIDERATIONS FOR FUTURE STUDY DESIGN, ARE DISCUSSED. TAKEN TOGETHER, THE LITERATURE ON CHILDHOOD MALTREATMENT AND DNA METHYLATION UNDERSCORES THE COMPLEXITY OF TRANSACTIONS BETWEEN THE ENVIRONMENT AND BIOLOGY ACROSS DEVELOPMENT. 2021 10 6729 25 VULNERABILITY TO STROKE: IMPLICATIONS OF PERINATAL PROGRAMMING OF THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS. CHRONIC STRESS IS CAPABLE OF EXACERBATING EACH MAJOR, MODIFIABLE, ENDOGENOUS RISK FACTOR FOR CEREBROVASCULAR AND CARDIOVASCULAR DISEASE. INDEED, EXPOSURE TO STRESS CAN INCREASE BOTH THE INCIDENCE AND SEVERITY OF STROKE, PRESUMABLY THROUGH ACTIVATION OF THE HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS. NOW THAT CHARACTERIZATION OF THE MECHANISMS UNDERLYING EPIGENETIC PROGRAMMING OF THE HPA AXIS IS WELL UNDERWAY, THERE HAS BEEN RENEWED INTEREST IN EXAMINING THE ROLE OF EARLY ENVIRONMENT ON THE EVOLUTION OF HEALTH CONDITIONS ACROSS THE ENTIRE LIFESPAN. INDEED, NEONATAL MANIPULATIONS IN RODENTS THAT REDUCE STRESS RESPONSIVITY, AND SUBSEQUENT LIFE-TIME EXPOSURE TO GLUCOCORTICOIDS, ARE ASSOCIATED WITH A REDUCTION IN THE DEVELOPMENT OF NEUROENDOCRINE, NEUROANATOMICAL, AND COGNITIVE DYSFUNCTIONS THAT TYPICALLY PROGRESS WITH AGE. ALTHOUGH IMPROVED DAY TO DAY REGULATION OF THE HPA AXIS ALSO MAY BE ACCOMPANIED BY A DECREASE IN STROKE RISK, EVIDENCE FROM RODENT STUDIES SUGGEST THAT AN ASSOCIATED COST COULD BE INCREASED SUSCEPTIBILITY TO INFLAMMATION AND NEURONAL DEATH IN THE EVENT THAT A STROKE DOES OCCUR AND THE INDIVIDUAL IS EXPOSED TO PERSISTENTLY ELEVATED CORTICOSTEROIDS. GIVEN ITS IMPORTANCE IN REGULATION OF HEALTH AND DISEASE STATES, ANY LONG-TERM MODULATION OF THE HPA AXIS IS LIKELY TO BE ASSOCIATED WITH BOTH BENEFITS AND POTENTIAL RISKS. THE GOALS OF THIS REVIEW ARTICLE ARE TO EXAMINE (1) THE CLINICAL AND EXPERIMENTAL DATA SUGGESTING THAT NEONATAL EXPERIENCES CAN SHAPE HPA AXIS REGULATION, (2) THE INFLUENCE OF STRESS AND THE HPA AXIS ON STROKE INCIDENCE AND SEVERITY, AND (3) THE POTENTIAL FOR NEONATAL PROGRAMMING OF THE HPA AXIS TO IMPACT ADULT CEREBROVASCULAR HEALTH. 2009 11 2520 24 EPIGENETICS AND THE GLUCOCORTICOID RECEPTOR: A REVIEW OF THE IMPLICATIONS IN DEPRESSION. DEPRESSION IS A SERIOUS PSYCHIATRIC DISORDER THAT EFFECTS AT LEAST 350 MILLION PEOPLE WORLDWIDE TODAY. DYSREGULATION OF THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS (HPAA) IS A ROBUST FINDING IN THE PATHOPHYSIOLOGY OF DEPRESSION. THIS DYSREGULATION IS HYPOTHESIZED TO RESULT FROM ALTERED CENTRAL GLUCOCORTICOID RECEPTOR (GR) LEVELS AND/OR FUNCTION AS A CONSEQUENCE OF CHRONIC GLUCOCORTICOID (GC) RELEASE, LEADING TO RECEPTOR RESISTANCE. PIVOTAL ANIMAL AND HUMAN RESEARCH TO DATE HAS IDENTIFIED THAT EARLY LIFE EXPOSURE TO PROLONGED LEVELS OF GCS, STRESS AND/OR DEPRESSION, CAN INDUCE EPIGENETIC MODIFICATIONS AT KEY REGIONS ON THE GR GENE THAT LEAD TO ALTERATIONS IN GR EXPRESSION AND FUNCTION. EPIGENETICS PROVIDES AN ATTRACTIVE MECHANISM TO EXPLAIN HOW ONES' GENES AND ENVIRONMENT CAN INTERACT TO PRODUCE DIFFERENT DISEASE PHENOTYPES. THIS REVIEW AIMS TO COMPILE THE INFORMATION THAT HAS BEEN COLLECTED TO DATE AND TO IDENTIFY KEY AREAS FOR FURTHER INVESTIGATION. 2016 12 6065 32 THE DEVELOPMENTAL ORIGINS OF CHRONIC PHYSICAL AGGRESSION: BIOLOGICAL PATHWAYS TRIGGERED BY EARLY LIFE ADVERSITY. LONGITUDINAL EPIDEMIOLOGICAL STUDIES WITH BIRTH COHORTS HAVE SHOWN THAT PHYSICAL AGGRESSION IN HUMANS DOES NOT APPEAR SUDDENLY IN ADOLESCENCE AS COMMONLY THOUGHT. IN FACT, PHYSICALLY AGGRESSIVE BEHAVIOUR IS OBSERVED AS EARLY AS 12 MONTHS AFTER BIRTH, ITS FREQUENCY PEAKS AROUND 2-4 YEARS OF AGE AND DECREASES IN FREQUENCY UNTIL EARLY ADULTHOOD. HOWEVER, A MINORITY OF CHILDREN (3-7%) MAINTAIN A HIGH FREQUENCY OF PHYSICAL AGGRESSION FROM CHILDHOOD TO ADOLESCENCE AND DEVELOP SERIOUS SOCIAL ADJUSTMENT PROBLEMS DURING ADULTHOOD. GENETIC FACTORS AND EARLY SOCIAL EXPERIENCES, AS WELL AS THEIR INTERACTION, HAVE BEEN SHOWN TO PLAY AN IMPORTANT ROLE IN THE DEVELOPMENT OF CHRONIC AGGRESSIVE BEHAVIOUR. HOWEVER, THE BIOLOGICAL MECHANISMS UNDERLYING THESE ASSOCIATIONS ARE JUST BEGINNING TO BE UNCOVERED. RECENT EVIDENCE SUGGESTS THAT EPIGENETIC MECHANISMS ARE RESPONSIVE TO ADVERSE ENVIRONMENTS AND COULD BE INVOLVED IN THE DEVELOPMENT OF CHRONIC AGGRESSION. USING BOTH GENE CANDIDATE AND GENOMIC APPROACHES, RECENT STUDIES HAVE IDENTIFIED EPIGENETIC MARKS, SUCH AS DNA METHYLATION ALTERATIONS IN GENES INVOLVED IN THE STRESS RESPONSE AND THE SEROTONIN AND IMMUNE SYSTEMS TO BE PARTLY RESPONSIBLE FOR THE LONG-LASTING EFFECTS OF EARLY ADVERSITY. FURTHER LONGITUDINAL STUDIES WITH BIOLOGICAL, ENVIRONMENTAL AND BEHAVIOURAL ASSESSMENTS FROM BIRTH ONWARDS ARE NEEDED TO ELUCIDATE THE SEQUENCE OF EVENTS THAT LEADS TO THESE LONG-LASTING EPIGENETIC MARKS ASSOCIATED WITH EARLY ADVERSITY AND AGGRESSION. 2015 13 6853 33 [NEUROBIOLOGY OF EARLY LIFE TRAUMATIC STRESS AND TRAUMA: PROLONGED NEUROENDOCRINE DYSREGULATION AS A NEURODEVELOPMENTAL RISK FACTOR]. EARLY LIFE STRESSORS DISPLAY A HIGH UNIVERSAL PREVALENCE AND CONSTITUTE A MAJOR PUBLIC HEALTH PROBLEM WITH TWO THIRDS OF YOUTH BEING EXPOSED TO POTENTIALLY TRAUMATIC EXPERIENCES BY THE AGE OF 17. TRAUMATIC STRESS EXPOSURE DURING CRITICAL PERIODS OF DEVELOPMENT MAY HAVE ESSENTIAL AND LONG-LASTING EFFECTS ON THE PHYSICAL AND MENTAL HEALTH OF INDIVIDUALS AND REPRESENTS A DEVELOPMENTAL RISK FACTOR MEDIATING RISK FOR DISEASE. EARLY-LIFE STRESS (ELS) AND CHILDHOOD TRAUMA (CT) CAN BOTH HAVE AN IMPACT ON SENSITIVE NEURONAL BRAIN NETWORKS INVOLVED IN STRESS REACTIONS, AND COULD EXERT A PROGRAMMING EFFECT ON GLUCOCORTICOID SIGNALING LEADING TO CHRONIC HYPER- OR HYPO-ACTIVATION OF THE STRESS SYSTEM. IN ADDITION, ALTERATIONS IN EMOTIONAL AND AUTONOMIC REACTIVITY, CIRCADIAN RHYTHM DISRUPTION, FUNCTIONAL AND STRUCTURAL CHANGES IN THE BRAIN, AS WELL AS IMMUNE AND METABOLIC DYSREGULATION HAVE BEEN LATELY IDENTIFIED AS IMPORTANT RISK FACTORS FOR A CHRONICALLY IMPAIRED HOMEOSTATIC BALANCE AFTER ELS/CT. FURTHERMORE, HUMAN GENETIC BACKGROUND AND EPIGENETIC MODIFICATIONS THROUGH STRESS-RELATED GENE EXPRESSION COULD INTERACT WITH THESE ALTERATIONS AND EXPLAIN INTER-INDIVIDUAL VARIATION IN VULNERABILITY OR RESILIENCE TO STRESS. THIS NARRATIVE REVIEW PRESENTS RELEVANT EVIDENCE FROM MAINLY HUMAN RESEARCH ON THE MOST ACKNOWLEDGED NEUROBIOLOGICAL ALLOSTATIC PATHWAYS EXERTING ENDURING ADVERSE EFFECTS OF ELS/CT EVEN DECADES LATER. FUTURE STUDIES SHOULD PROSPECTIVELY INVESTIGATE POTENTIAL CONFOUNDERS, THEIR TEMPORAL SEQUENCE AND COMBINED EFFECTS AT THE BIOLOGICAL LEVEL, WHILE CONSIDERING THE POTENTIALLY DELAYED TIME-FRAME FOR THE EXPRESSION OF THEIR EFFECTS. FINALLY, SCREENING STRATEGIES FOR ELS/CT AND TRAUMA NEED TO BE IMPROVED. INFORMATION ABOUT ELS/CT HISTORY AND THE NUMBER OF ADVERSE EXPERIENCES COULD HELP TO BETTER IDENTIFY THE INDIVIDUAL RISK FOR DISEASE DEVELOPMENT, PREDICT INDIVIDUAL TREATMENT RESPONSE AND DESIGN PREVENTION STRATEGIES TO REDUCE THE NEGATIVE EFFECTS OF ELS/CT. 2023 14 5756 35 SOCIOECONOMIC DEPRIVATION, ADVERSE CHILDHOOD EXPERIENCES AND MEDICAL DISORDERS IN ADULTHOOD: MECHANISMS AND ASSOCIATIONS. SEVERE SOCIOECONOMIC DEPRIVATION (SED) AND ADVERSE CHILDHOOD EXPERIENCES (ACE) ARE SIGNIFICANTLY ASSOCIATED WITH THE DEVELOPMENT IN ADULTHOOD OF (I) ENHANCED INFLAMMATORY STATUS AND/OR HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS DYSFUNCTION AND (II) NEUROLOGICAL, NEUROPROGRESSIVE, INFLAMMATORY AND AUTOIMMUNE DISEASES. THE MECHANISMS BY WHICH THESE ASSOCIATIONS TAKE PLACE ARE DETAILED. THE TWO SETS OF CONSEQUENCES ARE THEMSELVES STRONGLY ASSOCIATED, WITH THE FIRST SET LIKELY CONTRIBUTING TO THE SECOND. MECHANISMS ENABLING BIDIRECTIONAL COMMUNICATION BETWEEN THE IMMUNE SYSTEM AND THE BRAIN ARE DESCRIBED, INCLUDING COMPLEX SIGNALLING PATHWAYS FACILITATED BY FACTORS AT THE LEVEL OF IMMUNE CELLS. ALSO DETAILED ARE MECHANISMS UNDERPINNING THE ASSOCIATION BETWEEN SED, ACE AND THE GENESIS OF PERIPHERAL INFLAMMATION, INCLUDING EPIGENETIC CHANGES TO IMMUNE SYSTEM-RELATED GENE EXPRESSION. THE DURATION AND MAGNITUDE OF INFLAMMATORY RESPONSES CAN BE INFLUENCED BY GENETIC FACTORS, INCLUDING SINGLE NUCLEOTIDE POLYMORPHISMS, AND BY EPIGENETIC FACTORS, WHEREBY PRO-INFLAMMATORY CYTOKINES, REACTIVE OXYGEN SPECIES, REACTIVE NITROGEN SPECIES AND NUCLEAR FACTOR-KAPPAB AFFECT GENE DNA METHYLATION AND HISTONE ACETYLATION AND ALSO INDUCE SEVERAL MICRORNAS INCLUDING MIR-155, MIR-181B-1 AND MIR-146A. ADULT HPA AXIS ACTIVITY IS REGULATED BY (I) GENETIC FACTORS, SUCH AS GLUCOCORTICOID RECEPTOR POLYMORPHISMS; (II) EPIGENETIC FACTORS AFFECTING GLUCOCORTICOID RECEPTOR FUNCTION OR EXPRESSION, INCLUDING THE METHYLATION STATUS OF ALTERNATIVE PROMOTER REGIONS OF NR3C1 AND THE METHYLATION OF FKBP5 AND HSD11BETA2; (III) CHRONIC INFLAMMATION AND CHRONIC NITROSATIVE AND OXIDATIVE STRESS. FINALLY, IT IS SHOWN HOW SEVERE PSYCHOLOGICAL STRESS ADVERSELY AFFECTS MITOCHONDRIAL STRUCTURE AND FUNCTIONING AND IS ASSOCIATED WITH CHANGES IN BRAIN MITOCHONDRIAL DNA COPY NUMBER AND TRANSCRIPTION; MITOCHONDRIA CAN ACT AS COURIERS OF CHILDHOOD STRESS INTO ADULTHOOD. 2019 15 1747 15 EARLY LIFE ADVERSITY: EPIGENETIC REGULATION UNDERLYING DRUG ADDICTION SUSCEPTIBILITY. DRUG ADDICTION IS A LEADING CAUSE OF DISABILITY WORLDWIDE, WITH MORE THAN 70,000 AMERICANS DYING FROM DRUG OVERDOSE IN 2019 ALONE. WHILE ONLY A SMALL PERCENTAGE OF CHRONIC DRUG USERS ESCALATE TO DRUG ADDICTION, LITTLE IS UNDERSTOOD ON THE PRECISE MECHANISMS OF THIS SUSCEPTIBILITY. EARLY LIFE ADVERSITY IS CAUSALLY RELEVANT TO ADULT PSYCHIATRIC DISEASE AND MAY CONTRIBUTE TO THE RISK OF ADDICTION. HERE WE REVIEW RECENT PRE-CLINICAL EVIDENCE SHOWING THAT EARLY LIFE EXPOSURE TO STRESS AND/OR DRUGS REGULATES CHANGES IN BEHAVIOR, GENE EXPRESSION, AND THE EPIGENOME THAT PERSIST INTO ADULTHOOD. WE SUMMARIZE THE MAJOR FINDINGS AND GAPS IN THE PRECLINICAL LITERATURE, HIGHLIGHTING STUDIES THAT DEMONSTRATE THE OFTEN PROFOUND DIFFERENCES BETWEEN FEMALE AND MALE SUBJECTS. 2023 16 2021 26 EPIGENETIC CHANGES ASSOCIATED WITH DIFFERENT TYPES OF STRESSORS AND SUICIDE. STRESS IS ASSOCIATED WITH VARIOUS EPIGENETIC CHANGES. SOME STRESS-INDUCED EPIGENETIC CHANGES ARE HIGHLY DYNAMIC, WHEREAS OTHERS ARE ASSOCIATED WITH LASTING MARKS ON THE EPIGENOME. IN OUR STUDY, A COMPREHENSIVE NARRATIVE REVIEW OF THE LITERATURE WAS PERFORMED BY INVESTIGATING THE EPIGENETIC CHANGES THAT OCCUR WITH ACUTE STRESS, CHRONIC STRESS, EARLY CHILDHOOD STRESS, AND TRAUMATIC STRESS EXPOSURES, ALONG WITH EXAMINING THOSE OBSERVED IN POST-MORTEM BRAINS OR BLOOD SAMPLES OF SUICIDE COMPLETERS AND ATTEMPTERS. IN ADDITION, THE TRANSGENERATIONAL EFFECTS OF THESE CHANGES ARE REPORTED. FOR ALL TYPES OF STRESS STUDIES EXAMINED, THE GENES NR3C1, OXTR, SLC6A4, AND BDNF REPRODUCIBLY SHOWED EPIGENETIC CHANGES, WITH SOME MODIFICATIONS OBSERVED TO BE PASSED DOWN TO SUBSEQUENT GENERATIONS FOLLOWING STRESS EXPOSURES. THE AFOREMENTIONED GENES ARE KNOWN TO BE INVOLVED IN NEURONAL DEVELOPMENT AND HORMONAL REGULATION AND ARE ALL ASSOCIATED WITH SUSCEPTIBILITY TO MENTAL HEALTH DISORDERS INCLUDING DEPRESSION, ANXIETY, PERSONALITY DISORDERS, AND PTSD (POST-TRAUMATIC STRESS DISORDER). FURTHER RESEARCH IS WARRANTED IN ORDER TO DETERMINE THE SCOPE OF EPIGENETIC ACTIONABLE TARGETS IN INDIVIDUALS SUFFERING FROM THE LONG-LASTING EFFECTS OF STRESSFUL EXPERIENCES. 2023 17 5649 15 SEX DIFFERENCES IN PSYCHOSTIMULANT ABUSE: IMPLICATIONS FOR ESTROGEN RECEPTORS AND HISTONE DEACETYLASES. SUBSTANCE ABUSE IS A CHRONIC PATHOLOGICAL DISORDER THAT NEGATIVELY AFFECTS MANY HEALTH AND NEUROLOGICAL PROCESSES. A GROWING BODY OF LITERATURE HAS REVEALED GENDER DIFFERENCES IN SUBSTANCE USE. COMPARED TO MEN, WOMEN DISPLAY DISTINCT DRUG-USE PHENOTYPES ACCOMPANIED BY RECOVERY AND REHABILITATION DISPARITIES. THESE OBSERVATIONS HAVE LED TO THE NOTION THAT SEX-DEPENDENT SUSCEPTIBILITIES EXIST ALONG THE PROGRESSION TO ADDICTION. WITHIN THIS SCOPE, NEUROADAPTATIONS FOLLOWING PSYCHOSTIMULANT EXPOSURE ARE THOUGHT TO BE DISTINCT FOR EACH SEX. THIS REVIEW SUMMARIZES CLINICAL FINDINGS AND ANIMAL RESEARCH REPORTING SEX DIFFERENCES IN THE SUBJECTIVE AND BEHAVIORAL RESPONSES TO COCAINE, METHAMPHETAMINE, AND NICOTINE. THIS DISCUSSION IS FOLLOWED BY AN EXAMINATION OF EPIGENETIC AND MOLECULAR ALTERATIONS IMPLICATED IN THE ADDICTION PROCESS. SPECIAL CONSIDERATION IS GIVEN TO HISTONE DEACETYLASES AND ESTROGEN RECEPTOR-MEDIATED GENE EXPRESSION. 2022 18 678 29 BRAIN DEVELOPMENT UNDER STRESS: HYPOTHESES OF GLUCOCORTICOID ACTIONS REVISITED. ONE OF THE CONUNDRUMS IN TODAY'S STRESS RESEARCH IS WHY SOME INDIVIDUALS FLOURISH AND OTHERS PERISH UNDER SIMILAR STRESSFUL CONDITIONS. IT IS RECOGNIZED THAT THIS INDIVIDUAL VARIABILITY IN ADAPTATION TO STRESS DEPENDS ON THE OUTCOME OF THE INTERACTION OF GENETIC AND COGNITIVE/EMOTIONAL INPUTS IN WHICH GLUCOCORTICOID HORMONES AND RECEPTORS PLAY A CRUCIAL ROLE. HENCE ONE APPROACH TOWARDS UNDERSTANDING INDIVIDUAL VARIATION IN STRESS COPING IS HOW GLUCOCORTICOID ACTIONS CAN CHANGE FROM PROTECTIVE TO HARMFUL. TO ADDRESS THIS QUESTION WE FOCUS ON FOUR HYPOTHESES THAT ARE CONNECTED AND NOT MUTUAL EXCLUSIVE. FIRST, THE CLASSICAL GLUCOCORTICOID CASCADE HYPOTHESIS, IN WHICH THE INABILITY TO COPE WITH CHRONIC STRESS CAUSES A VICIOUS CYCLE OF EXCESS GLUCOCORTICOID AND DOWNREGULATION OF GLUCOCORTICOID RECEPTORS (GR) IN THE HIPPOCAMPUS TRIGGERING A FEED-FORWARD CASCADE OF DEGENERATION AND DISEASE. SECOND, THE BALANCE HYPOTHESIS, WHICH TAKES ALSO THE LIMBIC MINERALOCORTICOID RECEPTORS (MR) INTO ACCOUNT AND PROPOSES THAT AN INTEGRAL LIMBIC MR:GR IMBALANCE IS CAUSAL TO ALTERED PROCESSING OF INFORMATION IN CIRCUITS UNDERLYING FEAR, REWARD, SOCIAL BEHAVIOUR AND RESILIENCE, DYSREGULATION OF THE HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS AND IMPAIRMENT OF BEHAVIOURAL ADAPTATION. THE MR:GR BALANCE IS ALTERED BY GENE VARIANTS OF THESE RECEPTOR COMPLEXES AND EXPERIENCE-RELATED FACTORS, WHICH CAN INDUCE LASTING EPIGENETIC CHANGES IN THE EXPRESSION OF THESE RECEPTORS. A PARTICULAR POTENT EPIGENETIC STIMULUS IS THE MATERNAL ENVIRONMENT WHICH IS FUNDAMENTAL FOR THE MATERNAL MEDIATION HYPOTHESIS. THE OUTCOME OF PERINATAL GENE X ENVIRONMENT INTERACTION, AND THUS OF MR:GR-MEDIATED FUNCTIONS DEPENDS HOWEVER, ON THE DEGREE OF 'MATCHING' WITH ENVIRONMENTAL DEMANDS IN LATER LIFE. THE PREDICTIVE ADAPTATION HYPOTHESIS THEREFORE PRESENTS A CONCEPTUAL FRAMEWORK TO EXAMINE THE ROLE OF GLUCOCORTICOIDS IN UNDERSTANDING INDIVIDUAL PHENOTYPIC DIFFERENCES IN STRESS-RELATED BEHAVIOURS OVER THE LIFESPAN. 2010 19 634 23 BIOLOGICAL EMBEDDING OF EARLY-LIFE ADVERSITY AND A SCOPING REVIEW OF THE EVIDENCE FOR INTERGENERATIONAL EPIGENETIC TRANSMISSION OF STRESS AND TRAUMA IN HUMANS. SEVERE OR CHRONIC STRESS AND TRAUMA CAN HAVE A DETRIMENTAL IMPACT ON HEALTH. EVIDENCE SUGGESTS THAT EARLY-LIFE ADVERSITY CAN BECOME BIOLOGICALLY EMBEDDED AND HAS THE POTENTIAL TO INFLUENCE HEALTH OUTCOMES DECADES LATER. EPIGENETICS IS ONE MECHANISM THAT HAS BEEN IMPLICATED IN THESE LONG-LASTING EFFECTS. OBSERVATIONAL STUDIES IN HUMANS INDICATE THAT THE EFFECTS OF STRESS COULD EVEN PERSIST ACROSS GENERATIONS, ALTHOUGH WHETHER OR NOT EPIGENETIC MECHANISMS ARE INVOLVED REMAINS UNDER DEBATE. HERE, WE PROVIDE AN OVERVIEW OF STUDIES IN ANIMALS AND HUMANS THAT DEMONSTRATE THE EFFECTS OF EARLY-LIFE STRESS ON DNA METHYLATION, ONE OF THE MOST WIDELY STUDIED EPIGENETIC MECHANISMS, AND SUMMARIZE FINDINGS FROM ANIMAL MODELS DEMONSTRATING THE INVOLVEMENT OF EPIGENETICS IN THE TRANSMISSION OF STRESS ACROSS GENERATIONS. WE THEN DESCRIBE THE RESULTS OF A SCOPING REVIEW TO DETERMINE THE EXTENT TO WHICH THE TERMS INTERGENERATIONAL OR TRANSGENERATIONAL HAVE BEEN USED IN HUMAN STUDIES INVESTIGATING THE TRANSMISSION OF TRAUMA AND STRESS VIA EPIGENETIC MECHANISMS. WE END WITH A DISCUSSION OF KEY AREAS FOR FUTURE RESEARCH TO ADVANCE UNDERSTANDING OF THE ROLE OF EPIGENETICS IN THE LEGACY EFFECTS OF STRESS AND TRAUMA. 2023 20 247 29 ADULTHOOD ASTHMA AS A CONSEQUENCE OF CHILDHOOD ADVERSITY: A SYSTEMATIC REVIEW OF EPIGENETICALLY AFFECTED GENES. THERE IS AN ACCUMULATING DATA THAT SHOWS RELATION BETWEEN CHILDHOOD ADVERSITY AND VULNERABILITY TO CHRONIC DISEASES AS WELL AS EPIGENETIC INFLUENCES THAT IN TURN GIVE RISE TO THESE DISEASES. ASTHMA IS ONE OF THE CHRONIC DISEASES THAT IS INFLUENCED FROM GENETIC REGULATION OF THE INFLAMMATORY BIOMOLECULES AND THEREFORE THE HYPOTHESIS IN THIS RESEARCH WAS CHILDHOOD ADVERSITY MIGHT HAVE CAUSED EPIGENETIC DIFFERENTIATION IN THE ASTHMA-RELATED GENES IN THE POPULATION WHO HAD CHILDHOOD TRAUMA. TO TEST THIS HYPOTHESIS, THE LITERATURE WAS SYSTEMATICALLY REVIEWED TO EXTRACT EPIGENETICALLY MODIFIED GENE DATA OF THE ADULTS WHO HAD CHILDHOOD ADVERSITY, AND AFFECTED GENES WERE FURTHER EVALUATED FOR THEIR ASSOCIATION WITH ASTHMA. PRISMA GUIDELINES WERE ADOPTED AND PUBMED AND GOOGLE SCHOLAR WERE INCLUDED IN THE SEARCHED DATABASES, TO EVALUATE EPIGENETIC MODIFICATIONS IN ASTHMA-RELATED GENES OF PHYSICALLY, EMOTIONALLY OR SEXUALLY ABUSED CHILDREN. AFTER RETRIEVING A TOTAL OF 5245 ARTICLES, 36 OF THEM WERE INCLUDED IN THE STUDY. SEVERAL GENES AND PATHWAYS THAT MAY CONTRIBUTE TO PATHOGENESIS OF ASTHMA DEVELOPMENT, INCREASED INFLAMMATION, OR RESPONSE TO ASTHMA TREATMENT WERE FOUND EPIGENETICALLY AFFECTED BY CHILDHOOD TRAUMAS. CHILDHOOD ADVERSITY, CAUSING EPIGENETIC CHANGES IN DNA, MAY LEAD TO ASTHMA DEVELOPMENT OR INFLUENCE THE COURSE OF THE DISEASE AND THEREFORE SHOULD BE TAKEN INTO ACCOUNT FOR THE PROLONGED HEALTH CONSEQUENCES. 2022