1 5172 155 PREDICTING PAIN AFTER STANDARD PAIN THERAPY FOR KNEE OSTEOARTHRITIS - THE FIRST STEPS TOWARDS PERSONALIZED MECHANISTIC-BASED PAIN MEDICINE IN OSTEOARTHRITIS. OBJECTIVES: THE PREVALENCE OF OSTEOARTHRITIS (OA) IS RISING, AND PAIN IS THE HALLMARK SYMPTOM OF OA. PAIN IN OA IS COMPLICATED AND CAN BE INFLUENCED BY MULTIPLE JOINT-RELATED FACTORS AND FACTORS RELATED TO, E.G., PHYSIOLOGICAL, EPIGENETIC, AND PAIN SENSORY PROFILES. INCREASING EVIDENCE SUGGESTS THAT A SUBSET OF PATIENTS WITH OA ARE PAIN SENSITIVE. THIS CAN BE ASSESSED USING QUANTITATIVE SENSORY TESTING (QST). COMMON TREATMENTS OF OA ARE TOTAL KNEE ARTHROPLASTY (TKA) AND ADMINISTRATION OF 3-WEEKS OF NON-STEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDS), WHICH PROVIDE PAIN RELIEF TO MANY PATIENTS WITH OA. HOWEVER, APPROX. 20% OF PATIENTS EXPERIENCE CHRONIC POSTOPERATIVE PAIN AFTER TKA, WHEREAS NSAIDS PROVIDE AN AVERAGE PAIN RELIEF OF APPROX. 25%. THE CURRENT TOPICAL REVIEW FOCUSES ON THE EMERGING EVIDENCE LINKING PRETREATMENT QST TO THE TREATMENT RESPONSE OF TKA AND NSAID TREATMENTS. CONTENT: MEDLINE WAS SYSTEMATICALLY SEARCHED FOR ALL STUDIES FROM 2000 TO 2022 ON PRETREATMENT QST, TKA, AND NSAIDS. PRE-CLINICAL STUDIES, REVIEWS, AND META-ANALYSES WERE EXCLUDED. SUMMARY: CURRENTLY, 14 STUDIES ON TKA AND FOUR STUDIES ON NSAIDS HAVE BEEN PUBLISHED WITH THE AIM TO ATTEMPT PREDICTION OF THE TREATMENT RESPONSE. THE QST METHODOLOGIES IN THE STUDIES ARE INCONSISTENT, BUT 11/14 (79%) STUDIES ON TKA AND 4/4 (100%) STUDIES ON NSAIDS REPORT STATISTICALLY SIGNIFICANT ASSOCIATIONS BETWEEN PRETREATMENT QST AND CHRONIC POSTOPERATIVE PAIN AFTER TKA OR ANALGESIC EFFECT AFTER NSAID TREATMENT. THE STRENGTH OF THE ASSOCIATIONS REMAINS LOW-TO-MODERATE. THE MOST CONSISTENT PRETREATMENT QST PREDICTORS ARE PRESSURE PAIN THRESHOLDS, TEMPORAL SUMMATION OF PAIN, AND CONDITIONED PAIN MODULATION. OUTLOOK: THE USE OF QST AS PREDICTORS OF STANDARD OA TREATMENT IS INTERESTING, BUT THE PREDICTIVE STRENGTH REMAINS LOW-TO-MODERATE. A TRANSITION OF QST FROM A RESEARCH-BASED SETTING AND INTO THE CLINIC IS NOT ADVISED UNTIL THE PREDICTIVE STRENGTH HAS BEEN IMPROVED AND THE METHODOLOGY HAS BEEN STANDARDIZED. 2023 2 3146 42 GLOBAL RESEARCH TRENDS ON EPIGENETICS AND NEUROPATHIC PAIN: A BIBLIOMETRIC ANALYSIS. OBJECTIVE: NEUROPATHIC PAIN (NP) IS A COMMON DISEASE THAT MANIFESTS WITH PATHOLOGICAL CHANGES IN THE SOMATOSENSORY SYSTEM. IN RECENT YEARS, THE INTERACTIONS OF NP WITH THE EPIGENETIC MECHANISM HAVE BEEN INCREASINGLY ELUCIDATED. HOWEVER, ONLY A FEW STUDIES HAVE USED BIBLIOMETRIC TOOLS TO SYSTEMATICALLY ANALYZE KNOWLEDGE IN THIS FIELD. THE OBJECTIVE OF THIS STUDY IS TO VISUALLY ANALYZE THE TRENDS, HOTSPOTS, AND FRONTIERS IN EPIGENETICS AND NP RESEARCH BY USING A BIBLIOMETRIC METHOD. METHODS: STUDIES RELATED TO EPIGENETICS AND NP WERE SEARCHED FROM THE SCIENCE CITATION INDEX-EXPANDED OF THE WEB OF SCIENCE CORE COLLECTION DATABASE. SEARCH TIME IS FROM INCEPTION TO NOVEMBER 30, 2022. NO RESTRICTIONS WERE PLACED ON LANGUAGE. ONLY ARTICLES AND REVIEWS WERE INCLUDED AS DOCUMENT TYPES. DATA ON INSTITUTIONS, COUNTRIES, AUTHORS, JOURNAL DISTRIBUTION, AND KEYWORDS WERE IMPORTED INTO CITESPACE SOFTWARE FOR VISUAL ANALYSIS. RESULTS: A TOTAL OF 867 PUBLICATIONS MET THE INCLUSION CRITERIA, WHICH SPANNED THE PERIOD FROM 2000 TO 2022. OVER THE YEARS, THE NUMBER OF PUBLICATIONS AND THE FREQUENCY OF CITATIONS EXHIBITED A CLEAR UPWARD TREND IN GENERAL, REACHING A PEAK IN 2021. THE MAJOR CONTRIBUTING COUNTRIES IN TERMS OF THE NUMBER OF PUBLICATIONS WERE CHINA, THE UNITED STATES, AND JAPAN. THE TOP THREE INSTITUTIONS WERE RUTGERS STATE UNIVERSITY, XUZHOU MEDICAL UNIVERSITY, AND NANJING MEDICAL UNIVERSITY. MOLECULAR PAIN, PAIN, AND JOURNAL OF NEUROINFLAMMATION CONTRIBUTED SIGNIFICANTLY TO THE VOLUME OF ISSUES. AMONG THE TOP 10 AUTHORS IN TERMS OF THE NUMBER OF PUBLICATIONS, TAO YUAN-XIANG CONTRIBUTED 30 ENTRIES, FOLLOWED BY ZHANG YI WITH 24 AND WU SHAO-GEN WITH 20. ON THE BASIS OF THE BURST AND CLUSTERS OF KEYWORDS, "DNA METHYLATION," "CIRCULAR RNA," "ACETYLATION," "LONG NON-CODING RNA," AND "MICROGLIA" ARE GLOBAL HOTSPOTS IN THE FIELD. CONCLUSION: THE BIBLIOMETRIC ANALYSIS INDICATES THAT THE NUMBER OF PUBLICATIONS RELATED TO EPIGENETICS AND NP IS EXHIBITING A RAPID INCREASE. KEYWORD ANALYSIS SHOWS THAT "DNA METHYLATION," "CIRCULAR RNA," "ACETYLATION," "LONG NON-CODING RNA" AND "MICROGLIA" ARE THE MOST INTERESTING TERMS FOR RESEARCHERS IN THE FIELD. MORE RIGOROUS CLINICAL TRIALS AND ADDITIONAL STUDIES THAT EXPLORE RELEVANT MECHANISMS ARE REQUIRED IN THE FUTURE. 2023 3 6141 38 THE ETIOLOGY OF PEYRONIE'S DISEASE: PATHOGENESIS AND GENETIC CONTRIBUTIONS. INTRODUCTION: PEYRONIE'S DISEASE (PD) IS A CHRONIC FIBROSING CONDITION THAT CONTRIBUTES TO PENILE DEFORMITY, CURVATURE, AND PAIN. INITIAL FAMILIAL STUDIES DEMONSTRATED POTENTIAL GENETIC LINKS TO PD. SINCE THAT TIME, VERY FEW INVESTIGATIONS HAVE SIGNIFICANTLY ADVANCED THE SCIENCE IN THIS AREA. HENCE, THERE IS A LARGE OPPORTUNITY AND SIGNIFICANT NEED TO BETTER STUDY THE UNDERLYING GENOMICS AND PATHOGENESIS OF PD. AIM: TO SUMMARIZE THE CURRENT GENOMIC LITERATURE RELEVANT TO PD. METHODS: A REVIEW WAS PERFORMED OF ALL PUBMED-INDEXED LITERATURE FROM 1970-2018 RELATING TO THE PATHOPHYSIOLOGY AND GENETICS OF PD. KEY FINDINGS WERE CATEGORICALLY SUMMARIZED TO INCLUDE EPIDEMIOLOGY, RISK FACTORS, INHERITANCE PATTERNS, CHROMOSOMAL INSTABILITY, GENETIC ASSOCIATIONS, EPIGENETICS, DIFFERENTIAL GENE EXPRESSION, AND PRECLINICAL MODELS OF PD. MAIN OUTCOME MEASURES: SUMMARY OF THE CURRENT LITERATURE ON THE GENETICS OF PD. RESULTS: PD IS A COMMON CONDITION AND HAS SEVERAL KNOWN RISK FACTORS AND COMORBID DISEASE ASSOCIATIONS. ALTHOUGH MEN WITH PD ARE BELIEVED TO BE GENETICALLY PREDISPOSED, THERE ARE LIKELY SEVERAL SUBTYPES OF THE CONDITION, EACH WITH VARIED PATHOPHYSIOLOGICAL DISORDERS AND CONTRIBUTING FACTORS. AVAILABLE DATA SUGGEST THAT PD IS ASSOCIATED WITH UNDERLYING GENETIC INSTABILITY, INCLUDING DYSREGULATION OF GENES RELATING TO FIBROSIS AND CELLULAR DEGRADATION, THUS, RESULTING IN ABNORMAL PLAQUE DEVELOPMENT AND PENILE DEFORMITY. PRECLINICAL MODELS, INCLUDING CELL CULTURES AND RAT MODELS, DEMONSTRATE SEVERAL CONSISTENCIES WITH PD CLINICAL AND HISTOPATHOLOGIC CHARACTERISTICS; HOWEVER, AN IDEAL MODEL WITH SPONTANEOUS DEVELOPMENT OF PD IS LACKING. CONCLUSION: BASED ON LIMITED DATA, PD LIKELY REPRESENTS A HETEROGENEOUS CONDITION, WITH BOTH HERITABLE AND ENVIRONMENTALLY-DRIVEN EPIGENETIC FACTORS CONTRIBUTING TO ITS DEVELOPMENT AND PROGRESSION. HOWEVER, THERE REMAINS A SIGNIFICANT GAP IN THE LITERATURE ON THE UNDERLYING CAUSE AND PATHOPHYSIOLOGY OF THE CONDITION, SUGGESTING A SUBSTANTIAL NEED FOR FURTHER INVESTIGATION AND STUDY. SHARMA KL, ALOM M, TROST L. THE ETIOLOGY OF PEYRONIE'S DISEASE: PATHOGENESIS AND GENETIC CONTRIBUTIONS. SEX MED REV 2020;8:314-323. 2020 4 2967 41 GENETIC AND EPIGENETIC REGULATION OF CATECHOL-O-METHYLTRANSFERASE IN RELATION TO INFLAMMATION IN CHRONIC FATIGUE SYNDROME AND FIBROMYALGIA. BACKGROUND: CATECHOL-O-METHYLTRANSFERASE (COMT) HAS BEEN SHOWN TO INFLUENCE CLINICAL PAIN, DESCENDING MODULATION, AND EXERCISE-INDUCED SYMPTOM WORSENING. COMT REGULATES NOCICEPTIVE PROCESSING AND INFLAMMATION, KEY PATHOPHYSIOLOGICAL FEATURES OF CHRONIC FATIGUE SYNDROME AND FIBROMYALGIA (CFS/FM). WE AIMED TO DETERMINE THE INTERACTIONS BETWEEN GENETIC AND EPIGENETIC MECHANISMS REGULATING COMT AND ITS INFLUENCE ON INFLAMMATORY MARKERS AND SYMPTOMS IN PATIENTS WITH CFS/FM. METHODS: A CASE-CONTROL STUDY WITH REPEATED-MEASURES DESIGN WAS USED TO REDUCE THE CHANCE OF FALSE POSITIVE AND INCREASE THE POWER OF OUR FINDINGS. FIFTY-FOUR PARTICIPANTS (28 PATIENTS WITH CFS/FM AND 26 CONTROLS) WERE ASSESSED TWICE WITHIN 4 DAYS. THE ASSESSMENT INCLUDED CLINICAL QUESTIONNAIRES, NEUROPHYSIOLOGICAL ASSESSMENT (PAIN THRESHOLDS, TEMPORAL SUMMATION, AND CONDITIONED PAIN MODULATION), AND BLOOD WITHDRAWAL IN ORDER TO ASSESS RS4818, RS4633, AND RS4680 COMT POLYMORPHISMS AND PERFORM HAPLOTYPE ESTIMATION, DNA METHYLATION IN THE COMT GENE (BOTH MB-COMT AND S-COMT PROMOTERS), AND CYTOKINE EXPRESSION (TNF-ALPHA, IFN-GAMMA, IL-6, AND TGF-BETA). RESULTS: COMT HAPLOTYPES WERE ASSOCIATED WITH DNA METHYLATION IN THE S-COMT PROMOTER, TGF-BETA EXPRESSION, AND SYMPTOMS. HOWEVER, THIS WAS NOT SPECIFIC FOR ONE CONDITION. SIGNIFICANT BETWEEN-GROUP DIFFERENCES WERE FOUND FOR INCREASED DNA METHYLATION IN THE MB-COMT PROMOTER AND DECREASED IFN-GAMMA EXPRESSION IN PATIENTS. DISCUSSION: OUR RESULTS ARE CONSISTENT WITH BASIC AND CLINICAL RESEARCH, PROVIDING INTERESTING INSIGHTS INTO GENETIC-EPIGENETIC REGULATORY MECHANISMS. MB-COMT DNA METHYLATION MIGHT BE AN INDEPENDENT FACTOR CONTRIBUTING TO THE PATHOPHYSIOLOGY OF CFS/FM. FURTHER RESEARCH ON DNA METHYLATION IN COMPLEX CONDITIONS SUCH AS CFS/FM IS WARRANTED. WE RECOMMEND FUTURE RESEARCH TO EMPLOY A REPEATED-MEASURE DESIGN TO CONTROL FOR BIOMARKERS VARIABILITY AND WITHIN-SUBJECT CHANGES. 2022 5 6127 33 THE EPIGENETIC OVERLAP BETWEEN OBESITY AND MOOD DISORDERS: A SYSTEMATIC REVIEW. (1) BACKGROUND: OBESITY AND MOOD DISORDERS ARE CONSIDERED AS THE MOST PREVALENT MORBIDITIES IN MANY COUNTRIES. WE SUPPOSE THAT EPIGENETIC MECHANISMS MAY INDUCE HIGHER RATES OF OBESITY IN SUBJECTS WHO SUFFER FROM MOOD DISORDERS. IN THIS SYSTEMATIC REVIEW, WE FOCUSED ON THE POTENTIAL ROLES OF DNA METHYLATION ON MOOD DISORDERS AND OBESITY DEVELOPMENT. (2) METHODS: THIS SYSTEMATIC REVIEW WAS CONDUCTED IN ACCORDANCE WITH THE PRISMA STATEMENT AND REGISTERED IN PROSPERO. A SYSTEMATIC SEARCH WAS CONDUCTED IN MEDLINE, SCOPUS, WEB OF SCIENCE, COCHRANE CENTRAL DATABASE, EMBASE, AND CINHAL. WE ALSO CONDUCTED A GREY LITERATURE SEARCH, SUCH AS GOOGLE SCHOLAR. (3) RESULTS: AFTER DEDUPLICATION, WE IDENTIFIED 198 POTENTIALLY RELATED CITATIONS. FINALLY, TEN UNIQUE STUDIES MET OUR INCLUSION CRITERIA. WE HAVE FOUND THREE OVERLAP GENES THAT SHOW SIGNIFICANT DNA METHYLATION CHANGES, BOTH IN OBESITY AND DEPRESSION. PATHWAY ANALYSIS INTERACTION FOR TAPBP, BDNF, AND SORBS2 CONFIRMED THE RELATION OF THESE GENES IN BOTH OBESITY AND MOOD DISORDERS. (4) CONCLUSIONS: WHILE MECHANISMS LINKING BOTH OBESITY AND MOOD DISORDERS TO EPIGENETIC RESPONSE ARE STILL UNKNOWN, WE HAVE ALREADY KNOWN CHRONIC INFLAMMATION INDUCES A NOVEL EPIGENETIC PROGRAM. AS THE RESULTS OF GENE ENRICHMENT, PATHWAYS ANALYSIS SHOWED THAT TAPBP, BDNF, AND SORBS2 LINKED TOGETHER BY INFLAMMATORY PATHWAYS. HYPERMETHYLATION IN THESE GENES MIGHT PLAY A CRUCIAL RULE IN THE CO-OCCURRENCE OF OBESITY AND MOOD DISORDERS. 2020 6 3076 30 GENOME-WIDE EPIGENOMIC ANALYSES IN PATIENTS WITH NOCICEPTIVE AND NEUROPATHIC CHRONIC PAIN SUBTYPES REVEALS ALTERATIONS IN METHYLATION OF GENES INVOLVED IN THE NEURO-MUSCULOSKELETAL SYSTEM. NOCICEPTIVE PAIN INVOLVES THE ACTIVATION OF NOCICEPTORS WITHOUT DAMAGE TO THE NERVOUS SYSTEM, WHEREAS NEUROPATHIC PAIN IS RELATED TO AN ALTERATION IN THE CENTRAL OR PERIPHERAL NERVOUS SYSTEM. CHRONIC PAIN ITSELF AND THE TRANSITION FROM ACUTE TO CHRONIC PAIN MAY BE EPIGENETICALLY CONTROLLED. IN THIS CROSS-SECTIONAL STUDY, A GENOME-WIDE DNA METHYLATION ANALYSIS WAS PERFORMED USING THE BLOOD DNA REDUCED REPRESENTATION BISULFITE SEQUENCING (RRBS) TECHNIQUE. THREE PROSPECTIVE COHORTS INCLUDING 20 HEALTHY CONTROLS (CTL), 18 PATIENTS WITH CHRONIC NOCICEPTIVE PAIN (NOCI), AND 19 PATIENTS WITH CHRONIC NEUROPATHIC PAIN (NEURO) WERE COMPARED AT BOTH THE SINGLE CPG AND DIFFERENTIALLY METHYLATED REGION (DMR) LEVELS. GENES WITH DMRS WERE SEEN IN THE NOCI AND NEURO GROUPS BELONGED TO THE NEURO-MUSCULOSKELETAL SYSTEM AND DIFFERED BETWEEN NOCI AND NEURO PATIENTS. OUR RESULTS DEMONSTRATE THAT THE EPIGENETIC DISTURBANCES ACCOMPANYING NOCICEPTIVE PAIN ARE VERY DIFFERENT FROM THOSE ACCOMPANYING NEUROPATHIC PAIN. IN THE FORMER, AMONG OTHERS, THE EPIGENETIC DISTURBANCE OBSERVED WOULD AFFECT THE FUNCTION OF THE OPIOID ANALGESIC SYSTEM, WHEREAS IN THE LATTER IT WOULD AFFECT THAT OF THE GABAERGIC REWARD SYSTEM. THIS STUDY PRESENTS BIOLOGICAL FINDINGS THAT HELP TO CHARACTERIZE NOCI- AND NEURO-AFFECTED PATHWAYS AND OPENS THE POSSIBILITY OF DEVELOPING EPIGENETIC DIAGNOSTIC ASSAYS. PERSPECTIVE: OUR RESULTS HELP TO EXPLAIN THE VARIOUS BIOLOGICAL PATHWAYS MODIFICATIONS UNDERLYING THE DIFFERENT CLINICAL MANIFESTATIONS OF NOCICEPTIVE AND NEUROPATHIC PAINS. FURTHERMORE, THE NEW TARGETS IDENTIFIED IN OUR STUDY MIGHT HELP TO DISCOVER MORE SPECIFIC TREATMENTS FOR NOCICEPTIVE OR NEUROPATHIC PAINS. 2022 7 6720 31 VITAMIN D METABOLISM GENES ARE DIFFERENTIALLY METHYLATED IN INDIVIDUALS WITH CHRONIC KNEE PAIN. CONTEXT: RECENT EVIDENCE SUGGESTS THAT VITAMIN D MAY INTERACT WITH THE EPIGENOME AND PLAY A ROLE IN THE PAIN EXPERIENCE. IN ORDER FOR PROPER FUNCTIONING TO OCCUR, THERE MUST BE AN ADEQUATE LEVEL OF VITAMIN D PRESENT, MADE POSSIBLE BY ENZYMATIC REACTIONS THAT ALLOW VITAMIN D TO BE BIOLOGICALLY ACTIVE. THE PURPOSE OF THIS STUDY WAS TO EXPLORE THE EPIGENETIC LANDSCAPE OF GENES INVOLVED IN VITAMIN D METABOLISM IN INDIVIDUALS WITH AND WITHOUT CHRONIC KNEE PAIN. PROCEDURES: COMMUNITY-DWELLING INDIVIDUALS RECRUITED AS PART OF A LARGER STUDY FOCUSED ON KNEE PAIN PROVIDED DEMOGRAPHIC, CLINICAL AND PAIN-RELATED INFORMATION, AS WELL AS AN INTRAVENOUS BLOOD SAMPLE TO DETERMINE DNA METHYLATION LEVELS AT CPG SITES. MAIN FINDINGS: THERE WERE DIFFERENCES IN DNA METHYLATION BETWEEN THOSE WITH AND WITHOUT PAIN IN GENES THAT CODE FOR ENZYMES RELATED TO VITAMIN D METABOLISM: CYP24A1 (24-HYDROXYLASE) AND CYP27B1 (1-?-HYDROXYLASE). THERE WAS ALSO HYPERMETHYLATION ON THE GENE THAT CODES FOR THE VITAMIN D RECEPTOR (VDR). PRINCIPAL CONCLUSIONS: THE PRESENCE OF CHRONIC PAIN IS ASSOCIATED WITH EPIGENETIC MODIFICATIONS IN GENES RESPONSIBLE FOR THE EXPRESSION OF ENZYMES INVOLVED IN VITAMIN D METABOLISM AND CELLULAR FUNCTION. THESE RESULTS LAY GROUNDWORK IN UNDERSTANDING THE MECHANISM UNDERLYING THE ASSOCIATION BETWEEN VITAMIN D AND CHRONIC PAIN. 2023 8 6678 40 USING GENETIC BURDEN SCORES FOR GENE-BY-METHYLATION INTERACTION ANALYSIS ON METABOLIC SYNDROME IN AFRICAN AMERICANS. WITH THE RAPID ADVANCEMENT OF OMICS-BASED RESEARCH, PARTICULARLY BIG DATA SUCH AS GENOME- AND EPIGENOME-WIDE ASSOCIATION STUDIES THAT INCLUDE EXTENSIVE ENVIRONMENTAL AND CLINICAL VARIABLES, DATA ANALYTICS HAVE BECOME INCREASINGLY COMPLEX. RESEARCHERS FACE SIGNIFICANT CHALLENGES REGARDING HOW TO ANALYZE MULTIFACTORIAL DATA AND MAKE USE OF THE FINDINGS FOR CLINICAL TRANSLATION. THE PURPOSE OF THIS ARTICLE IS TO PROVIDE A SCIENTIFIC EXEMPLAR FOR USE OF GENETIC BURDEN SCORES AS A DATA ANALYSIS METHOD FOR STUDIES WITH BOTH GENOTYPE AND DNA METHYLATION DATA IN WHICH THE GOAL IS TO EVALUATE ASSOCIATIONS WITH CHRONIC CONDITIONS SUCH AS METABOLIC SYNDROME (METS). THIS STUDY INCLUDED 739 AFRICAN AMERICAN MEN AND WOMEN FROM THE GENETIC EPIDEMIOLOGY NETWORK OF ARTERIOPATHY STUDY WHO MET DIAGNOSTIC CRITERIA FOR METS AND HAD AVAILABLE GENETIC AND EPIGENETIC DATA. GENETIC BURDEN SCORES FOR EVALUATED GENES WERE NOT SIGNIFICANT AFTER MULTIPLE TESTING CORRECTIONS, BUT DNA METHYLATION AT 2 CPG SITES (DIHYDROOROTATE DEHYDROGENASE CG22381196 PFDR = .014; CTNNA3 CG00132141 PFDR = .043) WAS SIGNIFICANTLY ASSOCIATED WITH METS AFTER CONTROLLING FOR MULTIPLE COMPARISONS. INTERACTIONS BETWEEN THE MARGINALLY SIGNIFICANT CPG SITES AND BURDEN SCORES, HOWEVER, WERE NOT SIGNIFICANT. MORE WORK IS REQUIRED IN THIS AREA TO IDENTIFY INTERMEDIATE BIOLOGICAL PATHWAYS INFLUENCED BY ENVIRONMENTAL, GENETIC, AND EPIGENETIC VARIATION THAT MAY EXPLAIN THE HIGH PREVALENCE OF METS AMONG AFRICAN AMERICANS. THIS STUDY DOES SERVE, HOWEVER, AS AN EXAMPLE OF THE USE OF THE GENETIC BURDEN SCORE AS AN ALTERNATIVE DATA ANALYSIS APPROACH FOR COMPLEX STUDIES INVOLVING THE ANALYSIS OF GENETIC AND EPIGENETIC DATA SIMULTANEOUSLY. 2019 9 6137 31 THE EPIGENETICS OF PSYCHOSIS: A STRUCTURED REVIEW WITH REPRESENTATIVE LOCI. THE EVIDENCE FOR AN ENVIRONMENTAL COMPONENT IN CHRONIC PSYCHOTIC DISORDERS IS STRONG AND RESEARCH ON THE EPIGENETIC MANIFESTATIONS OF THESE ENVIRONMENTAL IMPACTS HAS COMMENCED IN EARNEST. IN REVIEWING THIS RESEARCH, THE FOCUS IS ON THREE GENES AS MODELS FOR DIFFERENTIAL METHYLATION, MCHR1, AKT1 AND TDO2, EACH OF WHICH HAVE BEEN INVESTIGATED FOR GENETIC ASSOCIATION WITH PSYCHOTIC DISORDERS. ENVIRONMENTAL FACTORS ASSOCIATED WITH PSYCHOTIC DISORDERS, AND WHICH INTERACT WITH THESE MODEL GENES, ARE EXPLORED IN DEPTH. THE LOCATION OF TRANSCRIPTION FACTOR MOTIFS RELATIVE TO KEY METHYLATION SITES IS EVALUATED FOR PREDICTED GENE EXPRESSION RESULTS, AND FOR OTHER SITES, EVIDENCE IS PRESENTED FOR METHYLATION DIRECTING ALTERNATIVE SPLICING. EXPERIMENTAL RESULTS FROM KEY STUDIES SHOW DIFFERENTIAL METHYLATION: FOR MCHR1, IN PSYCHOSIS CASES VERSUS CONTROLS; FOR AKT1, AS A PRE-EXISTING METHYLATION PATTERN INFLUENCING BRAIN ACTIVATION FOLLOWING ACUTE ADMINISTRATION OF A PSYCHOSIS-ELICITING ENVIRONMENTAL STIMULUS; AND FOR TDO2, IN A PATTERN ASSOCIATED WITH A DEVELOPMENTAL FACTOR OF RISK FOR PSYCHOSIS, IN ALL CASES THE PREDICTED EXPRESSION IMPACT BEING HIGHLY DEPENDENT ON LOCATION. METHYLATION INDUCED BY SMOKING, A CONFOUNDING VARIABLE, EXHIBITS AN INTRIGUING PATTERN FOR ALL THREE GENES. FINALLY, HOW DIFFERENTIAL METHYLATION MESHES WITH DARWINIAN PRINCIPLES IS EXAMINED, IN PARTICULAR AS IT RELATES TO THE "FLEXIBLE STEM" THEORY OF EVOLUTION. 2022 10 4198 33 METABOLIC PROFILING DISTINGUISHES THREE SUBTYPES OF ALZHEIMER'S DISEASE. THE CAUSE OF ALZHEIMER'S DISEASE IS INCOMPLETELY DEFINED, AND NO TRULY EFFECTIVE THERAPY EXISTS. HOWEVER, MULTIPLE STUDIES HAVE IMPLICATED METABOLIC ABNORMALITIES SUCH AS INSULIN RESISTANCE, HORMONAL DEFICIENCIES, AND HYPERHOMOCYSTEINEMIA. OPTIMIZING METABOLIC PARAMETERS IN A COMPREHENSIVE WAY HAS YIELDED COGNITIVE IMPROVEMENT, BOTH IN SYMPTOMATIC AND ASYMPTOMATIC INDIVIDUALS. THEREFORE, EXPANDING THE STANDARD LABORATORY EVALUATION IN PATIENTS WITH DEMENTIA MAY BE REVEALING. HERE I REPORT THAT METABOLIC PROFILING REVEALS THREE ALZHEIMER'S DISEASE SUBTYPES. THE FIRST IS INFLAMMATORY, IN WHICH MARKERS SUCH AS HS-CRP AND GLOBULIN:ALBUMIN RATIO ARE INCREASED. THE SECOND TYPE IS NON-INFLAMMATORY, IN WHICH THESE MARKERS ARE NOT INCREASED, BUT OTHER METABOLIC ABNORMALITIES ARE PRESENT. THE THIRD TYPE IS A VERY DISTINCTIVE CLINICAL ENTITY THAT AFFECTS RELATIVELY YOUNG INDIVIDUALS, EXTENDS BEYOND THE TYPICAL ALZHEIMER'S DISEASE INITIAL DISTRIBUTION TO AFFECT THE CORTEX WIDELY, IS CHARACTERIZED BY EARLY NON-AMNESTIC FEATURES SUCH AS DYSCALCULIA AND APHASIA, IS OFTEN MISDIAGNOSED OR LABELED ATYPICAL ALZHEIMER'S DISEASE, TYPICALLY AFFECTS APOE4-NEGATIVE INDIVIDUALS, AND IS ASSOCIATED WITH STRIKING ZINC DEFICIENCY. GIVEN THE INVOLVEMENT OF ZINC IN MULTIPLE ALZHEIMER'S-RELATED METABOLIC PROCESSES, SUCH AS INSULIN RESISTANCE, CHRONIC INFLAMMATION, ADAM10 PROTEOLYTIC ACTIVITY, AND HORMONAL SIGNALING, THIS SYNDROME OF ALZHEIMER'S-PLUS WITH LOW ZINC (APLZ) WARRANTS FURTHER METABOLIC, GENETIC, AND EPIGENETIC CHARACTERIZATION. 2015 11 6226 24 THE LINK BETWEEN EPIGENETICS, PAIN SENSITIVITY AND CHRONIC PAIN. INCREASING EVIDENCE SUGGESTS AN ASSOCIATION BETWEEN GENE EXPRESSION AND CLINICAL PAIN. EPIGENETIC MODIFICATIONS ARE THE MAIN MODULATORS OF GENE EXPRESSION OR PROTEIN TRANSLATION IN RESPONSE TO ENVIRONMENTAL STIMULI AND PATHOPHYSIOLOGICAL CONDITIONS. PRECLINICAL AND CLINICAL STUDIES INDICATE THAT EPIGENETIC MODIFICATIONS COULD ALSO IMPACT THE DEVELOPMENT OF PAIN, THE TRANSITION FROM ACUTE TO CHRONIC PAIN, AND THE MAINTENANCE HEREOF. 2022 12 5087 31 PIMECROLIMUS FOR THE TREATMENT OF ATOPIC DERMATITIS IN INFANTS: AN ASIAN PERSPECTIVE. ATOPIC DERMATITIS (AD) IS A COMMON CHRONIC, MULTISYSTEM INFLAMMATORY SKIN DISEASE IN PEDIATRIC PATIENTS. THERE HAS BEEN AN INCREASE IN THE INCIDENCE OF AD IN THE PEDIATRIC POPULATION OF THE ASIA-PACIFIC REGION. STUDIES HAVE SHOWN THAT GENETIC, EPIGENETIC, ENVIRONMENTAL AND CULTURAL FACTORS MAY LEAD TO DIFFERENCES IN THE CLINICAL MANIFESTATION AND PREVALENCE OF AD BETWEEN RACES. EARLY TREATMENT OF AD IS NECESSARY TO PREVENT THE ATOPIC MARCH LEADING TO COMORBIDITIES SUCH AS ASTHMA AND ALLERGIC RHINITIS. TOPICAL CORTICOSTEROIDS (TCS) ARE USED AS FIRST-LINE THERAPY FOR THE TREATMENT OF AD, BUT THEIR LONG-TERM USAGE POSES A RISK TO THE PATIENT'S HEALTH. PIMECROLIMUS (1%) IS A TOPICAL CALCINEURIN INHIBITOR (TCI) THAT IS INDICATED FOR THE TREATMENT OF MILD TO MODERATE AD. PIMECROLIMUS HAS NO APPARENT INCREASE IN ADVERSE EVENTS COMPARED TO TCS, AND IT CAUSES LESS OF A BURNING SENSATION THAN TACROLIMUS. THE SAFETY AND EFFICACY OF PIMECROLIMUS HAS BEEN ESTABLISHED THROUGH VARIOUS CLINICAL TRIALS; YET, IN MANY ASIAN COUNTRIES, THE USE OF PIMECROLIMUS IN INFANTS IS STILL RESTRICTED DUE TO SAFETY CONCERNS. BASED ON THE AVAILABLE EVIDENCE, THE EXPERT PANEL RECOMMENDS PIMECROLIMUS IN INFANTS BETWEEN 3 MONTHS AND 2 YEARS OF AGE IN THE ASIAN POPULATION. 2023 13 686 32 BRAIN-SPECIFIC GENES CONTRIBUTE TO CHRONIC BUT NOT TO ACUTE BACK PAIN. INTRODUCTION: BACK PAIN IS THE LEADING CAUSE OF DISABILITY WORLDWIDE. ALTHOUGH MOST BACK PAIN CASES ARE ACUTE, 20% OF ACUTE PAIN PATIENTS EXPERIENCE CHRONIC BACK PAIN SYMPTOMS. IT IS UNCLEAR WHETHER ACUTE PAIN AND CHRONIC PAIN HAVE SIMILAR OR DISTINCT UNDERLYING GENETIC MECHANISMS. OBJECTIVES: TO CHARACTERIZE THE MOLECULAR AND CELLULAR PATHWAYS CONTRIBUTING TO ACUTE AND CHRONIC PAIN STATES. METHODS: CROSS-SECTIONAL OBSERVATIONAL GENOME-WIDE ASSOCIATION STUDY. RESULTS: A TOTAL OF 375,158 INDIVIDUALS FROM THE UK BIOBANK COHORT WERE INCLUDED IN THE DISCOVERY OF GENOME-WIDE ASSOCIATION STUDY. OF THOSE, 70,633 (19%) AND 32,209 (9%) INDIVIDUALS MET THE DEFINITION OF CHRONIC AND ACUTE BACK PAIN, RESPECTIVELY. A TOTAL OF 355 SINGLE NUCLEOTIDE POLYMORPHISM GROUPED INTO 13 LOCI REACHED THE GENOME-WIDE SIGNIFICANCE THRESHOLD (5X10(-8)) FOR CHRONIC BACK PAIN, BUT NONE FOR ACUTE. OF THESE, 7 LOCI WERE REPLICATED IN THE NORD-TRONDELAG HEALTH STUDY (HUNT) COHORT (19,760 CHRONIC LOW BACK PAIN CASES AND 28,674 PAIN-FREE CONTROLS). SINGLE NUCLEOTIDE POLYMORPHISM HERITABILITY WAS 4.6% (P=1.4X10(-78)) FOR CHRONIC BACK PAIN AND 0.81% (P=1.4X10-8) FOR ACUTE BACK PAIN. SIMILAR DIFFERENCES IN HERITABILITY ESTIMATES BETWEEN ACUTE AND CHRONIC BACK PAIN WERE FOUND IN THE HUNT COHORT: 3.4% (P=0.0011) AND 0.6% (P=0.851), RESPECTIVELY. PATHWAY ANALYSES, TISSUE-SPECIFIC HERITABILITY ENRICHMENT ANALYSES, AND EPIGENETIC CHARACTERIZATION SUGGEST A SUBSTANTIAL GENETIC CONTRIBUTION TO CHRONIC BUT NOT ACUTE BACK PAIN FROM THE LOCI PREDOMINANTLY EXPRESSED IN THE CENTRAL NERVOUS SYSTEM. CONCLUSION: CHRONIC BACK PAIN IS SUBSTANTIALLY MORE HERITABLE THAN ACUTE BACK PAIN. THIS HERITABILITY IS MOSTLY ATTRIBUTED TO GENES EXPRESSED IN THE BRAIN. 2022 14 4926 41 PARKINSON'S DISEASE AND SARS-COV-2 INFECTION: PARTICULARITIES OF MOLECULAR AND CELLULAR MECHANISMS REGARDING PATHOGENESIS AND TREATMENT. ACCUMULATING DATA SUGGEST THAT CHRONIC NEUROINFLAMMATION-MEDIATED NEURODEGENERATION IS A SIGNIFICANT CONTRIBUTING FACTOR FOR PROGRESSIVE NEURONAL AND GLIAL CELL DEATH IN AGE-RELATED NEURODEGENERATIVE PATHOLOGY. FURTHERMORE, IT COULD BE ENCOUNTERED AS LONG-TERM CONSEQUENCES IN SOME VIRAL INFECTIONS, INCLUDING POST-COVID-19 PARKINSONISM-RELATED CHRONIC SEQUELAE. THE CURRENT SYSTEMATIC REVIEW IS FOCUSED ON A RECENT QUESTION AROUSED DURING THE PANDEMIC'S SUCCESSIVE WAVES: ARE THERE POST-SARS-COV-2 IMMUNE-MEDIATED REACTIONS RESPONSIBLE FOR PROMOTING NEURODEGENERATION? DOES THE HOST'S DYSREGULATED IMMUNE COUNTER-OFFENSIVE CONTRIBUTE TO THE PATHOGENESIS OF NEURODEGENERATIVE DISEASES, EMERGING AS PARKINSON'S DISEASE, IN A COMPLEX INTERRELATION BETWEEN GENETIC AND EPIGENETIC RISK FACTORS? A SYNTHETIC AND SYSTEMATIC LITERATURE REVIEW WAS ACCOMPLISHED BASED ON THE "PREFERRED REPORTING ITEMS FOR SYSTEMATIC PRINCIPLES REVIEWS AND META-ANALYSES" (PRISMA) METHODOLOGY, INCLUDING REGISTRATION ON THE SPECIFIC ONLINE PLATFORM: INTERNATIONAL PROSPECTIVE REGISTER OF SYSTEMATIC REVIEWS-PROSPERO, NO. 312183. INITIALLY, 1894 ARTICLES WERE DETECTED. AFTER FULFILLING THE FIVE STEPS OF THE SELECTION METHODOLOGY, 104 PAPERS WERE SELECTED FOR THIS SYNTHETIC REVIEW. DOCUMENTATION WAS ENHANCED WITH A SUPPLEMENTARY 47 BIBLIOGRAPHIC RESOURCES IDENTIFIED IN THE LITERATURE WITHIN A NON-STANDARDIZED SEARCH CONNECTED TO THE SUBJECT. AS A FINAL STEP OF THE PRISMA METHOD, WE HAVE FULFILLED A POPULATION-INTERVENTION-COMPARISON-OUTCOME-TIME (PICOT)/POPULATION-INTERVENTION-COMPARISON-OUTCOME-STUDY TYPE (PICOS)-BASED METANALYSIS OF CLINICAL TRIALS IDENTIFIED AS CONNECTED TO OUR SEARCH, TARGETING THE OUTCOMES OF REHABILITATIVE KINESITHERAPEUTIC INTERVENTIONS COMPARED TO CLINICAL APPROACHES LACKING SUCH KIND OF TREATMENT. ACCORDINGLY, WE IDENTIFIED 10 CLINICAL TRIALS RELATED TO OUR ARTICLE. THE MULTI/INTERDISCIPLINARY CONVENTIONAL THERAPY OF PARKINSON'S DISEASE AND NON-CONVENTIONAL MULTITARGET APPROACH TO AN INTEGRATIVE TREATMENT WAS BRIEFLY ANALYZED. THIS ARTICLE SYNTHESIZES THE CURRENT FINDINGS ON THE PATHOGENIC INTERFERENCE BETWEEN THE DYSREGULATED COMPLEX MECHANISMS INVOLVED IN AGING, NEUROINFLAMMATION, AND NEURODEGENERATION, FOCUSING ON PARKINSON'S DISEASE AND THE ACUTE AND CHRONIC REPERCUSSIONS OF COVID-19. TIME WILL TELL WHETHER COVID-19 NEUROINFLAMMATORY EVENTS COULD TRIGGER LONG-TERM NEURODEGENERATIVE EFFECTS AND CONTRIBUTE TO THE WORSENING AND/OR EXPLOSION OF NEW CASES OF PD. THE EXTENT OF THE INTERRELATED NEUROPATHOGENIC PHENOMENON REMAINS OBSCURE, SO FURTHER CLINICAL OBSERVATIONS AND PROSPECTIVE LONGITUDINAL COHORT STUDIES ARE NEEDED. 2022 15 4522 37 MULTIDIMENSIONAL EVALUATION OF THE PAIN PROFILE AS PROGNOSTIC FACTOR IN INDIVIDUALS WITH HIP OR KNEE OSTEOARTHRITIS RECEIVING TOTAL JOINT REPLACEMENT: PROTOCOL OF A 2-YEAR LONGITUDINAL PROGNOSTIC COHORT STUDY. INTRODUCTION: KNEE AND HIP OSTEOARTHRITIS ARE TWO HIGHLY PREVALENT MUSCULOSKELETAL PAIN CONDITIONS. UNSUCCESSFUL RATES AFTER HIP/KNEE REPLACEMENT RANGE FROM 10% TO 20%. SUBJECTS WITH SENSITISATION MANIFESTATIONS ARE VULNERABLE TO WORSE CLINICAL OUTCOMES. MOST STUDIES HAVE ANALYSED OUTCOMES UP TO 1 YEAR AFTER SURGERY. THE AIM OF THIS 2-YEAR LONGITUDINAL STUDY WILL BE TO EVALUATE SENSORY-RELATED, PSYCHOLOGICAL AND PSYCHOPHYSICAL PAIN SENSITISATION MANIFESTATIONS AND A POTENTIAL EPIGENETIC BIOMARKER AS PROGNOSTIC CLINICAL OUTCOMES FOR THE DEVELOPMENT OF CHRONIC POSTOPERATIVE PAIN AFTER KNEE OR HIP REPLACEMENT. METHODS AND ANALYSIS: A PROSPECTIVE LONGITUDINAL STUDY WITH A 2-YEAR FOLLOW-UP PERIOD WILL BE CONDUCTED. THE PROGNOSTIC VARIABLES WILL INCLUDE PAIN, FUNCTION, RELATED-DISABILITY, ANXIETY, DEPRESSION, QUALITY OF LIFE, SENSITISATION-ASSOCIATED SYMPTOMS, KINESIOPHOBIA, NEUROPATHIC PAIN AND CATASTROPHISING, AND EXPECTATIVE OF THE INTERVENTION WILL BE ASSESSED BEFORE SURGERY. WE WILL ALSO EVALUATE THE PRESENCE OF THE VAL158MET POLYMORPHISM AS A POSSIBLE EPIGENETIC MARKER. CLINICAL OUTCOMES INCLUDING PAIN, RELATED-DISABILITY AND SELF-PERCEIVED SATISFACTION, SENSITISATION-ASSOCIATED SYMPTOMS AND NEUROPATHIC PAIN WILL BE ASSESSED 3, 6, 12, 18 AND 24 MONTHS AFTER SURGERY. THESE VARIABLES WILL BE USED TO CONSTRUCT THREE PREDICTION MODELS: (1) PAIN AND FUNCTION, (2) SENSITISATION-ASSOCIATED SYMPTOMATOLOGY AND (3) NEUROPATHIC PAIN FEATURES CLASSIFYING THOSE PATIENTS IN RESPONDERS AND NON-RESPONDERS. DATA FROM KNEE OR HIP OSTEOARTHRITIS WILL BE ANALYSED SEPARATELY. STATISTICAL ANALYSES WILL BE CONDUCTED WITH LOGISTIC REGRESSIONS. ETHICS AND DISSEMINATION: THE STUDY HAS BEEN APPROVED BY THE ETHICS COMMITTEE OF BOTH INSTITUTIONS INVOLVED (HOSPITAL UNIVERSITARIO FUNDACION ALCORCON (HUFA) 19-141 AND UNIVERSIDAD REY JUAN CARLOS (URJC) 0312201917319). PARTICIPANTS WILL SIGN THE WRITTEN INFORMED CONSENT BEFORE THEIR INCLUSION. STUDY RESULTS WILL BE DISSEMINATED THROUGH PEER-REVIEWED PUBLICATIONS AND PRESENTATIONS AT SCIENTIFIC MEETINGS. 2023 16 4509 34 MSELENI JOINT DISEASE: A POTENTIAL MODEL OF EPIGENETIC CHONDRODYSPLASIA. OBJECTIVE: IN THIS PAPER PAST RESEARCH ON THE NATURAL HISTORY OF MSELENI JOINT DISEASE, A CRIPPLING ENDEMIC OSTEOARTHRITIS, ITS SOCIO-ECONOMIC IMPACTS, THE DEMOGRAPHICS, DIET, GEOLOGY AND THE GENETIC BACKGROUND OF AFFECTED PEOPLE ARE REVIEWED. IN ADDITION, SOME NEW RESEARCH IDEAS ARE SUGGESTED TO CONTINUE THE SEARCH FOR ETIOLOGICAL AVENUES FOR THIS DISEASE SUCH AS STABLE ISOTOPE ANALYSIS AND EPIGENETIC MECHANISMS. RESULTS: MSELENI JOINT DISEASE IS A CHONDRODYSPLASIA FIRST DESCRIBED IN 1970. IT IS GEOGRAPHICALLY CONFINED TO A REMOTE AREA IN THE MAPUTALAND REGION IN NORTHERN KWAZULU NATAL, SOUTH AFRICA. THIS DISEASE AFFECTS MOST JOINTS BUT PRIMARILY THOSE OF THE HIP; IT IS A PROGRESSIVE CONDITION BEGINNING WITH PAIN AND STIFFNESS UNTIL THE PATIENT'S ABILITY TO WALK BECOMES COMPROMISED. MSELENI JOINT DISEASE IS CHARACTERIZED BY TWO DISTINCT ABNORMALITIES, PROTRUSIO ACETABULI THAT MAINLY AFFECTS FEMALES AND INCREASES IN FREQUENCY WITH AGE, AND HIP DYSPLASIA THAT IS MORE FREQUENT WITH AGE. MUCH RESEARCH HAS BEEN CONDUCTED ON THE PEOPLE WITH THE DISEASE AND THEIR SURROUNDING ENVIRONMENT. CONCLUSION: DESPITE INTENSIVE INVESTIGATIONS INTO THE ETIOLOGY OF MSELENI JOINT DISEASE, IT REMAINS UNKNOWN. AS A RESULT THE EXAMINATION OF EPIGENETIC MECHANISMS AND STABLE ISOTOPE ANALYSIS OF TEETH ARE SUGGESTED AS A MEANS OF PROVIDING INFORMATION ON THE ETIOLOGY OF THE DISEASE. THESE METHODS CAN ALSO BE APPLIED TO OTHER CHONDROPLASIAS OF UNKNOWN ETIOLOGY. 2010 17 5038 26 PHARMACOGENETICS OF CHRONIC PAIN AND ITS TREATMENT. THIS PAPER REVIEWS THE IMPACT OF GENETIC VARIABILITY OF DRUG METABOLIZING ENZYMES, TRANSPORTERS, RECEPTORS, AND PATHWAYS INVOLVED IN CHRONIC PAIN PERCEPTION ON THE EFFICACY AND SAFETY OF ANALGESICS AND OTHER DRUGS USED FOR CHRONIC PAIN TREATMENT. SEVERAL CANDIDATE GENES HAVE BEEN IDENTIFIED IN THE LITERATURE, WHILE THERE IS USUALLY ONLY LIMITED CLINICAL EVIDENCE SUBSTANTIATING FOR THE PENETRATION OF THE TESTING FOR THESE CANDIDATE BIOMARKERS INTO THE CLINICAL PRACTICE. FURTHER, THE PAIN-PERCEPTION REGULATION AND MODULATION ARE STILL NOT FULLY UNDERSTOOD, AND THUS MORE COMPLEX KNOWLEDGE OF GENETIC AND EPIGENETIC BACKGROUND FOR ANALGESIA WILL BE NEEDED PRIOR TO THE CLINICAL USE OF THE CANDIDATE GENETIC BIOMARKERS. 2013 18 5037 40 PHARMACOGENETICS IN PAIN TREATMENT. PAIN IS AN UNPLEASANT FEELING USUALLY RESULTING FROM TISSUE DAMAGE THAT CAN PERSIST ALONG WEEKS, MONTHS, OR EVEN YEARS AFTER THE INJURY, TURNING INTO PATHOLOGICAL CHRONIC PAIN, THE LEADING CAUSE OF DISABILITY. CURRENTLY, PHARMACOLOGY INTERVENTIONS ARE USUALLY THE FIRST-LINE THERAPY BUT THERE IS A HIGHLY VARIABLE ANALGESIC DRUG RESPONSE. PHARMACOGENETICS (PGX) OFFERS A MEANS TO IDENTIFY GENETIC BIOMARKERS THAT CAN PREDICT INDIVIDUAL ANALGESIC RESPONSE OPENING DOORS TO PRECISION MEDICINE. PGX ANALYZE THE WAY IN WHICH THE PRESENCE OF VARIATIONS IN THE DNA SEQUENCE (SINGLE-NUCLEOTIDE POLYMORPHISMS, SNPS) COULD BE RESPONSIBLE FOR PORTIONS OF THE POPULATION REACHING DIFFERENT LEVELS OF PAIN RELIEF (PHENOTYPE) DUE TO GENE INTERFERENCE IN THE DRUG MECHANISM OF ACTION (PHARMACODYNAMICS) AND/OR ITS CONCENTRATION AT THE PLACE OF ACTION (PHARMACOKINETICS). SNPS IN THE CYTOCHROME P450 ENZYMES GENES (CYP2D6) INFLUENCE METABOLISM OF CODEINE, TRAMADOL, HYDROCODONE, OXYCODONE, AND TRICYCLIC ANTIDEPRESSANTS. BLOOD CONCENTRATIONS OF SOME NSAIDS DEPEND ON CYP2C9 AND/OR CYP2C8 ACTIVITY. ADDITIONAL CANDIDATE GENES ENCODE FOR OPIOID RECEPTORS, TRANSPORTERS, AND OTHER MOLECULES IMPORTANT FOR PHARMACOTHERAPY IN PAIN MANAGEMENT. HOWEVER, PGX STUDIES ARE OFTEN CONTRADICTORY, SLOWING THE UPTAKE OF THIS INFORMATION. THIS IS LIKELY DUE, IN LARGE PART, TO A LACK OF ROBUST EVIDENCE DEMONSTRATING CLINICAL UTILITY AND TO ITS POLYGENIC RESPONSE MODULATED BY OTHER EXOGENOUS OR EPIGENETICS FACTORS. NOVEL THERAPIES, INCLUDING TARGETING OF EPIGENETIC CHANGES AND GENE THERAPY-BASED APPROACHES, BROADEN FUTURE OPTIONS TO IMPROVE UNDERSTANDING OF PAIN AND THE TREATMENT OF PEOPLE WHO SUFFER IT. 2018 19 5464 24 RESILIENCE IN LONG-TERM VIRAL INFECTION: GENETIC DETERMINANTS AND INTERACTIONS. VIRUS-INDUCED NEUROLOGICAL SEQUELAE RESULTING FROM INFECTION BY THEILER'S MURINE ENCEPHALOMYELITIS VIRUS (TMEV) ARE USED FOR STUDYING HUMAN CONDITIONS RANGING FROM EPILEPTIC SEIZURES TO DEMYELINATING DISEASE. MOUSE STRAINS ARE TYPICALLY CONSIDERED SUSCEPTIBLE OR RESISTANT TO TMEV INFECTION BASED ON VIRAL PERSISTENCE AND EXTREME PHENOTYPES, SUCH AS DEMYELINATION. WE HAVE IDENTIFIED A BROADER SPECTRUM OF PHENOTYPIC OUTCOMES BY INFECTING STRAINS OF THE GENETICALLY DIVERSE COLLABORATIVE CROSS (CC) MOUSE RESOURCE. WE EVALUATED THE CHRONIC-INFECTION GENE EXPRESSION PROFILES OF HIPPOCAMPI AND THORACIC SPINAL CORDS FOR 19 CC STRAINS IN RELATION TO PHENOTYPIC SEVERITY AND TMEV PERSISTENCE. STRAINS WERE CLUSTERED BASED ON SIMILAR PHENOTYPIC PROFILES AND TMEV LEVELS AT 90 DAYS POST-INFECTION, AND WE CATEGORIZED DISTINCT TMEV RESPONSE PROFILES. THE THREE MOST COMMON PROFILES INCLUDED "RESISTANT" AND "SUSCEPTIBLE," AS BEFORE, AS WELL AS A "RESILIENT" TMEV RESPONSE GROUP WHICH EXPERIENCED BOTH TMEV PERSISTENCE AND MILD NEUROLOGICAL PHENOTYPES EVEN AT 90 DAYS POST-INFECTION. EACH PROFILE HAD A DISTINCT GENE EXPRESSION SIGNATURE, ALLOWING THE IDENTIFICATION OF PATHWAYS AND NETWORKS SPECIFIC TO EACH TMEV RESPONSE GROUP. CC FOUNDER HAPLOTYPES FOR GENES INVOLVED IN THESE PATHWAYS/NETWORKS REVEALED CANDIDATE RESPONSE-SPECIFIC ALLELES. THESE ALLELES DEMONSTRATED PLEIOTROPY AND EPIGENETIC (MIRNA) REGULATION IN LONG-TERM TMEV INFECTION, WITH PARTICULAR RELEVANCE FOR RESILIENT MOUSE STRAINS. 2021 20 3851 41 IS IRRITABLE BOWEL SYNDROME OUT OF DATE AND MISLEADING AS A DIAGNOSIS? AIM: THIS STUDY AIMED AT ASSESSING THE EFFICACY OF TARGETED INTERVENTIONS ADDRESSING COMMON FOOD SENSITIVITIES AND LIFESTYLE FACTORS THAT COMMONLY CONTRIBUTE TO THE PRESENTATION OF GASTROINTESTINAL PROBLEMS IDENTIFIED AS IRRITABLE BOWEL SYNDROME (IBS). BACKGROUND: IBS HAS SERVED TO COVER THE EXPRESSION OF MULTIFACTORIAL DISORDERS WITH VARIABLE AETIOLOGY AND PATHOPHYSIOLOGY. FOOD ANTIGENS IMPLICATED IN THE MODERN LIFESTYLE, ACTING AS STRONG EPIGENETIC FACTORS IS STRONGLY IMPLICATED IN PATHOPHYSIOLOGY OF CONDITIONS UNDER IBS. IDENTIFYING AND ADDRESSING FOOD SENSITIVITIES IN PATIENTS PRESENTING WITH IBS LIKE SYMPTOMS ARE CURRENTLY UNDEREMPHASISED IN CLINICAL GUIDELINES YET HAVE THE POTENTIAL TO PROVIDE MAJOR BENEFITS FOR PATIENTS. METHODS: INFORMATION WAS COLLECTED FROM THE MEDICAL RECORDS OF PATIENTS THAT WERE REFERRED TO THE GASTROENTEROLOGY UNIT OF PALMERSTON NORTH DHB WITH UNEXPLAINED GASTROINTESTINAL (GI) SYMPTOMS WITH OR WITHOUT OTHER GI COMORBIDITIES BETWEEN SEPTEMBER 2018 AND NOVEMBER 2021. RESULTS: THE MAIN MANAGEMENT OPTION OFFERED TO THE 121 PATIENTS INCLUDED IN THIS STUDY, WAS LIFESTYLE ADJUSTMENT AND/OR A TRIAL OF 6 WEEKS, ELIMINATING GLUTEN AND LACTOSE FROM THE DIET. THE MOST PREVALENT SYMPTOMS WERE ABDOMINAL PAIN 96/121 (79%), DIARRHOEA 83/121 (69%), FOLLOWED BY BLOATING AND CONSTIPATION. SEVENTY-EIGHT PATIENTS HAD THE OUTCOMES OF THEIR IMPROVEMENT AVAILABLE. A TOTAL OF 42 OUT OF 78 PATIENTS (54%) WERE TREATED EXCLUSIVELY WITH GLUTEN AND LACTOSE-FREE DIET, IN THIS GROUP OF PATIENTS 86% (36/42) REPORTED A SIGNIFICANT IMPROVEMENT IN THEIR SYMPTOMS WITH A SCORE IN THE RANGE OF 40-100%. CONCLUSION: OUR STUDY ILLUSTRATES THE IMPORTANCE OF FOCUSING ON TRIGGERING FACTORS WHEN ASSESSING PATIENTS WITH IBS. WE SUGGEST THAT CAREFUL IDENTIFYING AND ELIMINATING THE TRIGGERING FOOD ANTIGENS AS MONOTHERAPY OR IN ADDITION TO THE LIFESTYLE ADJUSTMENT WHERE APPROPRIATE SHOULD BE THE MAIN OBJECTIVE IN SYMPTOMATIC PATIENTS FULFILLING THE IBS DIAGNOSTIC CRITERIA. THESE COMBINATIONS AND HOLISTIC APPROACH IN TREATING IBS' PATIENTS' SYMPTOMS ARE LESS EXPENSIVE, NON-TOXIC, AND HIGHLY EFFECTIVE IN ACHIEVING OPTIMAL OUTCOMES AND IMPROVING THESE PATIENT'S QUALITY OF LIFE. 2023