The impact of adverse childhood experiences on multimorbidity: a systematic review and meta-analysis.

BACKGROUND: Adverse childhood experiences (ACEs) have been implicated in the aetiology of a range of health outcomes, including multimorbidity. In this systematic review and meta-analysis, we aimed to identify, synthesise, and quantify the current evidence linking ACEs and multimorbidity. METHODS: We searched seven databases from inception to 20 July 2023: APA PsycNET, CINAHL Plus, Cochrane CENTRAL, Embase, MEDLINE, Scopus, and Web of Science. We selected studies investigating adverse events occurring during childhood (< 18 years) and an assessment of multimorbidity in adulthood (≥ 18 years). Studies that only assessed adverse events in adulthood or health outcomes in children were excluded. Risk of bias was assessed using the ROBINS-E tool. Meta-analysis of prevalence and dose-response meta-analysis methods were used for quantitative data synthesis. This review was pre-registered with PROSPERO (CRD42023389528). RESULTS: From 15,586 records, 25 studies were eligible for inclusion (total participants = 372,162). The prevalence of exposure to ≥ 1 ACEs was 48.1% (95% CI 33.4 to 63.1%). The prevalence of multimorbidity was 34.5% (95% CI 23.4 to 47.5%). Eight studies provided sufficient data for dose-response meta-analysis (total participants = 197,981). There was a significant dose-dependent relationship between ACE exposure and multimorbidity (p < 0.001), with every additional ACE exposure contributing to a 12.9% (95% CI 7.9 to 17.9%) increase in the odds for multimorbidity. However, there was heterogeneity among the included studies (I2 = 76.9%, Cochran Q = 102, p < 0.001). CONCLUSIONS: This is the first systematic review and meta-analysis to synthesise the literature on ACEs and multimorbidity, showing a dose-dependent relationship across a large number of participants. It consolidates and enhances an extensive body of literature that shows an association between ACEs and individual long-term health conditions, risky health behaviours, and other poor health outcomes.

Impact of adverse childhood experiences on analgesia-related outcomes: a systematic review.

BACKGROUND: There is well-established evidence linking adverse childhood experiences (ACEs) and chronic pain in adulthood. It is less clear how ACE exposure might influence the response to chronic pain treatment. In this systematic review, we synthesise the literature assessing the impact of ACE exposure on outcomes relating to the use, benefits, and harms of analgesic medications (analgesia-related outcomes). METHODS: We searched seven databases from inception to September 26, 2023, for studies investigating adverse events in childhood (<18 yr) and any analgesia-related outcome during adulthood (≥18 yr). Title/abstract screening, full-text review, data extraction, and risk of bias assessment were performed independently by two authors. Given the high degree of study heterogeneity, a narrative synthesis was performed. RESULTS: From 7531 records, 66 studies met inclusion criteria, involving 137 395 participants. Analgesia-related outcomes were classed into six categories: use of analgesics (n=12), analgesic side-effects (n=4), substance misuse (n=45), lifetime drug overdose (n=2), endogenous pain signalling (n=4), and other outcomes (n=2). No studies assessed the effect of ACE exposure on the potential benefits of analgesics. ACE exposure was associated with greater use of analgesic medication, higher incidence of analgesic medication side-effects, greater risk and severity of substance misuse, greater risk of drug overdose, and greater risk of attempted suicide in opioid dependency. CONCLUSIONS: Adverse childhood experience exposure is associated with poor analgesia-related outcomes, so individual assessment adverse childhood experiences is important when considering the treatment of chronic pain. However, significant gaps in the literature remain, especially relating to the use and harms of non opioid analgesics. SYSTEMATIC REVIEW PROTOCOL: CRD42023389870 (PROSPERO).

Sex-stratified genome-wide association study of multisite chronic pain in UK Biobank.

Chronic pain is highly prevalent worldwide and imparts a significant socioeconomic and public health burden. Factors influencing susceptibility to, and mechanisms of, chronic pain development, are not fully understood, but sex is thought to play a significant role, and chronic pain is more prevalent in women than in men. To investigate sex differences in chronic pain, we carried out a sex-stratified genome-wide association study of Multisite Chronic Pain (MCP), a derived chronic pain phenotype, in UK Biobank on 178,556 men and 209,093 women, as well as investigating sex-specific genetic correlations with a range of psychiatric, autoimmune and anthropometric phenotypes and the relationship between sex-specific polygenic risk scores for MCP and chronic widespread pain. We also assessed whether MCP-associated genes showed expression pattern enrichment across tissues. A total of 123 SNPs at five independent loci were significantly associated with MCP in men. In women, a total of 286 genome-wide significant SNPs at ten independent loci were discovered. Meta-analysis of sex-stratified GWAS outputs revealed a further 87 independent associated SNPs. Gene-level analyses revealed sex-specific MCP associations, with 31 genes significantly associated in females, 37 genes associated in males, and a single gene, DCC, associated in both sexes. We found evidence for sex-specific pleiotropy and risk for MCP was found to be associated with chronic widespread pain in a sex-differential manner. Male and female MCP were highly genetically correlated, but at an rg of significantly less than 1 (0.92). All 37 male MCP-associated genes and all but one of 31 female MCP-associated genes were found to be expressed in the dorsal root ganglion, and there was a degree of enrichment for expression in sex-specific tissues. Overall, the findings indicate that sex differences in chronic pain exist at the SNP, gene and transcript abundance level, and highlight possible sex-specific pleiotropy for MCP. Results support the proposition of a strong central nervous-system component to chronic pain in both sexes, additionally highlighting a potential role for the DRG and nociception.

Age and cancer type: associations with increased odds of receiving a late diagnosis in people with advanced cancer.

PURPOSE: In order to deliver appropriate and timely care planning and minimise avoidable late diagnoses, clinicians need to be aware of which patients are at higher risk of receiving a late cancer diagnosis. We aimed to determine which demographic and clinical factors are associated with receiving a 'late' cancer diagnosis (within the last 12 weeks of life). METHOD: Retrospective cohort study of 2,443 people who died from cancer ('cancer decedents') in 2013-2015. Demographic and cancer registry datasets linked using patient-identifying Community Health Index numbers. Analysis used binary logistic regression, with univariate and adjusted odds ratios (SPSS v25). RESULTS: One third (n = 831,34.0%) received a late diagnosis. Age and cancer type were significantly associated with late cancer diagnosis (p < 0.001). Other demographic factors were not associated with receiving a late diagnosis. Cancer decedents with lung cancer (Odds Ratios presented in abstract are the inverse of those presented in the main text, where lung cancer is the reference category. Presented as 1/(OR multivariate)) were more likely to have late diagnosis than those with bowel (95% Confidence Interval [95%CI] Odds Ratio (OR)1.52 (OR1.12 to 2.04)), breast or ovarian (95%CI OR3.33 (OR2.27 to 5.0) or prostate (95%CI OR9.09 (OR4.0 to 20.0)) cancers. Cancer decedents aged > 85 years had higher odds of late diagnosis (95%CI OR3.45 (OR2.63 to 4.55)), compared to those aged < 65 years. CONCLUSIONS: Cancer decedents who were older and those with lung cancer were significantly more likely to receive late cancer diagnoses than those who were younger or who had other cancer types.

Joint European Academy of Neurology-European Pain Federation-Neuropathic Pain Special Interest Group of the International Association for the Study of Pain guidelines on neuropathic pain assessment.

BACKGROUND AND PURPOSE: In these guidelines, we aimed to develop evidence-based recommendations for the use of screening questionnaires and diagnostic tests in patients with neuropathic pain (NeP). METHODS: We systematically reviewed studies providing information on the sensitivity and specificity of screening questionnaires, and quantitative sensory testing, neurophysiology, skin biopsy, and corneal confocal microscopy. We also analysed how functional neuroimaging, peripheral nerve blocks, and genetic testing might provide useful information in diagnosing NeP. RESULTS: Of the screening questionnaires, Douleur Neuropathique en 4 Questions (DN4), I-DN4 (self-administered DN4), and Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) received a strong recommendation, and S-LANSS (self-administered LANSS) and PainDETECT weak recommendations for their use in the diagnostic pathway for patients with possible NeP. We devised a strong recommendation for the use of skin biopsy and a weak recommendation for quantitative sensory testing and nociceptive evoked potentials in the NeP diagnosis. Trigeminal reflex testing received a strong recommendation in diagnosing secondary trigeminal neuralgia. Although many studies support the usefulness of corneal confocal microscopy in diagnosing peripheral neuropathy, no study specifically investigated the diagnostic accuracy of this technique in patients with NeP. Functional neuroimaging and peripheral nerve blocks are helpful in disclosing pathophysiology and/or predicting outcomes, but current literature does not support their use for diagnosing NeP. Genetic testing may be considered at specialist centres, in selected cases. CONCLUSIONS: These recommendations provide evidence-based clinical practice guidelines for NeP diagnosis. Due to the poor-to-moderate quality of evidence identified by this review, future large-scale, well-designed, multicentre studies assessing the accuracy of diagnostic tests for NeP are needed.

A genome-wide association study finds genetic variants associated with neck or shoulder pain in UK Biobank.

BACKGROUND: Common types of musculoskeletal conditions include pain in the neck and shoulder areas. This study seeks to identify the genetic variants associated with neck or shoulder pain based on a genome-wide association approach using 203 309 subjects from the UK Biobank cohort and look for replication evidence from the Generation Scotland: Scottish Family Health Study (GS:SFHS) and TwinsUK. METHODS: A genome-wide association study was performed adjusting for age, sex, BMI and nine population principal components. Significant and independent genetic variants were then sent to GS:SFHS and TwinsUK for replication. RESULTS: We identified three genetic loci that were associated with neck or shoulder pain in the UK Biobank samples. The most significant locus was in an intergenic region in chromosome 17, rs12453010, having P = 1.66 × 10-11. The second most significant locus was located in the FOXP2 gene in chromosome 7 with P = 2.38 × 10-10 for rs34291892. The third locus was located in the LINC01572 gene in chromosome 16 with P = 4.50 × 10-8 for rs62053992. In the replication stage, among four significant and independent genetic variants, rs2049604 in the FOXP2 gene and rs62053992 in the LINC01572 gene were weakly replicated in GS:SFHS (P = 0.0240 and P = 0.0202, respectively). CONCLUSIONS: We have identified three loci associated with neck or shoulder pain in the UK Biobank cohort, two of which were weakly supported in a replication cohort. Further evidence is needed to confirm their roles in neck or shoulder pain.

Genetic and shared couple environmental contributions to smoking and alcohol use in the UK population.

Alcohol use and smoking are leading causes of death and disability worldwide. Both genetic and environmental factors have been shown to influence individual differences in the use of these substances. In the present study we tested whether genetic factors, modelled alongside common family environment, explained phenotypic variance in alcohol use and smoking behaviour in the Generation Scotland (GS) family sample of up to 19,377 individuals. SNP and pedigree-associated effects combined explained between 18 and 41% of the variance in substance use. Shared couple effects explained a significant amount of variance across all substance use traits, particularly alcohol intake, for which 38% of the phenotypic variance was explained. We tested whether the within-couple substance use associations were due to assortative mating by testing the association between partner polygenic risk scores in 34,987 couple pairs from the UK Biobank (UKB). No significant association between partner polygenic risk scores were observed. Associations between an individual's alcohol PRS (b = 0.05, S.E. = 0.006, p < 2 × 10-16) and smoking status PRS (b = 0.05, S.E. = 0.005, p < 2 × 10-16) were found with their partner's phenotype. In support of this, G carriers of a functional ADH1B polymorphism (rs1229984), known to be associated with greater alcohol intake, were found to consume less alcohol if they had a partner who carried an A allele at this SNP. Together these results show that the shared couple environment contributes significantly to patterns of substance use. It is unclear whether this is due to shared environmental factors, assortative mating, or indirect genetic effects. Future studies would benefit from longitudinal data and larger sample sizes to assess this further.

System-level policies on appropriate opioid use, a multi-stakeholder consensus.

BACKGROUND: This consensus statement was developed because there are concerns about the appropriate use of opioids for acute pain management, with opposing views in the literature. Consensus statement on policies for system-level interventions may help inform organisations such as management structures, government agencies and funding bodies. METHODS: We conducted a multi-stakeholder survey using a modified Delphi methodology focusing on policies, at the system level, rather than at the prescriber or patient level. We aimed to provide consensus statements for current developments and priorities for future developments. RESULTS: Twenty-five experts from a variety of fields with experience in acute pain management were invited to join a review panel, of whom 23 completed a modified Delphi survey of policies designed to improve the safety and quality of opioids prescribing for acute pain in the secondary care setting. Strong agreement, defined as consistent among> 75% of panellists, was observed for ten statements. CONCLUSIONS: Using a modified Delphi study, we found agreement among a multidisciplinary panel, including patient representation, on prioritisation of policies for system-level interventions, to improve governance, pain management, patient/consumers care, safety and engagement.

Community prescribing trends and prevalence in the last year of life, for people who die from cancer.

BACKGROUND: People who die from cancer ('cancer decedents') may latterly experience unpleasant and distressing symptoms. Prescribing medication for pain and symptom control is essential for good-quality palliative care; however, such provision is variable, difficult to quantify and poorly characterised in current literature. This study aims to characterise trends in prescribing analgesia, non-analgesic palliative care medication and non-palliative medications, to cancer decedents, in their last year of life, and to assess any associations with demographic or clinical factors. METHODS: This descriptive study, analysed all 181,247 prescriptions issued to a study population of 2443 cancer decedents in Tayside, Scotland (2013-2015), in the last year of life, linking prescribing data to demographic, and cancer registry datasets using the unique patient-identifying Community Health Index (CHI) number. Anonymised linked data were analysed in Safe Haven using chi-squared test for trend, binary logistic regression and Poisson regression in SPSSv25. RESULTS: In their last year of life, three in four cancer decedents were prescribed strong opioids. Two-thirds of those prescribed opioids were also prescribed laxatives and/or anti-emetics. Only four in ten cancer decedents were prescribed all medications in the 'Just in Case' medication categories and only one in ten was prescribed breakthrough analgesia in the last year of life. The number of prescriptions for analgesia and palliative care drugs increased in the last 12 weeks of life. The number of prescriptions for non-palliative care medications, including anti-hypertensives, statins and bone protection, decreased over the last year, but was still substantial. Cancer decedents who were female, younger, or had lung cancer were more likely to be prescribed strong opioids; however, male cancer decedents had higher odds of being prescribed breakthrough analgesia. Cancer decedents who had late diagnoses had lower odds of being prescribed strong opioids. CONCLUSIONS: A substantial proportion of cancer decedents were not prescribed strong opioids, breakthrough medication, or medication to alleviate common palliative care symptoms (including 'Just in Case' medication). Many patients continued to be prescribed non-palliative care medications in their last days and weeks of life. Age, gender, cancer type and timing of diagnosis affected patients' odds of being prescribed analgesic and non-analgesic palliative care medication.

Classification of painful or painless diabetic peripheral neuropathy and identification of the most powerful predictors using machine learning models in large cross-sectional cohorts.

BACKGROUND: To improve the treatment of painful Diabetic Peripheral Neuropathy (DPN) and associated co-morbidities, a better understanding of the pathophysiology and risk factors for painful DPN is required. Using harmonised cohorts (N = 1230) we have built models that classify painful versus painless DPN using quality of life (EQ5D), lifestyle (smoking, alcohol consumption), demographics (age, gender), personality and psychology traits (anxiety, depression, personality traits), biochemical (HbA1c) and clinical variables (BMI, hospital stay and trauma at young age) as predictors. METHODS: The Random Forest, Adaptive Regression Splines and Naive Bayes machine learning models were trained for classifying painful/painless DPN. Their performance was estimated using cross-validation in large cross-sectional cohorts (N = 935) and externally validated in a large population-based cohort (N = 295). Variables were ranked for importance using model specific metrics and marginal effects of predictors were aggregated and assessed at the global level. Model selection was carried out using the Mathews Correlation Coefficient (MCC) and model performance was quantified in the validation set using MCC, the area under the precision/recall curve (AUPRC) and accuracy. RESULTS: Random Forest (MCC = 0.28, AUPRC = 0.76) and Adaptive Regression Splines (MCC = 0.29, AUPRC = 0.77) were the best performing models and showed the smallest reduction in performance between the training and validation dataset. EQ5D index, the 10-item personality dimensions, HbA1c, Depression and Anxiety t-scores, age and Body Mass Index were consistently amongst the most powerful predictors in classifying painful vs painless DPN. CONCLUSIONS: Machine learning models trained on large cross-sectional cohorts were able to accurately classify painful or painless DPN on an independent population-based dataset. Painful DPN is associated with more depression, anxiety and certain personality traits. It is also associated with poorer self-reported quality of life, younger age, poor glucose control and high Body Mass Index (BMI). The models showed good performance in realistic conditions in the presence of missing values and noisy datasets. These models can be used either in the clinical context to assist patient stratification based on the risk of painful DPN or return broad risk categories based on user input. Model's performance and calibration suggest that in both cases they could potentially improve diagnosis and outcomes by changing modifiable factors like BMI and HbA1c control and institute earlier preventive or supportive measures like psychological interventions.

Genome-wide meta-analysis of 158,000 individuals of European ancestry identifies three loci associated with chronic back pain.

Back pain is the #1 cause of years lived with disability worldwide, yet surprisingly little is known regarding the biology underlying this symptom. We conducted a genome-wide association study (GWAS) meta-analysis of chronic back pain (CBP). Adults of European ancestry were included from 15 cohorts in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, and from the UK Biobank interim data release. CBP cases were defined as those reporting back pain present for ≥3-6 months; non-cases were included as comparisons ("controls"). Each cohort conducted genotyping using commercially available arrays followed by imputation. GWAS used logistic regression models with additive genetic effects, adjusting for age, sex, study-specific covariates, and population substructure. The threshold for genome-wide significance in the fixed-effect inverse-variance weighted meta-analysis was p<5×10(-8). Suggestive (p<5×10(-7)) and genome-wide significant (p<5×10(-8)) variants were carried forward for replication or further investigation in the remaining UK Biobank participants not included in the discovery sample. The discovery sample comprised 158,025 individuals, including 29,531 CBP cases. A genome-wide significant association was found for the intronic variant rs12310519 in SOX5 (OR 1.08, p = 7.2×10(-10)). This was subsequently replicated in 283,752 UK Biobank participants not included in the discovery sample, including 50,915 cases (OR 1.06, p = 5.3×10(-11)), and exceeded genome-wide significance in joint meta-analysis (OR 1.07, p = 4.5×10(-19)). We found suggestive associations at three other loci in the discovery sample, two of which exceeded genome-wide significance in joint meta-analysis: an intergenic variant, rs7833174, located between CCDC26 and GSDMC (OR 1.05, p = 4.4×10(-13)), and an intronic variant, rs4384683, in DCC (OR 0.97, p = 2.4×10(-10)). In this first reported meta-analysis of GWAS for CBP, we identified and replicated a genetic locus associated with CBP (SOX5). We also identified 2 other loci that reached genome-wide significance in a 2-stage joint meta-analysis (CCDC26/GSDMC and DCC).

Genome-wide association study of antidepressant treatment resistance in a population-based cohort using health service prescription data and meta-analysis with GENDEP.

Antidepressants demonstrate modest response rates in the treatment of major depressive disorder (MDD). Despite previous genome-wide association studies (GWAS) of antidepressant treatment response, the underlying genetic factors are unknown. Using prescription data in a population and family-based cohort (Generation Scotland: Scottish Family Health Study; GS:SFHS), we sought to define a measure of (a) antidepressant treatment resistance and (b) stages of antidepressant resistance by inferring antidepressant switching as non-response to treatment. GWAS were conducted separately for antidepressant treatment resistance in GS:SFHS and the Genome-based Therapeutic Drugs for Depression (GENDEP) study and then meta-analysed (meta-analysis n = 4213, cases = 358). For stages of antidepressant resistance, a GWAS on GS:SFHS only was performed (n = 3452). Additionally, we conducted gene-set enrichment, polygenic risk scoring (PRS) and genetic correlation analysis. We did not identify any significant loci, genes or gene sets associated with antidepressant treatment resistance or stages of resistance. Significant positive genetic correlations of antidepressant treatment resistance and stages of resistance with neuroticism, psychological distress, schizotypy and mood disorder traits were identified. These findings suggest that larger sample sizes are needed to identify the genetic architecture of antidepressant treatment response, and that population-based observational studies may provide a tractable approach to achieving the necessary statistical power.

Perioperative management of patients with suspected or confirmed COVID-19: review and recommendations for perioperative management from a retrospective cohort study.

BACKGROUND: Current guidelines for perioperative management of coronavirus disease 19 (COVID-19) are mainly based on extrapolated evidence or expert opinion. We aimed to systematically investigate how COVID-19 affects perioperative management and clinical outcomes, to develop evidence-based guidelines. METHODS: First, we conducted a rapid literature review in EMBASE, MEDLINE, PubMed, Scopus, and Web of Science (January 1 to July 1, 2020), using a predefined protocol. Second, we performed a retrospective cohort analysis of 166 women undergoing Caesarean section at Tongji Hospital, Wuhan during the COVID-19 pandemic. Demographic, imaging, laboratory, and clinical data were obtained from electronic medical records. RESULTS: The review identified 26 studies, mainly case reports/series. One large cohort reported greater mortality in elective surgery patients diagnosed after, rather than before surgery. Higher 30 day mortality was associated with emergency surgery, major surgery, poorer preoperative condition and surgery for malignancy. Regional anaesthesia was favoured in most studies and personal protective equipment (PPE) was generally used by healthcare workers (HCWs), but its use was poorly described for patients. In the retrospective cohort study, duration of surgery, oxygen therapy and hospital stay were longer in suspected or confirmed patients than negative patients, but there were no differences in neonatal outcomes. None of the 262 participating HCWs was infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) when using level 3 PPE perioperatively. CONCLUSIONS: When COVID-19 is suspected, testing should be considered before non-urgent surgery. Until further evidence is available, HCWs should use level 3 PPE perioperatively for suspected or confirmed patients, but research is needed on its timing and specifications. Further research must examine longer-term outcomes. CLINICAL TRIAL REGISTRATION: CRD42020182891 (PROSPERO).

Trends in gabapentinoid prescribing, co-prescribing of opioids and benzodiazepines, and associated deaths in Scotland.

BACKGROUND: Gabapentinoid drugs (gabapentin and pregabalin) are effective in neuropathic pain, which has a prevalence of ∼7%. Concerns about increased prescribing have implications for patient safety, misuse, and diversion. Drug-related deaths (DRDs) have increased and toxicology often implicates gabapentinoids. We studied national and regional prescribing rates (2006-2016) and identified associated sociodemographic factors, co-prescriptions and mortality, including DRDs. METHODS: National data from the Information Service Division, NHS Scotland were analysed for prescribing, sociodemographic, and mortality data from the Health Informatics Centre, University of Dundee. DRDs in which gabapentinoids were implicated were identified from National Records of Scotland and Tayside Drug Death Databases. RESULTS: From 2006 to 2016, the number of gabapentin prescriptions in Scotland increased 4-fold (164 630 to 694 293), and pregabalin 16-fold (27 094 to 435 490). In 2016 'recurrent users' (three or more prescriptions) had mean age 58.1 yr, were mostly females (62.5%), and were more likely to live in deprived areas. Of these, 60% were co-prescribed an opioid, benzodiazepine, or both (opioid 49.9%, benzodiazepine 26.8%, both 17.1%). The age-standardised death rate in those prescribed gabapentinoids was double that in the Scottish population (relative risk 2.16, 95% confidence interval 2.08-2.25). Increases in gabapentinoids contributing to cause of DRDs were reported regionally and nationally (gabapentin 23% vs 15%; pregabalin 21% vs 7%). In Tayside, gabapentinoids were implicated in 22 (39%) of DRDs, 17 (77%) of whom had not received a prescription. CONCLUSIONS: Gabapentinoid prescribing has increased dramatically since 2006, as have dangerous co-prescribing and death (including DRDs). Older people, women, and those living in deprived areas were particularly likely to receive prescriptions. Their contribution to DRDs may be more related to illegal use with diversion of prescribed medication.

Chronic pain: a review of its epidemiology and associated factors in population-based studies.

Chronic pain is a common, complex, and distressing problem that has a profound impact on individuals and society. It frequently presents as a result of a disease or an injury; however, it is not merely an accompanying symptom, but rather a separate condition in its own right, with its own medical definition and taxonomy. Studying the distribution and determinants of chronic pain allows us to understand and manage the problem at the individual and population levels. Targeted and appropriate prevention and management strategies need to take into account the biological, psychological, socio-demographic, and lifestyle determinants and outcomes of pain. We present a narrative review of the current understanding of these factors.

An Empirical Comparison of Joint and Stratified Frameworks for Studying G × E Interactions: Systolic Blood Pressure and Smoking in the CHARGE Gene-Lifestyle Interactions Working Group.

Studying gene-environment (G × E) interactions is important, as they extend our knowledge of the genetic architecture of complex traits and may help to identify novel variants not detected via analysis of main effects alone. The main statistical framework for studying G × E interactions uses a single regression model that includes both the genetic main and G × E interaction effects (the "joint" framework). The alternative "stratified" framework combines results from genetic main-effect analyses carried out separately within the exposed and unexposed groups. Although there have been several investigations using theory and simulation, an empirical comparison of the two frameworks is lacking. Here, we compare the two frameworks using results from genome-wide association studies of systolic blood pressure for 3.2 million low frequency and 6.5 million common variants across 20 cohorts of European ancestry, comprising 79,731 individuals. Our cohorts have sample sizes ranging from 456 to 22,983 and include both family-based and population-based samples. In cohort-specific analyses, the two frameworks provided similar inference for population-based cohorts. The agreement was reduced for family-based cohorts. In meta-analyses, agreement between the two frameworks was less than that observed in cohort-specific analyses, despite the increased sample size. In meta-analyses, agreement depended on (1) the minor allele frequency, (2) inclusion of family-based cohorts in meta-analysis, and (3) filtering scheme. The stratified framework appears to approximate the joint framework well only for common variants in population-based cohorts. We conclude that the joint framework is the preferred approach and should be used to control false positives when dealing with low-frequency variants and/or family-based cohorts.

Mosaic structural variation in children with developmental disorders.

Delineating the genetic causes of developmental disorders is an area of active investigation. Mosaic structural abnormalities, defined as copy number or loss of heterozygosity events that are large and present in only a subset of cells, have been detected in 0.2-1.0% of children ascertained for clinical genetic testing. However, the frequency among healthy children in the community is not well characterized, which, if known, could inform better interpretation of the pathogenic burden of this mutational category in children with developmental disorders. In a case-control analysis, we compared the rate of large-scale mosaicism between 1303 children with developmental disorders and 5094 children lacking developmental disorders, using an analytical pipeline we developed, and identified a substantial enrichment in cases (odds ratio = 39.4, P-value 1.073e - 6). A meta-analysis that included frequency estimates among an additional 7000 children with congenital diseases yielded an even stronger statistical enrichment (P-value 1.784e - 11). In addition, to maximize the detection of low-clonality events in probands, we applied a trio-based mosaic detection algorithm, which detected two additional events in probands, including an individual with genome-wide suspected chimerism. In total, we detected 12 structural mosaic abnormalities among 1303 children (0.9%). Given the burden of mosaicism detected in cases, we suspected that many of the events detected in probands were pathogenic. Scrutiny of the genotypic-phenotypic relationship of each detected variant assessed that the majority of events are very likely pathogenic. This work quantifies the burden of structural mosaicism as a cause of developmental disorders.

Physical activity and exercise for chronic pain in adults: an overview of Cochrane Reviews.

BACKGROUND: Chronic pain is defined as pain lasting beyond normal tissue healing time, generally taken to be 12 weeks. It contributes to disability, anxiety, depression, sleep disturbances, poor quality of life, and healthcare costs. Chronic pain has a weighted mean prevalence in adults of 20%.For many years, the treatment choice for chronic pain included recommendations for rest and inactivity. However, exercise may have specific benefits in reducing the severity of chronic pain, as well as more general benefits associated with improved overall physical and mental health, and physical functioning.Physical activity and exercise programmes are increasingly being promoted and offered in various healthcare systems, and for a variety of chronic pain conditions. It is therefore important at this stage to establish the efficacy and safety of these programmes, and furthermore to address the critical factors that determine their success or failure. OBJECTIVES: To provide an overview of Cochrane Reviews of adults with chronic pain to determine (1) the effectiveness of different physical activity and exercise interventions in reducing pain severity and its impact on function, quality of life, and healthcare use; and (2) the evidence for any adverse effects or harm associated with physical activity and exercise interventions. METHODS: We searched theCochrane Database of Systematic Reviews (CDSR) on the Cochrane Library (CDSR 2016, Issue 1) for systematic reviews of randomised controlled trials (RCTs), after which we tracked any included reviews for updates, and tracked protocols in case of full review publication until an arbitrary cut-off date of 21 March 2016 (CDSR 2016, Issue 3). We assessed the methodological quality of the reviews using the AMSTAR tool, and also planned to analyse data for each painful condition based on quality of the evidence.We extracted data for (1) self-reported pain severity, (2) physical function (objectively or subjectively measured), (3) psychological function, (4) quality of life, (5) adherence to the prescribed intervention, (6) healthcare use/attendance, (7) adverse events, and (8) death.Due to the limited data available, we were unable to directly compare and analyse interventions, and have instead reported the evidence qualitatively. MAIN RESULTS: We included 21 reviews with 381 included studies and 37,143 participants. Of these, 264 studies (19,642 participants) examined exercise versus no exercise/minimal intervention in adults with chronic pain and were used in the qualitative analysis.Pain conditions included rheumatoid arthritis, osteoarthritis, fibromyalgia, low back pain, intermittent claudication, dysmenorrhoea, mechanical neck disorder, spinal cord injury, postpolio syndrome, and patellofemoral pain. None of the reviews assessed 'chronic pain' or 'chronic widespread pain' as a general term or specific condition. Interventions included aerobic, strength, flexibility, range of motion, and core or balance training programmes, as well as yoga, Pilates, and tai chi.Reviews were well performed and reported (based on AMSTAR), and included studies had acceptable risk of bias (with inadequate reporting of attrition and reporting biases). However the quality of evidence was low due to participant numbers (most included studies had fewer than 50 participants in total), length of intervention and follow-up (rarely assessed beyond three to six months). We pooled the results from relevant reviews where appropriate, though results should be interpreted with caution due to the low quality evidence. Pain severity: several reviews noted favourable results from exercise: only three reviews that reported pain severity found no statistically significant changes in usual or mean pain from any intervention. However, results were inconsistent across interventions and follow-up, as exercise did not consistently bring about a change (positive or negative) in self-reported pain scores at any single point. Physical function: was the most commonly reported outcome measure. Physical function was significantly improved as a result of the intervention in 14 reviews, though even these statistically significant results had only small-to-moderate effect sizes (only one review reported large effect sizes). Psychological function and quality of life: had variable results: results were either favourable to exercise (generally small and moderate effect size, with two reviews reporting significant, large effect sizes for quality of life), or showed no difference between groups. There were no negative effects. Adherence to the prescribed intervention: could not be assessed in any review. However, risk of withdrawal/dropout was slightly higher in the exercising group (82.8/1000 participants versus 81/1000 participants), though the group difference was non-significant. Healthcare use/attendance: was not reported in any review. Adverse events, potential harm, and death: only 25% of included studies (across 18 reviews) actively reported adverse events. Based on the available evidence, most adverse events were increased soreness or muscle pain, which reportedly subsided after a few weeks of the intervention. Only one review reported death separately to other adverse events: the intervention was protective against death (based on the available evidence), though did not reach statistical significance. AUTHORS' CONCLUSIONS: The quality of the evidence examining physical activity and exercise for chronic pain is low. This is largely due to small sample sizes and potentially underpowered studies. A number of studies had adequately long interventions, but planned follow-up was limited to less than one year in all but six reviews.There were some favourable effects in reduction in pain severity and improved physical function, though these were mostly of small-to-moderate effect, and were not consistent across the reviews. There were variable effects for psychological function and quality of life.The available evidence suggests physical activity and exercise is an intervention with few adverse events that may improve pain severity and physical function, and consequent quality of life. However, further research is required and should focus on increasing participant numbers, including participants with a broader spectrum of pain severity, and lengthening both the intervention itself, and the follow-up period.

Physical activity and exercise for chronic pain in adults: an overview of Cochrane Reviews.

BACKGROUND: Chronic pain is defined as pain lasting beyond normal tissue healing time, generally taken to be 12 weeks. It contributes to disability, anxiety, depression, sleep disturbances, poor quality of life, and healthcare costs. Chronic pain has a weighted mean prevalence in adults of 20%.For many years, the treatment choice for chronic pain included recommendations for rest and inactivity. However, exercise may have specific benefits in reducing the severity of chronic pain, as well as more general benefits associated with improved overall physical and mental health, and physical functioning.Physical activity and exercise programmes are increasingly being promoted and offered in various healthcare systems, and for a variety of chronic pain conditions. It is therefore important at this stage to establish the efficacy and safety of these programmes, and furthermore to address the critical factors that determine their success or failure. OBJECTIVES: To provide an overview of Cochrane Reviews of adults with chronic pain to determine (1) the effectiveness of different physical activity and exercise interventions in reducing pain severity and its impact on function, quality of life, and healthcare use; and (2) the evidence for any adverse effects or harm associated with physical activity and exercise interventions. METHODS: We searched theCochrane Database of Systematic Reviews (CDSR) on the Cochrane Library (CDSR 2016, Issue 1) for systematic reviews of randomised controlled trials (RCTs), after which we tracked any included reviews for updates, and tracked protocols in case of full review publication until an arbitrary cut-off date of 21 March 2016 (CDSR 2016, Issue 3). We assessed the methodological quality of the reviews using the AMSTAR tool, and also planned to analyse data for each painful condition based on quality of the evidence.We extracted data for (1) self-reported pain severity, (2) physical function (objectively or subjectively measured), (3) psychological function, (4) quality of life, (5) adherence to the prescribed intervention, (6) healthcare use/attendance, (7) adverse events, and (8) death.Due to the limited data available, we were unable to directly compare and analyse interventions, and have instead reported the evidence qualitatively. MAIN RESULTS: We included 21 reviews with 381 included studies and 37,143 participants. Of these, 264 studies (19,642 participants) examined exercise versus no exercise/minimal intervention in adults with chronic pain and were used in the qualitative analysis.Pain conditions included rheumatoid arthritis, osteoarthritis, fibromyalgia, low back pain, intermittent claudication, dysmenorrhoea, mechanical neck disorder, spinal cord injury, postpolio syndrome, and patellofemoral pain. None of the reviews assessed 'chronic pain' or 'chronic widespread pain' as a general term or specific condition. Interventions included aerobic, strength, flexibility, range of motion, and core or balance training programmes, as well as yoga, Pilates, and tai chi.Reviews were well performed and reported (based on AMSTAR), and included studies had acceptable risk of bias (with inadequate reporting of attrition and reporting biases). However the quality of evidence was low due to participant numbers (most included studies had fewer than 50 participants in total), length of intervention and follow-up (rarely assessed beyond three to six months). We pooled the results from relevant reviews where appropriate, though results should be interpreted with caution due to the low quality evidence. Pain severity: several reviews noted favourable results from exercise: only three reviews that reported pain severity found no statistically significant changes in usual or mean pain from any intervention. However, results were inconsistent across interventions and follow-up, as exercise did not consistently bring about a change (positive or negative) in self-reported pain scores at any single point. Physical function: was the most commonly reported outcome measure. Physical function was significantly improved as a result of the intervention in 14 reviews, though even these statistically significant results had only small-to-moderate effect sizes (only one review reported large effect sizes). Psychological function and quality of life: had variable results: results were either favourable to exercise (generally small and moderate effect size, with two reviews reporting significant, large effect sizes for quality of life), or showed no difference between groups. There were no negative effects. Adherence to the prescribed intervention: could not be assessed in any review. However, risk of withdrawal/dropout was slightly higher in the exercising group (82.8/1000 participants versus 81/1000 participants), though the group difference was non-significant. Healthcare use/attendance: was not reported in any review. Adverse events, potential harm, and death: only 25% of included studies (across 18 reviews) actively reported adverse events. Based on the available evidence, most adverse events were increased soreness or muscle pain, which reportedly subsided after a few weeks of the intervention. Only one review reported death separately to other adverse events: the intervention was protective against death (based on the available evidence), though did not reach statistical significance. AUTHORS' CONCLUSIONS: The quality of the evidence examining physical activity and exercise for chronic pain is low. This is largely due to small sample sizes and potentially underpowered studies. A number of studies had adequately long interventions, but planned follow-up was limited to less than one year in all but six reviews.There were some favourable effects in reduction in pain severity and improved physical function, though these were mostly of small-to-moderate effect, and were not consistent across the reviews. There were variable effects for psychological function and quality of life.The available evidence suggests physical activity and exercise is an intervention with few adverse events that may improve pain severity and physical function, and consequent quality of life. However, further research is required and should focus on increasing participant numbers, including participants with a broader spectrum of pain severity, and lengthening both the intervention itself, and the follow-up period.

Common genetic variants associated with cognitive performance identified using the proxy-phenotype method.

We identify common genetic variants associated with cognitive performance using a two-stage approach, which we call the proxy-phenotype method. First, we conduct a genome-wide association study of educational attainment in a large sample (n = 106,736), which produces a set of 69 education-associated SNPs. Second, using independent samples (n = 24,189), we measure the association of these education-associated SNPs with cognitive performance. Three SNPs (rs1487441, rs7923609, and rs2721173) are significantly associated with cognitive performance after correction for multiple hypothesis testing. In an independent sample of older Americans (n = 8,652), we also show that a polygenic score derived from the education-associated SNPs is associated with memory and absence of dementia. Convergent evidence from a set of bioinformatics analyses implicates four specific genes (KNCMA1, NRXN1, POU2F3, and SCRT). All of these genes are associated with a particular neurotransmitter pathway involved in synaptic plasticity, the main cellular mechanism for learning and memory.