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Chronic pain is pathological, persisting beyond normal tissue healing time. Previous work has suggested ∼50% variation in chronic pain development is heritable. No data are currently available on the heritability of pain categorized using the Chronic Pain Grade (CPG). Furthermore, few existing studies have accounted for potential confounders that may themselves be under genetic control or indeed ‘heritable’ non-genetic traits. This study aimed to determine the relative contributions of genetic, measured and shared environmental and lifestyle factors to chronic pain. Chronic pain status was determined and CPG measured in participants from Generation Scotland: the Scottish Family Health Study, a large cohort of well-characterized, extended families from throughout Scotland, UK. Heritability estimates (h 2) for ‘any chronic pain’ and ‘severe’ chronic pain (CPG 3 or 4) were generated using SOLAR software, with and without adjustment for shared household effects and measured covariates age, body mass index, gender, household income, occupation and physical activity. Data were available for 7644 individuals in 2195 extended families. Without adjustment, h 2 for ‘any chronic pain’ was 29% [standard errors (SE) 6%; p

RATIONALE: Genomic loci are associated with FEV1 or the ratio of FEV1 to FVC in population samples, but their association with chronic obstructive pulmonary disease (COPD) has not yet been proven, nor have their combined effects on lung function and COPD been studied. OBJECTIVES: To test association with COPD of variants at five loci (TNS1, GSTCD, HTR4, AGER, and THSD4) and to evaluate joint effects on lung function and COPD of these single-nucleotide polymorphisms (SNPs), and variants at the previously reported locus near HHIP. METHODS: By sampling from 12 population-based studies (n = 31,422), we obtained genotype data on 3,284 COPD case subjects and 17,538 control subjects for sentinel SNPs in TNS1, GSTCD, HTR4, AGER, and THSD4. In 24,648 individuals (including 2,890 COPD case subjects and 13,862 control subjects), we additionally obtained genotypes for rs12504628 near HHIP. Each allele associated with lung function decline at these six SNPs contributed to a risk score. We studied the association of the risk score to lung function and COPD. MEASUREMENTS AND MAIN RESULTS: Association with COPD was significant for three loci (TNS1, GSTCD, and HTR4) and the previously reported HHIP locus, and suggestive and directionally consistent for AGER and TSHD4. Compared with the baseline group (7 risk alleles), carrying 10-12 risk alleles was associated with a reduction in FEV1 (β = -72.21 ml, P = 3.90 × 10(-4)) and FEV1/FVC (β = -1.53%, P = 6.35 × 10(-6)), and with COPD (odds ratio = 1.63, P = 1.46 × 10(-5)) CONCLUSIONS: Variants in TNS1, GSTCD, and HTR4 are associated with COPD. Our highest risk score category was associated with a 1.6-fold higher COPD risk than the population average score.

The effects of aging present a major medical challenge in the 21st century, which will cause fundamental changes in demography. By 2031, it is estimated that 22% of the UK population will be aged over 65 years, and there will be more people in this age group than aged under 25 years. As well as implications for infrastructure and productivity, this change will alter the prevalence and impact of many illnesses and pathologies. The research priorities of many of the major funding bodies reflect this challenge. The Medical Research Council in the UK, for example, leads the Lifelong Health and Wellbeing program on behalf of all the country’s research councils. This initiative aims to identify factors that affect or improve health in later life, to inform relevant policy and practice. The Wellcome Trust lists the investigation of development, aging and chronic disease as one of its five major research challenges, and the European Commission presents the health of the aging population as one of its three overarching issues of the Health Theme in its 7th Framework Program of research. Chronic pain is a major health condition associated with aging, whose management (pharmacological and nonpharmacological) is generally unsatisfactory. The International Association for the Study of Pain designated 2006/07 as its Global Year Against Pain in Older Adults. This article reviews the relevance of existing and potential research on the assessment and management of chronic pain in older adults.

To examine recent and current evidence available to guide the management of chronic pain in primary care.The growing profile of chronic pain has facilitated some important consensus and guideline statements. Pharmacological management, based on available evidence and consensus, is essential in managing chronic pain in primary care, as part of a holistic approach, and with regular review. Studies of primary care management of chronic pain face considerable challenges, with assessment and interventions that are complex, and involving multidisciplinary approaches. Recent research evidence points to the effectiveness and feasibility of multidisciplinary interventions, with appropriate assessment and training. Specifically, a self-management programme, 'collaborative care', a cognitive-behavioural approach, and the Alexander technique show evidence of effectiveness in primary care, the latter two also proving cost-effective.Most chronic pain presents and is managed in primary care; yet, most evidence for its management is difficult to apply in the primary care setting. Despite growing evidence for the management of chronic pain generally, management in primary care must be largely guided by consensus, experience, and judicious extrapolation from research in other contexts or conditions. A need for increased and on-going education and resources is apparent, as is the need for more research based in primary care.

Background Alcohol consumption is linked to over 200 diseases and is responsible for over 5% of the global disease burden. Well known genetic variants in alcohol metabolizing genes, e.g. ALDH2, ADH1B, are strongly associated with alcohol consumption but have limited impact in European populations where they are found at lower frequencies. Methods We performed a Genome-Wide Association Study (GWAS) of self-reported alcohol consumption in 112,117 individuals in the UK Biobank (UKB) sample of white British individuals. The SNP heritability of alcohol consumption was also investigated and the genetic correlation with health and behavioural traits. Results Thirteen genome-wide significant associations were detected. These include SNPs in alcohol metabolizing genes (ADH1B/ADH1C/ADH5) and 2 loci in KLB, a gene recently associated with alcohol consumption. We also identify SNPs at novel loci including GCKR, CADM2 and FAM69C. Gene-based analyses found significant associations with genes implicated in the neurobiology of substance use (DRD2, PDE4B). GCTA-GREML analyses found a significant SNP-based heritability of self-reported alcohol consumption of 13% (S.E.=0.01). Sex-specific analyses found largely overlapping GWAS loci and the genetic correlation between male and female alcohol consumption to be 0.90 (S.E.=0.09, p-value = 7.16 × 10–23). Using LD score regression, genetic overlap was found between alcohol consumption and years of schooling (rG=0.18, S.E.=0.03), HDL cholesterol (rG=0.28, S.E.=0.05), smoking (rG=0.40, S.E.=0.06) and various anthropometric traits (e.g. Overweight, Rg=-0.19, S.E.=0.05). Discussion This study replicates the association between alcohol consumption and alcohol metabolizing genes and KLB, and identifies novel gene associations that should be the focus of future studies investigating the neurobiology of alcohol consumption.

Epidemiology is an essential clinical tool in designing and evaluating management and prevention strategies, and is particularly relevant to neuropathic pain. Despite its relevance to neuropathic pain however, there is a paucity of accurate information on its prevalence, distribution and determinants, for several reasons. In many ways, it is appropriate to study neuropathic pain merely as a symptom or a pain mechanism rather than a specific disease. However, the different causes display sufficient similarities in their clinical and personal impact, and in their response to treatment, to make it worthwhile to consider neuropathic pain as a distinct condition. There are, however, important specific disease-based factors that need to be considered separately. Older estimates of the prevalence of neuropathic pain (based on specific diagnoses) tend to be lower (1–2%) than newer estimates that are based on questionnaires examining classic symptoms (6–8%). Further methodological research is needed to clarify these. Associated poor general health is a feature of all neuropathic pain, similar to other severe chronic diseases.

Chronic pain, defined as pain lasting beyond normal tissue healing time (taken to be 3 months),1 is a syndrome that affects a large proportion of the primary care population. It is ‘significant’ in around 14% of UK adults, imposing a heavy burden on the physical and psychosocial health of sufferers, their families and society, at high cost to the healthcare services.2 It was estimated in 2002 that people with chronic pain account for 4.6 million GP appointments in the UK, at an annual cost to the NHS of £69 million, equivalent to the employment of 793 GPs.3 Although many clinical conditions can lead to chronic pain, there are common underlying neurobiological and psychosocial mechanisms, and the impact is generally independent of the clinical aetiology. Effective assessment and treatment of chronic pain therefore means that GPs should have: Unfortunately, none of these requirements is generally in place. Undergraduate training in management of pain is demonstrably minimal, accounting for

People with higher general cognitive ability in early life have more favourable levels of cardiovascular disease (CVD) risk factors in adulthood and CVD itself. The mechanism of these associations is not known. Here we examine whether general cognitive ability and CVD risk factors share genetic and/or environmental aetiology. In this large, pedigree-based cross-sectional study of Scottish families (N = 1983 families; 6086 individuals) we estimate the heritability (ranging from 0.08 to 0.91) of a diverse battery of CVD risk factors, and also examine the extent and causes of their relationship with general cognitive ability. General cognitive ability was associated significantly with almost all the risk factors investigated, explaining between 0.2% and 11% of variance. For those measures with an effect size greater than around 1%, the relationship was primarily influenced by genes (30 to 94%) rather than the environment. These findings have relevance to the growing field of cognitive epidemiology, in which intelligence is used to predict morbidity and mortality. We provide evidence that risk factors such as education and income – which are typically treated as environmental indicators by epidemiologists and controlled for in their studies of morbidity – are genetically confounded with IQ.

Previous research has clearly demonstrated a link between chronic pain and poor health, and has suggested a link with increased mortality, though the latter is less consistent. In 1996 a cohort of 6940 individuals was recruited, and information collected, about reported chronic pain status, general health and socio-demographic details. Ten years later, a record linkage was conducted between these data and the routinely collected national dataset for death registration. Primary cause of death was classified according to ICD-10 codes. Survival analysis was conducted to obtain unadjusted and multi-adjusted hazard ratios (HR) for all-cause, system-specific and disease-specific mortality by chronic pain status. A total of 5858 (84.4%) of individuals from the original cohort were linked, including 1557 (26.6%) who had died. Survival analysis found significant associations between any reported chronic pain and all-cause mortality (HR 1.32, 99% CI, 1.14-1.54) and a number of specific causes. However, when we adjusted for socio-demographic factors and reported long-term limiting illness, the significant association was lost. Survival among those reporting severe chronic pain was significantly worse than among those reporting mild or no chronic pain. After adjustment for socio-demographic factors and reported long-term limiting illness, severe chronic pain remained significantly associated with all-cause mortality (HR 1.49, 99% CI 1.21-1.84) and all circulatory system disease deaths (HR 1.68, 99% CI 1.20-2.35). The evident association between any chronic pain and increased mortality can apparently be explained by confounding caused by socio-demographic factors. However, severe chronic pain is associated with increased risk of mortality, independent of socio-demographic factors.

Background The Medical Outcomes Study 36 Item Short-Form (SF-36) questionnaire is one of the most widely used measures of health related quality of life in medical research, including studies on pain-related conditions. Although scores in each of its eight domains rarely conform to a normal distribution, it is most widely analysed using simple parametric statistical techniques. Some have suggested a need for more complex or non-parametric analytical approaches, and this quandary faces researchers recurrently when using the SF-36. In this study of chronic pain, we compared results arising from the SF-36 between three study sub-samples, using conventional parametric, non-parametric, bootstrapping and log transforming methods. Methods Respondents to a postal survey conducted in Aberdeen, Leeds and London (n = 3002, response rate 52%) were categorized in three groups according to previously validated questionnaires: those with chronic pain of predominantly neuropathic origin (POPNO, n = 241), those with chronic pain (non-POPNO, n = 1179), and those with no chronic pain (n = 1537). SF-36 scores were compared between these groups, using: ANOVA and t-tests; Kruskall–Wallis and Mann–Whitney U-tests; bootstrapping methods; and log transformation with ANOVA. Results There were highly significant differences between the three groups, with lower scores in all SF-36 domains found those with chronic pain (P < 0.001). Those with chronic POPNO had lower scores in all domains than those with chronic pain (non-POPNO) (P < 0.001). These results were the same after applying each statistical method Conclusions In this study, the choice of statistical approach had no influence on the results. We conclude that the conventional approach, using straightforward parametric tests, is both simplest and the best for allowing comparison with other studies. We are likely to adopt this in future studies.

Objective To define patient-centredness from the patient's perspective in the context of physiotherapy for chronic low back pain (CLBP). Design Qualitative study using semi-structured interviews to explore perceptions of various aspects of physiotherapy management of CLBP. Setting Physiotherapy departments in one geographical area of the UK National Health Service. Participants Twenty-five individuals who had received physiotherapy for CLBP within the previous 6 months. Results Six key themes emerged as the dimensions that the participants perceived to be important for patient-centred physiotherapy: communication; individual care; decision-making; information; the physiotherapist; and organisation of care. Communication was the most important dimension, underpinning the five other dimensions as well as being a distinct dimension of patient-centred physiotherapy. Conclusions Physiotherapists should have an understanding of the six dimensions of patient-centred physiotherapy for CLBP. Improving physiotherapists’ communication skills may better facilitate patient-centred physiotherapy, and therefore enhance the experience of physiotherapy for this client group.

Genetic determinants of cognition are poorly characterized, and their relationship to genes that confer risk for neurodevelopmental disease is unclear. Here we performed a systems-level analysis of genome-wide gene expression data to infer gene-regulatory networks conserved across species and brain regions. Two of these networks, M1 and M3, showed replicable enrichment for common genetic variants underlying healthy human cognitive abilities, including memory. Using exome sequence data from 6,871 trios, we found that M3 genes were also enriched for mutations ascertained from patients with neurodevelopmental disease generally, and intellectual disability and epileptic encephalopathy in particular. M3 consists of 150 genes whose expression is tightly developmentally regulated, but which are collectively poorly annotated for known functional pathways. These results illustrate how systems-level analyses can reveal previously unappreciated relationships between neurodevelopmental disease–associated genes in the developed human brain, and provide empirical support for a convergent gene-regulatory network influencing cognition and neurodevelopmental disease.

Background Several regions of the genome have shown to be associated with COPD in genome-wide association studies of common variants. Objective To determine rare and potentially functional single nucleotide polymorphisms (SNPs) associated with the risk of COPD and severity of airflow limitation. Methods 3226 current or former smokers of European ancestry with lung function measures indicative of Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2 COPD or worse were genotyped using an exome array. An analysis of risk of COPD was carried out using ever smoking controls (n=4784). Associations with %predicted FEV1 were tested in cases. We followed-up signals of interest (p−5) in independent samples from a subset of the UK Biobank population and also undertook a more powerful discovery study by meta-analysing the exome array data and UK Biobank data for variants represented on both arrays. Results Among the associated variants were two in regions previously unreported for COPD; a low frequency non-synonymous SNP in MOCS3 (rs7269297, pdiscovery=3.08×10−6, preplication=0.019) and a rare SNP in IFIT3, which emerged in the meta-analysis (rs140549288, pmeta=8.56×10−6). In the meta-analysis of % predicted FEV1 in cases, the strongest association was shown for a splice variant in a previously unreported region, SERPINA12 (rs140198372, pmeta=5.72×10−6). We also confirmed previously reported associations with COPD risk at MMP12, HHIP, GPR126 and CHRNA5. No associations in novel regions reached a stringent exome-wide significance threshold (p−7). Conclusions This study identified several associations with the risk of COPD and severity of airflow limitation, including novel regions MOCS3, IFIT3 and SERPINA12, which warrant further study.

Chronic pain is a common, complex, and challenging condition, where understanding the biological, social, physical and psychological contexts is vital to successful outcomes in primary care. In managing chronic pain the focus is often on promoting rehabilitation and maximizing quality of life rather than achieving cure. Recent screening tools and brief intervention techniques can be effective in helping clinicians identify, stratify and manage both patients already living with chronic pain and those who are at risk of developing chronic pain from acute pain. Frequent assessment and re-assessment are key to ensuring treatment is appropriate and safe, as well as minimizing and addressing side effects. Primary care management should be holistic and evidence-based (where possible) and incorporates both pharmacological and non-pharmacological approaches, including psychology, self-management, physiotherapy, peripheral nervous system stimulation, complementary therapies and comprehensive pain-management programmes. These may either be based wholly in primary care or supported by appropriate specialist referral.

Contains fulltext : 167137.pdf (Publisher’s version ) (Closed access) Educational attainment is strongly influenced by social and other environmental factors, but genetic factors are estimated to account for at least 20% of the variation across individuals. Here we report the results of a genome-wide association study (GWAS) for educational attainment that extends our earlier discovery sample of 101,069 individuals to 293,723 individuals, and a replication study in an independent sample of 111,349 individuals from the UK Biobank. We identify 74 genome-wide significant loci associated with the number of years of schooling completed. Single-nucleotide polymorphisms associated with educational attainment are disproportionately found in genomic regions regulating gene expression in the fetal brain. Candidate genes are preferentially expressed in neural tissue, especially during the prenatal period, and enriched for biological pathways involved in neural development. Our findings demonstrate that, even for a behavioural phenotype that is mostly environmentally determined, a well-powered GWAS identifies replicable associated genetic variants that suggest biologically relevant pathways. Because educational attainment is measured in large numbers of individuals, it will continue to be useful as a proxy phenotype in efforts to characterize the genetic influences of related phenotypes, including cognition and neuropsychiatric diseases.

Background. Neuropathic pain is widely recognized as one of the most difficult pain syndromes to treat and presents a significant challenge for pain clinicians and GPs. Methods. The Self-complete Leeds Assessment of Neuropathic Symptoms and Signs (S-LANSS) questionnaire, recently validated for identifying pain of predominantly neuropathic origin (POPNO), was sent to 6000 adults identified from general practices in the UK. The questionnaire also contained items about chronic pain identification, medications and treatments received for pain and the pain relief these provided. Results. In total, 1420/3002 (48%) of respondents indicated that they suffered with any chronic pain. These were further categorized as those with chronic pain who were S-LANSS negative [‘chronic pain (non-POPNO)’ group, n = 1179] and those with chronic pain who were S-LANSS positive, indicating the presence of POPNO (‘chronic POPNO’ group, n = 241). Questions relating to treatments and medications were completed by 88% of the respondents (1244/1420). The chronic POPNO group was more likely to receive multiple pain medications (37% versus 21% took two or more pain medications, P < 0.001) and stronger painkillers [e.g. opioids odds ratio 1.94; 95% confidence interval 1.10, 3.42]. Despite this, they reported less effective pain relief than the non-POPNO chronic pain group. Conclusion. Patients in primary care reporting chronic pain were found generally to obtain incomplete relief from their medication with chronic POPNO patients reporting less relief. It is important that patients with any chronic pain are identified and managed appropriately according to their distinct treatment needs. Keywords. Chronic pain, neuropathic pain, primary care, S-LANSS, treatment.

To assess the health and quality of life associated with chronic pain of predominantly neuropathic origin (POPNO) on health and daily activity in the general population.The Self-complete Leeds Assessment of Neuropathic Symptoms and Signs (S-LANSS) questionnaire, recently validated for identifying pain of predominantly neuropathic origin, was sent to 6000 adults identified from general practices in the United Kingdom, along with chronic pain identification and severity questions, the Brief Pain Inventory (BPI), the Neuropathic Pain Scale, and the SF-36 general health questionnaire.With a corrected response rate of 52%, 3 groups of respondents were identified: those without chronic pain ("No Chronic Pain" group, n=1537); those with chronic pain who were S-LANSS positive indicating the presence of POPNO ("Chronic POPNO" group, n =241); and those with chronic pain who were S-LANSS negative ["Chronic Pain (non-POPNO)" group, n=1179]. The chronic POPNO group reported higher pain severity and had significantly poorer scores for all interference items of the BPI than those with chronic pain (non-POPNO). Mean scores from the Neuropathic Pain Scale were also significantly higher for the Chronic POPNO group. There were significant differences between the groups in all domains of the SF-36, with the Chronic POPNO group reporting the worst health. After adjusting for pain severity, age, and sex, the chronic POPNO group was still found to have poorer scores than the other Chronic Pain (non-POPNO) group in all domains of the SF-36 and all interference items in the BPI, indicating poorer health and greater disability.This study confirms the importance of identifying neuropathic pain in the community, and the need for multidimensional management strategies that address all aspects of health.

Neuroticism is a personality trait of fundamental importance for psychological well-being and public health. It is strongly associated with major depressive disorder (MDD) and several other psychiatric conditions. Although neuroticism is heritable, attempts to identify the alleles involved in previous studies have been limited by relatively small sample sizes. Here we report a combined meta-analysis of genome-wide association study (GWAS) of neuroticism that includes 91 370 participants from the UK Biobank cohort, 6659 participants from the Generation Scotland: Scottish Family Health Study (GS:SFHS) and 8687 participants from a QIMR (Queensland Institute of Medical Research) Berghofer Medical Research Institute (QIMR) cohort. All participants were assessed using the same neuroticism instrument, the Eysenck Personality Questionnaire-Revised (EPQ-R-S) Short Form’s Neuroticism scale. We found a single-nucleotide polymorphism-based heritability estimate for neuroticism of ∼15% (s.e.=0.7%). Meta-analysis identified nine novel loci associated with neuroticism. The strongest evidence for association was at a locus on chromosome 8 (P=1.5 × 10−15) spanning 4 Mb and containing at least 36 genes. Other associated loci included interesting candidate genes on chromosome 1 (GRIK3 (glutamate receptor ionotropic kainate 3)), chromosome 4 (KLHL2 (Kelch-like protein 2)), chromosome 17 (CRHR1 (corticotropin-releasing hormone receptor 1) and MAPT (microtubule-associated protein Tau)) and on chromosome 18 (CELF4 (CUGBP elav-like family member 4)). We found no evidence for genetic differences in the common allelic architecture of neuroticism by sex. By comparing our findings with those of the Psychiatric Genetics Consortia, we identified a strong genetic correlation between neuroticism and MDD and a less strong but significant genetic correlation with schizophrenia, although not with bipolar disorder. Polygenic risk scores derived from the primary UK Biobank sample captured ∼1% of the variance in neuroticism in the GS:SFHS and QIMR samples, although most of the genome-wide significant alleles identified within a UK Biobank-only GWAS of neuroticism were not independently replicated within these cohorts. The identification of nine novel neuroticism-associated loci will drive forward future work on the neurobiology of neuroticism and related phenotypes.

The heritability of Major Depressive Disorder (MDD) has been estimated at 37% based largely on twin studies that rely on contested assumptions. More recently, the heritability of MDD has been estimated on large populations from registries such as the Swedish, Finnish, and Chinese cohorts. Family-based designs utilise a number of different relationships and provide an alternative means of estimating heritability. Generation Scotland: Scottish Family Health Study (GS:SFHS) is a large (n = 20,198), family-based population study designed to identify the genetic determinants of common diseases, including Major Depressive Disorder. Two thousand seven hundred and six individuals were SCID diagnosed with MDD, 13.5% of the cohort, from which we inferred a population prevalence of 12.2% (95% credible interval: 11.4% to 13.1%). Increased risk of MDD was associated with being female, unemployed due to a disability, current smokers, former drinkers, and living in areas of greater social deprivation. The heritability of MDD in GS:SFHS was between 28% and 44%, estimated from a pedigree model. The genetic correlation of MDD between sexes, age of onset, and illness course were examined and showed strong genetic correlations. The genetic correlation between males and females with MDD was 0.75 (0.43 to 0.99); between earlier (≤ age 40) and later (> age 40) onset was 0.85 (0.66 to 0.98); and between single and recurrent episodic illness course was 0.87 (0.72 to 0.98). We found that the heritability of recurrent MDD illness course was significantly greater than the heritability of single MDD illness course. The study confirms a moderate genetic contribution to depression, with a small contribution of the common family environment (variance proportion = 0.07, CI: 0.01 to 0.15), and supports the relationship of MDD with previously identified risk factors. This study did not find robust support for genetic differences in MDD due to sex, age of onset, or illness course. However, we found an intriguing difference in heritability between recurrent and single MDD illness course. These findings establish GS:SFHS as a valuable cohort for the genetic investigation of MDD.

Background: Individuals with exceptional longevity and their offspring have significantly larger high-density lipoprotein concentrations (HDL-C) particle sizes due to the increased homozygosity for the I405V variant in the cholesteryl ester transfer protein (CETP) gene. In this study, we investigate the association of CETP and HDL-C further to identify novel, independent CETP variants associated with HDL-C in humans. Methods: We performed a meta-analysis of HDL-C within the CETP region using 59,432 individuals imputed with 1000 Genomes data. We performed replication in an independent sample of 47,866 individuals and validation was done by Sanger sequencing. Results: The meta-analysis of HDL-C within the CETP region identified five independent variants, including an exonic variant and a common intronic insertion. We replicated these 5 variants significantly in an independent sample of 47,866 individuals. Sanger sequencing of the insertion within a single family confirmed segregation of this variant. The strongest reported association between HDL-C and CETP variants, was rs3764261; however, after conditioning on the five novel variants we identified the support for rs3764261 was highly reduced (βunadjusted=3.179 mg/dl (P value=5.25×10−509), βadjusted=0.859 mg/dl (P value=9.51×10−25)), and this finding suggests that these five novel variants may partly explain the association of CETP with HDL-C. Indeed, three of the five novel variants (rs34065661, rs5817082, rs7499892) are independent of rs3764261. Conclusions: The causal variants in CETP that account for the association with HDL-C remain unknown. We used studies imputed to the 1000 Genomes reference panel for fine mapping of the CETP region. We identified and validated five variants within this region that may partly account for the association of the known variant (rs3764261), as well as other sources of genetic contribution to HDL-C.

Introduction: Biobank-type studies are typically large but have very low participation rates. It has been suggested that these studies may provide biased estimates of prevalence but are likely to provide valid estimates of association. We test these hypotheses using data collected on pain in a large Biobank study in the United Kingdom. Methods: UK Biobank recruited 503,325 persons aged 40–69 years (participation rate 5.5%). Participants completed questionnaires, including pain, lifestyle and environment factors. As a comparison, we used both a large population study of pain (MUSICIAN: n = 8847, aged: 40–69 years) conducted 2008–2009 and the National Child Development study (NCDS) which recruited all persons in Great Britain born during one week of 1958 and followed them up at age 44 years ( n = 9377). Results: ‘Any pain’ (UK Biobank 61.0%; MUSICIAN 63.9%), chronic pain (42.9%, 52.2%) and site-specific musculoskeletal pain (back 26.2%, 29.7%; shoulder/neck 23.3%, 25.3%) were generally similar in UK Biobank and MUSICIAN. The prevalence of chronic pain and most regional musculoskeletal pains in UK Biobank were all within 2% of that in NCDS. Conclusion: UK Biobank has provided estimates of the prevalence of pain which are similar to those from previous large-scale studies, although a formal comparison of the estimates cannot be made. It has also confirmed known associations with the reporting of pain. Despite its very low participation rate, such a study provides the opportunity to investigate novel exposure–pain relationships and investigate rarer exposures and characteristics to further our knowledge of the epidemiology of pain.

Chronic pain is common and complex and has a large impact on individuals and society. Good epidemiological pain data provide key information on the use of resources (both in general practice and in specialist clinics), insight into factors that lead to or favour chronicity and the design of interventions aimed at reducing or preventing the effects of chronic pain. This review aims to highlight the important factors associated with chronic pain, including those factors which are amenable to lifestyle intervention.

For genetic research to contribute more fully to furthering our knowledge of neuropathic pain, we require an agreed, valid, and feasible approach to phenotyping, to allow collaboration and replication in samples of sufficient size. Results from genetic studies on neuropathic pain have been inconsistent and have met with replication difficulties, in part because of differences in phenotypes used for case ascertainment. Because there is no consensus on the nature of these phenotypes, nor on the methods of collecting them, this study aimed to provide guidelines on collecting and reporting phenotypes in cases and controls for genetic studies. Consensus was achieved through a staged approach: (1) systematic literature review to identify all neuropathic pain phenotypes used in previous genetic studies; (2) Delphi survey to identify the most useful neuropathic pain phenotypes and their validity and feasibility; and (3) meeting of experts to reach consensus on the optimal phenotype(s) to be collected from patients with neuropathic pain for genetic studies. A basic "entry level" set of phenotypes was identified for any genetic study of neuropathic pain. This set identifies cases of "possible" neuropathic pain, and controls, and includes: (1) a validated symptom-based questionnaire to determine whether any pain is likely to be neuropathic; (2) body chart or checklist to identify whether the area of pain distribution is neuroanatomically logical; and (3) details of pain history (intensity, duration, any formal diagnosis). This NeuroPPIC "entry level" set of phenotypes can be expanded by more extensive and specific measures, as determined by scientific requirements and resource availability.

Background Chronic pain can contribute to disability, depression, anxiety, sleep disturbances, poor quality of life and increased health care costs, with close to 20 % of the adult population in Europe reporting chronic pain. To empower the person to self-manage, it is advocated that education and training about the nature of pain and its effects and how to live with pain is provided. The objective of this review is to determine the level of evidence for education to facilitate knowledge about chronic pain, delivered as a stand-alone intervention for adults, to reduce pain and disability. Methods We identified randomised controlled trials of educational intervention for chronic pain by searching CENTRAL, MEDLINE, EMBASE and ongoing trials registries (inception to December 2013). Main inclusion criteria were (1) pain >3 months; (2) study design that allowed isolation of effects of education and (3) measures of pain or disability. Two reviewers independently screened and appraised each study. Results Nine studies were analysed. Pooled data from five studies, where the comparator group was usual care, showed no improvement in pain or disability. In the other four studies, comparing different types of education, there was no evidence for an improvement in pain; although, there was evidence (from one study) of a decrease in disability with a particular form of education—pain neurophysiology education (PNE). Post-hoc analysis of psychosocial outcomes reported in the studies showed evidence of a reduction in catastrophising and an increase of knowledge about pain following PNE. Conclusions The evidence base is limited by the small numbers of studies, their relatively small sample sizes, and the diversity in types of education studied. From that limited evidence, the only support for this type of education is for PNE, though it is insufficiently strong to recommend conclusively that PNE should be delivered as a stand-alone intervention. It therefore remains sensible to recommend that education be delivered in conjunction with other pain management approaches as we cannot confidently conclude that education alone is effective in reducing pain intensity or related disability in chronic pain in adults. Electronic supplementary material The online version of this article (doi:10.1186/s13643-015-0120-5) contains supplementary material, which is available to authorized users.

An association between blood markers of thrombosis and haemostasis and cognitive decline has been described. These results may be confounded by lifestyle and environmental factors. We used a Mendelian randomisation approach to describe the association between thrombosis/haemostasis genotypes and cognition. We studied the genetic variants (single nucleotide polymorphisms) of circulating markers of thrombosis and haemostasis. Our chosen blood factors and associated polymorphisms were D-dimer [rs12029080], fibrinogen [rs1800789], plasminogen activator inhibitor [rs2227631], and von Willebrand factor [rs1063857]. We described association with multidomain cognitive test scores using data from the Scottish Family Health Study. Cognitive data were analysed for individual tests and combined to give a general cognitive factor. In 20,288 subjects, we found no evidence of association between cognitive function (individual tests and combined scores) and any of the above-mentioned single nucleotide polymorphisms. Lower scores on cognitive measures were associated with increasing age, socioeconomic deprivation, blood pressure, waist-hip ratio, smoking, and vascular comorbidity (all p < 0.001). In a post hoc sensitivity analysis restricted to those aged over 50 years, there was still no signal of association. Our data add to our understanding of determinants of cognition but are not definitive; the variation in blood levels explained by SNPs was modest and our sample size may have been insufficient to detect a modest association.

The reported prevalence of neuropathic pain ranges from 6.9% to 10%; however the only Canadian study reported 17.9%. The objective of this study was to describe the epidemiology of neuropathic pain in Canada. A cross-sectional survey was conducted in a random sample of Canadian adults. The response rate was 21.1% (1504/7134).Likelyorpossibleneuropathic pain was defined using a neuropathic pain-related diagnosis and a positive outcome on the Self-Report Leeds Assessment of Neuropathic Symptoms and Signs pain scale (S-LANSS) or the Douleur Neuropathique 4 (DN4) Questions. The prevalence oflikelyneuropathic pain was 1.9% (S-LANSS) and 3.4% (DN4) and that ofpossibleneuropathic pain was 5.8% (S-LANSS) and 8.1% (DN4). Neuropathic pain was highest in economically disadvantaged males. There is a significant burden of neuropathic pain in Canada. The low response rate and a slightly older and less educated sample than the Canadian population may have led to an overestimate of neuropathic pain. Population prevalence varies by screening tool used, indicating more work is needed to develop reliable measures. Population level screening targeted towards high risk groups should improve the sensitivity and specificity of screening, while clinical examination of those with positive screening results will further refine the estimate of prevalence.

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 characterised, 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 1,303 children with developmental disorders and 5,094 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 7,000 children with congenital diseases yielded an even stronger statistical enrichment (p value 1.784e-11). In addition, to maximize 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 1,303 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.

Maternal diabetes in pregnancy affects offspring health. The impact of parental diabetes on offspring health is unclear. We investigated the impact of parental diabetes on the metabolic-health of adult-offspring who did not themselves have diabetes. Data from the Generation Scotland: Scottish Family Health Study, a population-based family cohort, were record-linked to subjects’ own diabetes medical records. From F0-parents, we identified F1-offspring of: mothers with diabetes (OMD, n = 409), fathers with diabetes (OFD, n = 468), no parent with diabetes (ONoPD, n = 2489). Metabolic syndrome, body, biochemical measurements and blood-pressures were compared between F1-offspring groups by sex. A higher proportion of female OMD had metabolic syndrome than female OFD or ONoPD (P

Neuropathic pain is a priority health issue [5], which currently is the topic of the 2014–2015 Global Year Against Neuropathic Pain campaign of the International Association for the Study of Pain (http://www.iasp-pain.org/GlobalYear/NeuropathicPain). Between 6% and 10% of adults are affected by chronic pain with neuropathic features [6,14,25], and this prevalence is significantly greater among individuals with specific conditions. For example, neuropathic pain is a common comorbidity in infectious diseases such as HIV, leprosy, and herpes zoster, and in non-infectious conditions such as diabetes mellitus, stroke, multiple sclerosis, and traumatic limb and spinal cord injury [7,13,16,19,21]. The pain is associated with significant decreases in quality of life and socioeconomic well-being, even more so than non-neuropathic chronic pain [9,20,22]. Developing and emerging countries share the greatest burden of conditions that predispose to development of neuropathic pain [5,10], and can ill afford the negative consequences of this pain. There are medicines with proven efficacy in the treatment of neuropathic pain [11,12]. Nevertheless, the pain can be difficult to treat, with significant inter-individual variation in efficacy within and between drug classes, independent of the presumed aetiology of the neuropathy [2,4]. Effective management of neuropathic pain within a population therefore requires access to a small, but crucial group of drug classes with proven efficacy. The World Health Organization’s (WHO) model list of essential medicines (http://www.who.int/selection_medicines/list/en/) presents those medicines deemed necessary to meet priority health needs, and local implementation of essential medicines policies is associated with improved quality use of medicines [15,18]. But, none of the analgesic medicines included in the WHO model list are recommended as first-line treatments for neuropathic pain [11]. Thus the WHO model list is not a good framework from which national policies on managing neuropathic pain can be structured and countries routinely adapt the model list according to local needs and resources [18]. To estimate the nominal availability of medicines recommended for the treatment of neuropathic pain in developing and emerging countries, we assessed national essential medicines lists (NEMLs) for the inclusion of recommended treatments. We also assessed whether the coverage of recommended drugs classes on these NEMLs was dependent on countries’ economic status.

Alcohol dependence is frequently co‐morbid with cognitive impairment. The relationship between these traits is complex as cognitive dysfunction may arise as a consequence of heavy drinking or exist prior to the onset of dependence. In the present study, we tested the genetic overlap between cognitive abilities and alcohol dependence using polygenic risk scores (PGRS). We created two independent PGRS derived from two recent genome‐wide association studies (GWAS) of alcohol dependence (SAGE GWAS: n = 2750; Yale‐Penn GWAS: n = 2377) in a population‐based cohort, Generation Scotland: Scottish Family Health Study (GS:SFHS) (n = 9863). Data on alcohol consumption and four tests of cognitive function [Mill Hill Vocabulary (MHV), digit symbol coding, phonemic verbal fluency (VF) and logical memory] were available. PGRS for alcohol dependence were negatively associated with two measures of cognitive function: MHV (SAGE: P = 0.009, β = −0.027; Yale‐Penn: P = 0.001, β = −0.034) and VF (SAGE: P = 0.0008, β = −0.036; Yale‐Penn: P = 0.00005, β = −0.044). VF remained robustly associated after adjustment for education and social deprivation; however, the association with MHV was substantially attenuated. Shared genetic variants may account for some of the phenotypic association between cognitive ability and alcohol dependence. A significant negative association between PGRS and social deprivation was found (SAGE: P = 5.2 × 10−7, β = −0.054; Yale‐Penn: P = 0.000012, β = −0.047). Individuals living in socially deprived regions were found to carry more alcohol dependence risk alleles which may contribute to the increased prevalence of problem drinking in regions of deprivation. Future work to identify genes which affect both cognitive impairment and alcohol dependence will help elucidate biological processes common to both disorders.

As an epidemiologist, I knew that I had none of the main risk factors for colorectal carcinoma.1 As a GP, I always had an irrational horror of per rectum investigation, colonoscopy being the one I prayed I would never need. Therefore, when my only symptom was intermittent, painless rectal bleeding, I made the standard response of a clinical academic meeting a concept outwith his or her paradigm. I ignored it. Well, it was probably just haemorrhoids, or something; I was otherwise fit and healthy, and I was far too busy and important to spend all that time attending clinics and being investigated. I was probably also reluctant to expose myself to the indignity and vulnerability of intimate examination by my professional colleagues. It was only after several months (or probably more) that I had an actual conversation with myself, in which part of me was a layman seeking informal advice from my medical self. Not until I heard my response — ‘For goodness’ sake, go and see your GP immediately! …

INTRODUCTION We compared the prevalence of chronic back pain (CBP) at two points 4 years apart and examined socio-demographic, health, and pain-related factors associated with its onset and persistence. METHOD A random population sample of 2,184 adults was surveyed in 1996 and resurveyed in 2000. The questionnaire included chronic pain case definition questions (pain for 3 months or longer); the cause (1996) or site (2000) of any chronic pain; the Chronic Pain Grade questionnaire; the Level of Expressed Need (LEN) questionnaire; the SF-36 general health questionnaire; and demographic questions. Those with CBP in 1996 and 2000 had "persistent" CBP; those with CBP in 1996 but not 2000 had "recovered" CBP; those with CBP in 2000 but not 1996 had "new" CBP. RESULTS Corrected response rates were 82.3% (1996) and 83.0% (2000). The sample prevalence of CBP was 16% (1996) and 27% (2000). Factors in 1996 independently associated with "persistent" compared with "recovered" CBP were preexisting arthritis, high LEN, poor mental health, and not living alone. Factors independently predicting "new" CBP compared with no previous CBP were previous chronic pain elsewhere and poor physical health. "Persistent" CBP was associated with more severe pain, higher LEN, and poorer general health than "new" CBP. DISCUSSION CBP is a common and lasting problem, whose persistence and onset are predicted by clinical (especially pain) and help-seeking behavior factors, rather than socio-demographic. Prevention should focus on these factors.

Chronic pain is a common problem affecting about half of the general population. This has implications for the utilization of both conventional and alternative health services.The aim of this study was to determine the use of conventional and alternative practitioners and medicines amongst individuals with chronic pain in the community.A total of 2422 individuals from a previous population-based survey in the Grampian region of the UK, who agreed to participate in further research, were sent a postal questionnaire. The questionnaire enquired about the presence, type and severity of chronic pain, socio-demographic details, consultations with conventional and alternative practitioners, and the consumption of conventional and alternative medicines. The main outcome measures were the number and frequency of self-reported consultations with GPs, hospital specialists, physical therapists and alternative therapists, and the consumption of prescription, non-prescription and alternative medicines amongst those with chronic pain.Of the 840 individuals reporting chronic pain, 67.2% had seen their GP, 34.0% a hospital specialist, 25.9% a physical therapist and 18.2% an alternative therapist in the preceding year. Prescription medicines had been taken by 58.4%, non-prescription medicines by 57.4% and alternative medicines by 15.7% of individuals with chronic pain. The majority (67.0%) of individuals with chronic pain who sought alternative health care did so in conjunction with conventional health care. Differences in consultations with practitioners and consumption of medicines were found by age, sex, socio-economic status, site of pain and severity of pain.Individuals with chronic pain consult their GP about their pain more than other practitioners and use conventional medicines more frequently than alternative medicines. Alternative health care is used most commonly in addition to conventional health care, although a small number of individuals with chronic pain use alternative care exclusively. The use of alternative health care amongst those with chronic pain is higher than previously estimated and suggests that the use of these services may be increasing amongst those with chronic pain.

INTRODUCTION: The General Practice Airways Group's Professional Development programme promotes the evidence-based management of acute asthma in line with current guidelines. METHOD: 4 GP practices, 2 Out-of-Hours services and 2 nurse-run Walk-In Centres were recruited to this pilot study. Participants provided organisational data and undertook a critical event analysis of acute attacks. Results were fed back prior to attendance at the GPIAG/NRTC Congress. The audit was repeated after six months. Feasibility and acceptability were assessed with evaluation questionnaires. RESULTS: Baseline data from 7 centres (160 attacks) suggested that management guidelines are not being fully adhered to. For practical reasons only four of the organisations attended the Congress. Organisations successfully formulated their own development plans: one introduced a standard proforma, one commissioned in-service training and two acquired a supply of steroids. Follow-up data was submitted by 5 organisations. (98 attacks) Programme evaluations were generally positive: the audit protocol was practical in all three settings, the feedback was appreciated and the educational intervention was well received by those able to attend. CONCLUSION: This pilot study has provided useful information on which to base the future development of the GPIAG acute asthma professional development programme. The initiative has been well received and innovation has been facilitated. Future projects should consider more flexible, local provision of workshops.

Background: Individuals with exceptional longevity and their offspring have significantly larger high-density lipoprotein concentrations (HDL-C) particle sizes due to the increased homozygosity for the I405V variant in the cholesteryl ester transfer protein (CETP) gene. In this study, we investigate the association of CETP and HDL-C further to identify novel, independent CETP variants associated with HDL-C in humans. Methods: We performed a meta-analysis of HDL-C within the CETP region using 59,432 individuals imputed with 1000 Genomes data. We performed replication in an independent sample of 47,866 individuals and validation was done by Sanger sequencing. Results: The meta-analysis of HDL-C within the CETP region identified five independent variants, including an exonic variant and a common intronic insertion. We replicated these 5 variants significantly in an independent sample of 47,866 individuals. Sanger sequencing of the insertion within a single family confirmed segregation of this variant. The strongest reported association between HDL-C and CETP variants, was rs3764261; however, after conditioning on the five novel variants we identified the support for rs3764261 was highly reduced (βunadjusted=3.179 mg/dl (P value=5.25×10−509), βadjusted=0.859 mg/dl (P value=9.51×10−25)), and this finding suggests that these five novel variants may partly explain the association of CETP with HDL-C. Indeed, three of the five novel variants (rs34065661, rs5817082, rs7499892) are independent of rs3764261. Conclusions: The causal variants in CETP that account for the association with HDL-C remain unknown. We used studies imputed to the 1000 Genomes reference panel for fine mapping of the CETP region. We identified and validated five variants within this region that may partly account for the association of the known variant (rs3764261), as well as other sources of genetic contribution to HDL-C.

Chronic pain has been recognized as pain that persists past normal healing time5 and hence lacks the acute warning function of physiological nociception.35 Usually pain is regarded as chronic when it lasts or recurs for more than 3 to 6 months.29 Chronic pain is a frequent condition, affecting an estimated 20% of people worldwide6,13,14,18 and accounting for 15% to 20% of physician visits.25,28 Chronic pain should receive greater attention as a global health priority because adequate pain treatment is a human right, and it is the duty of any health care system to provide it.4,13 The current version of the International Classification of Diseases (ICD) of the World Health Organization (WHO) includes some diagnostic codes for chronic pain conditions, but these diagnoses do not reflect the actual epidemiology of chronic pain, nor are they categorized in a systematic manner. The ICD is the preeminent tool for coding diagnoses and documenting investigations or therapeutic measures within the health care systems of many countries. In addition, ICD codes are commonly used to report target diseases and comorbidities of participants in clinical research. Consequently, the current lack of adequate coding in the ICD makes the acquisition of accurate epidemiological data related to chronic pain difficult, prevents adequate billing for health care expenses related to pain treatment, and hinders the development and implementation of new therapies.10,11,16,23,27,31,37 Responding to these shortcomings, the International Association for the Study of Pain (IASP) contacted the WHO and established a Task Force for the Classification of Chronic Pain. The IASP Task Force, which comprises pain experts from across the globe,19 has developed a new and pragmatic classification of chronic pain for the upcoming 11th revision of the ICD. The goal is to create a classification system that is applicable in primary care and in clinical settings for specialized pain management. A major challenge in this process was finding a rational principle of classification that suits the different types of chronic pain and fits into the general ICD-11 framework. Pain categories are variably defined based on the perceived location (headache), etiology (cancer pain), or the primarily affected anatomical system (neuropathic pain). Some diagnoses of pain defy these classification principles (fibromyalgia). This problem is not unique to the classification of pain, but exists throughout the ICD. The IASP Task Force decided to give first priority to pain etiology, followed by underlying pathophysiological mechanisms, and finally the body site. Developing this multilayered classification was greatly facilitated by a novel principle of assigning diagnostic codes in ICD-11, termed “multiple parenting.” Multiple parenting allows the same diagnosis to be subsumed under more than 1 category (for a glossary of ICD terms refer to Table ​Table1).1). Each diagnosis retains 1 category as primary parent, but is cross-referenced to other categories that function as secondary parents. Table 1 Glossary of ICD-11 terms. The new ICD category for “Chronic Pain” comprises the most common clinically relevant disorders. These disorders were divided into 7 groups (Fig. ​(Fig.1):1): (1) chronic primary pain, (2) chronic cancer pain, (3) chronic posttraumatic and postsurgical pain, (4) chronic neuropathic pain, (5) chronic headache and orofacial pain, (6) chronic visceral pain, and (7) chronic musculoskeletal pain. Experts assigned to each group are responsible for the definition of diagnostic criteria and the selection of the diagnoses to be included under these subcategories of chronic pain. Thanks to Bedirhan Ustun and Robert Jakob of the WHO, these pain diagnoses are now integrated in the beta version of ICD-11 (http://id.who.int/icd/entity/1581976053). The Task Force is generating content models for single entities to describe their clinical characteristics. After peer review overseen by the WHO Steering Committee,39 the classification of chronic pain will be voted into action by the World Health Assembly in 2017. Figure 1 Organizational chart of Task Force, IASP, and WHO interactions. The IASP Task Force was created by the IASP council and its scope defined in direct consultation of the chairs (R.D.T. and W.R.) with WHO representatives in 2012. The Task Force reports to ... 2. Classification of chronic pain Chronic pain was defined as persistent or recurrent pain lasting longer than 3 months. This definition according to pain duration has the advantage that it is clear and operationalized. Optional specifiers for each diagnosis record evidence of psychosocial factors and the severity of the pain. Pain severity can be graded based on pain intensity, pain-related distress, and functional impairment. 2.1. Chronic primary pain Chronic primary pain is pain in 1 or more anatomic regions that persists or recurs for longer than 3 months and is associated with significant emotional distress or significant functional disability (interference with activities of daily life and participation in social roles) and that cannot be better explained by another chronic pain condition. This is a new phenomenological definition, created because the etiology is unknown for many forms of chronic pain. Common conditions such as, eg, back pain that is neither identified as musculoskeletal or neuropathic pain, chronic widespread pain, fibromyalgia, and irritable bowel syndrome will be found in this section and biological findings contributing to the pain problem may or may not be present. The term “primary pain” was chosen in close liaison with the ICD-11 revision committee, who felt this was the most widely acceptable term, in particular, from a nonspecialist perspective.

BACKGROUND: New drug treatments, clinical trials, and standards of quality for assessment of evidence justify an update of evidence-based recommendations for the pharmacological treatment of neuropathic pain. Using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE), we revised the Special Interest Group on Neuropathic Pain (NeuPSIG) recommendations for the pharmacotherapy of neuropathic pain based on the results of a systematic review and meta-analysis.METHODS: Between April, 2013, and January, 2014, NeuPSIG of the International Association for the Study of Pain did a systematic review and meta-analysis of randomised, double-blind studies of oral and topical pharmacotherapy for neuropathic pain, including studies published in peer-reviewed journals since January, 1966, and unpublished trials retrieved from ClinicalTrials.gov and websites of pharmaceutical companies. We used number needed to treat (NNT) for 50% pain relief as a primary measure and assessed publication bias; NNT was calculated with the fixed-effects Mantel-Haenszel method.FINDINGS: 229 studies were included in the meta-analysis. Analysis of publication bias suggested a 10% overstatement of treatment effects. Studies published in peer-reviewed journals reported greater effects than did unpublished studies (r(2) 9·3%, p=0·009). Trial outcomes were generally modest: in particular, combined NNTs were 6·4 (95% CI 5·2-8·4) for serotonin-noradrenaline reuptake inhibitors, mainly including duloxetine (nine of 14 studies); 7·7 (6·5-9·4) for pregabalin; 7·2 (5·9-9·21) for gabapentin, including gabapentin extended release and enacarbil; and 10·6 (7·4-19·0) for capsaicin high-concentration patches. NNTs were lower for tricyclic antidepressants, strong opioids, tramadol, and botulinum toxin A, and undetermined for lidocaine patches. Based on GRADE, final quality of evidence was moderate or high for all treatments apart from lidocaine patches; tolerability and safety, and values and preferences were higher for topical drugs; and cost was lower for tricyclic antidepressants and tramadol. These findings permitted a strong recommendation for use and proposal as first-line treatment in neuropathic pain for tricyclic antidepressants, serotonin-noradrenaline reuptake inhibitors, pregabalin, and gabapentin; a weak recommendation for use and proposal as second line for lidocaine patches, capsaicin high-concentration patches, and tramadol; and a weak recommendation for use and proposal as third line for strong opioids and botulinum toxin A. Topical agents and botulinum toxin A are recommended for peripheral neuropathic pain only.INTERPRETATION: Our results support a revision of the NeuPSIG recommendations for the pharmacotherapy of neuropathic pain. Inadequate response to drug treatments constitutes a substantial unmet need in patients with neuropathic pain. Modest efficacy, large placebo responses, heterogeneous diagnostic criteria, and poor phenotypic profiling probably account for moderate trial outcomes and should be taken into account in future studies.FUNDING: NeuPSIG of the International Association for the Study of Pain.

Background— Smoking is an important cardiovascular disease risk factor, but the mechanisms linking smoking to blood pressure are poorly understood. Methods and Results— Data on 141 317 participants (62 666 never, 40 669 former, 37 982 current smokers) from 23 population-based studies were included in observational and Mendelian randomization meta-analyses of the associations of smoking status and smoking heaviness with systolic and diastolic blood pressure, hypertension, and resting heart rate. For the Mendelian randomization analyses, a genetic variant rs16969968/rs1051730 was used as a proxy for smoking heaviness in current smokers. In observational analyses, current as compared with never smoking was associated with lower systolic blood pressure and diastolic blood pressure and lower hypertension risk, but with higher resting heart rate. In observational analyses among current smokers, 1 cigarette/day higher level of smoking heaviness was associated with higher (0.21 bpm; 95% confidence interval 0.19; 0.24) resting heart rate and slightly higher diastolic blood pressure (0.05 mm Hg; 95% confidence interval 0.02; 0.08) and systolic blood pressure (0.08 mm Hg; 95% confidence interval 0.03; 0.13). However, in Mendelian randomization analyses among current smokers, although each smoking increasing allele of rs16969968/rs1051730 was associated with higher resting heart rate (0.36 bpm/allele; 95% confidence interval 0.18; 0.54), there was no strong association with diastolic blood pressure, systolic blood pressure, or hypertension. This would suggest a 7 bpm higher heart rate in those who smoke 20 cigarettes/day. Conclusions— This Mendelian randomization meta-analysis supports a causal association of smoking heaviness with higher level of resting heart rate, but not with blood pressure. These findings suggest that part of the cardiovascular risk of smoking may operate through increasing resting heart rate.

Little is known about the course of chronic pain in the community. Such information is needed for the prevention and management of chronic pain. We undertook a 4-year follow-up study of 2184 individuals living in Grampian, UK to describe patterns and predictors of change in chronic pain over time. In October 2000, participants completed a postal questionnaire including case definition questions, the chronic pain grade questionnaire, the SF-36 and socio-demographic questions. Information from this questionnaire was compared to information collected from a similar questionnaire in 1996. A response rate of 83% was achieved for the follow-up study. The overall prevalence of chronic pain (pain or discomfort present either all the time or on and off for 3 months or longer) increased from 45.5% at baseline to 53.8% at follow-up. Seventy-nine percent of those with chronic pain at baseline still had it at follow-up. The average annual incidence was 8.3% and the average annual recovery rate was 5.4%. Individuals in the study samples who are in lowest quartile of SF-36 domains--physical functioning, social functioning and bodily pain at baseline--were more likely to develop chronic pain at follow-up, and respondents who were retired were less likely to develop chronic pain. Individuals in the study samples in the lowest quartile of SF-36 domains, bodily pain and general health at baseline, were less likely to recover from their chronic pain, as were those aged 45-74 compared with those aged 25-34. We concluded that chronic pain is a common, persistent problem in the community with relatively high incidence and low recovery rates. The lack of association between onset or recovery from chronic pain and most traditional socio-demographic factors, highlights the need to broaden the range of factors included in studies of chronic pain aetiology.

© 2014 Schofield et al.; licensee BioMed Central Ltd. Background: The Engaging with older adults in the development of strategies for the self management of chronic pain (EOPIC) study aims to design and develop self management strategies to enable older adults to manage their own pain. Involving older adults in research into chronic pain management will better enable the identification and development of strategies that are more appropriate for their use, but how can perspectives really be utilised to the best possible outcomes?. Method. Seven older adults were recruited through a local advertising campaign to take part. We also invited participants from the local pain services, individuals who had been involved in earlier phase of the EOPIC study and a previous ESRC funded project. The group undertook library training and research skills training to facilitate searching of the literature and identified sources of material. A grading tool was developed using perceived essential criteria identified by the older adults and material was graded according to the criteria within this scale. Results: Fifty-seven resources from over twenty-eight sources were identified. These materials were identified as being easily accessible, readable and relevant. Many of the web based materials were not always easy to find or readily available so they were excluded by the participants. All but one were UK based. Forty-four items were identified as meeting the key criteria for inclusion in the study. This included five key categories as follows; books, internet, magazines, leaflets, CD's/Tapes. Conclusion: This project was able to identify a number of exemplars of self management material along with some general rules regarding the categories identified. We must point out that the materials identified were not age specific, were often locally developed and would need to be adapted to older adults with chronic pain. For copyright issues we have not included them in this paper. The key message is really related to the format rather than the content. However, the group acknowledge that these may vary according to the requirements of each individual older adult and therefore recommend the development of a leaflet to help others in their search for resources. This leaflet has been developed as part of Phase IV of the EOPIC study.

Background\ud Familial hypercholesterolaemia (FH) is a common Mendelian condition which, untreated, results in premature coronary heart disease. An estimated 88% of FH cases are undiagnosed in the UK. We previously validated a method for FH mutation detection in a lipid clinic population using next generation sequencing (NGS), but this did not address the challenge of identifying index cases in primary care where most undiagnosed patients receive healthcare. Here, we evaluate the targeted use of NGS as a potential route to diagnosis of FH in a primary care population subset selected for hypercholesterolaemia.\ud \ud Methods\ud We used microfluidics-based PCR amplification coupled with NGS and multiplex ligation-dependent probe amplification (MLPA) to detect mutations in LDLR, APOB and PCSK9 in three phenotypic groups within the Generation Scotland: Scottish Family Health Study including 193 individuals with high total cholesterol, 232 with moderately high total cholesterol despite cholesterol-lowering therapy, and 192 normocholesterolaemic controls.\ud \ud Results\ud Pathogenic mutations were found in 2.1% of hypercholesterolaemic individuals, in 2.2% of subjects on cholesterol-lowering therapy and in 42% of their available first-degree relatives. In addition, variants of uncertain clinical significance (VUCS) were detected in 1.4% of the hypercholesterolaemic and cholesterol-lowering therapy groups. No pathogenic variants or VUCS were detected in controls.\ud \ud Conclusions\ud We demonstrated that population-based genetic testing using these protocols is able to deliver definitive molecular diagnoses of FH in individuals with high cholesterol or on cholesterol-lowering therapy. The lower cost and labour associated with NGS-based testing may increase the attractiveness of a population-based approach to FH detection compared to genetic testing with conventional sequencing. This could provide one route to increasing the present low percentage of FH cases with a genetic diagnosis.

Chronic pain is a common and disabling condition, with a high impact on health and the health services in the community. The extent of help-seeking behaviour and factors that influence this are complex, but poorly understood. A simple, valid measure of help-seeking behaviour would be useful for community-based research, with a view to developing and evaluating interventions. The aims of the study were to test a hierarchical scale designed to measure help-seeking behaviour in chronic pain in postal surveys of the community, and to explore factors associated with responses. As part of a community survey of chronic pain, we developed the Level of Expressed Need (LEN) scale, based on questions about the use of treatment and professional advice for chronic pain. We compared this scale with two measures of chronic pain severity--the Chronic Pain Grade (CPG), and the Glasgow Pain Questionnaire (GPQ)--and analyzed associations with the SF36 general health questionnaire and demographic variables. Of 3605 respondents (corrected response rate 82%), 1817 reported chronic pain. Of these, 17% were at the mildest and 28% at the severest LEN. There were strong correlations with both the CPG (r=0.48) and the GPQ (r=0.55). There were, however, many important disparities in responses to these measures. Several other factors were independently associated with a high LEN in chronic pain: female gender, lower educational level, and physical, mental, pain and general health dimensions of the SF36 questionnaire. The LEN is a useful tool for measuring the help-seeking response to chronic pain in the general population. The findings confirm that this response is influenced by clinical and demographic factors in addition to the severity of the pain. Further development work will strengthen the instrument to explore these.

Chronic pain is known to be very common in the community. Less is known about the epidemiology of more significant or severe chronic pain. The impact of chronic pain in the community, in terms of general health, employment and interference with daily activity, has not been quantified.The aim of this study was to describe the prevalence and distribution in the community of chronic pain defined as 'significant' and 'severe', and to explore the impact of chronic pain on health and activity.A questionnaire survey was carried out of a sample drawn from the general population in the Grampian region of SCOTLAND: Questionnaires were sent to a random sample of 4611 individuals aged 25 years and over, stratified for age and gender, selected from the practice lists of 29 general practices (total practice population 136,383). The study instrument included a case definition questionnaire, from which were identified individuals with 'any chronic pain' (pain of at least 3 months duration). The instrument also included a level of expressed need questionnaire and the chronic pain grade questionnaire, from which were derived definitions for 'significant chronic pain' (based on the reported need for treatment and professional advice) and 'severe chronic pain' (based on reported intensity and pain-related disability). The SF-36 general health questionnaire and demographic questions were also included.Of the sample, 14.1% reported 'significant chronic pain', and this was more prevalent among women and older age groups. A total of 6.3% reported 'severe chronic pain', and this was more common in older age groups. On multiple logistic regression modelling, female gender, housing tenure, employment category and educational attainment were found to be independently associated with both 'significant' and 'severe' chronic pain. The presence of 'any', 'significant' and 'severe' chronic pain had progressively more marked adverse associations with employment, interference with daily activities and all measured dimensions of general health.Comparison of the epidemiology of 'significant chronic pain' and 'severe chronic pain' with 'any chronic pain' allows an understanding of the more clinically important end of the chronic pain spectrum. These results support the suggestion that chronic pain is multidimensional, both in its aetiology and in its effects, particularly at this end of the spectrum. This must be addressed in management and in further research.