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Proprotein convertase subtilisin kexin type 9 (PCSK9) inhibits the clearance of low-density lipoprotein (LDL) cholesterol (LDL-C) from plasma by directly binding with the LDL receptor (LDLR) and sending the receptor for lysosomal degradation. As the interaction promotes elevated plasma LDL-C levels, and therefore a predisposition to cardiovascular disease, PCSK9 has attracted intense interest as a therapeutic target. Despite this interest, an orally bioavailable small-molecule inhibitor of PCSK9 with extensive lipid-lowering activity is yet to enter the clinic. We report herein the discovery of NYX-PCSK9i, an orally bioavailable small-molecule inhibitor of PCSK9 with significant cholesterol-lowering activity in hyperlipidemic APOE∗3-Leiden.CETP mice. NYX-PCSK9i emerged from a medicinal chemistry campaign demonstrating potent disruption of the PCSK9-LDLR interaction in vitro and functional protection of the LDLR of human lymphocytes from PCSK9-directed degradation ex vivo. APOE∗3-Leiden.CETP mice orally treated with NYX-PCSK9i demonstrated a dose-dependent decrease in plasma total cholesterol of up to 57%, while its combination with atorvastatin additively suppressed plasma total cholesterol levels. Importantly, the majority of cholesterol lowering by NYX-PCSK9i was in non-HDL fractions. A concomitant increase in total plasma PCSK9 levels and significant increase in hepatic LDLR protein expression strongly indicated on-target function by NYX-PCSK9i. Determinations of hepatic lipid and fecal cholesterol content demonstrated depletion of liver cholesteryl esters and promotion of fecal cholesterol elimination with NYX-PCSK9i treatment. All measured in vivo biomarkers of health indicate that NYX-PCSK9i has a good safety profile. NYX-PCSK9i is a potential new therapy for hypercholesterolemia with the capacity to further enhance the lipid-lowering activities of statins.

Background\ud \ud Smoking is a well-documented risk for acute ST-segment elevation myocardial infarction (STEMI). The differential effect between sexes has yet to be quantified.\ud \ud \ud \ud Objectives\ud \ud The purpose of this study was to differentiate the effect of smoking on increased risk of STEMI between sexes.\ud \ud \ud \ud Methods\ud \ud For this retrospective ecological cohort study, all patients at a U.K. tertiary cardiothoracic center who presented between 2009 and 2014 with acute STEMI were combined with population data to generate incidence rates of STEMI. Age-standardized incidence rate ratios (IRRs) using the Poisson distribution were calculated comparing STEMI rates between smokers and nonsmokers stratified by sex and 3 age groups (18 to 49, 50 to 64, and >65 years).\ud \ud \ud \ud Results\ud \ud A total of 3,343 patients presented over 5,639,328 person-years. Peak STEMI rate for current smokers was in the 70 to 79 years age range for women (235 per 100,000 patient-years) and 50 to 59 years (425 per 100,000 patient-years) in men. Smoking was associated with a significantly greater increase in STEMI rate for women than men (IRR: 6.62; 95% confidence interval [CI]: 5.98 to 7.31, vs. 4.40; 95% CI: 4.15 to 4.67). The greatest increased risk was in women age 18 to 49 (IRR: 13.22; 95% CI: 10.33 to 16.66, vs. 8.60; 95% CI: 7.70 to 9.59 in men). The greatest risk difference was in the age 50 to 64 years group, with IRR of 9.66 (95% CI: 8.30 to 11.18) in women and 4.47 (95% CI: 4.10 to 4.86) in men.\ud \ud \ud \ud Conclusions\ud \ud This study quantifies the differential effect of smoking between sexes, with women having a significantly increased risk of STEMI than men. This information encourages continued efforts to prevent smoking uptake and promote cessation.

The "smoker's paradox", where smokers have improved survival post-myocardial infarction, was predominantly observed in the thrombolytic era. However, evidence for the smoker's paradox in the current era of PCI therapy is both limited and inconsistent. We aimed to examine the effect of smoking status on survival in unselected ST-elevation myocardial infarction (STEMI) patients managed by primary percutaneous coronary intervention (PCI). Data were collected for all patients with acute STEMI undergoing primary PCI at The South Yorkshire Cardiothoracic Centre, UK over a 5-year period between 2009 and 2014. Differences in survival by smoking status were assessed before and after adjustment for differences in baseline variables using a Kaplan-Meier curve and a Cox regression analysis, respectively. A total of 3133 STEMI patients were included in the study. After adjustment for differences in baseline variables, smoking was associated with a significantly increased mortality (hazard ratio 1.35 (95% CI 1.04-1.74)) compared to never smokers after 3 years. The risk for ex-smokers (hazard ratio 0.99 (0.76-1.28)) was similar to never smokers. There were no significant differences in survival by smoking status at 30 days and 1 year. In this large registry of STEMI patients managed by primary PCI, smokers had a significantly higher 3-year mortality than non-smokers. This study is the first to not only dispel the existence of the smoker's paradox, but to highlight a high-risk subgroup who may warrant tailored secondary prevention treatment, including smoking cessation.

ObjectivesThe aims of the present study were to assess the association and interactions of physical workload and poor health with health-related job loss (HRJL) among older workers, and the association and interactions of occupational social class and poor health with HRJL.MethodsData were used from an existing prospective cohort study, Health and Employment after Fifty, where employed or self-employed workers aged 50–64 years (n=4909) were followed-up between 2014 and 2016. Associations between potential determinants (self-perceived health status, physical workload and occupational social class) and 2-year HRJL were examined by Cox regression analyses. To study whether physical workload or occupational social class moderates the influence of poor health on HRJL, additive and multiplicative interactions were calculated.ResultsOlder workers with poor self-perceived health status had increased risk of HRJL during the 2-year follow-up period (men: HR 2.57 (95%CI: 1.68 to 3.92); women: HR 3.26 (95%CI: 2.33 to 4.55)). Furthermore, men with high physical workload were at increased risk for HRJL (HR 1.63 (95%CI: 1.09 to 2.43)). No significant interactions (pConclusionOur study indicates that older workers in poor health, and older workers with a physically demanding job, are at increased risk of HRJL. Having a physically demanding job or working in routine/manual occupations does not moderate the association between poor health and HRJL.

Issue : Medical educators and educational researchers continue to improve their processes for managing medical student and program evaluation data using sound ethical principles. This is becoming even more important as curricular innovations are occurring across undergraduate and graduate medical education. Dissemination of findings from this work is critical, and peer-reviewed journals often require an institutional review board (IRB) determination. Approach : IRB data repositories, originally designed for the longitudinal study of biological specimens, can be applied to medical education research. The benefits of such an approach include obtaining expedited review for multiple related studies within a single IRB application and allowing for more flexibility when conducting complex longitudinal studies involving large datasets from multiple data sources and/or institutions. In this paper, we inform educators and educational researchers on our analysis of the use of the IRB data repository approach to manage ethical considerations as part of best practices for amassing, pooling, and sharing data for educational research, evaluation, and improvement purposes. Implications : Fostering multi-institutional studies while following sound ethical principles in the study of medical education is needed, and the IRB data repository approach has many benefits, especially for longitudinal assessment of complex multi-site data. Keywords: educational research; ethical review; program evaluation; longitudinal assessment (Published: 20 July 2016) Citation: Med Educ Online 2016, 21 : 32021 - http://dx.doi.org/10.3402/meo.v21.32021

Proprotein convertase (PC) subtilisin kexin type 9 (PCSK9) inhibits the clearance of low density lipoprotein (LDL) cholesterol from plasma by directly interacting with the LDL receptor (LDLR). As the interaction promotes elevated plasma LDL cholesterol levels and a predisposition to cardiovascular disease (CVD), it has attracted much interest as a therapeutic target. While anti-PCSK9 monoclonal antibodies have been successful in the treatment of hypercholesteremia by decreasing CVD risk, their high cost and a requirement for injection have prohibited widespread use. The advent of an orally bioavailable small molecule inhibitor of the PCSK9-LDLR interaction is an attractive alternative, however efforts have been tempered as the binding interface is unfavourable for binding by small organic molecules. Despite its challenging nature, we report herein the discovery of compound 3f as a small molecule inhibitor of PCSK9. The kinase inhibitor nilotinib emerged from a computational screen that was applied to identify compounds that may bind to a cryptic groove within PCSK9 and proximal to the LDLR-binding interface. A subsequent in vitro PCSK9-LDLR binding assay established that nilotinib was a bona fide but modest inhibitor of the interaction (IC50 = 9.8 µM). Through multiple rounds of medicinal chemistry, 3f emerged as a lead-like molecule by demonstrating disruption of the PCSK9-LDLR interaction at nanomolar levels in vitro (IC50 = 537 nM) with no inhibitory activity (IC50 > 10 µM) against a small panel of kinases. Compound 3f restored LDL uptake by liver cells at sub-micromolar levels and demonstrated excellent bioavailability when delivered subcutaneously in mice. Most significantly, compound 3f lowered total cholesterol levels in the plasma of wild-type mice, thereby providing proof-of-concept that the notion of a small molecule inhibitor against PCSK9 is therapeutically viable.

Background Lower socioeconomic status (SES) has been associated with worse outcomes after acute myocardial infarction. Data for survival after ST-elevation myocardial infarction (STEMI) by SES in the current era of primary percutaneous coronary intervention (PCI) is more limited. Methods Data was collected for all patients with acute STEMI undergoing primary PCI at The South Yorkshire Cardiothoracic Centre, UK between 2009 and 2014. A Cox regression analysis was used to assess differences in survival by SES quartile (using an area-level measure). Results Of the 3126 STEMI patients, 2655 (84.9%) were first presentations of STEMI. Lower SES groups generally had a less favourable baseline cardiovascular risk factor profile, with higher rates of smoking (p = 0.001), diabetes (p = 0.007) and previous coronary heart disease (p = 0.025). With the exception of beta-blockers, the use of secondary preventative medications was similar between SES quartiles. Adjusting for age and gender, the most disadvantaged SES quartile trended to a non-significant increased mortality at 30 days (hazard ratio 1.35 (0.79–2.33)), 1 year (1.12 (0.76–1.65)), or 3 years (1.22 (0.88–1.70)) compared to the least disadvantaged SES quartile, but this was attenuated by adjusting for additional cardiovascular risk factors and medication use on discharge. Conclusions In this large study of unselected STEMI patients managed by primary PCI, we did not find any significant differences in survival by SES at 30 days, 1 year, or 3 years.

© 2018 The Author(s). Published by Oxford University Press. All rights reserved. Background Arm pain is common, costly to health services and society. Physiotherapy referral is standard management, and while awaiting treatment, advice is often given to rest, but the evidence base is weak. Objective To assess the cost-effectiveness of advice to remain active (AA) versus advice to rest (AR); and immediate physiotherapy (IP) versus usual care (waiting list) physiotherapy (UCP). Methods Twenty-six-week within-trial economic evaluation (538 participants aged ≥18 years randomized to usual care, i.e. AA (n = 178), AR (n = 182) or IP (n = 178). Regression analysis estimated differences in mean costs and Quality-Adjusted Life Years (QALYs). Incremental cost-effectiveness ratios (ICERs) and cost-effectiveness acceptability curves were generated. Primary analysis comprised the 193 patients with complete resource use (UK NHS perspective) and EQ-5D data. Sensitivity analysis investigated uncertainty. Results Baseline-adjusted cost differences were £88 [95% confidence interval (CI): -14, 201) AA versus AR; -£14 (95% CI: -87, 66) IP versus UCP. Baseline-adjusted QALY differences were 0.0095 (95% CI: -0.0140, 0.0344) AA versus AR; 0.0143 (95% CI: -0.0077, 0.0354) IP versus UCP. There was a 71 and 89% probability that AA (versus AR) and IP (versus UCP) were the most cost-effective option using a threshold of £20,000 per additional QALY. The results were robust in the sensitivity analysis. Conclusion The difference in mean costs and mean QALYs between the competing strategies was small and not statistically significant. However, decision-makers may judge that IP was not shown to be any more effective than delayed treatment, and was no more costly than delayed physiotherapy. AA is preferable to one that encourages AR, as it is more effective and more likely to be cost-effective than AR.

Introduction: Reductions in heavy manual work as a consequence of mechanisation might impact adversely on muscle strength at older ages. We investigated the association between grip strength at retirement age and lifetime occupational exposure to physically demanding activities. Grip strength is an important predictor of long-term health and physical function in older people. Methods: Grip strength (maximum of three readings in each hand) was measured in men from the Hertfordshire Cohort Study at a single examination when their mean age was 65.8 (SD 2.9) years. Associations with lifetime occupational exposure (ascertained by questionnaire) to three activities (standing/walking ≥4 hours/day; lifting ≥25 kg; and energetic work sufficient to induce sweating) were assessed by multivariable linear regression with adjustment for various potential confounders. Results: Complete data were available from 1,418 men who had worked for at least 20 years. After adjustment for age, height and weight, those with longer exposures to walking/standing and heavy lifting had lower grip strength, but the relationship disappeared after further adjustment for confounders. Working at physical intensity sufficient to induce sweating was not significantly associated with grip strength.Conclusions: We found no evidence that physically demanding occupational activities increase hand grip strength at normal retirement age. Any advantages of regular physical occupational activity may have been obscured by unmeasured socio-economic confounders.

Background: There is growing interest in the application of palliative care principles to improve care for patients and families affected by neurologic diseases. We developed an interdisciplinary outpatient clinic for patients and families affected by neurologic disorders to better address the problems faced by our highest need patients. We have developed and improved this program over the past three years and share several of our most important lessons as well as ongoing challenges and areas where we see our clinic evolving in the future. Methods: We provide a description of our clinic logistics, including key steps in the initiation of the clinic, and provide descriptions from similar clinics at other institutions to demonstrate some of the variability in this growing field. We also provide results from a formal one-year quality improvement project and a one-year retrospective study of patients attending this clinic. Results: Our clinic has grown steadily since its inception and maintains high satisfaction ratings from patients, caregivers, and referring providers. To maintain standardized and efficient care we have developed materials for patients and referring physicians as well as checklists and other processes used by our interdisciplinary team. Feedback from our quality improvement project helped define optimal visit duration and refine communication among team members and with patients and families. Results from our chart review suggest our clinic influences advance care planning and place of death. Common referral reasons include psychosocial support, complex symptom management, and advance care planning. Current challenges for our clinic include developing a strategy for continued growth, creating a sustainable financial model for interdisciplinary care, integrating our services with disease-specific sections, improving primary palliative care knowledge and skills within our referral base, and building effective alliances with community neurologists, geriatrics, primary care, nursing homes, and hospices. Conclusions: Specialized outpatient palliative care for neurologic disorders fills several important gaps in care for this patient population, provides important educational opportunities for trainees, and creates opportunities for patient and caregiver-centered research. Educational initiatives are needed to train general neurologists in primary palliative care, to train neurologists in specialist palliative care, and to train palliative medicine specialists in neurology. Research is needed to build an evidence base to identify patient and caregiver needs, support specific interventions, and to build more efficient models of care in both academic and community settings.

While much investment has gone into developing interprofessional education (IPE) curriculum for healthcare professional students, many of these efforts have focused on classroom rather than clinical environments. Implementing robust IPE experiences into clinical training is often complicated by obstacles such as differing rotating schedules and differing curricular requirements. The Combined Medical-Physician Assistant Student Rural Rotation (Med-PARR) at the Oregon Health and Science University takes a practical approach to these challenges. Med-PARR students participate in focused IPE activities that overlay, or 'float', on top of each trainee's profession-specific curricular requirements. Through critical reflection, goal setting, and a community-based project, students get the opportunity to critically reflect on their interprofessional roles while participating in their rural clinical settings. The practical approach of the Med-PARR can serve as a model for other institutions seeking to solve similar logistical issues in their own rural and community clinical IPE implementation efforts.

Objectives Mental illness and psychotropic drugs have been linked with workplace injury, but few studies have measured exposures and outcomes independently or established their relative timings. To address this shortcoming, we conducted a case–control study nested within a database prospectively recording injury consultations, diagnoses and drug prescriptions. Methods The Clinical Practice Research Datalink logs primary care data for 6% of the British population, coding all consultations (by the Read system) and drug prescriptions. We identified 1348 patients aged 16–64?years from this database who had consulted a family doctor or hospital over a 20-year period for workplace injury (cases, 479 diagnostic codes) and 6652 age, sex and practice-matched controls with no such consultation. Groups were compared in terms of consultations for mental health problems (1328 codes) and prescription of psychotropic drugs prior to the case's injury consultation using conditional logistic regression. Results In total, 1846 (23%) subjects had at least one psychiatric consultation before the index date and 1682 (21%) had been prescribed a psychotropic drug. The OR for prior mental health consultation was 1.44 (pConclusions Mental health problems and psychotropic treatments may account for an important minority of workplace injuries.

Study Design. A cross-sectional survey with a longitudinal follow-up.Objectives. The aim of this study was to test the hypothesis that pain, which is localized to the low back, differs epidemiologically from that which occurs simultaneously or close in time to pain at other anatomical sitesSummary of Background Data. Low back pain (LBP) often occurs in combination with other regional pain, with which it shares similar psychological and psychosocial risk factors. However, few previous epidemiological studies of LBP have distinguished pain that is confined to the low back from that which occurs as part of a wider distribution of pain.Methods. We analyzed data from CUPID, a cohort study that used baseline and follow-up questionnaires to collect information about musculoskeletal pain, associated disability, and potential risk factors, in 47 occupational groups (office workers, nurses, and others) from 18 countries.Results. Among 12,197 subjects at baseline, 609 (4.9%) reported localized LBP in the past month, and 3820 (31.3%) nonlocalized LBP. Nonlocalized LBP was more frequently associated with sciatica in the past month (48.1% vs. 30.0% of cases), occurred on more days in the past month and past year, was more often disabling for everyday activities (64.1% vs. 47.3% of cases), and had more frequently led to medical consultation and sickness absence from work. It was also more often persistent when participants were followed up after a mean of 14 months (65.6% vs. 54.1% of cases). In adjusted Poisson regression analyses, nonlocalized LBP was differentially associated with risk factors, particularly female sex, older age, and somatizing tendency. There were also marked differences in the relative prevalence of localized and nonlocalized LBP by occupational group.Conclusion. Future epidemiological studies should distinguish where possible between pain that is limited to the low back and LBP that occurs in association with pain at other anatomical locations.Level of Evidence: 2

Summary In a large cross-sectional survey, pain affecting 6–10 anatomical sites showed substantially different associations with risk factors from pain limited to 1–3 sites., To explore definitions for multisite pain, and compare associations with risk factors for different patterns of musculoskeletal pain, we analysed cross-sectional data from the Cultural and Psychosocial Influences on Disability (CUPID) study. The study sample comprised 12,410 adults aged 20–59 years from 47 occupational groups in 18 countries. A standardised questionnaire was used to collect information about pain in the past month at each of 10 anatomical sites, and about potential risk factors. Associations with pain outcomes were assessed by Poisson regression, and characterised by prevalence rate ratios (PRRs). Extensive pain, affecting 6–10 anatomical sites, was reported much more frequently than would be expected if the occurrence of pain at each site were independent (674 participants vs 41.9 expected). In comparison with pain involving only 1–3 sites, it showed much stronger associations (relative to no pain) with risk factors such as female sex (PRR 1.6 vs 1.1), older age (PRR 2.6 vs 1.1), somatising tendency (PRR 4.6 vs 1.3), and exposure to multiple physically stressing occupational activities (PRR 5.0 vs 1.4). After adjustment for number of sites with pain, these risk factors showed no additional association with a distribution of pain that was widespread according to the frequently used American College of Rheumatology criteria. Our analysis supports the classification of pain at multiple anatomical sites simply by the number of sites affected, and suggests that extensive pain differs importantly in its associations with risk factors from pain that is limited to only a small number of anatomical sites.

OBJECTIVES: We assessed the evidence relating preterm delivery (PTD), low birth weight, small for gestational age (SGA), pre-eclampsia and gestational hypertension to five occupational exposures (working hours, shift work, lifting, standing and physical workload). We conducted a systematic search in Medline and Embase (1966 to 2011), updating a previous search with a further 6 years of observations.METHODS: As before, combinations of keywords and medical subject headings were used. Each relevant paper was assessed for completeness of reporting and potential for important bias or confounding, and its effect estimates abstracted. Where similar definitions of exposure and outcome existed we calculated pooled estimates of relative risk (RR) in meta-analysis.RESULTS: Analysis was based on 86 reports (32 cohort investigations, 57 with usable data on PTD, 54 on birth weight and 11 on pre-eclampsia/gestational hypertension); 33 reports were new to this review. For PTD, findings across a substantial evidence base were generally consistent, effectively ruling out large effects (eg, RR>1.2). Larger and higher quality studies were less positive, while meta-estimates of risk were smaller than in previous analyses and best estimates pointed to modest or null effects (RR 1.04 to 1.18). For SGA, the position was similar but meta-estimates were even closer to the null (eight of nine RRs ? 1.07). For pre-eclampsia/gestational hypertension the evidence base remains insufficient.CONCLUSIONS: The balance of evidence is against large effects for the associations investigated. As the evidence base has grown, estimates of risk in relation to these outcomes have become smaller.

Summary Large international variation in the prevalence of disabling forearm and low back pain was only partially explained by established personal and socioeconomic risk factors., To compare the prevalence of disabling low back pain (DLBP) and disabling wrist/hand pain (DWHP) among groups of workers carrying out similar physical activities in different cultural environments, and to explore explanations for observed differences, we conducted a cross-sectional survey in 18 countries. Standardised questionnaires were used to ascertain pain that interfered with everyday activities and exposure to possible risk factors in 12,426 participants from 47 occupational groups (mostly nurses and office workers). Associations with risk factors were assessed by Poisson regression. The 1-month prevalence of DLBP in nurses varied from 9.6% to 42.6%, and that of DWHP in office workers from 2.2% to 31.6%. Rates of disabling pain at the 2 anatomical sites covaried (r = 0.76), but DLBP tended to be relatively more common in nurses and DWHP in office workers. Established risk factors such as occupational physical activities, psychosocial aspects of work, and tendency to somatise were confirmed, and associations were found also with adverse health beliefs and group awareness of people outside work with musculoskeletal pain. However, after allowance for these risk factors, an up-to 8-fold difference in prevalence remained. Systems of compensation for work-related illness and financial support for health-related incapacity for work appeared to have little influence on the occurrence of symptoms. Our findings indicate large international variation in the prevalence of disabling forearm and back pain among occupational groups carrying out similar tasks, which is only partially explained by the personal and socioeconomic risk factors that were analysed.

The aim of this study was to investigate whether whole-body vibration (WBV) is associated with prolapsed lumbar intervertebral disc (PID) and nerve root entrapment among patients with low-back pain (LBP) undergoing magnetic resonance imaging (MRI).A consecutive series of patients referred for lumbar MRI because of LBP were compared with controls X-rayed for other reasons. Subjects were questioned about occupational activities loading the spine, psychosocial factors, driving, personal characteristics, mental health, and certain beliefs about LBP. Exposure to WBV was assessed by six measures, including weekly duration of professional driving, hours driven at a spell, and current 8-hour daily equivalent root-mean-square acceleration A(8). Cases were sub-classified according to whether or not PID/nerve root entrapment was present. Associations with WBV were examined separately for cases with and without these MRI findings, with adjustment for age, sex, and other potential confounders.Altogether 237 cases and 820 controls were studied, including 183 professional drivers and 176 cases with PID and/or nerve root entrapment. Risks associated with WBV tended to be lower for LBP with PID/nerve root entrapment but somewhat higher for risks of LBP without these abnormalities. However, associations with the six metrics of exposure were all weak and not statistically significant. Neither exposure-response relationships nor increased risk of PID/nerve root entrapment from professional driving or exposure at an A(8) above the European Union daily exposure action level were found.WBV may be a cause of LBP but it was not associated with PID or nerve root entrapment in this study.

Objectives Demographic changes are requiring people to work longer. Labour force participation might be promoted by tackling sources of job dissatisfaction. We aimed to describe the epidemiology of job dissatisfaction in older British workers, to explore which perceptions of work contribute most importantly, and to assess possible impacts on health. Methods Subjects aged 50-64 years were recruited from 24 English general practices. At baseline, those currently in work (N=5,437) reported on their demographic and employment circumstances, overall job satisfaction, perceptions of their work that might contribute to dissatisfaction, and their general health, mood and well-being. Associations of job dissatisfaction with risk factors and potential health outcomes were assessed cross-sectionally by logistic regression and the potential contributions of different negative perceptions to overall dissatisfaction were summarised by population attributable fractions (PAFs). Results Job dissatisfaction was more common among men, below age 60 years, those living in London and the South East, in the more educated and in those working for larger employers. The main contributors to job dissatisfaction among employees were feeling unappreciated and/or lacking a sense of achievement (PAF 55%-56%), while in the self-employed, job insecurity was the leading contributor (PAF 79%). Job dissatisfaction was associated with all of the adverse health outcomes examined (odds ratios of 3-5), as were most of the negative perceptions of work that contributed to overall dissatisfaction. Conclusions Employment policies aimed at improving job satisfaction in older workers may benefit from focussing particularly on relationships in the workplace, fairness, job security and instilling a sense of achievement.

Objective: To critically review the criteria used to diagnose nonarticular soft-tissue rheumatic disorders of the neck and upper limb. Methods: An extensive search of the literature, including a search of Medline and EMBASE, authoritative recent reviews, and relevant textbooks, was completed. The diagnostic criteria used in epidemiologic studies were compared and the reliability and validity of these criteria were assessed. Results: Altogether, the search identified 117 relevant research articles, among which 69 included a physical examination component, but few specified diagnostic criteria. Evidence supported respectable levels of between-observer repeatability regarding: symptom questionnaires (κ, 0.52 to 0.79); measurement of shoulder range of motion with a goniometer (intraclass coefficients > 0.70); tests for carpal tunnel syndrome (Tinel's and Phalen's κ, 0.53 to 0.80); and demonstration of neck tenderness (κ = 0.43). The Katz hand diagram, and combinations of physical signs of carpal tunnel syndrome, show reasonable sensitivity and specificity for that diagnosis but only among patients referred to specialists with that putative diagnosis; no such validity has been shown among the general population. Only 1 diagnostic examination schedule has published data on both the reliability and the validity of its criteria and diagnoses. For the remaining soft-tissue upper-limb disorders, diagnostic criteria rely apparently on face and content validity and reliability data have not been published. Conclusion: Classification of specific disorders of the neck and upper limb requires a back to basics approach. At present, the diagnosis of most of these conditions relies heavily on the clinical opinions of investigators and there are insufficient data to indicate that these criteria are repeatable, sensitive, or specific. Recent European initiatives offer scope to follow a more disciplined approach, but more work is urgently required.

In Britain, as in many other countries, back pain is a major cause of disability, especially in adults of working age. During the decade to 1993, outpatient attendances for back pain rose fivefold, and the number of days of incapacity from back disorders for which social security benefits were paid more than doubled.1 It is unclear whether this represents an increase in the occurrence of diseases affecting the back or a change in people's behaviour when they have symptoms. To address this question we compared the prevalence of low back pain and associated disability in two postal surveys 10 years apart.

Background: we have previously proposed that sensory nerve conduction (SNC) in the median nerve should be classed as abnormal when the difference between conduction velocities in the little and index fingers is > 8 m/s. In a prospective longitudinal study, we investigated whether this case definition distinguished patients who were more likely to benefit from surgical treatment.Methods: we followed up 394 patients (response rate 56%), who were investigated by a neurophysiology service for suspected carpal tunnel syndrome. Information about symptoms, treatment and other possible determinants of outcome was obtained through questionnaires at baseline and after follow-up for a mean of 19.2 months. Analysis focused on 656 hands with numbness, tingling or pain at baseline. Associations of surgical treatment with resolution of symptoms were assessed by Poisson regression, and summarised by prevalence rate ratios (PRRs) and associated 95% confidence intervals (95% CIs).Results: during follow-up, 154 hands (23%) were treated surgically, and sensory symptoms resolved in 241 hands (37%). In hands with abnormal median SNC, surgery was associated with resolution of numbness, tingling and pain (PRR 1.5, 95% CI 1.0-2.2), and of numbness and tingling specifically (PRR 1.8, 95% CI 1.3-2.6). In contrast, no association was apparent for either outcome when median SNC was classed as normal.Conclusions: our definition of abnormal median SNC distinguished a subset of patients who appeared to benefit from surgical treatment. This predictive capacity gives further support to its validity as a diagnostic criterion in epidemiological research.

Musculoskeletal disorders of the upper limb and neck are a common cause of morbidity, and in some occupational groups they contribute importantly to loss of time from work.1-5Community-based surveys have indicated point prevalences of 4–20% for pain at specific sites in the neck and upper limb,6-9with lifetime prevalences as high as 60%. Morbidity surveys in primary care have found an annual incidence of first consultation for upper limb disorders of approximately 25 per 1000 person years, with rates increasing from 25 to 45 years of age and then levelling off.10 Upper limb pain may arise from discrete pathological conditions, such as adhesive capsulitis, rotator cuff tendinitis, lateral epicondylitis, and tenosynovitis, or as part of non-specific regional pain syndromes. However, few community surveys have included a clinical examination as an integral component, to enable a distinction to be drawn between these very different categories of disorder. Furthermore, the relative contribution of specific and non-specific rheumatic disorders of upper limb and neck to handicap from occupational and leisure activities is not clear (despite the fact that the risk factors may vary substantially between the two groups). As table 1 illustrates, investigations have differed in their choice of age range, source population, prevalence period, and …

Background: Epidemiological research in the field of soft tissue neck and upper limb disorders has been hampered by the lack of an agreed system of diagnostic classification. In 1997, a United Kingdom workshop agreed consensus definitions for nine of these conditions. From these criteria, an examination schedule was developed and validated in a hospital setting. Objective: To investigate the reliability of this schedule in the general population. Methods: Ninety seven adults of working age reporting recent neck or upper limb symptoms were invited to attend for clinical examination consisting of inspection and palpation of the upper limbs, measurement of active and passive ranges of motion, and clinical provocation tests. A doctor and a trained research nurse examined each patient separately, in random order and blinded to each other9s findings. Results: Between observer repeatability of the schedule was generally good, with a median κ coefficient of 0.66 (range 0.21 to 0.93) for each of the specific diagnoses considered. Conclusion: As expected, the repeatability of tests is poorer in the general population than in the hospital clinic, but the Southampton examination schedule is sufficiently reproducible for epidemiological research in the general population.

Background: Although some occupational sources of hand-transmitted vibration (HTV) have been extensively investigated, the risks associated with others are poorly characterized. Methods: A questionnaire was mailed to a community sample of 12,240 men aged 16- 64 years and 906 men from the armed forces. Questions covered current occupation, sources of HTV, numbness or tingling in the fingers in the past week, and finger blanching. In the 5,364 respondents who had been at work in the past week, associations between symptoms and exposures were examined by logistic regression, with odds ratios converted into prevalence ratios (PRs). Results: Altogether, 513 men (10%) reported cold-induced finger blanching and 769 (14%) sensory symptoms in the fingers. The risk of blanching was increased in builders (PR 2.4, 95% CI 1.0-5.2), carpenters and joiners (PR 1.9, 95% CI 1.0-3.4), motor mechanics (PR 2.3, 95% CI 1.1-4.6), and laborers (PR 2.8, 95% CI 1.3-6.0); while the risk of sensory symptoms was elevated in laborers (PR 4.0, 95% CI 2.3-6.6) and plant operatives (PR 3.5, 95% CI 1.9-5.9). Use of hand-guided mowers, concrete breakers, chain saws, and jig saws was significantly associated with symptoms. Conclusions: Little attention has been paid to the risks of vibration injury in construction workers, woodworkers, motor mechanics, and laborers, or to the risks from mowers, jig saws and several other common vibratory tools. These should be a focus for further investigation and preventive measures.

AIMS: To investigate the factors, including size of organisation, associated with job loss in patients awaiting surgery to the hip or knee joint. METHODS: A questionnaire was mailed to 498 consecutive patients of working age listed at a district general hospital for major joint replacement, knee arthroscopy, or periacetabular osteotomy. Questions were asked about level of physical disability, duration of symptoms, employment circumstances at the time the joint problem began, and job changes since the onset of symptoms with their reasons. Analysis focused on those in work when their health problem began. Cox regression was used to examine risk factors for job loss related and unrelated to the joint problem, and results were summarised as adjusted hazard ratios (HRs) with 95% confidence intervals (95% CI). RESULTS: Responses came from 370 (74%) of those mailed, including 278 who were in work when their joint problem began. Of these, 82 (30%) had left their original job mainly or partly because of their joint disorder. Such job loss was more common in those employed in small businesses (HR for or =10 employees: 1.9, 95% CI 1.2-3.0) and those whose work involved standing for >2 hours per day (HR 2.7, 95% CI 1.2-6.1) No similar associations were found when jobs were left for other reasons. After adjustment for non-sedentary work the association with small business employment remained but was weaker (HR 1.5, 95% CI 0.9-2.5). Modifications to work and access to occupational health advice were not associated with better job retention. CONCLUSIONS: In subjects with disabling hip or knee disease, job retention is poorer in those from small companies-a matter of concern given the rising prevalence of serious joint disease in the British workforce and the tendency of businesses to downsize and subcontract services to smaller enterprises.

OBJECTIVE: To assess the effectiveness of interventions in community and workplace settings to reduce sickness absence and job loss in workers with musculoskeletal disorders (MSDs). METHODS: Relevant randomized controlled trials (RCTs) and cohort studies, published since 1990, were identified by screening citations from 35 earlier systematic reviews and by searching MEDLINE and Embase until April 2010. Effects were estimated by intervention category and other features, including study quality. RESULTS: Among 42 studies (including 34 RCTs), 27 assessed return to work (RTW), 21 duration of sickness absence and 5 job loss. Interventions included exercise therapy, behavioural change techniques, workplace adaptations and provision of additional services. Studies were typically small {median sample 107 [inter-quartile range (IQR) 77-148]} and limited in quality. Most interventions appeared beneficial: the median relative risk (RR) for RTW was 1.21 (IQR 1.00-1.60) and that for avoiding MSD-related job loss was 1.25 (IQR 1.06-1.71); the median reduction in sickness absence was 1.11 (IQR 0.32-3.20) days/month. However, effects were smaller in larger and better-quality studies, suggesting publication bias. No intervention was clearly superior, although effort-intensive interventions were less effective than simple ones. No cost-benefit analyses established statistically significant net economic benefits. CONCLUSION: As benefits are small and of doubtful cost-effectiveness, employers' practice should be guided by their value judgements about the uncertainties. Expensive interventions should be implemented only with rigorous cost-benefit evaluation planned from the outset. Future research should focus on the cost-effectiveness of simple, low-cost interventions, and further explore impacts on job retention.

OBJECTIVES: To investigate the association between functional difficulties in using the upper limb and extent and frequency of finger blanching, and the merits of these markers in grading the severity of Raynaud's phenomenon (RP) and vibration-induced white finger (VWF). METHODS: A questionnaire was mailed to a randomly selected community sample of 22,194 working-aged adults. Information was collected on cold-induced finger blanching--including the extent and frequency of attacks in the past year, and on difficulty in using the upper limb in several everyday activities (e.g. doing up buttons, opening a tight screwtop jar, and pouring from a jug). Associations were examined by logistic regression with the resultant odds ratios converted into prevalence ratios (PRs) and 95% confidence intervals (95% CI). RESULTS: Among 12,907 respondents were 1,359 who reported finger blanching and provided details of its extent and frequency. Of these, 7.4% reported frequent attacks (50 or more over the year), and 12% reported extensive blanching (affecting nine or ten digits). After adjustment for potential confounders, subjects with finger blanching reported an excess of difficulties in using the limb. Thus, in men with blanching the PR for difficulty with buttons was 4.7 (95% CI 3.9-5.8), and that for pouring from a jug was 3.8 (3.0-4.9) in comparison with men who had never had blanching. Similar associations were found in women and in those men with exposure to hand-transmitted vibration. The risk of reporting difficulties increased markedly with frequency of blanching--up to four- or fivefold in those with 50 or more attacks in the past year compared with those who had none; but differences by extent were less marked, with PRs < or = 1.6 in those with nine to ten digits affected compared with one to two digits. CONCLUSIONS: RP and VWF are both associated with difficulties in using the upper limb in everyday tasks. Further investigation of potential reporting biases is warranted, but if the associations are causal, frequency of attacks influences impairment more than extent of disease. More account may need to be taken of frequency of blanching episodes in assessing and in compensating subjects with VWF.

Objectives: To explore the relation between smoking habits and regional pain in the general population. Methods: A questionnaire was mailed to 21 201 adults, aged 16–64 years, selected at random from the registers of 34 British general practices, and to 993 members of the armed services, randomly selected from pay records. Questions were asked about pain in the low back, neck, and upper and lower limbs during the past 12 months; smoking habits; physical activities at work; headaches; and tiredness or stress. Associations were examined by logistic regression and expressed as prevalence ratios (PRs). Results: Questionnaires were completed by 12 907 (58%) subjects, including 6513 who had smoked at some time, among whom 3184 were current smokers. Smoking habits were related to age, social class, report of headaches, tiredness or stress, and manual activities at work. After adjustment for potential confounders, current and ex-smokers had higher risks than lifetime non-smokers for pain at all of the sites considered. This was especially so for pain reported as preventing normal activities (with PRs up to 1.6 in current v never smokers). Similar associations were found in both sexes, and when analysis was restricted to non-manual workers. Conclusions: There is an association between smoking and report of regional pain, which is apparent even in ex-smokers. This could arise from a pharmacological effect of tobacco smoke (for example, on neurological processing of sensory information or nutrition of peripheral tissues); another possibility is that people with a low threshold for reporting pain and disability are more likely to take up and continue smoking.

To explore whether different distributions of numbness and tingling in the hand can be usefully distinguished in epidemiologic studies of disorders such as carpal tunnel syndrome, the authors used a postal questionnaire, an interview, and a physical examination to collect information about risk factors, symptoms, and signs from a general population sample of 2,142 adults in Southampton, England, during 1998-2000. The authors distinguished six distributions of numbness and tingling and compared their associations with other clinical findings and with known risk factors for upper limb disorders. Distinctive relations were found for symptoms that involved most of the palmar surface of the first three digits but not the dorsum of the hand or the little finger. Such symptoms were more often associated with positive Phalen's and Tinel's tests and, unlike other categories of sensory disturbance, were not related to neck pain or restriction of neck movement. They also differed in showing no association with lower vitality or poorer mental health but an association with repeated wrist and finger movements at work. These findings suggest that, in the classification of numbness and tingling of the hand, it may be useful to distinguish symptoms that involve most of the sensory distribution of the median nerve but not other parts of the hand.

Workers exposed to hand-transmitted vibration (HTV) often experience aches and pains in the upper limbs, but there have been few studies of the pattern and severity of symptoms, or their relationship to the estimated dose of vibration. As part of a wider survey of vibration, we mailed a questionnaire about exposures to HTV and pain in the neck and upper limbs to a sample of men selected at random from the registration lists of 34 British general practices and the pay records of the armed services. Analysis was confined to the 1856 male respondents who had been employed in manual occupations for a year or more and who reported the last week as being representative of their job. Inquiry was made about pain in the neck, shoulder, elbow and wrist/hand over the past week and past year (including pains that limited normal activity). Subjects were classed according to their lifetime exposure to HTV and their estimated average daily vibration dose [A(8) r.m.s.] in the previous week. A total of 283 men had a minimum estimated A(8) greater than a proposed action level of 2.8 m/s(2), and in this group symptoms were about twice as prevalent as in manual workers who had never used vibratory tools. The excess risk was somewhat higher for distal sites than for proximal ones (e.g. the prevalence ratio for hand/wrist pain in the past week was 2.7 versus 1.8 for neck pain). This accords with the pattern of transmission of HTV to the upper limb, although a confounding effect from other ergonomic risk factors cannot be discounted.

OBJECTIVES: Following a consensus statement from a multidisciplinary UK workshop, a structured examination schedule was developed for the diagnosis and classification of musculoskeletal disorders of the upper limb. The aim of this study was to test the repeatability and the validity of the newly developed schedule in a hospital setting. METHOD: 43 consecutive referrals to a soft tissue rheumatism clinic (group 1) and 45 subjects with one of a list of specific upper limb disorders (including shoulder capsulitis, rotator cuff tendinitis, lateral epicondylitis and tenosynovitis) (group 2), were recruited from hospital rheumatology and orthopaedic outpatient clinics. All 88 subjects were examined by a research nurse (blinded to diagnosis), and everyone from group 1 was independently examined by a rheumatologist. Between observer agreement was assessed among subjects from group 1 by calculating Cohen's kappa for dichotomous physical signs, and mean differences with limits of agreement for measured ranges of joint movement. To assess the validity of the examination, a pre-defined algorithm was applied to the nurse's examination findings in patients from both groups, and the sensitivity and specificity of the derived diagnoses were determined in comparison with the clinic's independent diagnosis as the reference standard. RESULTS: The between observer repeatability of physical signs varied from good to excellent, with kappa coefficients of 0.66 to 1.00 for most categorical observations, and mean absolute differences of 1.4 degrees -11.9 degrees for measurements of shoulder movement. The sensitivity of the schedule in comparison with the reference standard varied between diagnoses from 58%-100%, while the specificities ranged from 84%-100%. The nurse and the clinic physician generally agreed in their diagnoses, but in the presence of shoulder capsulitis the nurse usually also diagnosed shoulder tendinitis, whereas the clinic physician did not. CONCLUSION: The new examination protocol is repeatable and gives acceptable diagnostic accuracy in a hospital setting. Examination can feasibly be delegated to a trained nurse, and the protocol has the benefit of face and construct validity as well as consensus backing. Its performance in the community, where disease is less clear cut, merits separate evaluation, and further refinement is needed to discriminate between discrete pathologies at the shoulder.

OBJECTIVE: To explore the relationship between occupational exposures and lateral and medial epicondylitis, and the effect of epicondylitis on sickness absence in a population sample of working-aged adults. METHODS: This was a cross-sectional study of 9696 randomly selected adults aged 25-64 years involving a screening questionnaire and standardized physical examination. Age- and sex-specific prevalence rates of epicondylitis were estimated and associations with occupational risk factors explored. RESULTS: Among 6038 respondents, 636 (11%) reported elbow pain in the last week. Of those surveyed, 0.7% were diagnosed with lateral epicondylitis and 0.6% with medial epicondylitis. Lateral epicondylitis was associated with manual work [odds ratio (OR) 4.0, 95% CI 1.9, 8.4]. In multivariate analyses, repetitive bending/straightening elbow >1 h day was independently associated with lateral (OR 2.5, 95% CI 1.2, 5.5) and medial epicondylitis (OR 5.1, 95% CI 1.8, 14.3). Five per cent of adults with epicondylitis took sickness absence because of their elbow symptoms in the past 12 months (median 29 days). CONCLUSION: Repetitive exposure to bending/straightening the elbow was a significant risk factor for medial and lateral epicondylitis. Epicondylitis is associated with prolonged sickness absence in 5% of affected working-aged adults.

Because many medical students do not have access to electronic health records (EHRs) in the clinical environment, simulated EHR training is necessary. Explicitly training medical students to use EHRs appropriately during patient encounters equips them to engage patients while also attending to the accuracy of the record and contributing to a culture of information safety.Faculty developed and successfully implemented an EHR objective structured clinical examination (EHR-OSCE) for clerkship students at two institutions. The EHR-OSCE objectives include assessing EHR-related communication and data management skills.The authors collected performance data for students (n = 71) at the first institution during academic years 2011-2013 and for students (n = 211) at the second institution during academic year 2013-2014. EHR-OSCE assessment checklist scores showed that students performed well in EHR-related communication tasks, such as maintaining eye contact and stopping all computer work when the patient expresses worry. Findings indicated student EHR skill deficiencies in the areas of EHR data management including medical history review, medication reconciliation, and allergy reconciliation. Most students' EHR skills failed to improve as the year progressed, suggesting that they did not gain the EHR training and experience they need in clinics and hospitals.Cross-institutional data comparisons will help determine whether differences in curricula affect students' EHR skills. National and institutional policies and faculty development are needed to ensure that students receive adequate EHR education, including hands-on experience in the clinic as well as simulated EHR practice.

PurposeBehavioral and social science (BSS) competencies are needed to provide quality health care, but psychometrically validated measures to assess these competencies are difficult to find. Moreover, they have not been mapped to existing frameworks, like those from the Liaison Committee on Medical Education (LCME) and Accreditation Council for Graduate Medical Education (ACGME). This systematic review aimed to identify and evaluate the quality of assessment tools used to measure BSS competencies.MethodThe authors searched the literature published between January 2002 and March 2014 for articles reporting psychometric or other validity/reliability testing, using OVID, CINAHL, PubMed, ERIC, Research and Development Resource Base, SOCIOFILE, and PsycINFO. They reviewed 5,104 potentially relevant titles and abstracts. To guide their review, they mapped BSS competencies to existing LCME and ACGME frameworks. The final included articles fell into three categories: instrument development, which were of the highest quality; educational research, which were of the second highest quality; and curriculum evaluation, which were of lower quality.ResultsOf the 114 included articles, 33 (29%) yielded strong evidence supporting tools to assess communication skills, cultural competence, empathy/compassion, behavioral health counseling, professionalism, and teamwork. Sixty-two (54%) articles yielded moderate evidence and 19 (17%) weak evidence. Articles mapped to all LCME standards and ACGME core competencies; the most common was communication skills.ConclusionsThese findings serve as a valuable resource for medical educators and researchers. More rigorous measurement validation and testing and more robust study designs are needed to understand how educational strategies contribute to BSS competency development.

Welding of metals generates a complex mix of noxious gases and fumes,1 and has been linked with various respiratory diseases including metal fume fever,2 asthma,3 COPD4 and possibly bronchial carcinoma.1 ,2 In addition, there is now strong and consistent epidemiological evidence that welders are at increased risk of infectious, lobar pneumonia. Originally detected in national analyses of occupational mortality,5 the hazard was confirmed by a large case–control study of men admitted to hospitals in the English West Midlands with community-acquired pneumonia,6 and is supported by findings from more recent epidemiological investigations in the UK7 ,8 and other countries.9–11 The elevation of risk is associated specifically with recent exposure,6 and is not apparent in former welders after normal retirement age,5 ,7 suggesting that it reflects a reversible increase in susceptibility to infection. Moreover, it extends to other occupations such as furnacemen and moulders in foundries, who are exposed to metal fume but not to welding gases.5 ,12 It is demonstrable in men who work with ferrous metals,6 ,12 but the involvement of other metals cannot be ruled out. Resolution of this uncertainty with adequate statistical power is a challenge because lobar pneumonia is uncommon, and relatively few workers are exposed to fume exclusively from …

Somatising tendency, defined as a predisposition to worry about common somatic symptoms, is importantly associated with various aspects of health and health-related behaviour, including musculoskeletal pain and associated disability. To explore its epidemiological characteristics, and how it can be specified most efficiently, we analysed data from an international longitudinal study. A baseline questionnaire, which included questions from the Brief Symptom Inventory about seven common symptoms, was completed by 12,072 participants aged 20-59 from 46 occupational groups in 18 countries (response rate 70%). The seven symptoms were all mutually associated (odds ratios for pairwise associations 3.4 to 9.3), and each contributed to a measure of somatising tendency that exhibited an exposure-response relationship both with multi-site pain (prevalence rate ratios up to six), and also with sickness absence for non-musculoskeletal reasons. In most participants, the level of somatising tendency was little changed when reassessed after a mean interval of 14 months (75% having a change of 0 or 1 in their symptom count), although the specific symptoms reported at follow-up often differed from those at baseline. Somatising tendency was more common in women than men, especially at older ages, and varied markedly across the 46 occupational groups studied, with higher rates in South and Central America. It was weakly associated with smoking, but not with level of education. Our study supports the use of questions from the Brief Symptom Inventory as a method for measuring somatising tendency, and suggests that in adults of working age, it is a fairly stable trait.

Objectives To explore occupational and psychological risk factors for the incidence and persistence of multi-site musculoskeletal pain. Methods We conducted a longitudinal investigation of three occupational groups in Crete, Greece. Baseline information was obtained at interview about pain in the past year at each of six anatomical sites, and about possible risk factors for subsequent symptoms. Twelve months later, subjects were re-interviewed about pain at the same anatomical sites in the past month. Pain at two or more sites was classed as multi-site. Associations with new development and persistence of multi-site pain at follow-up were assessed by logistic regression. Results Analysis was based on 518 subjects (87% of those originally selected for study). At follow-up, multi-site pain persisted in 217 (62%) of those who had experienced it in the year before baseline, and was newly developed in 27 (17%) of those who had not. Persistence of multi-site pain was significantly related to physical loading at work, somatising tendency and beliefs about work as a cause of musculoskeletal pain, with OR (95% CI) for the highest relative to the lowest exposure categories of 2.3 (1.0 to 5.6), 2.6 (1.5 to 4.6) and 1.9 (1.1 to 3.3) respectively. Development of new multi-site pain was most strongly associated with working for ≥40 h per week (OR 5.0, 95% CI 1.1 to 24.0). Conclusions Our findings confirm the importance of both physical loading at work and somatising tendency as risk factors for multi-site pain, and suggest that persistence of pain is also influenced by adverse beliefs about work causation.

Objective To assess the importance of psychological and culturally-influenced factors as predictors of low back pain (LBP) incidence and persistence in Spanish workers. Methods As part of the international Cultural and Psychosocial Influences in Disability (CUPID) study, 1105 Spanish nurses and office workers answered questions at baseline about LBP in the past month and past year, associated disability, occupational lifting, smoking habits, health beliefs, mental health, and distress from common somatic symptoms. At 12-month follow-up, they were asked about LBP and associated disability in the past month. Associations with LBP incidence and persistence were assessed by log binomial regression, and characterised by prevalence rate ratios (PRRs) with associated 95% CIs. Results 971 participants (87.9%) completed follow-up. Among 579 with no LBP at baseline, 22.8% reported LBP at follow-up. After adjustment for sex, age and occupation, new LBP was predicted by poor mental health (PRR 1.5, 95% CI 1.0 to 2.2), somatising tendency (PRR 1.8, 95% CI 1.2 to 2.7) and presence of LBP for >1 month in the year before baseline (PRR 4.7, 95% CI 3.1 to 6.9). Among 392 subjects who had LBP at baseline, 59.4% reported persistence at follow-up, which was associated with presence of symptoms for >1 month in the 12 months before baseline (PRR 1.4, 95% CI 1.2 to 1.7) and more weakly with somatising tendency, and with adverse beliefs about LBP work-relatedness and prognosis. Conclusions In Spain, as in northern European countries, psychological and culturally-influenced factors have an important role in LBP development and persistence.

Purpose Cranial irradiation in pediatric patients is associated with serious long-term adverse effects. We sought to determine whether both three-dimensional conformal proton radiotherapy (3D-PRT) and intensity-modulated proton therapy (IMPT) compared with intensity-modulated radiotherapy (IMRT) decrease integral dose to brain areas known to harbor neuronal stem cells, major blood vessels, and other normal brain structures for pediatric patients with craniopharyngiomas. Methods and Materials IMRT, forward planned, passive scattering proton, and IMPT plans were generated and optimized for 10 pediatric patients. The dose was 50.4 Gy (or cobalt Gy equivalent) delivered in 28 fractions with the requirement for planning target volume (PTV) coverage of 95% or better. Integral dose data were calculated from differential dose–volume histograms. Results The PTV target coverage was adequate for all modalities. IMRT and IMPT yielded the most conformal plans in comparison to 3D-PRT. Compared with IMRT, 3D-PRT and IMPT plans had a relative reduction of integral dose to the hippocampus (3D-PRT, 20.4; IMPT, 51.3% ∗ ), dentate gyrus (27.3, 75.0% ∗ ), and subventricular zone (4.5, 57.8% ∗ ). Vascular organs at risk also had reduced integral dose with the use of proton therapy (anterior cerebral arteries, 33.3 ∗ , 100.0% ∗ ; middle cerebral arteries, 25.9% ∗ , 100% ∗ ; anterior communicating arteries, 30.8 ∗ , 41.7% ∗ ; and carotid arteries, 51.5 ∗ , 77.6 ∗ ). Relative reduction of integral dose to the infratentorial brain (190.7 ∗ , 109.7% ∗ ), supratentorial brain without PTV (9.6, 26.8% ∗ ), brainstem (45.6, 22.4% ∗ ), and whole brain without PTV (19.4 ∗ , 34.4% ∗ ) were recorded with the use of proton therapy. ( ∗ Differences were significant based on Friedman's test with Bonferroni-Dunn correction, α = 0.05) Conclusions The current study found that proton therapy was able to avoid excess integral radiation dose to a variety of normal structures at all dose levels while maintaining equal target coverage. Future studies will examine the clinical benefits of these dosimetric advantages.

Occupational exposures to vibration come in many guises, and they are very common at a population level. It follows that an important minority of working-aged patients seen by medical services will have been exposed to this hazard of employment. Vibration can cause human health effects, which may manifest in the patients that rheumatologists see. In this chapter, we identify the health effects of relevance to them, and review their epidemiology, pathophysiology, clinical presentation, differential diagnosis and vocational and clinical management. On either side of this, we describe the nature and assessment of the hazard, the scale and common patterns of exposure to vibration in the community and the legal basis for controlling health risks, and we comment on the role of health surveillance in detecting early adverse effects and what can be done to prevent the rheumatic effects of vibration at work.

Experts disagree about the optimal classification of upper limb disorders (ULDs). To explore whether differences in associations with occupational risk factors offer a basis for choosing between case definitions in aetiological research and surveillance, we analysed previously published research. Eligible reports (those with estimates of relative risk (RR) for >1 case definition relative to identical exposures were identified from systematic reviews of ULD and occupation and by hand-searching five peer-review journals published between January 1990 and June 2010. We abstracted details by anatomical site of the case and exposure definitions employed and paired estimates of RR, for alternative case definitions with identical occupational exposures. Pairs of case definitions were typically nested, a stricter definition being a subset of a simpler version. Differences in RR between paired definitions were expressed as the ratio of RRs, using that for the simpler definition as the denominator. We found 21 reports, yielding 320 pairs of RRs (82, 75 and 163 respectively at the shoulder, elbow, and distal arm). Ratios of RRs were frequently ≤1 (46%), the median ratio overall and by anatomical site being close to unity. In only 2% of comparisons did ratios reach ≥4. We conclude that complex ULD case definitions (e.g. involving physical signs, more specific symptom patterns, and investigations) yield similar associations with occupational risk factors to those using simpler definitions. Thus, in population-based aetiological research and surveillance, simple case definitions should normally suffice. Data on risk factors can justifiably be pooled in meta-analyses, despite differences in case definition.

Professional musicians have high rates of musculoskeletal pain, but few studies have analysed risks by work activities or the psychosocial work environment.To assess the prevalence and impact of musculoskeletal pain, and its relation to playing conditions, mental health and performance anxiety, in musicians from leading British symphony orchestras.Musicians from six professional orchestras completed a questionnaire concerning their orchestral duties and physical activities at work, mental health (somatizing tendency, mood, demand, support and control at work, performance anxiety) and regional pain in the past 4 weeks and past 12 months. Prevalence rates were estimated by anatomical site and associations with risk factors assessed by logistic regression.Responses were received from 243 musicians (51% of those approached), among whom 210 (86%) reported regional pain in the past 12 months, mainly affecting the neck, low back and shoulders. Risks tended to be higher in women, in those with low mood, and especially in those with high somatizing scores. Only weak associations were found with psychosocial work stressors and performance anxiety. However, risks differed markedly by instrument category. Relative to string players, the odds of wrist/hand pain were raised 2.9-fold in wind players, but 60% lower in brass players, while the odds of elbow pain were 50% lower among wind and brass players.Musculoskeletal pain is common in elite professional musicians. A major personal risk factor is somatizing tendency, but performance anxiety has less impact. Risks differ substantially by instrument played, offering pointers towards prevention.

We hypothesised that the relative importance of physical and psychological risk factors for mechanical low back pain (LBP) might differ importantly according to whether there is underlying spinal pathology, psychological risk factors being more common in patients without demonstrable pathology. If so, epidemiological studies of LBP could benefit from tighter case definitions. To test the hypothesis, we used data from an earlier case-control study on patients with mechanical LBP who had undergone magnetic resonance imaging (MRI) of the lumbosacral spine. MRI scans were classified for the presence of high-intensity zone (HIZ), disc degeneration, disc herniation, and nerve root displacement/compression. Information about symptoms and risk factors was elicited by postal questionnaire. Logistic regression was used to assess associations of MRI abnormalities with symptoms and risk factors, which were characterised by odds ratios (ORs) and 95% confidence intervals (CIs). Among 354 patients (52% response), 306 (86.4%) had at least 1, and 63 (17.8%) had all 4 of the MRI abnormalities. Radiation of pain below the knee (280 patients) and weakness or numbness below the knee (257 patients) were both associated with nerve root deviation/compression (OR 2.5, 95% CI 1.4 to 4.5; and OR 1.8, 95% CI 1.1 to 3.1, respectively). However, we found no evidence for the hypothesised differences in risk factors between patients with and without demonstrable spinal pathology. This suggests that when researching the causes and primary prevention of mechanical LBP, there may be little value in distinguishing between cases according to the presence or absence of the more common forms of potentially underlying spinal pathology.

BACKGROUND: National initiatives to prevent and/or manage sickness absence require a database from which trends can be monitored. AIMS: To evaluate the information provided by surveillance schemes and publicly available data sets on sickness absence nationally from musculoskeletal disorders (MSDs). METHODS: A grey literature search was undertaken using the search engine Google, supplemented by leads from consultees from academia, industry, employers, lay interest groups and government. We abstracted data on the outcomes and populations covered and made quantitative estimates of MSD-related sickness absence, overall and, where distinguishable, by subdiagnosis. The coverage and limitations of each source were evaluated. RESULTS: Sources included the Labour Force Survey (LFS) and its Self-reported Work-related Illness survey module, the THOR-GP surveillance scheme, surveys by national and local government, surveys by employers' organizations and a database of benefit statistics. Each highlighted MSDs as a leading cause of sickness absence. Data limitations varied by source, but typically included lack of diagnostic detail and restriction of focus to selected subgroups (e.g. work-ascribed or benefit-awarded cases, specific employment sectors). Additionally, some surveys had very low response rates, were completed only by proxy respondents or ranked only the perceived importance of MSD-related sickness absence, rather than measuring it. CONCLUSIONS: National statistics on MSD-related sickness absence are piecemeal and incomplete. This limits capacity to plan and monitor national policies in an important area of public health. Simple low-cost additions to the LFS would improve the situation.

Study design systematic review and meta-analysis. Objective to assess how confidently low back pain (LBP) can be attributed to abnormalities on magnetic resonance imaging (MRI), and thereby explore the potential value of MRI abnormalities in refining case definition for mechanical LBP in epidemiological research. Summary of background data most epidemiological studies of mechanical LBP have defined cases only by reported symptoms, but it is possible that the potency of causes differs depending on whether there is demonstrable underlying spinal pathology. Methods we reviewed the published data on MRI abnormalities, looking for data on the repeatability of their assessment, their prevalence in people free from LBP, and their association with LBP. Where data were sufficient, we calculated a summary estimate of prevalence in people without LBP and a meta-estimate of the odds ratio for the association with LBP. A formula was then applied to estimate the corresponding prevalence rate ratio, assuming 3 possible prevalence rates for LBP in the general population. Results data were most extensive for disc protrusion, nerve root displacement or compression, disc degeneration, and high intensity zone, all of which could be assessed repeatedly. All were associated with LBP, meta-estimates of odds ratios ranging from 2.3 (nerve root displacement or compression) to 3.6 (disc protrusion). However, even for disc protrusion, estimates of the corresponding prevalence rate ratios were mostly less than 2. Conclusion MRI findings of disc protrusion, nerve root displacement or compression, disc degeneration, and high intensity zone are all associated with LBP, but individually, none of these abnormalities provides a strong indication that LBP is attributable to underlying pathology. This limits their value in refining epidemiological case definitions for LBP.

Objectives: to assess the prevalence and correlates of regional pain and associated disability in four groups of Japanese workers.Methods: as part of a large international survey of musculoskeletal symptoms (the CUPID study), nurses, office workers, sales/marketing personnel and transportation operatives in Japan completed a self-administered questionnaire (response rate 83%) covering experience of pain in six anatomical regions, associated disability and sickness absence, and various possible occupational and psychosocial risk factors for these outcomes. Associations with risk factors were assessed by logistic regression.Results: analysis was based on 2290 subjects. Rates of regional pain were generally less than in the UK, with a particularly low prevalence of wrist/hand pain among office workers (6% in past month). The strongest and most consistent risk factor for regional pain in the past month was tendency to somatise (ORs (95% CIs) for report of ?2 versus 0 distressing somatic symptoms 3.1 (2.4 to 4.0) for low back pain, 2.8 (2.1 to 3.8) for shoulder pain, and 2.5 (1.6 to 4.1) for wrist/hand pain). Sickness absence for regional pain complaints in the past year was reported by 5% of participants, the major risk factor for this outcome being absence during the same period for other medical reasons (OR 3.7, 95% CI 2.4 to 5.8).Conclusions: Japanese office workers have markedly lower rates of wrist/hand pain than their UK counterparts. In Japan, as in Western Europe, somatising tendency is a major risk factor for regional pain. Sickness absence attributed to regional pain complaints appears to be much less common in Japan than in the UK, and to be driven principally by a general propensity to take sickness absence

Background To explore time trends in deaths attributable to work in England and Wales, and identify priorities for prevention, we conducted a proportional analysis of mortality by occupation over a 22-year period. Methods Analysis was based on deaths in men aged 20–74 years during 1979–1980 and 1982–2000 with a recorded occupation. Proportional mortality ratios, standardised for age and social class, were calculated for pre-specified combinations of occupation and cause of death, for which excess mortality could reasonably be attributed to work. Differences between observed and expected numbers of deaths by cause and occupation were expressed as annual excess death rates. Results Mortality attributable to work declined substantially over the period of study, with total excess death rates of 733.2 per year during 1979–1990 and 471.7 per year during 1991–2000. The largest contributing hazards were chronic obstructive pulmonary disease and pneumoconiosis in coal miners, pleural cancer from asbestos, and motor vehicle accidents in lorry drivers. In contrast to most other hazards, there was no clear decline in excess mortality attributable to asbestos, or in deaths from sino-nasal cancer associated with exposure to wood dust. Conclusions The overall decline in mortality attributable to work is likely to reflect reduced employment in more hazardous occupations, as well as improvements in working conditions. It is imperative to ensure that occupational exposures to asbestos and wood dust are now adequately controlled. Further research is needed on accidents involving lorries with the aim of developing more effective strategies for the prevention of injury.

BACKGROUND: To identify opportunities for targeted prevention, we explored differences in occupational mortality from diseases and injuries related to alcohol consumption, sexual habits and drug abuse. METHODS: Using data on all deaths among men and women aged 16-74 years in England and Wales during 1991-2000, we derived age- and social class-standardized proportional mortality ratios (PMRs) by occupation for cause of death categories defined a priori as potentially related to alcohol consumption, sexual habits or drug abuse. RESULTS: The highest mortality from alcohol-related diseases and injuries was observed in publicans and bar staff (both sexes) and in male caterers, cooks and kitchen porters and seafarers. Male seafarers had significantly elevated PMRs for cirrhosis (179), 'other alcohol-related diseases' (275), cancers of the liver (155), oral cavity (275) and pharynx (267) and injury by fall on the stairs (187). PMRs for human immunodeficiency virus infection (HIV)/acquired immunodeficiency syndrome (AIDS) were particularly high in tailors and dressmakers (918, 95% CI: 369-1890, in men; 804, 95% CI: 219-2060, in women) and male hairdressers (918, 95% CI: 717-1160). Most jobs with high mortality from HIV/AIDS also had more deaths than expected from viral hepatitis. Of seven jobs with significantly high PMRs for both drug dependence and accidental poisoning by drugs, four were in the construction industry (male painters and decorators, bricklayers and masons, plasterers, and roofers and glaziers). CONCLUSIONS: Our findings highlight major differences between occupations in mortality from diseases and injuries caused by alcohol, sexual habits and drug abuse. Priorities for preventive action include alcohol-related disorders in male seafarers and drug abuse in construction workers. Language: en

A series of phenylaminopyrimidines has been identified as inhibitors of Janus kinases (JAKs). Development of this initial series led to the potent JAK2/JAK1 inhibitor CYT387 (N-(cyanomethyl)-4-[2-[[4-(4-morpholinyl)phenyl]amino]-4-pyrimidinyl]-benzamide). Details of synthesis and SAR studies of these compounds are reported.

Background: National analyses of mortality in England and Wales have repeatedly shown excess deaths from pneumonia in welders. During 1979–90 the excess was attributable largely to deaths from lobar pneumonia and pneumonias other than bronchopneumonia, limited to men of working age and apparent in other occupations with exposure to metal fumes. The findings for 1991–2000 were assessed and compared with the mortality pattern from asthma in occupations exposed to known respiratory sensitisers. Methods: The Office of National Statistics supplied data on deaths by underlying cause among men aged 16–74 years in England and Wales during 1991–2000, including age and last held occupation. Data were abstracted on pneumonia for occupations with exposure to metal fumes and on asthma for occupations commonly reported to surveillance schemes as at risk of occupational asthma. The expected numbers of deaths were estimated by applying age-specific proportions of deaths by cause in the population to the total deaths by age in each occupational group. Observed and expected numbers were compared for each cause of death. Results: Among men of working age in occupations with exposure to metal fumes there was excess mortality from pneumococcal and lobar pneumonia (54 deaths vs 27.3 expected) and from pneumonias other than bronchopneumonia (71 vs 52.4), but no excess from these causes at older ages or from bronchopneumonia at any age. The attributable mortality from metal fume exposure was 45.3 excess deaths compared with an estimated 62.6 deaths from occupational asthma. Conclusion: Exposure to metal fumes is a material cause of occupational mortality. The hazard deserves far more attention than it presently receives.