Bradford Royal Infirmary

This meta-analysis explored the efficacy of the Theory of Planned Behaviour (TPB) dependent on behaviour and methodological moderators. A lack of hierarchical analysis in previous reviews risks confounding these moderators. Here moderating roles of behaviour type, length of follow-up, sample age and behavioural measure are explored hierarchically amongst prospective tests of the TPB, controlling for past behaviour where possible. Searching identified 237 prospective tests from 206 articles. Random-effects meta-analytic procedures were used to correcting correlations for sampling and measurement error. Behaviour type moderated the model; physical activity and diet behaviours were better predicted (23.9% and 21.2% variance explained, respectively) whilst risk, detection, safer sex and abstinence from drugs were poorly predicted (between 13.8 and 15.3% variance explained). Methodological moderators were also apparent: age of sample moderated relations with student samples better predicted for physical activity, and adolescent samples better predicted for abstinence behaviours. Behaviours assessed in the shorter term, and those assessed with self-reports (compared with objective measures) were also better predicted. Both behavioural and methodological characteristics moderated relations amongst model components. The results can aid selection of appropriate targets upon which to base interventions.

Abstract The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-19 1,2 , host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases 3–7 . They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease.

BACKGROUND: Obstructive sleep apnoea is the periodic reduction (hypopnoea) or cessation (apnoea) of breathing due to narrowing or occlusion of the upper airway during sleep. The main symptom is daytime sleepiness and it has been suggested it is linked to premature death, hypertension, ischaemic heart disease, stroke and road traffic accidents. OBJECTIVES: The main treatment for sleep apnoea is with the use of continuous positive airways pressure (CPAP), which requires a flow generator and mask. These are used at night to prevent apnoea, hypoxia and sleep disturbance. The objective was to assess the effects of CPAP in the treatment of obstructive sleep apnoea in adults. SEARCH STRATEGY: We searched the Cochrane Airways Group Trials Register and reference lists of articles. We consulted experts in the field. Searches were current to July 2005. SELECTION CRITERIA: We included randomised trials comparing nocturnal CPAP with an inactive control or oral appliances in adults with obstructive sleep apnoea (an apnoea and hypopnoea index greater than five per hour). Trials had a minimum intervention period of two weeks. DATA COLLECTION AND ANALYSIS: Trial quality was assessed and two review authors extracted data independently. Study authors were contacted for missing information. Parallel and crossover group trials were analysed separately. MAIN RESULTS: Thirty-six trials involving 1718 people met the inclusion criteria. Study quality was mixed. Compared with control, CPAP showed significant improvements in certain objective and subjective sleepiness, measures of quality of life and cognitive function (parallel-group studies: Epworth sleepiness scale (ESS) -3.83 units, 95% CI -4.57 to -3.09; crossover studies: ESS -1.84 units, 95% CI -2.57 to -1.11). Twenty-four hour systolic and diastolic blood pressures were lower with CPAP compared with control (parallel-group trials). Compared with oral appliances, CPAP significantly reduced the apnoea and hypopnoea index (crossover studies: -7.97 events/hr, 95% CI -9.56 to -6.38) and improved sleep efficiency (crossover studies: 2.31%, 95% CI 0.02 to 4.6) and minimum oxygen saturation (4.14%, 95% CI 3.25 to 5.03). Responders to both treatments expressed a strong preference for the oral appliance. However, participants were more likely to withdraw on OA than on CPAP therapy. AUTHORS' CONCLUSIONS: CPAP is effective in reducing symptoms of sleepiness and improving quality of life measures in people with moderate and severe obstructive sleep apnoea (OSA). It is more effective than oral appliances in reducing respiratory disturbances in these people but subjective outcomes are more equivocal. Certain people tend to prefer oral appliances to CPAP where both are effective. This could be because they offer a more convenient way of controlling OSA. Short-term data indicate that CPAP leads to lower blood pressure than control. Long-term data are required for all outcomes in order to determine whether the initial benefits seen in short-term clinical trials persist.

BACKGROUND: Pre-eclampsia is associated with deficient intravascular production of prostacyclin, a vasodilator, and excessive production of thromboxane, a vasoconstrictor and stimulant of platelet aggregation. These observations led to the hypotheses that antiplatelet agents, low-dose aspirin in particular, might prevent or delay development of pre-eclampsia. OBJECTIVES: To assess the effectiveness and safety of antiplatelet agents for women at risk of developing pre-eclampsia. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (July 2006), the Cochrane Central Register of Controlled Trials (The Cochrane Library 2005, Issue 1), EMBASE (1994 to November 2005) and handsearched congress proceedings of the International and European Societies for the Study of Hypertension in Pregnancy. SELECTION CRITERIA: All randomised trials comparing antiplatelet agents with either placebo or no antiplatelet agent were included. Quasi-random studies were excluded. Participants were pregnant women at risk of developing pre-eclampsia. Interventions were any comparisons of an antiplatelet agent (such as low-dose aspirin or dipyridamole) with either placebo or no antiplatelet. DATA COLLECTION AND ANALYSIS: Two authors assessed trials for inclusion and extracted data independently. MAIN RESULTS: Fifty-nine trials (37,560 women) are included. There is a 17% reduction in the risk of pre-eclampsia associated with the use of antiplatelet agents ((46 trials, 32,891 women, relative risk (RR) 0.83, 95% confidence interval (CI) 0.77 to 0.89), number needed to treat (NNT) 72 (52, 119)). Although there is no statistical difference in RR based on maternal risk, there is a significant increase in the absolute risk reduction of pre-eclampsia for high risk (risk difference (RD) -5.2% (-7.5, -2.9), NNT 19 (13, 34)) compared with moderate risk women (RD -0.84 (-1.37, -0.3), NNT 119 (73, 333)). Antiplatelets were associated with an 8% reduction in the relative risk of preterm birth (29 trials, 31,151 women, RR 0.92, 95% CI 0.88 to 0.97); NNT 72 (52, 119)), a 14% reduction in fetal or neonatal deaths (40 trials, 33,098 women, RR 0.86, 95% CI 0.76 to 0.98); NNT 243 (131, 1,666) and a 10% reduction in small-for-gestational age babies (36 trials, 23,638 women, RR 0.90, 95% CI0.83 to 0.98). There were no statistically significant differences between treatment and control groups for any other outcomes. AUTHORS' CONCLUSIONS: Antiplatelet agents, largely low-dose aspirin, have moderate benefits when used for prevention of pre-eclampsia and its consequences. Further information is required to assess which women are most likely to benefit, when treatment is best started, and at what dose.

Aicardi-Goutières syndrome is an inflammatory disease occurring due to mutations in any of TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR or IFIH1. We report on 374 patients from 299 families with mutations in these seven genes. Most patients conformed to one of two fairly stereotyped clinical profiles; either exhibiting an in utero disease-onset (74 patients; 22.8% of all patients where data were available), or a post-natal presentation, usually within the first year of life (223 patients; 68.6%), characterized by a sub-acute encephalopathy and a loss of previously acquired skills. Other clinically distinct phenotypes were also observed; particularly, bilateral striatal necrosis (13 patients; 3.6%) and non-syndromic spastic paraparesis (12 patients; 3.4%). We recorded 69 deaths (19.3% of patients with follow-up data). Of 285 patients for whom data were available, 210 (73.7%) were profoundly disabled, with no useful motor, speech and intellectual function. Chilblains, glaucoma, hypothyroidism, cardiomyopathy, intracerebral vasculitis, peripheral neuropathy, bowel inflammation and systemic lupus erythematosus were seen frequently enough to be confirmed as real associations with the Aicardi-Goutieres syndrome phenotype. We observed a robust relationship between mutations in all seven genes with increased type I interferon activity in cerebrospinal fluid and serum, and the increased expression of interferon-stimulated gene transcripts in peripheral blood. We recorded a positive correlation between the level of cerebrospinal fluid interferon activity assayed within one year of disease presentation and the degree of subsequent disability. Interferon-stimulated gene transcripts remained high in most patients, indicating an ongoing disease process. On the basis of substantial morbidity and mortality, our data highlight the urgent need to define coherent treatment strategies for the phenotypes associated with mutations in the Aicardi-Goutières syndrome-related genes. Our findings also make it clear that a window of therapeutic opportunity exists relevant to the majority of affected patients and indicate that the assessment of type I interferon activity might serve as a useful biomarker in future clinical trials.

OBJECTIVE: To assess the separate and combined associations of maternal pre-pregnancy body mass index (BMI) and gestational weight gain with the risks of pregnancy complications and their population impact. DESIGN: Individual participant data meta-analysis of 39 cohorts. SETTING: Europe, North America, and Oceania. POPULATION: 265 270 births. METHODS: Information on maternal pre-pregnancy BMI, gestational weight gain, and pregnancy complications was obtained. Multilevel binary logistic regression models were used. MAIN OUTCOME MEASURES: Gestational hypertension, pre-eclampsia, gestational diabetes, preterm birth, small and large for gestational age at birth. RESULTS: Higher maternal pre-pregnancy BMI and gestational weight gain were, across their full ranges, associated with higher risks of gestational hypertensive disorders, gestational diabetes, and large for gestational age at birth. Preterm birth risk was higher at lower and higher BMI and weight gain. Compared with normal weight mothers with medium gestational weight gain, obese mothers with high gestational weight gain had the highest risk of any pregnancy complication (odds ratio 2.51, 95% CI 2.31- 2.74). We estimated that 23.9% of any pregnancy complication was attributable to maternal overweight/obesity and 31.6% of large for gestational age infants was attributable to excessive gestational weight gain. CONCLUSIONS: Maternal pre-pregnancy BMI and gestational weight gain are, across their full ranges, associated with risks of pregnancy complications. Obese mothers with high gestational weight gain are at the highest risk of pregnancy complications. Promoting a healthy pre-pregnancy BMI and gestational weight gain may reduce the burden of pregnancy complications and ultimately the risk of maternal and neonatal morbidity. TWEETABLE ABSTRACT: Promoting a healthy body mass index and gestational weight gain might reduce the population burden of pregnancy complications.

BACKGROUND: Eclampsia, the occurrence of a seizure (fit) in association with pre-eclampsia, is rare but potentially life-threatening. Magnesium sulphate is the drug of choice for treating eclampsia. This review assesses its use for preventing eclampsia. OBJECTIVES: To assess the effects of magnesium sulphate, and other anticonvulsants, for prevention of eclampsia. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (4 June 2010), and the Cochrane Central Register of Controlled Trials Register (The Cochrane Library 2010, Issue 3). SELECTION CRITERIA: Randomised trials comparing anticonvulsants with placebo or no anticonvulsant, or comparisons of different drugs, for pre-eclampsia. DATA COLLECTION AND ANALYSIS: Two authors assessed trial quality and extracted data independently. MAIN RESULTS: We included 15 trials. Six (11,444 women) compared magnesium sulphate with placebo or no anticonvulsant: magnesium sulphate more than a halved the risk of eclampsia (risk ratio (RR) 0.41, 95% confidence interval (CI) 0.29 to 0.58; number needed to treat for an additional beneficial outcome (NNTB) 100, 95% CI 50 to 100), with a non-significant reduction in maternal death (RR 0.54, 95% CI 0.26 to 1.10) but no clear difference in serious maternal morbidity (RR 1.08, 95% CI 0.89 to 1.32). It reduced the risk of placental abruption (RR 0.64, 95% CI 0.50 to 0.83; NNTB 100, 95% CI 50 to 1000), and increased caesarean section (RR 1.05, 95% CI 1.01 to 1.10). There was no clear difference in stillbirth or neonatal death (RR 1.04, 95% CI 0.93 to 1.15). Side effects, primarily flushing, were more common with magnesium sulphate (24% versus 5%; RR 5.26, 95% CI 4.59 to 6.03; number need to treat for an additional harmful outcome (NNTH) 6, 95% CI 5 to 6).Follow-up was reported by one trial comparing magnesium sulphate with placebo: for 3375 women there was no clear difference in death (RR 1.79, 95% CI 0.71 to 4.53) or morbidity potentially related to pre-eclampsia (RR 0.84, 95% CI 0.55 to 1.26) (median follow-up 26 months); for 3283 children exposed in utero there was no clear difference in death (RR 1.02, 95% CI 0.57 to 1.84) or neurosensory disability (RR 0.77, 95% CI 0.38 to 1.58) at age 18 months.Magnesium sulphate reduced eclampsia compared to phenytoin (three trials, 2291 women; RR 0.08, 95% CI 0.01 to 0.60) and nimodipine (one trial, 1650 women; RR 0.33, 95% CI 0.14 to 0.77). AUTHORS' CONCLUSIONS: Magnesium sulphate more than halves the risk of eclampsia, and probably reduces maternal death. There is no clear effect on outcome after discharge from hospital. A quarter of women report side effects with magnesium sulphate.

The rare coagulation disorders are heritable abnormalities of haemostasis that may present significant difficulties in diagnosis and management. This review summarizes the current literature for disorders of fibrinogen, and deficiencies of prothrombin, factor V, FV + VIII, FVII, FX, the combined vitamin K-dependent factors, FXI and FXIII. Based on both collective clinical experience and the literature, guidelines for management of bleeding complications are suggested with specific advice for surgery, spontaneous bleeding, management of pregnancy and the neonate. We have chosen to include a section on Ehlers-Danlos Syndrome because haematologists may be consulted about bleeding manifestations in such patients.

Abstract Objective To examine the association of physician burnout with the career engagement and the quality of patient care globally. Design Systematic review and meta-analysis. Data sources Medline, PsycINFO, Embase, and CINAHL were searched from database inception until May 2021. Eligibility criteria for selecting studies Observational studies assessing the association of physician burnout (including a feeling of overwhelming emotional exhaustion, feelings of cynicism and detachment from job defined as depersonalisation, and a sense of ineffectiveness and little personal accomplishment) with career engagement (job satisfaction, career choice regret, turnover intention, career development, and productivity loss) and the quality of patient care (patient safety incidents, low professionalism, and patient satisfaction). Data were double extracted by independent reviewers and checked through contacting all authors, 84 (49%) of 170 of whom confirmed their data. Random-effect models were used to calculate the pooled odds ratio, prediction intervals expressed the amount of heterogeneity, and meta-regressions assessed for potential moderators with significance set using a conservative level of P<0.10. Results 4732 articles were identified, of which 170 observational studies of 239 246 physicians were included in the meta-analysis. Overall burnout in physicians was associated with an almost four times decrease in job satisfaction compared with increased job satisfaction (odds ratio 3.79, 95% confidence interval 3.24 to 4.43, I 2 =97%, k=73 studies, n=146 980 physicians). Career choice regret increased by more than threefold compared with being satisfied with their career choice (3.49, 2.43 to 5.00, I 2 =97%, k=16, n=33 871). Turnover intention also increased by more than threefold compared with retention (3.10, 2.30 to 4.17, I 2 =97%, k=25, n=32 271). Productivity had a small but significant effect (1.82, 1.08 to 3.07, I 2 =83%, k=7, n=9581) and burnout also affected career development from a pooled association of two studies (3.77, 2.77 to 5.14, I 2 =0%, n=3411). Overall physician burnout doubled patient safety incidents compared with no patient safety incidents (2.04, 1.69 to 2.45, I 2 =87%, k=35, n=41 059). Low professionalism was twice as likely compared with maintained professionalism (2.33, 1.96 to 2.70, I 2 =96%, k=40, n=32 321), as was patient dissatisfaction compared with patient satisfaction (2.22, 1.38 to 3.57, I 2 =75%, k=8, n=1002). Burnout and poorer job satisfaction was greatest in hospital settings (1.88, 0.91 to 3.86, P=0.09), physicians aged 31-50 years (2.41, 1.02 to 5.64, P=0.04), and working in emergency medicine and intensive care (2.16, 0.98 to 4.76, P=0.06); burnout was lowest in general practitioners (0.16, 0.03 to 0.88, P=0.04). However, these associations did not remain significant in the multivariable regressions. Burnout and patient safety incidents were greatest in physicians aged 20-30 years (1.88, 1.07 to 3.29, P=0.03), and people working in emergency medicine (2.10, 1.09 to 3.56, P=0.02). The association of burnout with low professionalism was smallest in physicians older than 50 years (0.36, 0.19 to 0.69, P=0.003) and greatest in physicians still in training or residency (2.27, 1.45 to 3.60, P=0.001), in those who worked in a hospital (2.16, 1.46 to 3.19, P<0.001), specifically in emergency medicine specialty (1.48, 1.01 to 2.34, P=0.042), or situated in a low to middle income country (1.68, 0.94 to 2.97, P=0.08). Conclusions This meta-analysis provides compelling evidence that physician burnout is associated with poor function and sustainability of healthcare organisations primarily by contributing to the career disengagement and turnover of physicians and secondarily by reducing the quality of patient care. Healthcare organisations should invest more time and effort in implementing evidence-based strategies to mitigate physician burnout across specialties, and particularly in emergency medicine and for physicians in training or residency. Systematic review registration PROSPERO number CRD42021249492.

BACKGROUND: Maternal obesity and excessive gestational weight gain may have persistent effects on offspring fat development. However, it remains unclear whether these effects differ by severity of obesity, and whether these effects are restricted to the extremes of maternal body mass index (BMI) and gestational weight gain. We aimed to assess the separate and combined associations of maternal BMI and gestational weight gain with the risk of overweight/obesity throughout childhood, and their population impact. METHODS AND FINDINGS: We conducted an individual participant data meta-analysis of data from 162,129 mothers and their children from 37 pregnancy and birth cohort studies from Europe, North America, and Australia. We assessed the individual and combined associations of maternal pre-pregnancy BMI and gestational weight gain, both in clinical categories and across their full ranges, with the risks of overweight/obesity in early (2.0-5.0 years), mid (5.0-10.0 years) and late childhood (10.0-18.0 years), using multilevel binary logistic regression models with a random intercept at cohort level adjusted for maternal sociodemographic and lifestyle-related characteristics. We observed that higher maternal pre-pregnancy BMI and gestational weight gain both in clinical categories and across their full ranges were associated with higher risks of childhood overweight/obesity, with the strongest effects in late childhood (odds ratios [ORs] for overweight/obesity in early, mid, and late childhood, respectively: OR 1.66 [95% CI: 1.56, 1.78], OR 1.91 [95% CI: 1.85, 1.98], and OR 2.28 [95% CI: 2.08, 2.50] for maternal overweight; OR 2.43 [95% CI: 2.24, 2.64], OR 3.12 [95% CI: 2.98, 3.27], and OR 4.47 [95% CI: 3.99, 5.23] for maternal obesity; and OR 1.39 [95% CI: 1.30, 1.49], OR 1.55 [95% CI: 1.49, 1.60], and OR 1.72 [95% CI: 1.56, 1.91] for excessive gestational weight gain). The proportions of childhood overweight/obesity prevalence attributable to maternal overweight, maternal obesity, and excessive gestational weight gain ranged from 10.2% to 21.6%. Relative to the effect of maternal BMI, excessive gestational weight gain only slightly increased the risk of childhood overweight/obesity within each clinical BMI category (p-values for interactions of maternal BMI with gestational weight gain: p = 0.038, p < 0.001, and p = 0.637 in early, mid, and late childhood, respectively). Limitations of this study include the self-report of maternal BMI and gestational weight gain for some of the cohorts, and the potential of residual confounding. Also, as this study only included participants from Europe, North America, and Australia, results need to be interpreted with caution with respect to other populations. CONCLUSIONS: In this study, higher maternal pre-pregnancy BMI and gestational weight gain were associated with an increased risk of childhood overweight/obesity, with the strongest effects at later ages. The additional effect of gestational weight gain in women who are overweight or obese before pregnancy is small. Given the large population impact, future intervention trials aiming to reduce the prevalence of childhood overweight and obesity should focus on maternal weight status before pregnancy, in addition to weight gain during pregnancy.

BACKGROUND: Controversy exists concerning the necessary margin of excision for cutaneous melanoma 2 mm or greater in thickness. METHODS: We conducted a randomized clinical trial comparing 1-cm and 3-cm margins. RESULTS: Of the 900 patients who were enrolled, 453 were randomly assigned to undergo surgery with a 1-cm margin of excision and 447 with a 3-cm margin of excision; the median follow-up was 60 months. A 1-cm margin of excision was associated with a significantly increased risk of locoregional recurrence. There were 168 locoregional recurrences (as first events) in the group with 1-cm margins of excision, as compared with 142 in the group with 3-cm margins (hazard ratio, 1.26; 95 percent confidence interval, 1.00 to 1.59; P=0.05). There were 128 deaths attributable to melanoma in the group with 1-cm margins, as compared with 105 in the group with 3-cm margins (hazard ratio, 1.24; 95 percent confidence interval, 0.96 to 1.61; P=0.1); overall survival was similar in the two groups (hazard ratio for death, 1.07; 95 percent confidence interval, 0.85 to 1.36; P=0.6). CONCLUSIONS: A 1-cm margin of excision for melanoma with a poor prognosis (as defined by a tumor thickness of at least 2 mm) is associated with a significantly greater risk of regional recurrence than is a 3-cm margin, but with a similar overall survival rate.

OBJECTIVES: To assess the extent and pattern of implementation of guidance issued by the National Institute for Clinical Excellence (NICE). DESIGN: Interrupted time series analysis, review of case notes, survey, and interviews. SETTING: Acute and primary care trusts in England and Wales. PARTICIPANTS: All primary care prescribing, hospital pharmacies; a random sample of 20 acute trusts, 17 mental health trusts, and 21 primary care trusts; and senior clinicians and managers from five acute trusts. MAIN OUTCOME MEASURES: Rates of prescribing and use of procedures and medical devices relative to evidence based guidance. RESULTS: 6308 usable patient audit forms were returned. Implementation of NICE guidance varied by trust and by topic. Prescribing of some taxanes for cancer (P < 0.002) and orlistat for obesity (P < 0.001) significantly increased in line with guidance. Prescribing of drugs for Alzheimer's disease and prophylactic extraction of wisdom teeth showed trends consistent with, but not obviously a consequence of, the guidance. Prescribing practice often did not accord with the details of the guidance. No change was apparent in the use of hearing aids, hip prostheses, implantable cardioverter defibrillators, laparoscopic hernia repair, and laparoscopic colorectal cancer surgery after NICE guidance had been issued. CONCLUSIONS: Implementation of NICE guidance has been variable. Guidance seems more likely to be adopted when there is strong professional support, a stable and convincing evidence base, and no increased or unfunded costs, in organisations that have established good systems for tracking guidance implementation and where the professionals involved are not isolated. Guidance needs to be clear and reflect the clinical context.

INTRODUCTION: Recent research on health inequalities moves beyond illustrating the importance of psychosocial factors for health to a more in-depth study of the specific psychosocial pathways involved. Social capital is a concept that captures both a buffer function of the social environment on health, as well as potential negative effects arising from social inequality and exclusion. This systematic review assesses the current evidence, and identifies gaps in knowledge, on the associations and interactions between social capital and socioeconomic inequalities in health. METHODS: Through this systematic review we identified studies on the interactions between social capital and socioeconomic inequalities in health published before July 2012. RESULTS: The literature search resulted in 618 studies after removal of duplicates, of which 60 studies were eligible for analysis. Self-reported measures of health were most frequently used, together with different bonding, bridging and linking components of social capital. A large majority, 56 studies, confirmed a correlation between social capital and socioeconomic inequalities in health. Twelve studies reported that social capital might buffer negative health effects of low socioeconomic status and five studies concluded that social capital has a stronger positive effect on health for people with a lower socioeconomic status. CONCLUSIONS: There is evidence for both a buffer effect and a dependency effect of social capital on socioeconomic inequalities in health, although the studies that assess these interactions are limited in number. More evidence is needed, as identified hypotheses have implications for community action and for action on the structural causes of social inequalities.

BACKGROUND: Research shows that stroke patients and their families are dissatisfied with the information provided and have a poor understanding of stroke and associated issues. OBJECTIVES: To assess the effectiveness of information provision strategies in improving the outcome for stroke patients or their identified caregivers, or both. SEARCH METHODS: For this update we searched the Cochrane Stroke Group Trials Register (June 2012), the Cochrane Central Register of Controlled trials (CENTRAL), the Cochrane Database of Systematic Reviews (CDSR), the Database of Abstracts of Reviews of Effects (DARE), the NHS Economic Evaluation Database (EED), and the Health Technology Assessment (HTA) Database (The Cochrane Library June, 2012), MEDLINE (1966 to June 2012), EMBASE (1980 to June 2012), CINAHL (1982 to June 2012) and PsycINFO (1974 to June 2012). We also searched ongoing trials registers, scanned bibliographies of relevant articles and books and contacted researchers. SELECTION CRITERIA: Randomised trials involving patients or carers of patients with a clinical diagnosis of stroke or transient ischaemic attack (TIA) where an information intervention was compared with standard care, or where information and another therapy were compared with the other therapy alone. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial eligibility and methodological quality and extracted data. Primary outcomes were knowledge about stroke and stroke services, and impact on mood. MAIN RESULTS: We have added four new trials to this update. This review now includes 21 trials involving 2289 patient and 1290 carer participants. Nine trials evaluated a passive and 12 trials an active information intervention. Meta-analyses showed a significant effect in favour of the intervention on patient knowledge (standardised mean difference (SMD) 0.29, 95% confidence interval (CI) 0.12 to 0.46, P < 0.001), carer knowledge (SMD 0.74, 95% CI 0.06 to 1.43, P = 0.03), one aspect of patient satisfaction (odds ratio (OR) 2.07, 95% CI 1.33 to 3.23, P = 0.001), and patient depression scores (mean difference (MD) -0.52, 95% CI -0.93 to -0.10, P = 0.01). There was no significant effect (P > 0.05) on number of cases of anxiety or depression in patients, carer mood or satisfaction, or death. Qualitative analyses found no strong evidence of an effect on other outcomes. Post-hoc subgroup analyses showed that active information had a significantly greater effect than passive information on patient mood but not on other outcomes. AUTHORS' CONCLUSIONS: There is evidence that information improves patient and carer knowledge of stroke, aspects of patient satisfaction, and reduces patient depression scores. However, the reduction in depression scores was small and may not be clinically significant. Although the best way to provide information is still unclear there is some evidence that strategies that actively involve patients and carers and include planned follow-up for clarification and reinforcement have a greater effect on patient mood.

OBJECTIVES: To assess the association between maternal glucose concentrations and adverse perinatal outcomes in women without gestational or existing diabetes and to determine whether clear thresholds for identifying women at risk of perinatal outcomes can be identified. DESIGN: Systematic review and meta-analysis of prospective cohort studies and control arms of randomised trials. DATA SOURCES: Databases including Medline and Embase were searched up to October 2014 and combined with individual participant data from two additional birth cohorts. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Studies including pregnant women with oral glucose tolerance (OGTT) or challenge (OGCT) test results, with data on at least one adverse perinatal outcome. APPRAISAL AND DATA EXTRACTION: Glucose test results were extracted for OGCT (50 g) and OGTT (75 g and 100 g) at fasting and one and two hour post-load timings. Data were extracted on induction of labour; caesarean and instrumental delivery; pregnancy induced hypertension; pre-eclampsia; macrosomia; large for gestational age; preterm birth; birth injury; and neonatal hypoglycaemia. Risk of bias was assessed with a modified version of the critical appraisal skills programme and quality in prognostic studies tools. RESULTS: 25 reports from 23 published studies and two individual participant data cohorts were included, with up to 207 172 women (numbers varied by the test and outcome analysed in the meta-analyses). Overall most studies were judged as having a low risk of bias. There were positive linear associations with caesarean section, induction of labour, large for gestational age, macrosomia, and shoulder dystocia for all glucose exposures across the distribution of glucose concentrations. There was no clear evidence of a threshold effect. In general, associations were stronger for fasting concentration than for post-load concentration. For example, the odds ratios for large for gestational age per 1 mmol/L increase of fasting and two hour post-load glucose concentrations (after a 75 g OGTT) were 2.15 (95% confidence interval 1.60 to 2.91) and 1.20 (1.13 to 1.28), respectively. Heterogeneity was low between studies in all analyses. CONCLUSIONS: This review and meta-analysis identified a large number of studies in various countries. There was a graded linear association between fasting and post-load glucose concentration across the whole glucose distribution and most adverse perinatal outcomes in women without pre-existing or gestational diabetes. The lack of a clear threshold at which risk increases means that decisions regarding thresholds for diagnosing gestational diabetes are somewhat arbitrary. Research should now investigate the clinical and cost-effectiveness of applying different glucose thresholds for diagnosis of gestational diabetes on perinatal and longer term outcomes. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42013004608.

A 47-year-old man presented with complaints of breakthrough seizures, psychiatric and behavioural changes and catatonic features. MRI of the brain showed mild cerebral and right hippocampal atrophy, while the electroencephalogram showed intermittent right temporal slowing. With a presumed diagnosis of autoimmune encephalitis, he was treated with intravenous immunoglobulin (IVIG) and methylprednisolone, which significantly improved the symptoms. Serological testing later was positive for antileucine-rich glioma inactivated 1 antibody. Two months after the initial presentation, patient had a relapse of the symptoms without any further episodes of seizures. Repeat MRI of the brain showed a significant rapidly progressive diffuse cortical atrophy and hippocampal atrophy, more prominent on the right side along with hydrocephalus ex vacuo when compared with the initial MRI. He is currently on monthly IVIG therapy. At 4 months follow-up from the second imagining study, the patient had persistent MRI findings.

BACKGROUND: Obstructive sleep apnoea-hypopnoea (OSAH) is a syndrome characterised by recurrent episodes of partial or complete upper airway obstruction during sleep that are usually terminated by an arousal. Nasal continuous positive airway pressure (CPAP) is the primary treatment for OSAH , but many patients are unable or unwilling to comply with this treatment. Oral appliances (OA) are an alternative treatment for OSAH. OBJECTIVES: The objective was to review the effects of OA in the treatment of OSAH in adults. SEARCH STRATEGY: We searched the Cochrane Airways Group Specialised Register. Searches were current as of June 2005. Reference lists of articles were also searched. SELECTION CRITERIA: Randomised trials comparing OA with control or other treatments in adults with OSAH . DATA COLLECTION AND ANALYSIS: Two authors independently extracted data and assessed trial quality. Study authors were contacted for missing information. MAIN RESULTS: Sixteen studies (745 participants) met the inclusion criteria. All the studies had some shortcomings, such as small sample size, under-reporting of methods and data, and lack of blinding. OA versus control appliances (six studies): OA reduced daytime sleepiness in two crossover trials (WMD -1.81;95%CI -2.72 to -0.90), and improved apnoea-hypopnoea index (AHI) (-10.78; 95% CI-15.53 to -6.03 parallel group data - five studies). OA versus CPAP (nine studies): OA were less effective than CPAP in reducing apnoea-hypopnoea index (parallel group studies: WMD 13 (95% CI 7.63 to 18.36), two trials; crossover studies: WMD 7.97; (95% CI 6.38 to 9.56, seven trials). However, no significant difference was observed on symptom scores. CPAP was more effective at improving minimum arterial oxygen saturation during sleep compared with OA. In two small crossover studies, participants preferred OA therapy to CPAP. OA versus corrective upper airway surgery (one study): Symptoms of daytime sleepiness were initially lower with surgery, but this difference disappeared at 12 months. AHI did not differ significantly initially, but did so after 12 months in favour of OA. AUTHORS' CONCLUSIONS: There is increasing evidence suggesting that OA improves subjective sleepiness and sleep disordered breathing compared with a control. CPAP appears to be more effective in improving sleep disordered breathing than OA. The difference in symptomatic response between these two treatments is not significant, although it is not possible to exclude an effect in favour of either therapy. Until there is more definitive evidence on the effectiveness of OA in relation to CPAP, with regard to symptoms and long-term complications, it would appear to be appropriate to recommend OA therapy to patients with mild symptomatic OSAH, and those patients who are unwilling or unable to tolerate CPAP therapy. Future research should recruit patients with more severe symptoms of sleepiness, to establish whether the response to therapy differs between subgroups in terms of quality of life, symptoms and persistence with usage. Long-term data on cardiovascular health are required.

Abstract Additional data from this article are available on the www.bmj.com/ Objective: To examine the research evidence for the health consequences of obstructive sleep apnoea and the effectiveness of continuous positive airways pressure. Design: A systematic review of published research, studies being identified by searching Medline (1966-96), Embase (1974-96), and CINAHL (Cumulative Index to Nursing and Allied Health Literature) (1982-95); scanning citations; and consulting experts. Studies in all languages were considered which either investigated the association between obstructive sleep apnoea in adults and key health outcomes or evaluated the effectiveness of treatment of obstructive sleep apnoea with continuous positive airways pressure in adults. Main outcome measures: Mortality, systematic hypertension, cardiac arrhythmias, ischaemic heart disease, left ventricular hypertrophy, pulmonary hypertension, stroke, vehicle accidents, measures of daytime sleepiness, and quality of life. Results: 54 epidemiological studies examined the association between sleep apnoea and health related outcomes. Most were poorly designed and only weak or contradictory evidence was found of an association with cardiac arrhythmias, ischaemic heart disease, cardiac failure, systemic or pulmonary hypertension, and stroke. Evidence of a link with sleepiness and road traffic accidents was stronger but inconclusive. Only one small randomised controlled trial evaluated continuous positive airways pressure. Five non-randomised controlled trials and 38 uncontrolled trials were identified. Small changes in objectively measured daytime sleepiness were consistently found, but improvements in morbidity, mortality, and quality of life indicators were not adequately assessed. Conclusions: The relevance of sleep apnoea to public health has been exaggerated. The effectiveness of continuous positive airways pressure in improving health outcomes has been poorly evaluated. There is enough evidence suggesting benefit in reducing daytime sleepiness in some patients to warrant large randomised placebo controlled trials of continuous positive airways pressure versus an effective weight reduction programme and other interventions. Key messages Obstructive sleep apnoea is claimed to be an important cause of premature death and disability There is increasing pressure to provide sleep services for the treatment of patients with sleep apnoea Epidemiological evidence suggests that sleep apnoea causes daytime sleepiness and possibly vehicle accidents Evidence for a causal association between sleep apnoea and other adverse health outcomes is weak There is a paucity of robust evidence for the clinical and cost effectiveness of continuous positive airways pressure in the treatment of most patients with sleep apnoea

BACKGROUND: Statin treatment and variants in the gene encoding HMG-CoA reductase are associated with reductions in both the concentration of LDL cholesterol and the risk of coronary heart disease, but also with modest hyperglycaemia, increased bodyweight, and modestly increased risk of type 2 diabetes, which in no way offsets their substantial benefits. We sought to investigate the associations of LDL cholesterol-lowering PCSK9 variants with type 2 diabetes and related biomarkers to gauge the likely effects of PCSK9 inhibitors on diabetes risk. METHODS: , fasting insulin, bodyweight, waist-to-hip ratio, BMI, and risk of type 2 diabetes, using a standardised analysis plan, meta-analyses, and weighted gene-centric scores. FINDINGS: , -0·09 to 0·30). INTERPRETATION: PCSK9 variants associated with lower LDL cholesterol were also associated with circulating higher fasting glucose concentration, bodyweight, and waist-to-hip ratio, and an increased risk of type 2 diabetes. In trials of PCSK9 inhibitor drugs, investigators should carefully assess these safety outcomes and quantify the risks and benefits of PCSK9 inhibitor treatment, as was previously done for statins. FUNDING: British Heart Foundation, and University College London Hospitals NHS Foundation Trust (UCLH) National Institute for Health Research (NIHR) Biomedical Research Centre.

Obstructive sleep apnoea is the periodic reduction (hypopnoea) or cessation (apnoea) of breathing due to narrowing or occlusion of the upper airway during sleep. The main symptom is daytime sleepiness and it has been suggested it is linked to premature death, hypertension, ischaemic heart disease, stroke and road traffic accidents.The main treatment for sleep apnoea is with the use of continuous positive airways pressure (CPAP), which requires a flow generator and mask. These are used at night to prevent apnoea, hypoxia and sleep disturbance. The objective was to assess the effects of CPAP in the treatment of obstructive sleep apnoea in adults.We searched the Cochrane Airways Group Trials Register and reference lists of articles. We consulted experts in the field. Searches were current to July 2005.We included randomised trials comparing nocturnal CPAP with an inactive control or oral appliances in adults with obstructive sleep apnoea (an apnoea and hypopnoea index greater than five per hour). Trials had a minimum intervention period of two weeks.Trial quality was assessed and two review authors extracted data independently. Study authors were contacted for missing information. Parallel and crossover group trials were analysed separately.Thirty-six trials involving 1718 people met the inclusion criteria. Study quality was mixed. Compared with control, CPAP showed significant improvements in certain objective and subjective sleepiness, measures of quality of life and cognitive function (parallel-group studies: Epworth sleepiness scale (ESS) -3.83 units, 95% CI -4.57 to -3.09; crossover studies: ESS -1.84 units, 95% CI -2.57 to -1.11). Twenty-four hour systolic and diastolic blood pressures were lower with CPAP compared with control (parallel-group trials). Compared with oral appliances, CPAP significantly reduced the apnoea and hypopnoea index (crossover studies: -7.97 events/hr, 95% CI -9.56 to -6.38) and improved sleep efficiency (crossover studies: 2.31%, 95% CI 0.02 to 4.6) and minimum oxygen saturation (4.14%, 95% CI 3.25 to 5.03). Responders to both treatments expressed a strong preference for the oral appliance. However, participants were more likely to withdraw on OA than on CPAP therapy.CPAP is effective in reducing symptoms of sleepiness and improving quality of life measures in people with moderate and severe obstructive sleep apnoea (OSA). It is more effective than oral appliances in reducing respiratory disturbances in these people but subjective outcomes are more equivocal. Certain people tend to prefer oral appliances to CPAP where both are effective. This could be because they offer a more convenient way of controlling OSA. Short-term data indicate that CPAP leads to lower blood pressure than control. Long-term data are required for all outcomes in order to determine whether the initial benefits seen in short-term clinical trials persist.