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Background: Asthma is one of the most frequent reasons children visit a general practitioner (GP). The diagnosis of childhood asthma is challenging, and a variety of diagnostic tests for asthma exist. GPs may refer to clinical practice guidelines when deciding which tests, if any, are appropriate, but the quality of these guidelines is unknown., Objectives: To determine (i) the methodological quality and reporting of paediatric guidelines for the diagnosis of childhood asthma in primary care, and (ii) the strength of evidence supporting diagnostic test recommendations., Design: Meta-epidemiological study of English-language guidelines from the United Kingdom and other high-income countries with comparable primary care systems including diagnostic testing recommendations for childhood asthma in primary care. The AGREE-II tool was used to assess the quality and reporting of the guidelines. The quality of the evidence was assessed using GRADE., Results: Eleven guidelines met the eligibility criteria. The methodology and reporting quality varied across the AGREE II domains (median score 4.5 out of 7, range 2-6). The quality of evidence supporting diagnostic recommendations was generally of very low quality. All guidelines recommended the use of spirometry and reversibility testing for children aged ≥5 years, however, the recommended spirometry thresholds for diagnosis differed across guidelines. There were disagreements in testing recommendations for 3 of the 7 included tests., Conclusions: The variable quality of guidelines, lack of good quality evidence, and inconsistent recommendations for diagnostic tests may contribute to poor clinician adherence to guidelines and variation in testing for diagnosing childhood asthma., (© The Author(s) 2023. Published by Oxford University Press.)

Background: Most healthcare contacts for children in the UK occur in general practice. Diagnostic tests can be beneficial in narrowing differential diagnoses; however, there is substantial variation in the use of tests for children in general practice. Unwarranted variation in testing can lead to variation in quality of care and may exacerbate health inequities. To our knowledge, no previous study has tried to understand why variation in testing exists for children in general practice., Aim: To explore GPs' perspectives on using diagnostic tests for children in primary care and the underlying drivers of variation., Design and Setting: Qualitative study in which semi-structured interviews were conducted with GPs and trainee GPs in England., Method: Interviews were conducted with 18 GPs and two trainee GPs between April and June 2023. The interviews were transcribed and analysed using reflexive thematic analysis., Results: GPs reflected that their approach to testing in children differed from their approach to testing in adults: their threshold to test was higher, and their threshold to refer to specialists was lower. GPs' perceptions of test utility varied, including objective testing for asthma. Perceived drivers of variation in testing were intrinsic (clinician-specific) factors relating to their risk tolerance and experience; and extrinsic factors, including disease prevalence, parental concern and expectations of health care, workforce changes leading to fragmentation in care, time constraints, and differences in guidelines., Conclusion: The findings of this study identify actionable issues for clinicians, researchers, and policymakers to address gaps in education, evidence, and guidance, reduce unwarranted differences in test use, and improve the quality of health care delivered to children in general practice., (© The Authors.)

Background: Solid organ and haematopoietic stem cell transplant recipients are more vulnerable to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) than non-transplant recipients due to immunosuppression, and may pose a continued transmission risk, especially within hospital settings. Detailed case reports including symptoms, viral load and infectiousness, defined by the presence of replication-competent viruses in culture, provide an opportunity to examine the relationship between clinical course, burden and contagiousness, and provide guidance on release from isolation., Objectives: To investigate the relationship between serial SARS-CoV-2 reverse transcription polymerase chain reaction (RT-PCR) cycle threshold (Ct) value or cycle of quantification value, or other measures of viral burden and the likelihood and duration of the presence of infectious virus based on viral culture, including the influence of age, sex, underlying pathologies, degree of immunosuppression, and/or vaccination on this relationship, in transplant recipients., Methods: LitCovid, medRxiv, Google Scholar and the World Health Organization COVID-19 database were searched from 1 st November 2019 to 26 th October 2022. Studies reporting relevant data (results from serial RT-PCR testing and viral culture data from the same respiratory samples) for transplant recipients with SARS-CoV-2 infection were included in this systematic review: Methodological quality was assessed using five criteria, and the data were synthesized narratively and graphically., Results: Thirteen case reports and case series reporting on 41 transplant recipients (22 renal, five cardiac, one bone marrow, two liver, one bilateral lung and 10 blood stem cell) were included in this review. A relationship was observed between proxies of viral burden and likelihood of shedding replication-competent SARS-CoV-2. Three individuals shed replication-competent viruses for >100 days after symptom onset. Lack of standardization of testing and reporting platforms precludes establishing a definitive viral burden cut-off. However, the majority of transplant recipients stopped shedding replication-competent viruses when the Ct value was >30 despite differences across platforms., Conclusions: Viral burden is a reasonable proxy for infectivity when considered within the context of the clinical status of each patient. Standardized study design and reporting are essential to standardize guidance based on an increasing evidence base., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Antimicrobial stewardship (AMS) initiatives in hospitals often include the implementation of clustered intervention components to improve the surveillance and targeting of antibiotics. However, impacts of the individual components of AMS interventions are not well known, especially in low- and lower-middle-income countries (LLMICs)., Objective: A scoping review was conducted to summarize evidence from systematic reviews (SRs) on the impact of common hospital-implemented healthcare-worker-targeted components of AMS interventions that may be appropriate for LLMICs., Methods: Major databases were searched systematically for SRs of AMS interventions that were evaluated in hospitals. For SRs to be eligible, they had to report on at least one intervention that could be categorized according to the Effective Practice and Organisation of Care taxonomy. Clinical and process outcomes were considered. Primary studies from LLMICs were consulted for additional information., Results: Eighteen SRs of the evaluation of intervention components met the inclusion criteria. The evidence shows that audit and feedback, and clinical practice guidelines improved several clinical and process outcomes in hospitals. An unintended consequence of interventions was an increase in the use of antibiotics. There was a cumulative total of 547 unique studies, but only 2% (N=12) were conducted in hospitals in LLMICs. Two studies in LLMICs reported that guidelines and educational meetings were effective in hospitals., Conclusion: Evidence from high- and upper-middle-income countries suggests that audit and feedback, and clinical practice guidelines have the potential to improve various clinical and process outcomes in hospitals. The lack of evidence in LLMIC settings prevents firm conclusions from being drawn, and highlights the need for further research., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The role of fomites in the transmission of SARS-CoV-2 is unclear., Aim: To assess whether SARS-CoV-2 can be transmitted through fomites, using evidence from viral culture studies., Methods: Searches were conducted in the World Health Organization COVID-19 Database, PubMed, LitCovid, medRxiv, and Google Scholar to December 31 st , 2021. Studies that investigated fomite transmission and performed viral culture to assess the cytopathic effect (CPE) of positive fomite samples and confirmation of SARS-CoV-2 as the cause of the CPE were included. The risk of bias using a checklist modified from the modified Quality Assessment of Diagnostic Accuracy Studies - 2 (QUADAS-2) criteria was assessed., Findings: Twenty-three studies were included. The overall risk of bias was moderate. Five studies demonstrated replication-competent virus from fomite cultures and three used genome sequencing to match fomite samples with human clinical specimens. The mean cycle threshold (C T ) of samples with positive viral culture was significantly lower compared with cultured samples that returned negative results (standardized mean difference: -1.45; 95% confidence interval (CI): -2.00 to -0.90; I 2  = 0%; P < 0.00001). The likelihood of isolating replication-competent virus was significantly greater when C T was <30 (relative risk: 3.10; 95% CI: 1.32 to 7.31; I 2  = 71%; P = 0.01). Infectious specimens were mostly detected within seven days of symptom onset. One study showed possible transmission of SARS-CoV-2 from fomites to humans., Conclusion: The evidence from published studies suggests that replication-competent SARS-CoV-2 is present on fomites. Replication-competent SARS-CoV-2 is significantly more likely when the PCR C T for clinical specimens and fomite samples is <30. Further studies should investigate the duration of infectiousness of SARS-CoV-2 and the frequency of transmission from fomites., (Crown Copyright © 2022. Published by Elsevier Ltd. All rights reserved.)

Mathematical models were used widely to inform policy during the COVID pandemic. However, there is a poor understanding of their limitations and how they influence decision-making. We used systematic review search methods to find early modelling studies that determined the reproduction number and analysed its use and application to interventions and policy in the UK. Up to March 2020, we found 42 reproduction number estimates (39 based on Chinese data: R 0 range 2.1-6.47). Several biases affect the quality of modelling studies that are infrequently discussed, and many factors contribute to significant differences in the results of individual studies that go beyond chance. The sources of effect estimates incorporated into mathematical models are unclear. There is often a lack of a relationship between transmission estimates and the timing of imposed restrictions, which is further affected by the lag in reporting. Modelling studies lack basic evidence-based methods that aid their quality assessment, reporting and critical appraisal. If used judiciously, models may be helpful, especially if they openly present the uncertainties and use sensitivity analyses extensively, which need to consider and explicitly discuss the limitations of the evidence. However, until the methodological and ethical issues are resolved, predictive models should be used cautiously., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: TJ’s competing interests are accessible at: https://restoringtrials.org/competing-interests-tom-jefferson . CH holds grant funding from the NIHR School of Primary Care Research, and previously received funding from the World Health Organization for a series of Living rapid review on the modes of transmission of SARs-CoV-2 reference WHO registration No2020/1077093. CH’s Conflicts of interest and payments are accessible at: https://www.phc.ox.ac.uk/team/carl-heneghan, (Copyright © 2022. Published by Elsevier Ltd.)

Systematic reviews of 591 primary studies of the modes of transmission for SARS-CoV-2 show significant methodological shortcomings and heterogeneity in the design, conduct, testing, and reporting of SARS-CoV-2 transmission. While this is partly understandable at the outset of a pandemic, evidence rules of proof for assessing the transmission of this virus are needed for present and future pandemics of viral respiratory pathogens. We review the history of causality assessment related to microbial etiologies with a focus on respiratory viruses and suggest a hierarchy of evidence to integrate clinical, epidemiologic, molecular, and laboratory perspectives on transmission. The hierarchy, if applied to future studies, should narrow the uncertainty over the twin concepts of causality and transmission of human respiratory viruses. We attempt to address the translational gap between the current research evidence and the assessment of causality in the transmission of respiratory viruses with a focus on SARS-CoV-2. Experimentation, consistency, and independent replication of research alongside our proposed framework provide a chain of evidence that can reduce the uncertainty over the transmission of respiratory viruses and increase the level of confidence in specific modes of transmission, informing the measures that should be undertaken to prevent transmission.

Background: The optimal time for initiation of dialysis and which modality to choose as the starting therapy is currently unclear. This systematic review aimed to assess the recommendations across high-quality clinical practice guidelines (CPGs) related to the start of dialysis., Methods: We systematically searched MEDLINE, EMBASE, Web of Science, LILACS, and databases of organisations that develop CPGs between September 2008 to August 2021 for CPGs that addressed recommendations on the timing of initiation of dialysis, selection of dialysis modality, and interventions to support the decision-making process to select a dialysis modality. We used the Appraisal of Guidelines for Research and Evaluation instrument to assess the methodological quality of the CPGs and included only high-quality CPGs. This study is registered in PROSPERO, number CRD42018110325., Results: We included 12 high-quality CPGs. Six CPGs addressed recommendations related to the timing of initiating dialysis, and all agreed on starting dialysis in the presence of symptoms or signs. Six CPGs addressed recommendations related to the selection of modality but varied greatly in their content. Nine CPGs addressed recommendations related to interventions to support the decision-making process. Eight CPGs agreed on recommended educational programs that include information about dialysis options. One CPG considered using patient decision aids a strong recommendation., Limitations: We could have missed potentially relevant guidelines since we limited our search to CPGs published from 2008, and we set up a cut-off point of 60% in domains of the rigour of development and editorial independence., Conclusion: High-quality CPGs related to the process of starting dialysis were consistent in initiating dialysis in the presence of symptoms or signs and offering patients education at the point of decision-making. There was variability in how CPGs addressed the issue of dialysis modality selection. CPGs should improve strategies on putting recommendations into practice and the quality of evidence to aid decision-making for patients., Registration: The protocol of this systematic review has been registered in the international prospective register of systematic reviews (PROSPERO) under the registration number: CRD CRD42018110325. https://clinicaltrials.gov/ct2/show/CRD42018110325., Competing Interests: IJO and CJH have held grant funding from the NIHR Evidence Synthesis Working Group (ESWG Grant no: 390). CJH has received expenses and fees for his media work (including payments from BBC Radio 4 Inside Health). He has received expenses from the WHO, FDA, and holds grant funding from the NIHR, the NIHR School of Primary Care Research, the NIHR BRC Oxford and the WHO. He has received financial remuneration from an asbestos case and given free legal advice on mesh cases. He has also received income from the publication of a series of toolkit books published by Blackwells. On occasion, he receives expenses for teaching EBM and is also paid for his GP work in NHS out of hours (contract with Oxford Health NHS Foundation Trust). RP hold grant funding from the NIHR Programme of Applied Research. He leads a programme looking at how general practitioners manage chronic kidney disease and chronic heart failure. This does not alter our adherence to PLOS ONE policies on sharing data and materials. KS and JC have no interests to declare.

Background: The views of women with acute, uncomplicated urinary tract infection (auUTI) on the acceptability of non-antibiotic treatment options are poorly understood., Aim: To establish women's thoughts on and experience of non-antibiotic treatment for auUTIs., Design and Setting: Qualitative interview study with primary care patients in Oxfordshire, UK, embedded within the Cranberry for Urinary Tract Infection (CUTI) feasibility trial., Method: One-to-one, semi-structured interviews were conducted between August 2019 and January 2020 with some CUTI trial participants and some patients who were not part of the CUTI trial who had experienced at least one urinary tract infection (UTI) in the preceding 12 months in Oxfordshire, UK. Interviews were analysed using thematic analysis., Results: In total, 26 interviews were conducted and analysed. Women expected to receive an immediate antibiotic for their UTI but were aware of the potential harms of this approach. They were keen to find a non-antibiotic, 'natural' alternative that could effectively manage their symptoms. In certain situations (early illness, milder illness, and with no important upcoming engagements), women indicated they would be prepared to postpone antibiotic treatment by up to 3 days, especially if offered an interim non-antibiotic option with perceived therapeutic potential., Conclusion: Many women with auUTIs are open to trying non-antibiotic treatments first in certain situations. There is scope for more dialogue between primary care clinicians and patients with auUTI around delaying antibiotic treatment and using non-antibiotic options initially, which could reduce antibiotic consumption for this common infection., (© The Authors.)

Background: The role of SARS-Cov-2-infected persons who develop symptoms after testing (presymptomatics) or not at all (asymptomatics) in the pandemic spread is unknown., Objectives: To determine infectiousness and probable contribution of asymptomatic persons (at the time of testing) to pandemic SARS-CoV-2 spread., Data Sources: LitCovid, medRxiv, Google Scholar, and WHO Covid-19 databases (to 31 March 2021) and references in included studies., Study Eligibility Criteria: Studies with a proven or hypothesized transmission chain based either on serial PCR cycle threshold readings and/or viral culture and/or gene sequencing, with adequate follow-up., Participants: People exposed to SARS-CoV-2 within 2-14 days to index asymptomatic (at time of observation) infected individuals., Interventions: Reliability of symptom and signs was assessed within contemporary knowledge; transmission likelihood was assessed using adapted causality criteria., Methods: Systematic review. We contacted all included studies' corresponding authors requesting further details., Results: We included 18 studies from a diverse setting with substantial methodological variation (this field lacks standardized methodology). At initial testing, prevalence of asymptomatic cases was 12.5-100%. Of these, 6-100% were later determined to be presymptomatic, this proportion varying according to setting, methods of case ascertainment and population. Nursing/care home facilities reported high rates of presymptomatic: 50-100% (n = 3 studies). Fourteen studies were classified as high risk of, and four studies as at moderate risk of symptom ascertainment bias. High-risk studies may be less likely to distinguish between presymptomatic and asymptomatic cases. Six asymptomatic studies and four presymptomatic studies reported culturing infectious virus; data were too sparse to determine infectiousness duration. Three studies provided evidence of possible and three of probable/likely asymptomatic transmission; five studies provided possible and two probable/likely presymptomatic SARS-CoV-2 transmission., Conclusion: High-quality studies provide probable evidence of SARS-CoV-2 transmission from presymptomatic and asymptomatic individuals, with highly variable estimated transmission rates., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Effective alternatives to antibiotics for alleviating symptoms of acute infections may be appealing to patients and enhance antimicrobial stewardship. Cranberry-based products are already in wide use for symptoms of acute urinary tract infection (UTI). The aim of this review was to identify and critically appraise the supporting evidence., Methods: The protocol was registered on PROSPERO. Searches were conducted of Medline, Embase, Amed, Cinahl, The Cochrane library, Clinicaltrials.gov and WHO International Clinical Trials Registry Platform. We included randomised clinical trials (RCTs) and non-randomised studies evaluating the effect of cranberry extract in the management of acute, uncomplicated UTI on symptoms, antibiotic use, microbiological assessment, biochemical assessment and adverse events. Study risk of bias assessments were made using Cochrane criteria., Results: We included three RCTs ( n = 688) judged to be at moderate risk of bias. One RCT ( n = 309) found that advice to consume cranberry juice had no statistically significant effect on UTI frequency symptoms (mean difference (MD) -0.01 (95% CI: -0.37 to 0.34), p = 0.94)), on UTI symptoms of feeling unwell (MD 0.02 (95% CI: -0.36 to 0.39), p = 0.93)) or on antibiotic use (odds ratio 1.27 (95% CI: 0.47 to 3.43), p = 0.64), when compared with promoting drinking water. One RCT ( n = 319) found no symptomatic benefit from combining cranberry juice with immediate antibiotics for an acute UTI, compared with placebo juice combined with immediate antibiotics. In one RCT ( n = 60), consumption of cranberry extract capsules was associated with a within-group improvement in urinary symptoms and Escherichia coli load at day 10 compared with baseline ( p < 0.01), which was not found in untreated controls ( p = 0.72). Two RCTs were under-powered to detect differences between groups for outcomes of interest. There were no serious adverse effects associated with cranberry consumption., Conclusion: The current evidence base for or against the use of cranberry extract in the management of acute, uncomplicated UTIs is inadequate; rigorous trials are needed.

Background: There is uncertainty about the usefulness of ambulatory blood pressure (ABP) in predicting cardiovascular disease (CVD) risk. Our objective was to compare the prognostic value of ABP versus clinic blood pressure (BP) in CVD., Methods: We conducted electronic searches on Medline, Embase, and the Cochrane library up to July 2018. We included prospective longitudinal studies that compared 24-h ABP with clinic BP measurement in adults. Our main outcomes were all-cause mortality, CVD mortality, and/or CVD events. We assessed study quality based on four domains and pooled data using a random effects model of STATA for meta-analyses., Results: We included 13 studies comprising 81 736 participants. The overall quality of the studies was moderate. Both systolic and diastolic 24-h ABP as well as systolic clinic BP significantly predicted all-cause mortality, CVD mortality, and CVD events. Systolic 24-h ABP was significantly better than systolic clinic BP at predicting future risk of CVD events: combined hazard ratio for 24-h ABP = 1.27 (95% confidence interval 1.21-1.34) per 10 mmHg increase in SBP compared with 1.13 (1.06-1.21) for clinic BP (interaction test P = 0.02). After adjusting for clinic BP, both systolic and diastolic 24-h ABP measurements were significantly better than their corresponding clinic measurements at predicting all-cause mortality, CVD mortality, and CVD events (P = 0.001 and P = 0.000, respectively)., Conclusion: Systolic 24-h ABP is a better predictor of future CVD events than systolic clinic BP. Future studies should incorporate the use of individual patient data to assess the prognostic value of 24-h ABP.

Background: Sore throat is a common condition associated with a high rate of antibiotic prescriptions, despite limited evidence for the effectiveness of antibiotics. Corticosteroids may improve symptoms of sore throat by reducing inflammation of the upper respiratory tract. This review is an update to our review published in 2012., Objectives: To assess the clinical benefit and safety of corticosteroids in reducing the symptoms of sore throat in adults and children., Search Methods: We searched CENTRAL (Issue 4, 2019), MEDLINE (1966 to 14 May 2019), Embase (1974 to 14 May 2019), the Database of Abstracts of Reviews of Effects (DARE, 2002 to 2015), and the NHS Economic Evaluation Database (inception to 2015). We also searched the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) and ClinicalTrials.gov., Selection Criteria: We included randomised controlled trials (RCTs) that compared steroids to either placebo or standard care in adults and children (aged over three years) with sore throat. We excluded studies of hospitalised participants, those with infectious mononucleosis (glandular fever), sore throat following tonsillectomy or intubation, or peritonsillar abscess., Data Collection and Analysis: We used standard methodological procedures expected by Cochrane., Main Results: We included one new RCT in this update, for a total of nine trials involving 1319 participants (369 children and 950 adults). In eight trials, participants in both corticosteroid and placebo groups received antibiotics; one trial offered delayed prescription of antibiotics based on clinical assessment. Only two trials reported funding sources (government and a university foundation). In addition to any effect of antibiotics and analgesia, corticosteroids increased the likelihood of complete resolution of pain at 24 hours by 2.40 times (risk ratio (RR) 2.4, 95% confidence interval (CI) 1.29 to 4.47; P = 0.006; I² = 67%; high-certainty evidence) and at 48 hours by 1.5 times (RR 1.50, 95% CI 1.27 to 1.76; P < 0.001; I² = 0%; high-certainty evidence). Five people need to be treated to prevent one person continuing to experience pain at 24 hours. Corticosteroids also reduced the mean time to onset of pain relief and the mean time to complete resolution of pain by 6 and 11.6 hours, respectively, although significant heterogeneity was present (moderate-certainty evidence). At 24 hours, pain (assessed by visual analogue scales) was reduced by an additional 10.6% by corticosteroids (moderate-certainty evidence). No differences were reported in recurrence/relapse rates, days missed from work or school, or adverse events for participants taking corticosteroids compared to placebo. However, the reporting of adverse events was poor, and only two trials included children or reported days missed from work or school. The included studies were assessed as moderate quality evidence, but the small number of included studies has the potential to increase the uncertainty, particularly in terms of applying these results to children., Authors' Conclusions: Oral or intramuscular corticosteroids, in addition to antibiotics, moderately increased the likelihood of both resolution and improvement of pain in participants with sore throat. Given the limited benefit, further research into the harms and benefits of short courses of steroids is needed to permit informed decision-making., (Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Aims: To compare the benefits and harms of naltrexone-bupropion using evidence from clinical study reports., Methods: We searched Food and Drug Administration and European Medicines Agency websites, PubMed, and Clinicaltrials.gov (May 2016) to identify pivotal trials; we then sent a freedom of information request to the European Medicines Agency (July 2016). We included pivotal, phase III placebo-controlled trials. We assessed the risks of bias using the Cochrane criteria, and the quality of the evidence using GRADE. We used a random-effects model for meta-analyses., Results: Over a 27-month period (July 2016 to August 2018), we received 31 batches of clinical study report documents containing over 65 000 pages of data from 4 pivotal trials (n = 4536). Significantly more participants who took naltrexone-bupropion achieved ≥5% reduction in body weight: risk ratio (RR) = 2.1 (95% confidence interval 1.35-3.28), P = .001, GRADE = low, number needed to treat (NNT) to benefit = 5 (3-17); this represents a 2.53 kg (1.85-3.21) reduction in baseline body weight compared with placebo. Naltrexone-bupropion had significantly beneficial effects on other cardiovascular risk factors; however, the true effect sizes for these are uncertain because of incomplete outcome data. Naltrexone-bupropion significantly increased the risk of adverse events: RR = 1.11 (1.05-1.18, P = .0004, GRADE = low, NNT to harm = 12 7-27); serious adverse events: RR = 1.70 (1.38-2.1, P < .00001, GRADE = moderate, NNT to harm = 21 13-38); and discontinuation because of adverse events: RR = 1.92 (1.65-2.24, P < .00001, GRADE = moderate, NNT to discontinue treatment = 9 8-13)., Conclusions: Naltrexone-bupropion significantly reduces body weight by a small amount but significantly increases the risk of adverse events. A rigorous process of postmarketing surveillance is required., (© 2020 The British Pharmacological Society.)

Background: The risks of harms from opioids increase substantially at high doses, and high-dose prescribing has increased in primary care. However, little is known about what leads to high-dose prescribing, and studies exploring this have not been synthesized. We, therefore, systematically synthesized factors associated with the prescribing of high-dose opioids in primary care., Methods: We conducted a systematic review of observational studies in high-income countries that used patient-level primary care data and explored any factor(s) in people for whom opioids were prescribed, stratified by oral morphine equivalents (OME). We defined high doses as ≥ 90 OME mg/day. We searched MEDLINE, Embase, Web of Science, reference lists, forward citations, and conference proceedings from database inception to 5 April 2019. Two investigators independently screened studies, extracted data, and appraised the quality of included studies using the Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies. We pooled data on factors using random effects meta-analyses and reported relative risks (RR) or mean differences with 95% confidence intervals (CI) where appropriate. We also performed a number needed to harm (NNT H ) calculation on factors when applicable., Results: We included six studies with a total of 4,248,119 participants taking opioids, of whom 3.64% (n = 154,749) were taking high doses. The majority of included studies (n = 4) were conducted in the USA, one in Australia and one in the UK. The largest study (n = 4,046,275) was from the USA. Included studies were graded as having fair to good quality evidence. The co-prescription of benzodiazepines (RR 3.27, 95% CI 1.32 to 8.13, I 2  = 99.9%), depression (RR 1.38, 95% CI 1.27 to 1.51, I 2  = 0%), emergency department visits (RR 1.53, 95% CI 1.46 to 1.61, I 2  = 0%, NNT H 15, 95% CI 12 to 20), unemployment (RR 1.44, 95% CI 1.27 to 1.63, I 2  = 0%), and male gender (RR 1.21, 95% CI 1.14 to 1.28, I 2  = 78.6%) were significantly associated with the prescribing of high-dose opioids in primary care., Conclusions: High doses of opioids are associated with greater risks of harms. Associated factors such as the co-prescription of benzodiazepines and depression identify priority areas that should be considered when selecting, identifying, and managing people taking high-dose opioids in primary care. Coordinated strategies and services that promote the safe prescribing of opioids are needed., Study Registration: PROSPERO, CRD42018088057.

Background: The value of biomarkers for diagnosing bacterial infections in older outpatients is uncertain and limited official guidance exists for clinicians in this area. The aim of this review is to critically appraise and evaluate biomarkers for diagnosing bacterial infections in older adults (aged 65 years and above)., Methods: We searched Medline, Embase, Web of Science and the Cochrane Library, from inception to January 2018. We included studies assessing the diagnostic accuracy of blood, urinary, and salivary biomarkers in diagnosing bacterial infections in older adults. The QUADAS-2 tool was used to assess study quality., Results: We identified 11 eligible studies of moderate quality (11,034 participants) including 51 biomarkers at varying thresholds for diagnosing bacterial infections. An elevated Procalcitonin (≥ 0.2 ng/mL) may help diagnose bacteraemia in older adults [+ve LR range 1.50 to 2.60]. A CRP ≥ 50 mg/L only raises the probability of bacteraemia by 5%. A positive urine dipstick aids diagnosis of UTI (+ve LR range 1.23 to 54.90), and absence helps rule out UTI (-ve LR range 0.06 to 0.46). An elevated white blood cell count is unhelpful in diagnosing intra-abdominal infections (+ve LR range 0.75 to 2.62), but may aid differentiation of bacterial infection from other acute illness (+ve LR range 2.14 to 7.12)., Conclusions: The limited available evidence suggests that many diagnostic tests useful in younger patients, do not help to diagnose bacterial infections in older adults. Further evidence from high quality studies is urgently needed to guide clinical practice. Until then, symptoms and signs remain the mainstay of diagnosis in community based populations.

Background: Out-of-office blood pressure (BP) is recommended for diagnosing hypertension in primary care due to its increased accuracy compared to office BP. Moreover, being diagnosed as hypertensive has previously been linked to lower wellbeing. There is limited evidence regarding the acceptability of out-of-office BP and its impact on wellbeing., Aim: To assess the acceptability and psychological impact of out-of-office monitoring in people with suspected hypertension., Design and Setting: A pre- and post-evaluation of participants with elevated (≥130 mmHg) systolic BP, assessing the psychological impact of 28 days of self-monitoring followed by ambulatory BP monitoring for 24 hours., Method: Participants completed standardised psychological measures pre- and post-monitoring, and a validated acceptability scale post-monitoring. Descriptive data were compared using χ 2 tests and binary logistic regression. Pre- and post-monitoring comparisons were made using the paired t -test and Wilcoxon signed rank test., Results: Out-of-office BP monitoring had no impact on depression and anxiety status in 93% and 85% of participants, respectively. Self-monitoring was more acceptable than ambulatory monitoring ( n = 183, median 2.4, interquartile range [IQR] 1.9-3.1 versus median 3.2, IQR 2.7-3.7, P <0.01). When asked directly, 48/183 participants (26%, 95% confidence interval [CI] = 20 to 33%) reported that self-monitoring made them anxious, and 55/183 (30%, 95% CI = 24 to 37%) reported that ambulatory monitoring made them anxious., Conclusion: Out-of-office monitoring for hypertension diagnosis does not appear to be harmful. However, health professionals should be aware that in some patients it induces feelings of anxiety, and self-monitoring may be preferable to ambulatory monitoring., (© British Journal of General Practice 2019.)

Background: Older adults with bacterial skin infections may present with atypical symptoms, making diagnosis difficult. There is limited authoritative guidance on how older adults in the community present with bacterial skin infections. To date there have been no systematic reviews assessing the diagnostic value of symptoms and signs in identifying bacterial skin infections in older adults in the community., Methods: We searched Medline and Medline in process, Embase and Web of Science, from inception to September 2017. We included cohort and cross-sectional studies assessing the diagnostic accuracy of symptoms and signs in predicting bacterial skin infections in adults in primary care aged over 65 years. The QUADAS-2 tool was used to assess study quality., Results: We identified two observational studies of low-moderate quality, with a total of 7991 participants, providing data to calculate the diagnostic accuracy of 5 unique symptoms in predicting bacterial skin infections. The presence of wounds [LR+: 7.93 (CI 4.81-13.1)], pressure sores [LR+: 4.85 (CI 2.18-10.8)] and skin ulcers [LR+: 6.26 (CI 5.49-7.13)] help to diagnose bacterial skin infections. The presence of urinary incontinence does not help to predict bacterial skin infections (LR + 's of 0.99 and 1.04; LR-'s of 0.96 and 1.04)., Conclusions: Currently, there is insufficient evidence to inform the diagnosis of bacterial skin infections in older adults in the community; clinicians should therefore rely upon their clinical judgement and experience. Evidence from high quality primary care studies in older adults, including studies assessing symptoms traditionally associated with bacterial skin infections (e.g. erythema and warmth), is urgently needed to guide practice.

Objective: To assess the benefits and harms of pregabalin in the management of neuropathic pain., Design: Rapid review and meta-analysis of phase III, randomised, placebo-controlled trials., Participants: Adults aged 18 years and above with neuropathic pain defined according to the International Association for the Study of Pain criteria., Interventions: Pregabalin or placebo., Primary and Secondary Outcome Measures: Our primary outcomes were pain (as measured using validated scales) and adverse events. Our secondary outcomes were sleep disturbance, quality of life, Patient Global Impression of Change, Clinician Global Impression scale, anxiety and depression scores, overall discontinuations and discontinuations because of adverse events., Results: We included 28 trials comprising 6087 participants. The neuropathic pain conditions studied were diabetic peripheral neuropathy, postherpetic neuralgia, herpes zoster, sciatica (radicular pain), poststroke pain and spinal cord injury-related pain. Patients who took pregabalin reported significant reductions in pain (numerical rating scale (NRS)) compared with placebo (standardised mean difference (SMD) -0.49 (95% CI -0.66 to -0.32, p<0.00001), very low quality evidence). Pregabalin significantly reduced sleep interference scores (NRS) compared with placebo (SMD -0.38 (95% CI -0.50 to -0.26, p<0.00001), moderate quality evidence. Pregabalin significantly increased the risk of adverse events compared with placebo (RR 1.33 (95% CI 1.23 to 1.44, p<0.00001, low quality evidence)). The risks of experiencing weight gain, somnolence, dizziness, peripheral oedema, fatigue, visual disturbances, ataxia, non-peripheral oedema, vertigo and euphoria were significantly increased with pregabalin. Pregabalin was significantly more likely than placebo to lead to discontinuation of the drug because of adverse events (RR 1.91 (95% CI 1.54 to 2.37, p<0.00001), low quality evidence)., Conclusion: Pregabalin has beneficial effects on some symptoms of neuropathic pain. However, its use significantly increases the risk of a number of adverse events and discontinuation due to adverse events. The quality of the evidence from journal publications is low., Competing Interests: Competing interests: CJH has received expenses and fees for his media work. He has received expenses from the WHO and FDA and holds grant funding from the NIHR, the NIHR School of Primary Care Research, The Wellcome Trust and the WHO. He has received financial remuneration from an asbestos case. He has also received income from the publication of a series of toolkit books published by Blackwell’s. On occasion, he receives expenses for teaching EBM and is also paid for his general practitioner work in National Health Service out of hours. CEBM jointly runs the EvidenceLive Conference with the BMJ and the Overdiagnosis Conference with some international partners that are based on a non-profit making model. BG receives funding from the Laura and John Arnold Foundation and reports personal fees from intermittent additional personal income from speaking and writing for lay audiences on problems in science and medicine including regulatory shortcomings., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Out-of-office blood pressure (BP) measurement is advocated to confirm hypertension diagnosis. However, little is known about how primary care patients view and use such measurement., Aim: To investigate patient experience of out-of-office BP monitoring, particularly home and practice waiting room BP measurement, before, during, and after diagnosis., Design and Setting: A cross-sectional, qualitative study with patients from two UK GP surgeries participating in a feasibility study of waiting room BP measurement., Method: Interviewees were identified from recent additions to the practice hypertension register. Interviews were recorded, transcribed, and coded thematically., Results: Of 29 interviewees, 9 (31%) and 22 (76%) had used the waiting room monitor and/or monitored at home respectively. Out-of-office monitoring was used by patients as evidence of control or the lack of need for medication, with the printed results slips from the waiting room monitor perceived to improve 'trustworthiness'. The waiting room monitor enabled those experiencing uncertainty about their equipment or technique to double-check readings. Monitoring at home allowed a more intensive and/or flexible schedule to investigate BP fluctuations and the impact of medication and lifestyle changes. A minority used self-monitoring to inform drug holidays. Reduced intensity of monitoring was reported with both modalities following diagnosis as initial anxiety or patient and GP interest decreased., Conclusion: Home and practice waiting room measurements have overlapping but differing roles for patients. Waiting room BP monitors may be a useful out-of-office measurement modality for patients unwilling and/or unable to measure and record their BP at home., (© British Journal of General Practice 2018.)

Objective: To evaluate the benefits and harms of oral centrally acting antiobesity medicinal products in pivotal trials., Methods: The European Medicines Agency and Federal Drug Administration websites, PubMed, and ClinicalTrials.gov were searched to identify pivotal trials used to gain marketing authorizations. Pivotal phase III trials on which marketing authorizations were based were included. The data were analyzed by using Cochrane Review Manager (RevMan), and quality assessments for each outcome were performed by using the Grading of Recommendation, Assessment, Development, and Evaluation (GRADE)., Results: Five products (16 trials with 24,555 participants) were included. Significantly more participants who took the antiobesity products achieved ≥ 5% reduction in body weight (risk ratio [RR] 2.39; 95% CI: 2.09-2.74; GRADE = low). However, the products significantly increased the risk of adverse events (RR 1.12; 95% CI: 1.07-1.17; GRADE = very low) and the risk of discontinuation because of adverse events (RR 1.52; 95% CI: 1.33-1.74; GRADE = low). There were no significant differences for most outcomes between currently approved and withdrawn products., Conclusions: Although oral centrally acting antiobesity products generate modest weight losses, they also increase the risks of adverse events and discontinuations because of adverse events. The premarketing benefit-to-harm profiles of currently available products and products that were later withdrawn because of harms are similar. Targeted study designs, better outcomes reporting, and improved postmarketing monitoring of harms are needed., (© 2018 The Obesity Society.)

Introduction: Many analgesics have been withdrawn from the market because of adverse drug reactions. Controversy still surrounds the use of some approved analgesics for pain management. However, the trends and reasons for withdrawal of analgesics when harms are attributed to their use have not been systematically assessed. ., Areas Covered: We conducted searches in PubMed; Embase; Google Scholar; clinicaltrials.gov; WHO databases of withdrawn products; websites of the European Medicines Agency, the US Food and Drug Administration, the UK Medicines and Healthcare products Regulatory Agency; Meyler's Side Effects of Drugs; Stephens' Detection of New Adverse Drug Reactions; the Pharmaceutical Manufacturing Encyclopedia; and the Merck Index. We included licensed analgesics that were withdrawn after marketing because of adverse reactions between 1950 and March 2017. We excluded herbal products, non-human medicines, and non-prescription medicines. We used the Oxford Centre for Evidence Based Medicine criteria to document the levels of evidence, and chi-squared tests to compare withdrawal patterns across geographical regions., Expert Opinion: Pharmacovigilance systems in low-resource settings should be strengthened. Greater co-ordination across regulatory authorities in assessing and interpreting the benefit-harm balance of new analgesics should be encouraged. Future reporting of harms in clinical trials of analgesics should follow standardized guidelines.

Introduction: Transvaginal mesh devices are approved in the USA by the Food and Drug Administration (FDA), through the 510(k) system. However, there is uncertainty about the benefit to harm balance of mesh approved for pelvic organ prolapse. We, therefore, assessed the evidence at the time of approval for transvaginal mesh products and the impact of safety studies the FDA mandated in 2012 because of emerging harms., Methods: We used FDA databases to determine the evidence for approval of transvaginal mesh. To create a 'family tree' of device equivalence, we used the 510(k) regulatory approval of the 1985 Mersilene Mesh (Ethicon) and the 1996 ProteGen Sling (Boston Scientific), searched for all subsequently related device approvals, and for the first published randomised trial evidence. We assessed compliance with all FDA 522 orders issued in 2012 requiring postmarketing surveillance studies., Results: We found 61 devices whose approval ultimately relied on claimed equivalence to the Mersilene Mesh and the ProteGen Sling. We found no clinical trials evidence for these 61 devices at the time of approval. Publication of randomised clinical trials occurred at a median of 5 years after device approval (range 1-14 years). Analysis of 119 FDA 522 orders revealed that in 79 (66%) the manufacturer ceased market distribution of the device, and in 26 (22%) the manufacturer had changed the indication. Only seven studies (six cohorts and new randomised controlled trial) covering 11 orders were recruiting participants (none had reported outcomes)., Conclusions: Transvaginal mesh products for pelvic organ prolapse have been approved on the basis of weak evidence over the last 20 years. Devices have inherited approval status from a few products. A publicly accessible registry of licensed invasive devices, with details of marketing status and linked evidence, should be created and maintained at the time of approval., Competing Interests: Competing interests: CJH is an expert witness in a current medical device legal case and has received financial remuneration from an asbestos legal case. He has received expenses in the past from the US FDA to attend a working group on device regulation. CJH and BG receive funding from the National Institute of Health Research (NIHR) School of Primary Care. BG receives funding from the Laura and John Arnold Foundation and reports personal fees from intermittent additional personal income from speaking and writing for lay audiences on problems in science and medicine including regulatory shortcomings. TJ and CJH were recipients of a UK National Institute for Health Research grant for a Cochrane review of neuraminidase inhibitors for preventing and treating influenza. Also, TJ receives royalties from his books published by Il Pensiero Scientifico Editore, Rome and Blackwells. TJ is occasionally interviewed by market research companies about phase I or II pharmaceutical products. In 2011-2013, TJ acted as an expert witness in a litigation case related to the antiviral oseltamivir, in two litigation cases on potential vaccine-related damage, and in a labour case on influenza vaccines in healthcare workers in Canada. He has acted as a consultant for Roche (1997-1999), GSK (2001-2002), Sanofi-Synthelabo (2003) and IMS Health (2013), and in 2014 was retained as a scientific adviser to a legal team acting on oseltamivir. In 2014-2016 TJ was a member of three advisory boards for Boehringer Ingelheim and is the holder of a Cochrane Methods Innovations Fund grant to develop guidance on the use of regulatory data in Cochrane reviews. In 2016-2017 TJ was a member of an independent data monitoring committee for a Sanofi Pasteur clinical trial on an influenza vaccine. JKA has published papers and edited textbooks on adverse drug reactions; he has also acted as an expert witness in cases related to adverse drug reactions., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Purpose: We have identified human medicinal products for which animal data were used as evidence for withdrawal, determined whether the adverse reactions were reported in humans, established whether confirmatory human studies were conducted, and explored the withdrawal patterns over time., Methods: We searched the World Health Organization's Consolidated List of [Medicinal] Products, drug regulatory authorities' websites, PubMed, Google Scholar, and selected textbooks to identify medicinal products withdrawn from 1950 to June 2016. We included medicinal products for which animal data were specifically reported as a reason for withdrawal. We used a checklist adapted from the International Agency for Research on Cancer criteria to rate the evidence., Results: In 37 cases, evidence from animals was the reason given for withdrawal between 1963 and 2000. Evidence of carcinogenicity was cited in 23 cases (62%). Limited evidence for harms occasioned withdrawal in over 80% of cases. In 11 cases (30%), the adverse drug reactions were subsequently reported in humans. In 5 instances (14%), formal studies were conducted in humans. The median interval to withdrawal following reports of adverse reactions was 2 years (IQR = 1-9 y)., Conclusions: Regulatory authorities and drug manufacturers are likely to withdraw medicinal products quickly from the market when animal experiments suggest increased risks of cancers or congenital malformations. Human studies are seldom conducted when harms are suspected in animals. Future research should explore better methods of extrapolating harms data from animal research to humans., (Copyright © 2017 John Wiley & Sons, Ltd.)

Background: Blood pressure (BP) self-screening, whereby members of the public have access to BP monitoring equipment outside of healthcare consultations, may increase the detection and treatment of hypertension. Currently in the UK such opportunities are largely confined to GP waiting rooms., Aim: To investigate the reasons why people do or do not use BP self-screening facilities., Design and Setting: A cross-sectional, qualitative study in Oxfordshire, UK., Method: Semi-structured interviews with members of the general public recruited using posters in GP surgeries and community locations were recorded, transcribed, and coded thematically., Results: Of the 30 interviewees, 20% were hypertensive and almost half had self-screened. Those with no history of elevated readings had limited concern over their BP: self-screening filled the time waiting for their appointment or was done to help their doctor. Patients with hypertension self-screened to avoid the feelings they associated with 'white coat syndrome' and to introduce more control into the measurement process. Barriers to self-screening included a lack of awareness, uncertainty about technique, and worries over measuring BP in a public place. An unanticipated finding was that several interviewees preferred monitoring their BP in the waiting room than at home., Conclusion: BP self-screening appeared acceptable to service users. Further promotion and education could increase awareness among non-users of the need for BP screening, the existence of self-screening facilities, and its ease of use. Waiting room monitors could provide an alternative for patients with hypertension who are unwilling or unable to monitor at home., (© British Journal of General Practice 2017.)

Objective: The use of antibiotic prophylaxis (AP) for prevention of infective endocarditis (IE) is controversial. In recent years, guidelines to cardiologists and dentists have advised restriction of AP to high-risk groups (in Europe and the USA) or against its use at all (in the UK). The objective of this systematic review was to appraise the evidence for use of AP for prevention of bacteraemia or IE in patients undergoing dental procedures., Methods: We conducted electronic searches in Medline, Embase, Cochrane Library and ISI Web of Science. We assessed the methodological characteristics of included studies using the Strengthening the Reporting of Observational Studies in Epidemiology criteria for observational studies and the Cochrane Risk of Bias Tool for trials. Two reviewers independently determined the eligibility of studies, assessed the methodology of included studies and extracted the data., Results: We identified 178 eligible studies, of which 36 were included in the review. This included 10 time-trend studies, 5 observational studies and 21 trials. All trials identified used bacteraemia as an endpoint rather than IE. One time-trend study suggests that total AP restriction may be associated with a rising incidence of IE, while data on the consequences of relative AP restriction are conflicting. Meta-analysis of trials indicates that AP is effective in reducing the incidence of bacteraemia (risk ratio 0.53, 95% CI 0.49 to 0.57, p<0.01), but case-control studies suggest this may not translate to a statistically significant protective effect against IE in patients at low risk of disease., Conclusions: The evidence base for the use of AP is limited, heterogeneous and the methodological quality of many studies is poor. Postprocedural bacteraemia is not a good surrogate endpoint for IE. Given the logistical challenges of a randomised trial, high-quality case-control studies would help to evaluate the role of dental procedures in causing IE and the efficacy of AP in its prevention., Competing Interests: Competing interests: MJD was a non-voting member of the NICE panel who reviewed guidance concerning the use of antibiotic prophylaxis to prevent infective endocarditis in 2015., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background and Rationale: Certain nutritional supplements are being marketed for the management of Alzheimer's disease (AD), but the evidence for their effectiveness is not established. The objective of this review was to evaluate the evidence from randomized clinical trial (RCTs) examining the effect of Souvenaid in patients with AD., Methods: We conducted electronic searches in Medline, Embase, PsychINFO, CINAHL, and The Cochrane Library. The reporting quality of the included studies was determined using the Cochrane collaboration tool for assessing the risk of bias. Two reviewers independently determined eligibility, assessed the reporting quality of included studies and extracted data., Results: Three studies with a total of 1011 participants were included. All were of good reporting quality. Meta-analyses revealed non-significant differences in cognition (ADAS-cog scores MD: 0.08, 95% CI: -0.71 to 0.88) and function (ADCS-ADL scores MD: 0.36, 95% CI: -0.54 to 1.25) between Souvenaid and placebo. One study showed significant increase in neuropsychological test battery composite z-score with Souvenaid compared with placebo, and another reported significant improvement in delayed verbal recall for a subgroup of patients with very mild AD. There was no significant effect on global clinical function. No serious adverse events were observed., Conclusions: The evidence from published clinical trials does not show that supplementation with Souvenaid has beneficial effects on functional ability, behaviour, or global clinical change. Souvenaid may cause improvements in verbal recall in patients at early stages of AD. Few RCTs examining the effect of Souvenaid have been conducted, and they are all funded by same manufacturer. Future research should include using unified tools to measure cognition, function, and behaviour in AD.

Introduction: Several medicinal products have been withdrawn from the market because of drug-attributed deaths. However, there has been no investigation of whether such withdrawals were justified, and the extent to which confirmatory studies are used to investigate drug-adverse event relationships when deaths are reported is uncertain. We documented medicinal products withdrawn from the market because of drug-attributed deaths, identified confirmatory studies investigating the drug-adverse event relationships, examined whether withdrawals of medicinal products because of drug-attributed deaths after marketing were justified based on a mechanistic analysis, and examined the trends over time., Methods: We searched electronic and non-electronic sources to identify medicinal products that were withdrawn because of drug-attributed deaths. We used a previously published algorithm to examine whether the withdrawals of products were justified. We then searched PubMed and Google Scholar to identify studies investigating the drug-adverse event relationships, used the Oxford Centre for Evidence-Based Medicine criteria to document the levels of evidence, and assessed whether the evidence of an association was confirmed., Results: We included 83 medicinal products. The reasons for withdrawal appeared to have been justified in 80 cases (96%). The median interval between the first reported adverse reaction that was related to the cause of death and the first reported death was 1 year (interquartile range = 1-3); products were withdrawn sooner when the interval between the first reported relevant adverse reaction and the first death was shorter. Confirmatory studies were conducted in 57 instances (69%), and there was evidence of an association in 52 cases (63%). Four products (5%) were re-introduced after initial withdrawal., Conclusion: Regulatory authorities have been justified in making withdrawal decisions when deaths have been attributed to medicinal products, using the precautionary principle when alternative decisions could have been made. Medicinal products are likely to be quickly withdrawn from the market when there is a short interval to the first reported deaths. The use of an algorithm such as we have used in this study could help to expedite the process of decision making.

Aim: To critically appraise and evaluate the evidence for effectiveness of curcuminoids in the treatment of osteoarthritis (OA) in adults., Methods: We conducted electronic searches in Medline, Embase, AMED, Cinahl and the Cochrane library. We included randomized controlled trials (RCTs) that investigated the effectiveness of orally-administered curcuminoids in OA in adults, and assessed risk of bias using the Cochrane risk of bias criteria. We used a random-effect model for meta-analysis., Results: We included seven studies with a total of 797 participants with primarily knee OA. All studies were conducted in Asia. The overall risk of bias was moderate. Compared with placebo, curcuminoids significantly reduced knee pain (visual analogue scale): (standardized mean difference: -3.45; 95% CI: -5.52 to -1.38; I 2  = 95% P = 0.001), and improved quality of life (Lequesne pain-function index): (mean difference: -2.69; 95% CI: -3.48 to -1.90; I 2  = 0% P < 0.00001). There were significantly fewer effects on pain relief, knee stiffness and physical function with curcuminoids compared with ibuprofen. Significant improvements in Western Ontario and McMaster Universities Arthritis Index total scores, with significant reductions in the use of rescue medication were also observed with curcuminoids. No serious adverse events were reported., Conclusions: Curcuminoids may have some beneficial effects on knee pain and quality of life in patients with knee OA. However, they are less effective at relieving pain compared with ibuprofen. Curcuminoids appear safe on the short-term, and may reduce the need for rescue medication. Published RCTs vary in reporting quality, are characterized by small sample sizes, and have all been conducted in Asia. Further clinical trials are therefore warranted., (© 2017 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

Objective: To identify, critically appraise and summarise existing systematic reviews on the impact of global cardiovascular risk assessment in the primary prevention of cardiovascular disease (CVD) in adults., Design: Systematic review of systematic reviews published between January 2005 and October 2016 in The Cochrane Library, EMBASE, MEDLINE or CINAHL databases, and post hoc analysis of primary trials., Participants, Interventions, Outcomes: Systematic reviews of interventions involving global cardiovascular risk assessment relative to no formal risk assessment in adults with no history of CVD. The primary outcomes of interest were CVD-related morbidity and mortality and all-cause mortality; secondary outcomes were systolic blood pressure (SBP), cholesterol and smoking., Results: We identified six systematic reviews of variable but generally of low quality (mean Assessing the Methodological Quality of Systematic Reviews 4.2/11, range 0/11 to 7/11). No studies identified by the systematic reviews reported CVD-related morbidity or mortality or all-cause mortality. Meta-analysis of reported randomised controlled trials (RCTs) showed small reductions in SBP (mean difference (MD) -2.22 mm Hg (95% CI -3.49 to -0.95); I 2 =66%; n=9; GRADE: very low), total cholesterol (MD -0.11 mmol/L (95% CI -0.20 to -0.02); I 2 =72%; n=5; GRADE: very low), low-density lipoprotein cholesterol (MD -0.15 mmol/L (95% CI -0.26 to -0.05), I 2 =47%; n=4; GRADE: very low) and smoking cessation (RR 1.62 (95% CI 1.08 to 2.43); I 2 =17%; n=7; GRADE: low). The median follow-up time of reported RCTs was 12 months (range 2-36 months)., Conclusions: The quality of existing systematic reviews was generally poor and there is currently no evidence reported in these reviews that the prospective use of global cardiovascular risk assessment translates to reductions in CVD morbidity or mortality. There are reductions in SBP, cholesterol and smoking but they may not be clinically significant given their small effect size and short duration. Resources need to be directed to conduct high-quality systematic reviews focusing on hard patient outcomes, and likely further primary RCTs., Trial Registration Number: CRD42015019821., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Objectives: To (1) establish the extent of opportunities for members of the public to check their own blood pressure (BP) outside of healthcare consultations (BP self-screening), (2) investigate the reasons for and against hosting such a service and (3) ascertain how BP self-screening data are used in primary care., Design: A mixed methods, cross-sectional study., Setting: Primary care and community locations in Oxfordshire, UK., Participants: 325 sites were surveyed to identify where and in what form BP self-screening services were available. 23 semistructured interviews were then completed with current and potential hosts of BP self-screening services., Results: 18/82 (22%) general practices offered BP self-screening and 68/110 (62%) pharmacies offered professional-led BP screening. There was no evidence of permanent BP self-screening activities in other community settings.Healthcare professionals, managers, community workers and leaders were interviewed. Those in primary care generally felt that practice-based BP self-screening was a beneficial activity that increased the attainment of performance targets although there was variation in its perceived usefulness for patient care. The pharmacists interviewed provided BP checking as a service to the community but were unable to develop self-screening services without a clear business plan. Among potential hosts, barriers to providing a BP self-screening service included a perceived lack of healthcare commissioner and public demand, and a weak-if any-link to their core objectives as an organisation., Conclusions: BP self-screening currently occurs in a minority of general practices. Any future development of community BP self-screening programmes will require (1) public promotion and (2) careful consideration of how best to support-and reward-the community hosts who currently perceive little if any benefit., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Background: Heart failure is a condition in which the heart does not pump enough blood to meet all the needs of the body. Symptoms of heart failure include breathlessness, fatigue and fluid retention. Outcomes for patients with heart failure are highly variable; however on average, these patients have a poor prognosis. Prognosis can be improved with early diagnosis and appropriate use of medical treatment, use of devices and transplantation. Patients with heart failure are high users of healthcare resources, not only due to drug and device treatments, but due to high costs of hospitalisation care. B-type natriuretic peptide levels are already used as biomarkers for diagnosis and prognosis of heart failure, but could offer to clinicians a possible tool to guide drug treatment. This could optimise drug management in heart failure patients whilst allaying concerns over potential side effects due to drug intolerance., Objectives: To assess whether treatment guided by serial BNP or NT-proBNP (collectively referred to as NP) monitoring improves outcomes compared with treatment guided by clinical assessment alone., Search Methods: Searches were conducted up to 15 March 2016 in the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library; MEDLINE (OVID), Embase (OVID), the Database of Abstracts of Reviews of Effects (DARE) and the NHS Economic Evaluation Database in the Cochrane Library. Searches were also conducted in the Science Citation Index Expanded, the Conference Proceedings Citation Index on Web of Science (Thomson Reuters), World Health Organization International Clinical Trials Registry and ClinicalTrials.gov. We applied no date or language restrictions., Selection Criteria: We included randomised controlled trials of NP-guided treatment of heart failure versus treatment guided by clinical assessment alone with no restriction on follow-up. Adults treated for heart failure, in both in-hospital and out-of-hospital settings, and trials reporting a clinical outcome were included., Data Collection and Analysis: Two review authors independently selected studies for inclusion, extracted data and evaluated risk of bias. Risk ratios (RR) were calculated for dichotomous data, and pooled mean differences (MD) (with 95% confidence intervals (CI)) were calculated for continuous data. We contacted trial authors to obtain missing data. Using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, we assessed the quality of the evidence and GRADE profiler (GRADEPRO) was used to import data from Review Manager to create a 'Summary of findings' table., Main Results: We included 18 randomised controlled trials with 3660 participants (range of mean age: 57 to 80 years) comparing NP-guided treatment with clinical assessment alone. The evidence for all-cause mortality using NP-guided treatment showed uncertainty (RR 0.87, 95% CI 0.76 to 1.01; patients = 3169; studies = 15; low quality of the evidence), and for heart failure mortality (RR 0.84, 95% CI 0.54 to 1.30; patients = 853; studies = 6; low quality of evidence).The evidence suggested heart failure admission was reduced by NP-guided treatment (38% versus 26%, RR 0.70, 95% CI 0.61 to 0.80; patients = 1928; studies = 10; low quality of evidence), but the evidence showed uncertainty for all-cause admission (57% versus 53%, RR 0.93, 95% CI 0.84 to 1.03; patients = 1142; studies = 6; low quality of evidence).Six studies reported on adverse events, however the results could not be pooled (patients = 1144; low quality of evidence). Only four studies provided cost of treatment results, three of these studies reported a lower cost for NP-guided treatment, whilst one reported a higher cost (results were not pooled; patients = 931, low quality of evidence). The evidence showed uncertainty for quality of life data (MD -0.03, 95% CI -1.18 to 1.13; patients = 1812; studies = 8; very low quality of evidence).We completed a 'Risk of bias' assessment for all studies. The impact of risk of bias from lack of blinding of outcome assessment and high attrition levels was examined by restricting analyses to only low 'Risk of bias' studies., Authors' Conclusions: In patients with heart failure low-quality evidence showed a reduction in heart failure admission with NP-guided treatment while low-quality evidence showed uncertainty in the effect of NP-guided treatment for all-cause mortality, heart failure mortality, and all-cause admission. Uncertainty in the effect was further shown by very low-quality evidence for patient's quality of life. The evidence for adverse events and cost of treatment was low quality and we were unable to pool results.

Background: We identified anti-obesity medications withdrawn since 1950 because of adverse drug reactions after regulatory approval, and examined the evidence used to support such withdrawals, investigated the mechanisms of the adverse reactions, and explored the trends over time., Methods: We conducted searches in PubMed, the World Health Organization database of drugs, the websites of drug regulatory authorities, and selected full texts, and we hand searched references in retrieved documents. We included anti-obesity medications that were withdrawn between 1950 and December 2015 and assessed the levels of evidence used for making withdrawal decisions using the Oxford Centre for Evidence-Based Medicine criteria., Results: We identified 25 anti-obesity medications withdrawn between 1964 and 2009; 23 of these were centrally acting, via monoamine neurotransmitters. Case reports were cited as evidence for withdrawal in 80% of instances. Psychiatric disturbances, cardiotoxicity (mainly attributable to re-uptake inhibitors), and drug abuse or dependence (mainly attributable to neurotransmitter releasing agents) together accounted for 83% of withdrawals. Deaths were reportedly associated with seven products (28%). In almost half of the cases, the withdrawals occurred within 2 years of the first report of an adverse reaction., Conclusions: Most of the drugs that affect monoamine neurotransmitters licensed for the treatment of obesity over the past 65 years have been withdrawn because of adverse reactions. The reasons for withdrawal raise concerns about the wisdom of using pharmacological agents that target monoamine neurotransmitters in managing obesity. Greater transparency in the assessment of harms from anti-obesity medications is therefore warranted.

Background: The validity of blood pressure (BP)-measuring tools at very high altitudes is uncertain. Therefore, the objective of this review was to examine the degree of agreement of BP-measuring devices in Tibet., Methods: We conducted electronic searches in Medline, Embase, Cinahl, Cochrane Library, Global Health Library and the ISI Web of Science. Randomised and observational studies were considered for inclusion. The methodological characteristics of included studies were assessed using the Quality Assessment of Diagnostic Accuracy Studies-2 criteria. Our primary outcome was the difference in mean BP measurements between the new device and the gold standard., Results: We identified three eligible studies, out of which two with a total of 162 participants were included. The studies differed in their methodology. One study reported significantly higher systolic blood pressure (SBP) measurement with electronic sphygmomanometer (Omron) compared with mercury sphygmomanometer (mean difference 5.8±4.7 mm Hg; p<0.001), with no significant difference in diastolic blood pressure (DBP) measurement (0.4±3.9 mm Hg; p=0.23). The second study reported mean differences of 1.0±5.9 mm Hg and -3.1±4.6 mm Hg for SBP and DBP, respectively., Conclusion: The limited evidence from published studies suggests that automated (Omron) BP monitors show a high degree of agreement for DBP when compared against mercury sphygmomanometer at high altitudes. However, the degree of such agreement for SBP is not consistent. Few studies assessing the validity of automated BP monitors at high altitudes have been conducted, and they differ in design and methodology. Further research assessing the suitability of BP-measuring instruments at high altitudes is therefore warranted., Competing Interests: None

Background: The introduction of point-of-care devices for the management of patients on oral anticoagulation allows self-testing by the patient at home. Patients who self-test can either adjust their medication according to a pre-determined dose-INR (international normalized ratio) schedule (self-management), or they can call a clinic to be told the appropriate dose adjustment (self-monitoring). Increasing evidence suggests self-testing of oral anticoagulant therapy is equal to or better than standard monitoring. This is an updated version of the original review published in 2010., Objectives: To evaluate the effects on thrombotic events, major haemorrhages, and all-cause mortality of self-monitoring or self-management of oral anticoagulant therapy compared to standard monitoring., Search Methods: For this review update, we re-ran the searches of the Cochrane Central Register of Controlled Trials (CENTRAL), 2015, Issue 6, the Cochrane Library, MEDLINE (Ovid, 1946 to June week 4 2015), Embase (Ovid, 1980 to 2015 week 27) on 1 July 2015. We checked bibliographies and contacted manufacturers and authors of relevant studies. We did not apply any language restrictions ., Selection Criteria: Outcomes analysed were thromboembolic events, mortality, major haemorrhage, minor haemorrhage, tests in therapeutic range, frequency of testing, and feasibility of self-monitoring and self-management., Data Collection and Analysis: Review authors independently extracted data and we used a fixed-effect model with the Mantzel-Haenzel method to calculate the pooled risk ratio (RR) and Peto's method to verify the results for uncommon outcomes. We examined heterogeneity amongst studies with the Chi(2) and I(2) statistics and used GRADE methodology to assess the quality of evidence., Main Results: We identified 28 randomised trials including 8950 participants (newly incorporated in this update: 10 trials including 4227 participants). The overall quality of the evidence was generally low to moderate. Pooled estimates showed a reduction in thromboembolic events (RR 0.58, 95% CI 0.45 to 0.75; participants = 7594; studies = 18; moderate quality of evidence). Both, trials of self-management or self-monitoring showed reductions in thromboembolic events (RR 0.47, 95% CI 0.31 to 0.70; participants = 3497; studies = 11) and (RR 0.69, 95% CI 0.49 to 0.97; participants = 4097; studies = 7), respectively; the quality of evidence for both interventions was moderate. No reduction in all-cause mortality was found (RR 0.85, 95% CI 0.71 to 1.01; participants = 6358; studies = 11; moderate quality of evidence). While self-management caused a reduction in all-cause mortality (RR 0.55, 95% CI 0.36 to 0.84; participants = 3058; studies = 8); self-monitoring did not (RR 0.94, 95% CI 0.78 to 1.15; participants = 3300; studies = 3); the quality of evidence for both interventions was moderate. In 20 trials (8018 participants) self-monitoring or self-management did not reduce major haemorrhage (RR 0.95, 95% CI, 0.80 to 1.12; moderate quality of evidence). There was no significant difference found for minor haemorrhage (RR 0.97, 95% CI 0.67 to 1.41; participants = 5365; studies = 13). The quality of evidence was graded as low because of serious risk of bias and substantial heterogeneity (I(2) = 82%)., Authors' Conclusions: Participants who self-monitor or self-manage can improve the quality of their oral anticoagulation therapy. Thromboembolic events were reduced, for both those self-monitoring or self-managing oral anticoagulation therapy. A reduction in all-cause mortality was observed in trials of self-management but not in self-monitoring, with no effects on major haemorrhage.