The long-term impact of vaginal surgical mesh devices on pain clinic and psychological service referrals, anti-inflammatory testing and pelvic scans in UK primary care: A cohort study with the Clinical Practice Research Datalink.

OBJECTIVE: To examine long-term complications in women with stress urinary incontinence (SUI) and pelvic organ prolapse (POP), with and without surgical mesh implants. DESIGN: Longitudinal open cohort study from 1 April 2006 (or 1 April 2012) to 30 November 2018. SETTING: The Clinical Practice Research Datalink (CPRD) Gold database, which is linked to Hospital Episodes Statistics (HES) inpatient data, the HES Diagnostic Imaging Dataset (DID), Office for National Statistics mortality data and Index of Multiple Deprivation socio-economic status data. SAMPLE: Women aged ≥18 years with a diagnostic SUI/POP Read code. METHODS: Rates are estimated using negative binomial regression. MAIN OUTCOME MEASURES: Rates of referrals for: psychological and pain services; urinalysis, C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) testing; and pelvic ultrasound, computed tomography (CT) and magnetic resonance imaging (MRI) scans. RESULTS: A cohort of 220 544 women were eligible for inclusion; 74% (n = 162 687) had SUI, 37% (n = 82 123) had POP and 11% (n = 24 266) had both. Rates of psychological referrals and CT scans were lower in women with SUI mesh surgery, but this was offset by higher rates of CRP testing in women with SUI or POP mesh, MRI scans in women with SUI mesh, and urinalysis testing and referrals to pain clinics for women with POP mesh. CONCLUSIONS: Our results suggest a higher burden of morbidity in women with SUI/POP mesh surgery, and that these women may require ongoing follow-up in the primary care setting.

Predictors for success and failure in international medical graduates: a systematic review of observational studies.

BACKGROUND: International Medical Graduates (IMG) are an essential part of the international physician workforce, and exploring the predictors of success and failure for IMGs could help inform international and national physician labour workforce selection and planning. The objective of this study was to explore predictors for success for selection of IMGs into high stakes postgraduate training positions and practice and not necessarily for informing IMGs. METHODS: We searched 11 databases, including Medline, Embase and LILACS, from inception to February 2022 for studies that explored the predictors of success and failure in IMGs. We reported baseline probability, effect size in relative risk (RR), odds ratio (OR) or hazard ratio (HR) and absolute probability change for success and failure across six groups of outcomes, including success in qualifying exams, or certificate exams, successful matching into residency, retention in practice, disciplinary actions, and outcomes of IMG clinical practice. RESULTS: Twenty-five studies (375,549 participants) reported the association of 93 predictors of success and failure for IMGs. Female sex, English fluency, graduation recency, higher scores in USMLE step 2 and participation in a skill assessment program were associated with success in qualifying exams. Female sex, English fluency, previous internship and results of qualifying exams were associated with success in certification exams. Retention to work in Canada was associated with several factors, including male sex, graduating within the past five years, and completing residency over fellowships. In the UK, IMGs and candidates who attempted PLAB part 1, ≥ 4 times vs. first attempters, and candidates who attempted PLAB part 2, ≥ 3 times vs. first attempters were more likely to be censured in future practice. Patients treated by IMGs had significantly lower mortalities than those treated by US graduates, and patients of IMGs had lower mortalities [OR: 0.82 (95% CI: 0.62, 0.99)] than patients of US citizens who trained abroad. CONCLUSIONS: This study informed factors associated with the success and failure of IMGs and is the first systematic review on this topic, which can inform IMG selection and future studies. SYSTEMATIC REVIEW REGISTRATION: PROSPERO: CRD42021252678.

Drug shortages. Part 1. Definitions and harms.

Drug shortages are repeatedly in the news. The earliest drug shortages were reported during the First World War, but the numbers of shortages have increased in recent years. In the first part of this two-part review, we discuss definitions of drug shortages and so-called stockouts, which are localized shortages, and the harms that they can cause. Drug shortages make it difficult or impossible to meet the therapeutic needs of individual patients or populations, but we lack an adequate definition. The problems are too complicated to be encompassed in a brief intensional dictionary-style definition, and that is reflected in the many different attempts at definition that have been proposed. We therefore propose an extensional operational definition that incorporates the processes by which products are manufactured, the causes of shortages and the contributory factors. A definition of this sort allows one to identify the main causes of a particular drug shortage and therefore the remedies that might prevent, mitigate or manage it. In the second part of the review we discuss the causes and solutions in more detail. Adverse drug reactions and medication errors attributable to shortages occur but are not often reported. Adverse reactions to substitute medicines are possible, and errors can occur because of unfamiliarity or unnecessary treatment with replacement medicines. Other harmful outcomes include withdrawal reactions, undertreatment, treatment delays and cancellations, failure of alternatives and disruption of clinical trials.

Drug shortages. Part 2: Trends, causes and solutions.

Drug shortages make it difficult or impossible to meet the therapeutic needs of individual patients or populations. In the first part of this review we proposed an operational definition that incorporates the processes by which products are manufactured, the causes of shortages and stock-outs (local shortages), and the contributory factors. Here we discuss causes and possible solutions. Drug shortages have complex causes, and a single cause cannot always be identified. Reasons include lack or shortage of raw materials, manufacturing difficulties, regulatory and political actions, voluntary recalls, just-in-time inventory systems, halts in production for financial or other business reasons, low demand (eg, orphan products, reduced usage), mergers, market shifts (eg, diversion to home markets) and unexpected increases in demand (eg, improved diagnosis, new trial information, epidemics and pandemics, inappropriate use, off-label use). Potential solutions are as diverse as the potential causes. Prevention is hard, because shortages are not easily predicted. Everyone in the supply chain is involved in anticipating and managing shortages, with responsibilities for preventing them or at least trying to mitigate their effects. This includes manufacturers and suppliers, particularly of generic formulations, pharmacists, prescribers, patients and governments. Solutions can therefore be linked to the causes and classified according to where the responsibility for implementing them lies.

The quality of paediatric asthma guidelines: evidence underpinning diagnostic test recommendations from a meta-epidemiological study.

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.

Preventable deaths involving opioids in England and Wales, 2013-2022: a systematic case series of coroners' reports.

BACKGROUND: Opioid deaths have increased in England and Wales. Coroners' Prevention of Future Deaths reports (PFDs) provide important insights that may enable safer use and avert harms, yet reports implicating opioids have not been synthesized. We aimed to identify opioid-related PFDs and explore coroners' concerns to prevent future deaths. METHODS: In this systematic case series, we screened 3897 coronial PFDs dated between 01 July 2013 and 23 February 2022, obtained by web scraping the UK's Courts and Tribunals Judiciary website. PFDs were included when an opioid was implicated in the death. Included PFDs were descriptively analysed, and content analysis was used to assess concerns reported by coroners. RESULTS: Opioids were involved in 219 deaths reported in PFDs (5·6% of PFDs), equating to 4418 years of life lost (median 33 years/person). Morphine (29%), methadone (23%) and diamorphine (16%) were the most common implicated opioids. Coroners most frequently raised concerns regarding systems and protocols (52%) or safety issues (15%). These concerns were most often addressed to National Health Service (NHS) organizations (51%), but response rates were low overall (47%). CONCLUSIONS: Opioids could be used more safely if coroners' concerns in PFDs were addressed by national organizations such as NHS bodies, government agencies and policymakers, as well as individual prescribing clinicians.

The quality of diagnostic guidelines for children in primary care: A meta-epidemiological study.

AIM: To determine the quality of paediatric guidelines relevant to diagnosis of three of the most common conditions in primary care: fever, gastroenteritis and constipation. METHODS: We undertook a meta-epidemiological study of paediatric guidelines for fever, gastroenteritis and gastroenteritis. We systematically searched MEDLINE, Embase, Trip Database, Guidelines International Network, the National Guideline Clearinghouse and WHO from February 2011 to September 2022 for guidelines from high-income settings containing diagnostic recommendations. We assessed the quality of guideline reporting for included guidelines using the AGREE II tool. RESULTS: We included 16 guidelines: fever (n = 7); constipation (n = 4) and gastroenteritis (n = 5). The overall quality across the three conditions was graded moderate (median AGREE II score 4.5/7, range 2.5-6.5) with constipation guidelines rated the highest (median 6/7), and fever rated the lowest (median 3.8/7). Major methodological weaknesses included consideration of guideline applicability. Half of the guidelines did not report involving parent representatives, and 56% did not adequately declare or address their competing interests. CONCLUSIONS: Substantial variations exist in the quality of paediatric guidelines related to the diagnosis of primary care presentations. Better quality guidance is needed for general practitioners to improve diagnosis for children in primary care.

Viral Cultures for Coronavirus Disease 2019 Infectivity Assessment: A Systematic Review.

BACKGROUND: We aimed to review the evidence from studies relating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) culture with the results of reverse-transcription polymerase chain reaction (RT-PCR) and other variables that may influence the interpretation of the test, such as time from symptom onset. METHODS: We searched LitCovid, medRxiv, Google Scholar, and the World Health Organization coronavirus disease 2019 (COVID-19) database for COVID-19 up to 10 September 2020. We included studies attempting to culture or observe SARS-CoV-2 in specimens with RT-PCR positivity. Studies were dual-extracted and the data summarized narratively by specimen type. Where necessary, we contacted corresponding authors of included papers for additional information. We assessed quality using a modified Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS 2) risk-of-bias tool. RESULTS: We included 29 studies reporting attempts at culturing, or observing tissue infection by, SARS-CoV-2 in sputum, nasopharyngeal or oropharyngeal, urine, stool, blood, and environmental specimens. The quality of the studies was moderate with lack of standardized reporting. The data suggest a relationship between the time from onset of symptom to the timing of the specimen test, cycle threshold (Ct), and symptom severity. Twelve studies reported that Ct values were significantly lower and log copies higher in specimens producing live virus culture. Two studies reported that the odds of live virus culture were reduced by approximately 33% for every 1-unit increase in Ct. Six of 8 studies reported detectable RNA for >14 days, but infectious potential declined after day 8 even among cases with ongoing high viral loads. Four studies reported viral culture from stool specimens. CONCLUSIONS: Complete live viruses are necessary for transmission, not the fragments identified by PCR. Prospective routine testing of reference and culture specimens and their relationship to symptoms, signs, and patient co-factors should be used to define the reliability of PCR for assessing infectious potential. Those with high Ct are unlikely to have infectious potential.

Temporal trends in childhood cancer survival in Egypt, 2007 to 2017: A large retrospective study of 14 808 children with cancer from the Children's Cancer Hospital Egypt.

Childhood cancer is a priority in Egypt due to large numbers of children with cancer, suboptimal care and insufficient resources. It is difficult to evaluate progress in survival because of paucity of data in National Cancer Registry. In this study, we studied survival rates and trends in survival of the largest available cohort of children with cancer (n = 15 779, aged 0-18 years) from Egypt between 2007 and 2017, treated at Children's Cancer Hospital Egypt-(CCHE), representing 40% to 50% of all childhood cancers across Egypt. We estimated 5-year overall survival (OS) for 14 808 eligible patients using Kaplan-Meier method, and determined survival trends using Cox regression by single year of diagnosis and by diagnosis periods. We compared age-standardized rates to international benchmarks in England and the United States, identified cancers with inferior survival and provided recommendations for improvement. Five-year OS was 72.1% (95% CI 71.3-72.9) for all cancers combined, and survival trends increased significantly by single year of diagnosis (P < .001) and by calendar periods from 69.6% to 74.2% (P < .0001) between 2007-2012 and 2013-2017. Survival trends improved significantly for leukemias, lymphomas, CNS tumors, neuroblastoma, hepatoblastoma and Ewing Sarcoma. Survival was significantly lower by 9% and 11.2% (P < .001) than England and the United States, respectively. Significantly inferior survival was observed for the majority of cancers. Although survival trends are improving for childhood cancers in Egypt/CCHE, survival is still inferior in high-income countries. We provide evidence-based recommendations to improve survival in Egypt by reflecting on current obstacles in care, with further implications on practice and policy.

Benefits and harms of Risperidone and Paliperidone for treatment of patients with schizophrenia or bipolar disorder: a meta-analysis involving individual participant data and clinical study reports.

BACKGROUND: Schizophrenia and bipolar disorder are severe mental illnesses which are highly prevalent worldwide. Risperidone and Paliperidone are treatments for either illnesses, but their efficacy compared to other antipsychotics and growing reports of hormonal imbalances continue to raise concerns. As existing evidence on both antipsychotics are solely based on aggregate data, we aimed to assess the benefits and harms of Risperidone and Paliperidone in the treatment of patients with schizophrenia or bipolar disorder, using individual participant data (IPD), clinical study reports (CSRs) and publicly available sources (journal publications and trial registries). METHODS: We searched MEDLINE, Central, EMBASE and PsycINFO until December 2020 for randomised placebo-controlled trials of Risperidone, Paliperidone or Paliperidone palmitate in patients with schizophrenia or bipolar disorder. We obtained IPD and CSRs from the Yale University Open Data Access project. The primary outcome Positive and Negative Syndrome Scale (PANSS) score was analysed using one-stage IPD meta-analysis. Random-effect meta-analysis of harm outcomes involved methods for coping with rare events. Effect-sizes were compared across all available data sources using the ratio of means or relative risk. We registered our review on PROSPERO, CRD42019140556. RESULTS: Of the 35 studies, IPD meta-analysis involving 22 (63%) studies showed a significant clinical reduction in the PANSS in patients receiving Risperidone (mean difference - 5.83, 95% CI - 10.79 to - 0.87, I2 = 8.5%, n = 4 studies, 1131 participants), Paliperidone (- 6.01, 95% CI - 8.7 to - 3.32, I2 = 4.3%, n = 13, 3821) and Paliperidone palmitate (- 7.89, 95% CI - 12.1 to - 3.69, I2 = 2.9%, n = 5, 2209). CSRs reported nearly two times more adverse events (4434 vs. 2296 publication, relative difference (RD) = 1.93, 95% CI 1.86 to 2.00) and almost 8 times more serious adverse events (650 vs. 82; RD = 7.93, 95% CI 6.32 to 9.95) than the journal publications. Meta-analyses of individual harms from CSRs revealed a significant increased risk among several outcomes including extrapyramidal disorder, tardive dyskinesia and increased weight. But the ratio of relative risk between the different data sources was not significant. Three treatment-related gynecomastia events occurred, and these were considered mild to moderate in severity. CONCLUSION: IPD meta-analysis conclude that Risperidone and Paliperidone antipsychotics had a small beneficial effect on reducing PANSS score over 9 weeks, which is more conservative than estimates from reviews based on journal publications. CSRs also contained significantly more data on harms that were unavailable in journal publications or trial registries. Sharing of IPD and CSRs are necessary when performing meta-analysis on the efficacy and safety of antipsychotics.

The Oxford Catalogue of Opioids: A systematic synthesis of opioid drug names and their pharmacology.

AIM: The growing demand for analgesia, coupled with an increasing need to treat opioid dependence and overdose, has escalated the development of novel opioids. We aimed to quantify the number of opioid drugs developed and to catalogue them based on their pharmacology. METHODS: We conducted a systematic search of seven sources in November 2020, including the WHO's Anatomical Therapeutic Classification index, the British National Formulary, the IUPHAR/BPS Guide to Pharmacology, the International Narcotics Control Board Index of Names of Narcotic Drugs, the WHO's International Nonproprietary Names MedNet service, Martindale's Extra Pharmacopoeia and the Merck Index, to include opioid drugs that targeted or had an effect or coeffect at one or more opioid receptors. We extracted chemical and nonproprietary names, drug stems, molecular formulas, molecular weights, receptor targets, actions at opioid receptors and classes based on their origins. We used descriptive statistics and calculated medians and interquartile ranges where appropriate. RESULTS: We identified 233 opioid drugs and created an online resource (https://www.catalogueofopioids.net/). There were 10 unique drug stems, and "-fentanil" accounted for one-fifth (20%) of all opioids. Most of the drugs (n = 133) targeted mu-opioid receptors and the majority (n = 191) were agonists at one or more receptors. Most (82%) were synthetic opioids, followed by semisynthetic opioids (16%) and alkaloids (3%). CONCLUSION: This catalogue centralizes and disseminates information that could assist researchers, prescribers and the public to improve the safe use of opioids.

Childhood cancer hospital resource utilization and costs in Egypt, 2013-2017; patterns, trends, and associated factors for 8886 patients from Children's Cancer Hospital, Egypt.

INTRODUCTION: There is a lack ofevidence about resource use and costs of childhood cancer care in Egypt. Knowledge about resource use/costs can help in better resource planning to improve care and outcomes efficiently. In this study, we estimated patterns and trends of hospital resource use and costs for children with cancer (n = 8886, aged 0-18 years) treated at Children's Cancer Hospital, Egypt (CCHE), between 2013 and 2017, by ICCC-3 groups, at one and three years post-diagnosis. METHODS: We estimated costs from the healthcare provider perspective, expressed in USD 2019. We also studied resource use/cost trends, and factors associated with inpatient days and costs. RESULTS: For all cancers combined, median costs were $14,774 (IQR: $6,559-$23,738) at one year and $19,799 (IQR: $8,921-$34,204) at three years post-diagnosis. Median inpatient days were 38 days (IQR: 17-60) at one year, and 43 days (IQR: 20-74) at three years post-diagnosis. Patients with acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), and neuroblastoma imposed the greatest financial burden on CCHE, representing 53.1% of total costs. AML patients had the highest costs/resource use of all childhood cancers. Cost trends decreased by 2.9% (P < 0.001) for all cancers combined, due to economic instability in Egypt between 2013 and 2017. The use of IV supportive drugs increased by 24.3% (P < 0.001) over time for children with solid tumors. CONCLUSION: These findings will inform hospital resource planning and budgeting to promote value in care delivery, with implications for pediatric oncology practice and policy in Egypt/CCHE. Estimated costs provide the foundation for cost-effectiveness analysis.

Evaluating the impact of a very low-cost intervention to increase practices' engagement with data and change prescribing behaviour: a randomized trial in English primary care.

BACKGROUND: Unsolicited feedback can solicit changes in prescribing. OBJECTIVES: Determine whether a low-cost intervention increases clinicians' engagement with data, and changes prescribing; with or without behavioural science techniques. METHODS: Randomized trial (ISRCTN86418238). The highest prescribing practices in England for broad-spectrum antibiotics were allocated to: feedback with behavioural impact optimization; plain feedback; or no intervention. Feedback was sent monthly for 3 months by letter, fax and email. Each included a link to a prescribing dashboard. The primary outcomes were dashboard usage and change in prescribing. RESULTS: A total of 1401 practices were randomized: 356 behavioural optimization, 347 plain feedback, and 698 control. For the primary engagement outcome, more intervention practices had their dashboards viewed compared with controls [65.7% versus 55.9%; RD 9.8%, 95% confidence intervals (CIs): 4.76% to 14.9%, P < 0.001]. More plain feedback practices had their dashboard viewed than behavioural feedback practices (69.1% versus 62.4%); but not meeting the P < 0.05 threshold (6.8%, 95% CI: -0.19% to 13.8%, P = 0.069). For the primary prescribing outcome, intervention practices possibly reduced broad-spectrum prescribing to a greater extent than controls (1.42% versus 1.12%); but again not meeting the P < 0.05 threshold (coefficient -0.31%, CI: -0.7% to 0.1%, P = 0.104). The behavioural impact group reduced broad-spectrum prescribing to a greater extent than plain feedback practices (1.63% versus 1.20%; coefficient 0.41%, CI: 0.007% to 0.8%, P = 0.046). No harms were detected. CONCLUSIONS: Unsolicited feedback increased practices' engagement with data, with possible slightly reduced antibiotic prescribing (P = 0.104). Behavioural science techniques gave greater prescribing effects. The modest effects on prescribing may reflect saturation from similar initiatives on antibiotic prescribing. CLINICAL TRIAL REGISTRATION: ISRCTN86418238.

A randomised controlled trial of extended anticoagulation treatment versus standard treatment for the prevention of recurrent venous thromboembolism (VTE) and post-thrombotic syndrome in patients being treated for a first episode of unprovoked VTE (the ExACT study).

Venous thromboembolism (VTE) is prevalent and impactful, with a risk of death, morbidity and recurrence. Post-thrombotic syndrome (PTS) is a common consequence and associated with impaired quality of life (QoL). The ExACT study was a non-blinded, prospective, multicentred randomised controlled trial comparing extended versus limited duration anticoagulation following a first unprovoked VTE (proximal deep vein thrombosis or pulmonary embolism). Adults were eligible if they had completed ≥3 months anticoagulation (remaining anticoagulated). The primary outcome was time to first recurrent VTE from randomisation. The secondary outcomes included PTS severity, bleeding, QoL and D-dimers. Two-hundred and eighty-one patients were recruited, randomised and followed up for 24 months (mean age 63, male:female 2:1). There was a significant reduction in recurrent VTE for patients receiving extended anticoagulation [2·75 vs. 13·54 events/100 patient years, adjusted hazard ratio (aHR) 0·20 (95% confidence interval (CI): 0·09 to 0·46, P < 0·001)] with a non-significant increase in major bleeding [3·54 vs. 1·18 events/100 patient years, aHR 2·99 (95% CI: 0·81-11·05, P = 0·10)]. Outcomes of PTS and QoL were no different between groups. D-dimer results (on anticoagulation) did not predict VTE recurrence. In conclusion, extended anticoagulation reduced VTE recurrence but did not reduce PTS or improve QoL and was associated with a non-significant increase in bleeding. Results also suggest very limited clinical utility of D-dimer testing on anticoagulated patients.

Factors associated with the prescribing of high-dose opioids in primary care: a systematic review and meta-analysis.

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 (NNTH) 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, I2 = 99.9%), depression (RR 1.38, 95% CI 1.27 to 1.51, I2 = 0%), emergency department visits (RR 1.53, 95% CI 1.46 to 1.61, I2 = 0%, NNTH 15, 95% CI 12 to 20), unemployment (RR 1.44, 95% CI 1.27 to 1.63, I2 = 0%), and male gender (RR 1.21, 95% CI 1.14 to 1.28, I2 = 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.

Open-label randomised pragmatic trial (CONTACT) comparing naproxen and low-dose colchicine for the treatment of gout flares in primary care.

OBJECTIVES: To compare the effectiveness and safety of naproxen and low-dose colchicine for treating gout flares in primary care. METHODS: This was a multicentre open-label randomised trial. Adults with a gout flare recruited from 100 general practices were randomised equally to naproxen 750 mg immediately then 250 mg every 8 hours for 7 days or low-dose colchicine 500 mcg three times per day for 4 days. The primary outcome was change in worst pain intensity in the last 24 hours (0-10 Numeric Rating Scale) from baseline measured daily over the first 7 days: mean change from baseline was compared between groups over days 1-7 by intention to treat. RESULTS: Between 29 January 2014 and 31 December 2015, we recruited 399 participants (naproxen n=200, colchicine n=199), of whom 349 (87.5%) completed primary outcome data at day 7. There was no significant between-group difference in average pain-change scores over days 1-7 (colchicine vs naproxen: mean difference -0.18; 95% CI -0.53 to 0.17; p=0.32). During days 1-7, diarrhoea (45.9% vs 20.0%; OR 3.31; 2.01 to 5.44) and headache (20.5% vs 10.7%; 1.92; 1.03 to 3.55) were more common in the colchicine group than the naproxen group but constipation was less common (4.8% vs 19.3%; 0.24; 0.11 to 0.54). CONCLUSION: We found no difference in pain intensity over 7 days between people with a gout flare randomised to either naproxen or low-dose colchicine. Naproxen caused fewer side effects supporting naproxen as first-line treatment for gout flares in primary care in the absence of contraindications. TRIAL REGISTRATION NUMBER: ISRCTN (69836939), clinicaltrials.gov (NCT01994226), EudraCT (2013-001354-95).

Naltrexone-bupropion (Mysimba) in management of obesity: A systematic review and meta-analysis of unpublished clinical study reports.

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.

Corticosteroids as standalone or add-on treatment for sore throat.

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.

Self-management programmes for cirrhosis: A systematic review.

BACKGROUND AND AIMS: Liver cirrhosis severely decreases patients' quality of life. Since self-management programmes have improved quality of life and reduce hospital admissions in other chronic diseases, they have been suggested to decrease liver cirrhosis burden. METHODS: We performed a systematic review and meta-analysis to evaluate the clinical impact of self-management programmes in patients with liver cirrhosis, which followed the Preferred Reporting for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Primary outcomes include health-related quality of life (HRQOL) and hospitalisation. We searched MEDLINE, CENTRAL, Embase, CINAHL, PsycINFO and two trial registers to July 2017. RESULTS: We identified four randomised trials (299 patients) all rated at a high risk of bias. No difference was demonstrated for HRQOL (standardised mean difference -0.01, 95% CI: -0.48 to 0.46) and hospitalisation days (incidence rate ratio 1.6, 95% CI: 0.5-4.8). For secondary outcomes, one study found a statistically significant improvement in patient knowledge (mean difference (MD) 3.68, 95% CI: 2.11-5.25) while another study found an increase in model for end-stage liver disease scores (MD 2.8, 95% CI: 0.6-4.9) in the self-management group. No statistical difference was found for the other secondary outcomes (self-efficacy, psychological health outcomes, healthcare utilisation, mortality). Overall, the quality of the evidence was low. The content of self-management programmes varied across studies with little overlap. CONCLUSIONS: The current literature indicates that there is no evidence of a benefit of self-management programmes for people with cirrhosis. RELEVANCE TO CLINICAL PRACTICE: Practitioners should use self-management programmes with caution when delivering care to patients living with cirrhosis. Further research is required to determine what are the key features in a complex intervention like self-management. This review offers a preliminary framework for clinicians to develop a new self-management programme with key features of effective self-management interventions from established models.