Search

Preterm birth is the leading cause of death in newborns and children. Tocolytic drugs aim to delay preterm birth by suppressing uterine contractions to allow time for administration of corticosteroids for fetal lung maturation, magnesium sulphate for neuroprotection, and transport to a facility with appropriate neonatal care facilities. However, there is still uncertainty about their effectiveness and safety.To estimate relative effectiveness and safety profiles for different classes of tocolytic drugs for delaying preterm birth, and provide rankings of the available drugs.We searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov (21 April 2021) and reference lists of retrieved studies.We included all randomised controlled trials assessing effectiveness or adverse effects of tocolytic drugs for delaying preterm birth. We excluded quasi- and non-randomised trials. We evaluated all studies against predefined criteria to judge their trustworthiness.At least two review authors independently assessed the trials for inclusion and risk of bias, and extracted data. We performed pairwise and network meta-analyses, to determine the relative effects and rankings of all available tocolytics. We used GRADE to rate the certainty of the network meta-analysis effect estimates for each tocolytic versus placebo or no treatment.This network meta-analysis includes 122 trials (13,697 women) involving six tocolytic classes, combinations of tocolytics, and placebo or no treatment. Most trials included women with threatened preterm birth, singleton pregnancy, from 24 to 34 weeks of gestation. We judged 25 (20%) studies to be at low risk of bias. Overall, certainty in the evidence varied. Relative effects from network meta-analysis suggested that all tocolytics are probably effective in delaying preterm birth compared with placebo or no tocolytic treatment. Betamimetics are possibly effective in delaying preterm birth by 48 hours (risk ratio (RR) 1.12, 95% confidence interval (CI) 1.05 to 1.20; low-certainty evidence), and 7 days (RR 1.14, 95% CI 1.03 to 1.25; low-certainty evidence). COX inhibitors are possibly effective in delaying preterm birth by 48 hours (RR 1.11, 95% CI 1.01 to 1.23; low-certainty evidence). Calcium channel blockers are possibly effective in delaying preterm birth by 48 hours (RR 1.16, 95% CI 1.07 to 1.24; low-certainty evidence), probably effective in delaying preterm birth by 7 days (RR 1.15, 95% CI 1.04 to 1.27; moderate-certainty evidence), and prolong pregnancy by 5 days (0.1 more to 9.2 more; high-certainty evidence). Magnesium sulphate is probably effective in delaying preterm birth by 48 hours (RR 1.12, 95% CI 1.02 to 1.23; moderate-certainty evidence). Oxytocin receptor antagonists are probably effective in delaying preterm birth by 48 hours (RR 1.13, 95% CI 1.05 to 1.22; moderate-certainty evidence), are effective in delaying preterm birth by 7 days (RR 1.18, 95% CI 1.07 to 1.30; high-certainty evidence), and possibly prolong pregnancy by 10 days (95% CI 2.3 more to 16.7 more). Nitric oxide donors are probably effective in delaying preterm birth by 48 hours (RR 1.17, 95% CI 1.05 to 1.31; moderate-certainty evidence), and 7 days (RR 1.18, 95% CI 1.02 to 1.37; moderate-certainty evidence). Combinations of tocolytics are probably effective in delaying preterm birth by 48 hours (RR 1.17, 95% CI 1.07 to 1.27; moderate-certainty evidence), and 7 days (RR 1.19, 95% CI 1.05 to 1.34; moderate-certainty evidence). Nitric oxide donors ranked highest for delaying preterm birth by 48 hours and 7 days, and delay in birth (continuous outcome), followed by calcium channel blockers, oxytocin receptor antagonists and combinations of tocolytics. Betamimetics (RR 14.4, 95% CI 6.11 to 34.1; moderate-certainty evidence), calcium channel blockers (RR 2.96, 95% CI 1.23 to 7.11; moderate-certainty evidence), magnesium sulphate (RR 3.90, 95% CI 1.09 to 13.93; moderate-certainty evidence) and combinations of tocolytics (RR 6.87, 95% CI 2.08 to 22.7; low-certainty evidence) are probably more likely to result in cessation of treatment. Calcium channel blockers possibly reduce the risk of neurodevelopmental morbidity (RR 0.51, 95% CI 0.30 to 0.85; low-certainty evidence), and respiratory morbidity (RR 0.68, 95% CI 0.53 to 0.88; low-certainty evidence), and result in fewer neonates with birthweight less than 2000 g (RR 0.49, 95% CI 0.28 to 0.87; low-certainty evidence). Nitric oxide donors possibly result in neonates with higher birthweight (mean difference (MD) 425.53 g more, 95% CI 224.32 more to 626.74 more; low-certainty evidence), fewer neonates with birthweight less than 2500 g (RR 0.40, 95% CI 0.24 to 0.69; low-certainty evidence), and more advanced gestational age (MD 1.35 weeks more, 95% CI 0.37 more to 2.32 more; low-certainty evidence). Combinations of tocolytics possibly result in fewer neonates with birthweight less than 2500 g (RR 0.74, 95% CI 0.59 to 0.93; low-certainty evidence). In terms of maternal adverse effects, betamimetics probably cause dyspnoea (RR 12.09, 95% CI 4.66 to 31.39; moderate-certainty evidence), palpitations (RR 7.39, 95% CI 3.83 to 14.24; moderate-certainty evidence), vomiting (RR 1.91, 95% CI 1.25 to 2.91; moderate-certainty evidence), possibly headache (RR 1.91, 95% CI 1.07 to 3.42; low-certainty evidence) and tachycardia (RR 3.01, 95% CI 1.17 to 7.71; low-certainty evidence) compared with placebo or no treatment. COX inhibitors possibly cause vomiting (RR 2.54, 95% CI 1.18 to 5.48; low-certainty evidence). Calcium channel blockers (RR 2.59, 95% CI 1.39 to 4.83; low-certainty evidence), and nitric oxide donors probably cause headache (RR 4.20, 95% CI 2.13 to 8.25; moderate-certainty evidence).Compared with placebo or no tocolytic treatment, all tocolytic drug classes that we assessed (betamimetics, calcium channel blockers, magnesium sulphate, oxytocin receptor antagonists, nitric oxide donors) and their combinations were probably or possibly effective in delaying preterm birth for 48 hours, and 7 days. Tocolytic drugs were associated with a range of adverse effects (from minor to potentially severe) compared with placebo or no tocolytic treatment, although betamimetics and combination tocolytics were more likely to result in cessation of treatment. The effects of tocolytic use on neonatal outcomes such as neonatal and perinatal mortality, and on safety outcomes such as maternal and neonatal infection were uncertain.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection is associated with a range of persistent symptoms impacting everyday functioning, known as post-COVID-19 condition or long COVID. We undertook a retrospective matched cohort study using a UK-based primary care database, Clinical Practice Research Datalink Aurum, to determine symptoms that are associated with confirmed SARS-CoV-2 infection beyond 12 weeks in non-hospitalized adults and the risk factors associated with developing persistent symptoms. We selected 486,149 adults with confirmed SARS-CoV-2 infection and 1,944,580 propensity score-matched adults with no recorded evidence of SARS-CoV-2 infection. Outcomes included 115 individual symptoms, as well as long COVID, defined as a composite outcome of 33 symptoms by the World Health Organization clinical case definition. Cox proportional hazards models were used to estimate adjusted hazard ratios (aHRs) for the outcomes. A total of 62 symptoms were significantly associated with SARS-CoV-2 infection after 12 weeks. The largest aHRs were for anosmia (aHR 6.49, 95% CI 5.02–8.39), hair loss (3.99, 3.63–4.39), sneezing (2.77, 1.40–5.50), ejaculation difficulty (2.63, 1.61–4.28) and reduced libido (2.36, 1.61–3.47). Among the cohort of patients infected with SARS-CoV-2, risk factors for long COVID included female sex, belonging to an ethnic minority, socioeconomic deprivation, smoking, obesity and a wide range of comorbidities. The risk of developing long COVID was also found to be increased along a gradient of decreasing age. SARS-CoV-2 infection is associated with a plethora of symptoms that are associated with a range of sociodemographic and clinical risk factors.

Globally, chronic kidney disease (CKD) is one of the leading causes of mortality. Impaired renal function makes CKD patients vulnerable to drug-related problems (DRPs). The aim of this systematic review was to investigate the prevalence and nature of DRPs among hospital in-patients with CKD. A systematic review of the literature was conducted using Medline, EMBASE, PsycINFO, Web of Science (Core Collection), CINAHL plus (EBSCO), Cochrane Library (Wiley), Scopus (ELSEVIER) and PubMed (U.S.NLM) from index inception to January 2020. Studies investigating DRPs in hospitalised CKD patients published in the English language were included. Two independent reviewers extracted the data and undertook quality assessment using the Joanna Briggs Institute (JBI) tool. A total of 2895 unique titles were identified; with 20 meeting the inclusion criteria. DRPs prevalence in CKD was reported between 12 and 87%. The most common DRPs included ineffective treatment, inappropriate drug choice and dosing problems. Antibiotics, H2-antihistamines and oral antidiabetics (metformin) were common drug classes involved in DRPs. Factors associated with DRPs included severity of CKD, the number of medications taken, age, length of hospital stay, and gender. This systematic review provides evidence that DRPs are a frequent occurrence and burden for hospitalised patients with stage 1–4 CKD. Heterogeneity in study design, case detection and definitions are common, and future studies should use clearer definitions and study designs. Protocol Registration: PROSPERO: CRD42018096364

Objectives A national pre-registration pharmacist recruitment scheme, which replaces the local recruitment models, was introduced in England and Wales in 2017. This study aimed to explore pharmacy students' behaviour and associated factors in their selection of pre-registration training programmes. Methods A mixed-method study using (a) analysis of data from all applicants (n = 2694) of the national recruitment scheme, (b) an online survey and (c) a virtual focus group was undertaken. Survey and focus group questions were developed based on the Theoretical Domains Framework (TDF). Descriptive and inferential analysis of quantitative data was undertaken using Stata software. Qualitative data from focus groups and responses from the open-ended questions were analysed using framework technique. Key findings A vast majority of applicants (n = 2182, 83.9%) selected a hospital training programme as their first ranked preference, with the rest opting for community pharmacy. Urban areas, particularly London, were most popular geographically. A total of 307 survey responses were returned. Long-term career aspirations, followed by geographical factors, were rated most highly in applicants' decision-making. Qualitative data from survey and focus group demonstrated information about programmes/employers, perceived opportunity for skills development and aspiration towards a career path as key contributory factors in their decision-making. Conclusions Secondary care was the most desirable destination for pharmacy students to undertake early career training. The clinical roles and career opportunities in community pharmacy needs to be promoted as there is a risk that community pharmacy training programme places may be seen as a ‘left over’ opportunity for less competitive candidates to uptake.

STUDY QUESTION What is the association between serum progesterone levels on the day of frozen embryo transfer (FET) and the probability of live birth in women undergoing different FET regimens? SUMMARY ANSWER Overall, serum progesterone levels WHAT IS KNOWN ALREADY Progesterone is essential for pregnancy success. A recent systematic review showed that in FET cycles using vaginal progesterone for endometrial preparation, lower serum progesterone levels ( STUDY DESIGN, SIZE, DURATION This was a multicentre (n = 8) prospective cohort study conducted in the UK between January 2020 and February 2021. PARTICIPANTS/MATERIALS, SETTING, METHODS We included women having NC-FET or HRT-FET treatment with progesterone administration by any available route. Women underwent venepuncture on the day of embryo transfer. Participants and clinical personnel were blinded to the serum progesterone levels. We conducted unadjusted and multivariable logistic regression analyses to investigate the association between serum progesterone levels on the day of FET and treatment outcomes according to the type of cycle and route of exogenous progesterone administration. Our primary outcome was the live birth rate per participant. MAIN RESULTS AND THE ROLE OF CHANCE We studied a total of 402 women. The mean (SD) serum progesterone level was 14.9 (7.5) ng/ml. Overall, the mean adjusted probability of live birth increased non-linearly from 37.6% (95% CI 26.3–48.9%) to 45.5% (95% CI 32.1–58.9%) as serum progesterone rose between the 10th (7.8 ng/ml) and 90th (24.0 ng/ml) centiles. In comparison to participants whose serum progesterone level was ≥7.8 ng/ml, those with lower progesterone ( LIMITATIONS, REASONS FOR CAUTION The final sample size was smaller than originally planned, although our study was adequately powered to confidently identify a difference in live birth between optimal and inadequate progesterone levels. Furthermore, our cohort did not include women receiving oral or rectal progestogens. WIDER IMPLICATIONS OF THE FINDINGS Our results corroborate existing evidence suggesting that lower serum progesterone levels hinder FET success. However, the relationship between serum progesterone and the probability of live birth appears to be non-linear in women receiving exclusively subcutaneous progesterone, suggesting that in this subgroup of women, high serum progesterone may also be detrimental to treatment success. STUDY FUNDING/COMPETING INTERESTS This work was supported by CARE Fertility and a doctoral research fellowship (awarded to P.M.) by the Tommy’s Charity and the University of Birmingham. M.J.P. is supported by the NIHR Birmingham Biomedical Research Centre. S.F. is a minor shareholder of CARE Fertility but has no financial or other interest with progesterone testing or manufacturing companies. P.L. reports personal fees from Pharmasure, outside the submitted work. G.P. reports personal fees from Besins Healthcare, outside the submitted work. M.W. reports personal fees from Ferring Pharmaceuticals, outside the submitted work. The remaining authors have no conflict of interest to declare. TRIAL REGISTRATION NUMBER ClinicalTrials.gov: NCT04170517.

Interventions to reduce household air pollution (HAP) are key to reducing associated morbidity and mortality in low- and middle- income countries (LMICs); especially among pregnant women and young children. This systematic review aims to determine the effectiveness of interventions aimed to reduce HAP exposure associated with domestic solid biomass fuel combustion, compared to usual cooking practices, for improving health outcomes in pregnant women and children under five in LMIC settings. A systematic review and meta-analysis was undertaken with searches undertaken in MEDLINE, EMBASE, CENTRAL, GIM, ClinicalTrials.gov, and Greenfile in August 2020. Inclusion criteria were experimental, non-experimental, or quasi-experimental studies investigating the impact of interventions to reduce HAP exposure and improve associated health outcomes among pregnant women or children under 5 years. Study selection, data extraction, and quality assessment using the Effective Public Health Practice Project tool were undertaken independently by two reviewers. Seventeen out of 7293 retrieved articles (seven pregnancy, nine child health outcome; 13 studies) met the inclusion criteria. These assessed improved cookstoves (ICS; n = 10 studies), ethanol stoves (n = 1 study), and Liquefied Petroleum Gas (LPG; n = 2 studies) stoves interventions. Meta-analysis showed no significant effect of ICS interventions compared to traditional cooking for risk of preterm birth (n = 2 studies), small for gestational age (n = 2 studies), and incidence of acute respiratory infections (n = 6 studies). Although an observed increase in mean birthweight was observed, this was not statistically significant (n = 4). However, ICS interventions reduced the incidence of childhood burns (n = 3; observations = 41 723; Rate Ratio: 0.66 [95% CI: 0.45-0.96]; I

Background: The World Health Organisation reported that 45% of global acute respiratory infection (ARI) deaths in children under five years are attributable to household air pollution, which has been recognised to be strongly associated with solid biomass fuel usage in domestic settings. The introduction of legislative restrictions for charcoal production or purchase can result in unintended consequences, such as reversion to more polluting biomass fuels such as wood, which may increase health and environmental harms. However, there remains a paucity of evidence concerning the relative health risks between wood and charcoal. This study compares the risk of respiratory symptoms, ARI, and severe ARI among children aged under five years living in wood and charcoal fuel households across 30 low- and middle-income countries. Methods: Data from children (N = 475,089) residing in wood or charcoal cooking households were extracted from multiple population-based Demographic and Health Survey databases (DHS) (N = 30 countries). Outcome measures were obtained from a maternal report of respiratory symptoms (cough, shortness of breath and fever) occurring in the two weeks prior to the survey date, generating a composite measure of ARI (cough and shortness of breath) and severe ARI (cough, shortness of breath and fever). Multivariable logistic regression analyses were implemented, with adjustment at individual, household, regional and country level for relevant demographic, social, and health-related confounding factors. Results: Increased odds ratios of fever (AOR: 1.07, 95% CI: 1.02–1.12) were observed among children living in wood cooking households compared to the use of charcoal. However, no association was observed with shortness of breath (AOR: 1.03, 95% CI: 0.96–1.10), cough (AOR: 0.99, 95% CI: 0.95–1.04), ARI (AOR: 1.03, 95% CI: 0.96–1.11) or severe ARI (AOR: 1.07, 95% CI: 0.99–1.17). Within rural areas, only shortness of breath was observed to be associated with wood cooking (AOR: 1.08, 95% CI: 1.01–1.15). However, an increased odds ratio of ARI was observed in Asian (AOR: 1.25, 95% CI: 1.04–1.51) and East African countries (AOR: 1.11, 95% CI: 1.01–1.22) only. Conclusion: Our population-based observational data indicates that in Asia and East Africa there is a greater risk of ARI among children aged under 5 years living in wood compared to charcoal cooking households. These findings have major implications for understanding the existing health impacts of wood-based biomass fuel usage and may be of relevance to settings where charcoal fuel restrictions are under consideration.

BackgroundPelvic inflammatory disease (PID) is an outcome measure for the evaluation of chlamydia screening programs. We explore PID diagnoses in specialist sexual health services (SSHSs) in England to inform the evaluation of the National Chlamydia Screening Programme, which was implemented nationally in 2008.MethodsWe conducted descriptive analyses using data on diagnoses of PID—with and without Chlamydia trachomatis (CT) and/or Neisseria gonorrhoeae (GC)—by age and year of birth, in SSHSs between 2009 and 2019 from the GUMCAD STI Surveillance System database. Rates were calculated per 100 000 females residing in England.ResultsCT screening activity peaked in 2010. The rates of all PID diagnoses decreased between 2009 and 2019 by 39%. CT-associated PID (CT-PID) declined by 58%, and nonspecific PID declined by 37%. GC-PID increased by 34%. CT-PID decreased across all age groups with the highest observed decline, 71%, in 15- to 19-year-olds. A dose-response relationship was observed between CT-PID rates and screening, with rates lowest in those with the greatest exposure to screening.ConclusionsThere was a marked decline in diagnoses of CT-PID, and nonspecific PID, at SSHSs after the introduction of widespread chlamydia screening, whereas GC-PID diagnoses increased. This ecological trend was broadly consistent with what we would have expected to see if widespread screening reduced the incidence of chlamydia-associated PID (and of nonspecific PID), as has been observed in randomized controlled trials of screening.

Background Although the pharmacological approach may help with motor symptoms in Parkinson's disease (PD), they are clearly not the complete solution. Thus, for the treatment of PD motor symptoms, physical activity has been proposed as an effective intervention. Methods A systematic search in MEDLINE, Web of Science, Scopus, and Cochrane Central Register of Controlled Trials databases was conducted to identify randomized controlled trials testing the effectiveness of exercise interventions on motor symptoms of PD. Physical exercise interventions were divided into 9 categories: endurance, resistance, combined, balance, dance, alternative exercises, body weight supported, sensorimotor interventions including endurance exercise, and sensorimotor interventions not including endurance exercise. A pairwise meta-analysis for direct and indirect comparisons between intervention and control/nonintervention groups was carried out. Results Fifty-six studies met the inclusion criteria, including 2740 participants, aged between 57.6 and 77.7 years. Results of our analyses showed that sensorimotor training including endurance (effect size [ES]-1.09; 95% confidence interval [CI], -1.68 to -0.50), resistance (ES-0.82; 95% CI, -1.23 to -0.41), and dance (ES-0.64; 95% CI, -1.24 to -0.05) were the most effective physical activity interventions for mitigating PD motor symptoms. Conclusion Physical activity interventions are an effective strategy for the management of motor symptoms in patients with PD. Among the different exercise intervention programs, those including more complex and demanding activities (sensorimotor training including endurance, resistance, and dance) seem to be the most effective physical activity interventions.

Introduction Combined sexual health services have been provided in Birmingham and Solihull by ‘Umbrella’ since 2015. The local population is younger and more deprived than the average English sexual health service population. We investigated if the 2015 Umbrella redesign, and subsequent health promotion campaigns, affected uptake of chlamydia screening in those aged 15–24 in the most deprived groups compared to the total population. Methods Weekly aggregated data for gender, socioeconomic status (IMD-5) and chlamydia test status with test result were obtained from Public Health England’s STI and HIV Surveillance Team for the period 2012 – 2018. Overall percent positivity and yearly moving averages for tests, positive tests and percent positivity, by gender, were calculated by the study team for total population, and the most deprived. Number of positive tests and percent positivity were graphically represented and mapped against dates of service redesign and subsequent campaigns. Data analysis was completed using Microsoft Excel. Results Positive tests in all females decreased gradually between late 2014 and early 2016 before recovering partially in 2017: this effect was not replicated for all other groups, and neither Umbrella redesign nor health promotion campaigns showed any effect on absolute numbers. In females, percent positivity increased steadily during the study period, from 10% to 12% per week in the most deprived females and 8% to 10% per week in all females. Percent positivity showed a clear link with service redesign in males: in the year following redesign, rates in all males rose from 8% to 15% per week, and from 10% to 18% per week in the most deprived males. Conclusion Umbrella redesign had a significant effect on detection of chlamydia cases in males; this effect is less obvious in females, and appears not to relate to the promotional campaigns. Deprived populations appear well served by Umbrella.

Aims Type 1 diabetes is characterised by the destruction of pancreatic beta cells. Significant levels of beta cells remain at diagnosis. Preserving these cells improves glucose control and protects from long-term complications. We undertook a systematic review and meta-analyses of all randomised controlled trials (RCTs) of interventions to preserve beta cell function in people newly diagnosed with type 1 diabetes. This paper reports the results of interventions for improving glucose control to assess whether they preserve beta cell function. Methods Searches for RCTs in MEDLINE, Embase, Cochrane CENTRAL, ClinicalTrials.gov and WHO International Clinical Trials Registry. Eligible studies included newly diagnosed type 1 diabetes patients, any intervention to improve glucose control and at least one month of follow-up. Data were extracted using a pre-defined data-extraction sheet with 10% of extractions checked by a second reviewer. Results Twenty-eight studies with 1,662 participants were grouped by intervention into six subgroups (alternative insulins, subcutaneous and intravenous insulin delivery, intensive therapy, glucose sensing, adjuncts). Only three studies demonstrated an improvement in glucose control as well as beta cell function. These interventions included intensive insulin therapy and use of an alternative insulin. Conclusions This is the largest comprehensive review of RCTs in this area. It demonstrates a lack of robust evidence that interventions to improve glucose control preserve beta cell function in new onset type 1 diabetes, although analysis was hampered by low quality evidence and inconsistent reporting of studies. Development of guidelines to support the design of trials in this field is a priority.

Background Miscarriage, defined as the spontaneous loss of a pregnancy before 24 weeks' gestation, is common with approximately 25% of women experiencing a miscarriage in their lifetime. An estimated 15% of pregnancies end in miscarriage. Miscarriage can lead to serious morbidity, including haemorrhage, infection, and even death, particularly in settings without adequate healthcare provision. Early miscarriages occur during the first 14 weeks of pregnancy, and can be managed expectantly, medically or surgically. However, there is uncertainty about the relative effectiveness and risks of each option. Objectives To estimate the relative effectiveness and safety profiles for the different management methods for early miscarriage, and to provide rankings of the available methods according to their effectiveness, safety, and side-effect profile using a network meta-analysis. Search methods We searched the Cochrane Pregnancy and Childbirth's Trials Register (9 February 2021), ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform (ICTRP) (12 February 2021), and reference lists of retrieved studies. Selection criteria We included all randomised controlled trials assessing the effectiveness or safety of methods for miscarriage management. Early miscarriage was defined as less than or equal to 14 weeks of gestation, and included missed and incomplete miscarriage. Management of late miscarriages after 14 weeks of gestation (often referred to as intrauterine fetal deaths) was not eligible for inclusion in the review. Cluster- and quasi-randomised trials were eligible for inclusion. Randomised trials published only as abstracts were eligible if sufficient information could be retrieved. We excluded non-randomised trials. Data collection and analysis At least three review authors independently assessed the trials for inclusion and risk of bias, extracted data and checked them for accuracy. We estimated the relative effects and rankings for the primary outcomes of complete miscarriage and composite outcome of death or serious complications. The certainty of evidence was assessed using GRADE. Relative effects for the primary outcomes are reported subgrouped by the type of miscarriage (incomplete and missed miscarriage). We also performed pairwise meta-analyses and network meta-analysis to determine the relative effects and rankings of all available methods. Main results Our network meta-analysis included 78 randomised trials involving 17,795 women from 37 countries. Most trials (71/78) were conducted in hospital settings and included women with missed or incomplete miscarriage. Across 158 trial arms, the following methods were used: 51 trial arms (33%) used misoprostol; 50 (32%) used suction aspiration; 26 (16%) used expectant management or placebo; 17 (11%) used dilatation and curettage; 11 (6%) used mifepristone plus misoprostol; and three (2%) used suction aspiration plus cervical preparation. Of these 78 studies, 71 (90%) contributed data in a usable form for meta-analysis. Complete miscarriage Based on the relative effects from the network meta-analysis of 59 trials (12,591 women), we found that five methods may be more effective than expectant management or placebo for achieving a complete miscarriage: · suction aspiration after cervical preparation (risk ratio (RR) 2.12, 95% confidence interval (CI) 1.41 to 3.20, low-certainty evidence), · dilatation and curettage (RR 1.49, 95% CI 1.26 to 1.75, low-certainty evidence), · suction aspiration (RR 1.44, 95% CI 1.29 to 1.62, low-certainty evidence), · mifepristone plus misoprostol (RR 1.42, 95% CI 1.22 to 1.66, moderate-certainty evidence), · misoprostol (RR 1.30, 95% CI 1.16 to 1.46, low-certainty evidence). The highest ranked surgical method was suction aspiration after cervical preparation. The highest ranked non-surgical treatment was mifepristone plus misoprostol. All surgical methods were ranked higher than medical methods, which in turn ranked above expectant management or placebo. Composite outcome of death and serious complications Based on the relative effects from the network meta-analysis of 35 trials (8161 women), we found that four methods with available data were compatible with a wide range of treatment effects compared with expectant management or placebo: · dilatation and curettage (RR 0.43, 95% CI 0.17 to 1.06, low-certainty evidence), · suction aspiration (RR 0.55, 95% CI 0.23 to 1.32, low-certainty evidence), · misoprostol (RR 0.50, 95% CI 0.22 to 1.15, low-certainty evidence), · mifepristone plus misoprostol (RR 0.76, 95% CI 0.31 to 1.84, low-certainty evidence). Importantly, no deaths were reported in these studies, thus this composite outcome was entirely composed of serious complications, including blood transfusions, uterine perforations, hysterectomies, and intensive care unit admissions. Expectant management and placebo ranked the lowest when compared with alternative treatment interventions. Subgroup analyses by type of miscarriage (missed or incomplete) agreed with the overall analysis in that surgical methods were the most effective treatment, followed by medical methods and then expectant management or placebo, but there are possible subgroup differences in the effectiveness of the available methods. AUTHORS' CONCLUSIONS: Based on relative effects from the network meta-analysis, all surgical and medical methods for managing a miscarriage may be more effective than expectant management or placebo. Surgical methods were ranked highest for managing a miscarriage, followed by medical methods, which in turn ranked above expectant management or placebo. Expectant management or placebo had the highest chance of serious complications, including the need for unplanned or emergency surgery. A subgroup analysis showed that surgical and medical methods may be more beneficial in women with missed miscarriage compared to women with incomplete miscarriage. Since type of miscarriage (missed and incomplete) appears to be a source of inconsistency and heterogeneity within these data, we acknowledge that the main network meta-analysis may be unreliable. However, we plan to explore this further in future updates and consider the primary analysis as separate networks for missed and incomplete miscarriage.

Background Up to 15 per cent of colorectal cancers present with peritoneal metastases (CPM). Cytoreductive surgery and heated intraperitoneal chemotherapy (CRS + HIPEC) aims to achieve macroscopic tumour resection combined with HIPEC to destroy microscopic disease. CRS + HIPEC is a major operation with significant morbidity and effects on quality of life (QoL). Improving patient selection is crucial to maximize patient outcomes while minimizing morbidity and mortality. The aim of this study was to identify prognostic factors for patients with CPM undergoing CRS + HIPEC. Methods A systematic search of MEDLINE, Embase and Cochrane Library electronic databases was performed using terms for colorectal cancer, peritoneal metastasis and CRS + HIPEC. Included studies focused on the impact of prognostic factors on overall survival following CRS + HIPEC in patients with CPM. Results Twenty-four studies described 3128 patients. Obstruction or perforation of the primary tumour (hazard ratio (HR) 2·91, 95 per cent c.i. 1·5 to 5·65), extent of peritoneal metastasis as described by the Peritoneal Carcinomatosis Index (PCI) (per increase of 1 PCI point: HR 1·07, 1·02 to 1·12) and the completeness of cytoreduction (CC score above zero: HR 1·75, 1·18 to 2·59) were associated with reduced overall survival after CRS + HIPEC. Conclusion Primary tumour obstruction or perforation, PCI score and CC score are valuable prognostic factors in the selection of patients with CPM for CRS + HIPEC.

Background Multivariate meta-analysis (MVMA) jointly synthesizes effects for multiple correlated outcomes. The MVMA model is potentially more difficult and time-consuming to apply than univariate models, so if its use makes little difference to parameter estimates, it could be argued that it is redundant. Methods We assessed the applicability and impact of MVMA in Cochrane Pregnancy and Childbirth (CPCB) systematic reviews. We applied MVMA to CPCB reviews published between 2011 and 2013 with two or more binary outcomes with at least three studies and compared findings with results of univariate meta-analyses. Univariate random effects meta-analysis models were fitted using restricted maximum likelihood estimation (REML). Results Eighty CPCB reviews were published. MVMA could not be applied in 70 of these reviews. MVMA was not feasible in three of the remaining 10 reviews because the appropriate models failed to converge. Estimates from MVMA agreed with those of univariate analyses in most of the other seven reviews. Statistical significance changed in two reviews: In one, this was due to a very small change in P value; in the other, the MVMA result for one outcome suggested that previous univariate results may be vulnerable to small-study effects and that the certainty of clinical conclusions needs consideration. Conclusions MVMA methods can be applied only in a minority of reviews of interventions in pregnancy and childbirth and can be difficult to apply because of missing correlations or lack of convergence. Nevertheless, clinical and/or statistical conclusions from MVMA may occasionally differ from those from univariate analyses.

AIMS To assess whether glycaemic control is associated with a lifelong increased risk of fracture in people with newly diagnosed Type 1 diabetes. METHODS People with newly diagnosed Type 1 diabetes between 1 January 1995 and 10 May 2016 were identified in The Health Improvement Network database. Longitudinal HbA measurements from diagnosis to fracture or study end or loss to follow-up were collected. A Cox proportional hazards model with HbA included as a time-dependent variable was fitted to these data. RESULTS Some 5368 people with newly diagnosed Type 1 diabetes were included. The estimated adjusted hazard ratio (aHR) for HbA was statistically significant [aHR 1.007; 95% confidence interval (CI) 1.002-1.011 (mmol/mol) and aHR 1.07; 95% CI 1.03-1.12 (%)]. An incremental higher risk of fracture was observed with increasing levels of HbA . CONCLUSIONS In people with newly diagnosed Type 1 diabetes, higher HbA is associated with an increased risk for fractures. This article is protected by copyright. All rights reserved.

BACKGROUND: Miscarriage, defined as the spontaneous loss of a pregnancy before 24 weeks’ gestation, is common with approximately 25% of women experiencing a miscarriage in their lifetime, and 15% to 20% of pregnancies ending in a miscarriage. Progesterone has an important role in maintaining a pregnancy, and supplementation with different progestogens in early pregnancy has been attempted to rescue a pregnancy in women with early pregnancy bleeding (threatened miscarriage), and to prevent miscarriages in asymptomatic women who have a history of three or more previous miscarriages (recurrent miscarriage). OBJECTIVES: To estimate the relative effectiveness and safety profiles for the different progestogen treatments for threatened and recurrent miscarriage, and provide rankings of the available treatments according to their effectiveness, safety, and side‐effect profile. SEARCH METHODS: We searched the following databases up to 15 December 2020: Cochrane Central Register of Controlled Trials, Ovid MEDLINE(R), ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform (ICTRP), and reference lists of retrieved studies. SELECTION CRITERIA: We included all randomised controlled trials assessing the effectiveness or safety of progestogen treatment for the prevention of miscarriage. Cluster‐randomised trials were eligible for inclusion. Randomised trials published only as abstracts were eligible if sufficient information could be retrieved. We excluded quasi‐ and non‐randomised trials. DATA COLLECTION AND ANALYSIS: At least two review authors independently assessed the trials for inclusion and risk of bias, extracted data and checked them for accuracy. We performed pairwise meta‐analyses and indirect comparisons, where possible, to determine the relative effects of all available treatments, but due to the limited number of included studies only direct or indirect comparisons were possible. We estimated the relative effects for the primary outcome of live birth and the secondary outcomes including miscarriage (< 24 weeks of gestation), preterm birth (< 37 weeks of gestation), stillbirth, ectopic pregnancy, congenital abnormalities, and adverse drug events. Relative effects for all outcomes are reported separately by the type of miscarriage (threatened and recurrent miscarriage). We used the GRADE approach to assess the certainty of evidence. MAIN RESULTS: Our meta‐analysis included seven randomised trials involving 5,682 women, and all provided data for meta‐analysis. All trials were conducted in hospital settings. Across seven trials (14 treatment arms), the following treatments were used: three arms (21%) used vaginal micronized progesterone; three arms (21%) used dydrogesterone; one arm (7%) used oral micronized progesterone; one arm (7%) used 17‐α‐hydroxyprogesterone, and six arms (43%) used placebo. Women with threatened miscarriage Based on the relative effects from the pairwise meta‐analysis, vaginal micronized progesterone (two trials, 4090 women, risk ratio (RR) 1.03, 95% confidence interval (CI) 1.00 to 1.07, high‐certainty evidence), and dydrogesterone (one trial, 406 women, RR 0.98, 95% CI 0.89 to 1.07, moderate‐certainty evidence) probably make little or no difference to the live birth rate when compared with placebo for women with threatened miscarriage. No data are available to assess the effectiveness of 17‐α‐hydroxyprogesterone or oral micronized progesterone for the outcome of live birth in women with threatened miscarriage. The pre‐specified subgroup analysis by number of previous miscarriages is only possible for vaginal micronized progesterone in women with threatened miscarriage. In women with no previous miscarriages and early pregnancy bleeding, there is probably little or no improvement in the live birth rate (RR 0.99, 95% CI 0.95 to 1.04, high‐certainty evidence) when treated with vaginal micronized progesterone compared to placebo. However, for women with one or more previous miscarriages and early pregnancy bleeding, vaginal micronized progesterone increases the live birth rate compared to placebo (RR 1.08, 95% CI 1.02 to 1.15, high‐certainty evidence). Women with recurrent miscarriage Based on the results from one trial (826 women) vaginal micronized progesterone (RR 1.04, 95% CI 0.95 to 1.15, high‐certainty evidence) probably makes little or no difference to the live birth rate when compared with placebo for women with recurrent miscarriage. The evidence for dydrogesterone compared with placebo for women with recurrent miscarriage is of very low‐certainty evidence, therefore the effects remain unclear. No data are available to assess the effectiveness of 17‐α‐hydroxyprogesterone or oral micronized progesterone for the outcome of live birth in women with recurrent miscarriage. Additional outcomes All progestogen treatments have a wide range of effects on the other pre‐specified outcomes (miscarriage (< 24 weeks of gestation), preterm birth (< 37 weeks of gestation), stillbirth, ectopic pregnancy) in comparison to placebo for both threatened and recurrent miscarriage. Moderate‐ and low‐certainty evidence with a wide range of effects suggests that there is probably no difference in congenital abnormalities and adverse drug events with vaginal micronized progesterone for threatened (congenital abnormalities RR 1.00, 95% CI 0.68 to 1.46, moderate‐certainty evidence; adverse drug events RR 1.07 95% CI 0.81 to 1.39, moderate‐certainty evidence) or recurrent miscarriage (congenital abnormalities 0.75, 95% CI 0.31 to 1.85, low‐certainty evidence; adverse drug events RR 1.46, 95% CI 0.93 to 2.29, moderate‐certainty evidence) compared with placebo. There are limited data and very low‐certainty evidence on congenital abnormalities and adverse drug events for the other progestogens. AUTHORS' CONCLUSIONS: The overall available evidence suggests that progestogens probably make little or no difference to live birth rate for women with threatened or recurrent miscarriage. However, vaginal micronized progesterone may increase the live birth rate for women with a history of one or more previous miscarriages and early pregnancy bleeding, with likely no difference in adverse events. There is still uncertainty over the effectiveness and safety of alternative progestogen treatments for threatened and recurrent miscarriage.

To investigate the association between luteal serum progesterone levels and frozen embryo transfer (FET) outcomes.Systematic review and meta-analysis.Not applicable.Women undergoing FET.We conducted electronic searches of MEDLINE, PubMed, CINAHL, EMBASE, the Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, Web of Science, ClinicalTrials.gov, and grey literature (not widely available) from inception to March 2021 to identify cohort studies in which the serum luteal progesterone level was measured around the time of FET.Ongoing pregnancy or live birth rate, clinical pregnancy rate, and miscarriage rate.Among the studies analyzing serum progesterone level thresholds10 ng/mL, a higher serum progesterone level was associated with increased rates of ongoing pregnancy or live birth (relative risk [RR] 1.47, 95% confidence interval [CI] 1.28 to 1.70), higher chance of clinical pregnancy (RR 1.31, 95% CI 1.16 to 1.49), and lower risk of miscarriage (RR 0.62, 95% CI 0.50 to 0.77) in cycles using exclusively vaginal progesterone and blastocyst embryos. There was uncertainty about whether progesterone thresholds ≥10 ng/mL were associated with FET outcomes in sensitivity analyses including all studies, owing to high interstudy heterogeneity and wide CIs.Our findings indicate that there may be a minimum clinically important luteal serum concentration of progesterone required to ensure an optimal endocrine milieu during embryo implantation and early pregnancy after FET treatment. Future clinical trials are required to assess whether administering higher-dose luteal phase support improves outcomes in women with a low serum progesterone level at the time of FET.CRD42019157071.

Purpose This study aimed to estimate the prevalence, contributory factors, and severity of medication errors associated with direct acting oral anticoagulants (DOACs). Methods A systematic review and meta-analysis were undertaken by searching 11 databases including Medline, Embase, and CINHAL between January 2008 and September 2020. The pooled prevalence of errors and predictive intervals were estimated using random-effects models using Stata software. Data related to error causation were synthesised according to Reason’s accident causation model. Results From the 5205 titles screened, 32 studies were included which were mostly based in hospitals and included DOAC treatment for thromboembolism and atrial fibrillation. The proportion of study population who experienced either prescription, administration, or dispensing error ranged from 5.3 to 37.3%. The pooled percentage of patients experiencing prescribing error was 20% (95% CI 15–25%; I2 = 96%; 95% PrI 4–43%). Prescribing error constituted the majority of all error types with a pooled estimate of 78% (95%CI 73–82%; I2 = 0) of all errors. The common reported causes were active failures including wrong drug, and dose for the indication. Mistakes such as non-consideration of renal function, and error-provoking conditions such as lack of knowledge were common contributing factors. Adverse events such as potentially fatal intracranial haemorrhage or patient deaths were linked to the errors but causality assessments were often missing. Conclusions Despite their favourable safety profile, DOAC medication errors are common. There is a need to promote multidisciplinary working, guideline-adherence, training, and education of healthcare professionals, and the use of theory-based and technology-facilitated interventions to minimise errors and maximise the benefits of DOACs usage in all settings. Protocol A protocol developed as per PRISMA-P guideline is registered under PROSPERO ID = CRD42019122996

BACKGROUND Remission of type 2 diabetes following bariatric surgery is well established, but identifying patients who will go into remission is challenging. PURPOSE To perform a systematic review of currently available diabetes remission prediction models, compare their performance, and evaluate their applicability in clinical settings. DATA SOURCES A comprehensive systematic literature search of MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) was undertaken. The search was restricted to studies published in the last 15 years and in the English language. STUDY SELECTION All studies developing or validating a prediction model for diabetes remission in adults after bariatric surgery were included. DATA EXTRACTION The search identified 4,165 references, of which 38 were included for data extraction. We identified 16 model development and 22 validation studies. DATA SYNTHESIS Of the 16 model development studies, 11 developed scoring systems and 5 proposed logistic regression models. In model development studies, 10 models showed excellent discrimination with area under the receiver operating characteristic curve ≥0.800. Two of these prediction models, ABCD and DiaRem, were widely externally validated in different populations, in a variety of bariatric procedures, and for both short- and long-term diabetes remission. Newer prediction models showed excellent discrimination in test studies, but external validation was limited. LIMITATIONS While the key messages were consistent, a large proportion of the studies were conducted in small cohorts of patients with short duration of follow-up. CONCLUSIONS Among the prediction models identified, the ABCD and DiaRem models were the most widely validated and showed acceptable to excellent discrimination. More studies validating newer models and focusing on long-term diabetes remission are needed.

BackgroundPostpartum haemorrhage (PPH), defined as a blood loss of 500 mL or more after birth, is the leading cause of maternal death worldwide. The World Health Organization (WHO) recommends that all women giving birth should receive a prophylactic uterotonic agent. Despite the routine administration of a uterotonic agent for prevention, PPH remains a common complication causing one-quarter of all maternal deaths globally. When prevention fails and PPH occurs, further administration of uterotonic agents as 'first-line' treatment is recommended. However, there is uncertainty about which uterotonic agent is best for the 'first-line' treatment of PPH.ObjectivesTo identify the most effective uterotonic agent(s) with the least side-effects for PPH treatment, and generate a meaningful ranking among all available agents according to their relative effectiveness and side-effect profile.Search methodsWe searched the Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (5 May 2020), and the reference lists of all retrieved studies.Selection criteriaAll randomised controlled trials or cluster-randomised trials comparing the effectiveness and safety of uterotonic agents with other uterotonic agents for the treatment of PPH were eligible for inclusion.Data collection and analysisTwo review authors independently assessed all trials for inclusion, extracted data and assessed each trial for risk of bias. Our primary outcomes were additional blood loss of 500 mL or more after recruitment to the trial until cessation of active bleeding and the composite outcome of maternal death or severe morbidity. Secondary outcomes included blood loss-related outcomes, morbidity outcomes, and patient-reported outcomes. We performed pairwise meta-analyses and indirect comparisons, where possible, but due to the limited number of included studies, we were unable to conduct the planned network meta-analysis. We used the GRADE approach to assess the certainty of evidence.Main resultsSeven trials, involving 3738 women in 10 countries, were included in this review. All trials were conducted in hospital settings. Randomised women gave birth vaginally, except in one small trial, where women gave birth either vaginally or by caesarean section. Across the seven trials (14 trial arms) the following agents were used: six trial arms used oxytocin alone; four trial arms used misoprostol plus oxytocin; three trial arms used misoprostol; one trial arm used Syntometrine® (oxytocin and ergometrine fixed-dose combination) plus oxytocin infusion. Pairwise meta-analysis of two trials (1787 participants), suggests that misoprostol, as first-line treatment uterotonic agent, probably increases the risk of blood transfusion (risk ratio (RR) 1.47, 95% confidence interval (CI) 1.02 to 2.14, moderate-certainty) compared with oxytocin. Low-certainty evidence suggests that misoprostol administration may increase the incidence of additional blood loss of 1000 mL or more (RR 2.57, 95% CI 1.00 to 6.64). The data comparing misoprostol with oxytocin is imprecise, with a wide range of treatment effects for the additional blood loss of 500 mL or more (RR 1.66, 95% CI 0.69 to 4.02, low-certainty), maternal death or severe morbidity (RR 1.98, 95% CI 0.36 to 10.72, low-certainty, based on one study n = 809 participants, as the second study had zero events), and the use of additional uterotonics (RR 1.30, 95% CI 0.57 to 2.94, low-certainty). The risk of side-effects may be increased with the use of misoprostol compared with oxytocin: vomiting (2 trials, 1787 participants, RR 2.47, 95% CI 1.37 to 4.47, high-certainty) and fever (2 trials, 1787 participants, RR 3.43, 95% CI 0.65 to 18.18, low-certainty). According to pairwise meta-analysis of four trials (1881 participants) generating high-certainty evidence, misoprostol plus oxytocin makes little or no difference to the use of additional uterotonics (RR 0.99, 95% CI 0.94 to 1.05) and to blood transfusion (RR 0.95, 95% CI 0.77 to 1.17) compared with oxytocin. We cannot rule out an important benefit of using the misoprostol plus oxytocin combination over oxytocin alone, for additional blood loss of 500 mL or more (RR 0.84, 95% CI 0.66 to 1.06, moderate-certainty). We also cannot rule out important benefits or harms for additional blood loss of 1000 mL or more (RR 0.76, 95% CI 0.43 to 1.34, moderate-certainty, 3 trials, 1814 participants, one study reported zero events), and maternal mortality or severe morbidity (RR 1.09, 95% CI 0.35 to 3.39, moderate-certainty). Misoprostol plus oxytocin increases the incidence of fever (4 trials, 1866 participants, RR 3.07, 95% CI 2.62 to 3.61, high-certainty), and vomiting (2 trials, 1482 participants, RR 1.85, 95% CI 1.16 to 2.95, high-certainty) compared with oxytocin alone. For all outcomes of interest, the available evidence on the misoprostol versus Syntometrine® plus oxytocin combination was of very low-certainty and these effects remain unclear. Although network meta-analysis was not performed, we were able to compare the misoprostol plus oxytocin combination with misoprostol alone through the common comparator of oxytocin. This indirect comparison suggests that the misoprostol plus oxytocin combination probably reduces the risk of blood transfusion (RR 0.65, 95% CI 0.42 to 0.99, moderate-certainty) and may reduce the risk of additional blood loss of 1000 mL or more (RR 0.30, 95% CI 0.10 to 0.89, low-certainty) compared with misoprostol alone. The combination makes little or no difference to vomiting (RR 0.75, 95% CI 0.35 to 1.59, high-certainty) compared with misoprostol alone. Misoprostol plus oxytocin compared to misoprostol alone are compatible with a wide range of treatment effects for additional blood loss of 500 mL or more (RR 0.51, 95% CI 0.20 to 1.26, low-certainty), maternal mortality or severe morbidity (RR 0.55, 95% CI 0.07 to 4.24, low-certainty), use of additional uterotonics (RR 0.76, 95% CI 0.33 to 1.73, low-certainty), and fever (RR 0.90, 95% CI 0.17 to 4.77, low-certainty).Authors' conclusionsThe available evidence suggests that oxytocin used as first-line treatment of PPH probably is more effective than misoprostol with less side-effects. Adding misoprostol to the conventional treatment of oxytocin probably makes little or no difference to effectiveness outcomes, and is also associated with more side-effects. The evidence for most uterotonic agents used as first-line treatment of PPH is limited, with no evidence found for commonly used agents, such as injectable prostaglandins, ergometrine, and Syntometrine®.

ObjectivesTo assess the accuracy and completeness of information provided by websites selling home self-sampling and testing kits for COVID-19.DesignCross-sectional observational study.SettingAll websites (n=27) selling direct to user home self-sampling and testing kits for COVID-19 (41 tests) in the UK (39 tests) and USA (two tests) identified by a website search on 23 May 2020.Main outcome measuresThirteen predefined basic information items to communicate to a user, including who should be tested, when and how testing should be done, test accuracy, and interpretation of results.ResultsMany websites did not provide the name or manufacturer of the test (32/41; 78%), when to use the test (10/41; 24%), test accuracy (12/41; 29%), and how to interpret results (21/41; 51%). Sensitivity and specificity were the most commonly reported test accuracy measures (either reported for 27/41 [66%] tests): we could only link these figures to manufacturers’ documents or publications for four (10%) tests. Predictive values, most relevant to users, were rarely reported (five [12%] tests reported positive predictive values). For molecular virus tests, 9/23 (39%) websites explained that test positives should self-isolate, and 8/23 (35%) explained that test negatives may still have the disease. For antibody tests, 12/18 (67%) websites explained that testing positive does not necessarily infer immunity from future infection. Seven (39%) websites selling antibody tests claimed the test had a CE mark, when they were for a different intended use (venous blood rather than finger-prick samples).ConclusionsAt the point of online purchase of home self-sampling COVID-19 tests, users in the UK are provided with incomplete, and, in some cases, misleading information on test accuracy, intended use, and test interpretation. Best practice guidance for communication about tests to the public should be developed and enforced for online sales of COVID-19 tests.

ObjectivesRisk stratification is needed for patients referred to hospital eye services by Diabetic Eye Screening Programme UK. This requires a set of candidate predictors. The literature contains a large number of predictors. The objective of this research was to arrive at a small set of clinically important predictors for the outcome of the progression of diabetic retinopathy (DR). They need to be evidence based and readily available during the clinical consultation.Methods and analysisInitial list of predictors was obtained from a systematic review of prediction models. We sought the clinical expert opinion using a formal qualitative study design. A series of nominal group technique meetings to shorten the list and to rank the predictors for importance by voting were held with National Health Service hospital-based clinicians involved in caring for patients with DR in the UK. We then evaluated the evidence base for the selected predictors by critically appraising the evidence.ResultsThe source list was presented at nominal group meetings (n=4), attended by 44 clinicians. Twenty-five predictors from the original list were ranked as important predictors and eight new predictors were proposed. Two additional predictors were retained after evidence check. Of these 35, 21 had robust supporting evidence in the literature condensed into a set of 19 predictors by categorising DR.ConclusionWe identified a set of 19 clinically meaningful predictors of DR progression that can help stratify higher-risk patients referred to hospital eye services and should be considered in the development of an individual risk stratification model.Study designA qualitative study and evidence review.SettingSecondary eye care centres in North East, Midlands and South of England.

Background Chlamydia is the most commonly diagnosed sexually transmitted infection worldwide. Mathematical models used to plan and assess control measures rely on accurate estimates of chlamydia’s natural history, including the probability of transmission within a partnership. Several methods for estimating transmission probability have been proposed, but all have limitations. Methods We have developed a new model for estimating per-partnership chlamydia transmission probabilities from infected to uninfected individuals, using data from population-based surveys. We used data on sexual behaviour and prevalent chlamydia infection from the second UK National Study of Sexual Attitudes and Lifestyles (Natsal-2) and the US National Health and Nutrition Examination Surveys 2009–2014 (NHANES) for Bayesian inference of average transmission probabilities, across all new heterosexual partnerships reported. Posterior distributions were estimated by Markov chain Monte Carlo sampling using the Stan software. Results Posterior median male-to-female transmission probabilities per partnership were 32.1% [95% credible interval (CrI) 18.4–55.9%] (Natsal-2) and 34.9% (95%CrI 22.6–54.9%) (NHANES). Female-to-male transmission probabilities were 21.4% (95%CrI 5.1–67.0%) (Natsal-2) and 4.6% (95%CrI 1.0–13.1%) (NHANES). Posterior predictive checks indicated a well-specified model, although there was some discrepancy between reported and predicted numbers of partners, especially in women. Conclusions The model provides statistically rigorous estimates of per-partnership transmission probability, with associated uncertainty, which is crucial for modelling and understanding chlamydia epidemiology and control. Our estimates incorporate data from several sources, including population-based surveys, and use information contained in the correlation between number of partners and the probability of chlamydia infection. The evidence synthesis approach means that it is easy to include further data as it becomes available.

ObjectivesTo assess the accuracy and completeness of information provided by websites selling home self-sampling and testing kits for COVID-19.DesignCross-sectional observational study.SettingAll websites (n = 27) selling direct to user home self-sampling and testing for COVID-19 (41 tests) in the UK (39 tests) and US (2 tests) identified by a website search on 23rd May 2020.Main outcome measuresThirteen predefined basic information items to communicate to a user, including who should be tested, when and how testing should be done, test accuracy, and interpretation of results.ResultsMany websites did not provide the name or manufacturer of the test (32/41; 78%), when to use the test (10/41; 24%), test accuracy (12/41; 29%), and how to interpret results (21/41; 51%). Sensitivity and specificity were the most commonly reported test accuracy measures (either reported for 27/41 (66%) tests); we could only link these figures to manufacturers’ documents or publications for four (10%) tests. Predictive values, most relevant to users, were rarely reported (five [12%] tests reported positive predictive values). For molecular virus tests, 9/23 (39%) websites explained that test positives should self-isolate, and 8/23 (35%) explained that test negatives may still have the disease. For antibody tests, 12/18 (67%) websites explained that testing positive does not necessarily infer immunity from future infection. Seven (39%) websites selling antibody tests claimed the test had a CE mark, when they were for a different intended use (venous blood rather than finger-prick samples).ConclusionsAt the point of online purchase of home self-sampling COVID-19 tests, users in the UK are provided with incomplete, and in some cases misleading information on test accuracy, intended use and test interpretation. Best practice guidance for communication about tests to the public should be developed and enforced for online sales of COVID-19 tests.Strengths and WeaknessesWe believe this is the first research on accuracy of information provided by websites selling tests for COVID-19, where users may put themselves or others at increased risk of transmission if results are misinterpreted.We duplicated processes of searching and data extraction to minimise biasUsing pre-specified criteria, we found evidence that websites selling home self-sampling COVID-19 tests provided incomplete and inaccurate information on test accuracy and interpretation of test results at the point of purchase.We developed basic guidance on what should be communicated when selling tests, including the type of test; situations when the test should be used; the time when the test should be done and details of how it should be done; the name of the test and details from clinical accuracy studies; evidence of compliance with regulatory approvals; explanation of test results using accessible and relevant metrics such as predictive values; and guidance to the interpretation and actions based on results.We only included websites from the UK and US, so whilst the principles of what should be communicated apply to all countries, the results about data completeness are not generalisable beyond the UK and US.

ObjectivesTo determine any change in referral patterns and outcomes in children (0-18) referred for child protection medical examination (CPME) during the covid-19 pandemic compared to previous years.DesignRetrospective observational study, analysing routinely collected clinical data from CPME reports in a rapid response to the pandemic lockdown.SettingBirmingham Community Healthcare NHS Trust, which provides all routine CPME for Birmingham, England, population 1.1 million including 288,000 children.ParticipantsChildren aged under 18 years attending CPME during an 18 week period from late February to late June during the years 2018, 2019, and 2020.Main Outcome MeasuresNumbers of referrals, source of disclosure and outcomes from CPMEResultsThere were 78 CPME referrals in 2018, 75 in 2019 and 47 in 2020, this was a 39.7% (95%CI 12.4-59.0) reduction in referrals from 2018 to 2020, and a 37.3% (95%CI 8.6-57.4) reduction from 2019 to 2020. There were fewer CPME referrals initiated by school staff in 2020, 12(26%) compared to 36 (47%) and 38 (52%) in 2018 and 2019 respectively. In all years 75.9% of children were known to social care prior to CPME, and 94% of CPME concluded that there were significant safeguarding concerns.ConclusionsSchool closure due to covid-19 may have harmed children as child abuse has remained hidden. There needs to be either mandatory attendance at schools in future or viable alternatives found. There may be a significant increase in safeguarding referrals when schools fully re-open as children disclose the abuse they have experienced at home.Article summary: Strengths and Limitations of the StudyThis is a highly robust study: we obtained CPME reports for 97% of CPME referrals during the study period.We ensured consistency of data extraction by double reviewing every report, with further consensus discussions for the few cases that raised uncertainties.The team extracting the data comprised highly experienced paediatricians with expertise in child abuse.One weakness is that we only considered minor injuries from outpatient CPME, excluding those admitted to hospital, so our findings do not include those with more serious NAI, however they would be taken to hospital for treatment due to the severity of their injuries.

Objectives Poor discharge communication is associated with negative health outcomes in high-income countries. However, quality of discharge communication has received little attention in India and many other low and middle-income countries. Primary objective To investigate verbal and documented discharge communication for chronic non-communicable disease (NCD) patients. Secondary objective To explore the relationship between quality of discharge communication and health outcomes. Methods Design Prospective study. Setting Three public hospitals in Himachal Pradesh and Kerala states, India. Participants 546 chronic NCD (chronic respiratory disease, cardiovascular disease or diabetes) patients. Piloted questionnaires were completed at admission, discharge and five and eighteen-week follow-up covering health status, discharge communication practices and health-seeking behaviour. Logistic regression was used to explore the relationship between quality of discharge communication and health outcomes. Outcome measures Primary Patient recall and experiences of verbal and documented discharge communication. Secondary Death, hospital readmission and self-reported deterioration of NCD/s. Results All patients received discharge notes, predominantly on sheets of paper with basic pre-printed headings (71%) or no structure (19%); 31% of notes contained all the following information required for facilitating continuity of care: diagnosis, medication information, lifestyle advice, and follow-up instructions. Patient reports indicated notable variations in verbal information provided during discharge consultations; 50% received ongoing treatment/management information and 23% received lifestyle advice. Within 18 weeks of follow-up, 25 (5%) patients had died, 69 (13%) had been readmitted and 62 (11%) reported that their chronic NCD/s had deteriorated. Significant associations were found between low-quality documented discharge communication and death (AOR = 3.00; 95% CI 1.27,7.06) and low-quality verbal discharge communication and self-reported deterioration of chronic NCD/s (AOR = 0.46; 95% CI 0.25,0.83) within 18-weeks of follow-up. Conclusions Sub-optimal discharge practices may be compromising continuity and safety of chronic NCD patient care. Structured protocols, documents and training are required to improve discharge communication, healthcare integration and NCD management.

Carbon monoxide (CO) is harmful to human health, yet there is limited evidence concerning emissions associated with biomass fuel cooking in occupational settings. Real-time 48-hour monitoring of CO concentrations at breathing height, was undertaken in staff and student kitchen and serving areas of two commercial canteens. We characterized two diurnal CO peaks coinciding with cooking activities. Peak CO concentrations of 255.5 ppm and 1-hour average of 76.3 ppm (IQR: 57.8–109.0 ppm) were observed in the student kitchen; the staff kitchen levels were 208.5 ppm, and 76.3 ppm (IQR: 52.5–114.0 ppm), respectively. High magnitude CO concentrations (8-hour average: 40.7 ppm SD: 40.0 ppm) which exceed World Health Organisation (WHO) Indoor Air Quality standards were observed. Further investigation of personal exposure and health impacts among kitchen staff is required, to inform interventions in this setting.

Abstract Background A national pre-registration pharmacist training recruitment scheme, which replaces local recruitment models, was introduced in England and Wales in 2017. The national recruitment system allows pharmacy students to apply for the 52 weeks training programmes (mandatory requirement for registration as a pharmacist), through a single application system prior to undertaking a nationally administered assessment. This study aimed to explore experiences of pharmacy students on the national recruitment scheme, particularly their views on the selection methodology, application process, and offer outcomes. Methods This mixed method study involved a) an online survey of all (approximate n = 2800) year 4 (final year of MPharm degree) pharmacy students in England and Wales and b) a qualitative focus group with four students. The study population was eligible to participate in the 2017/18 national recruitment scheme. Survey respondents were invited to participate in a focus group. Quantitative data were analysed using descriptive and inferential analysis. Qualitative data were analysed using the framework technique. Participation was voluntary. Ethical approval from University of Birmingham was obtained. Results A total of 307 completed surveys were returned (approximate response rate 11%). Respondents were generally satisfied with the application process and commended the fairness of the selection methodology and convenience in allowing them to apply to multiple training providers. Most survey respondents (n = 181, 72.9%) were either satisfied or highly satisfied with the training programme they were offered based on their assessment performances. Three themes and eight sub-themes obtained from the analysis of over 200 open comments data from the survey and transcript of a focus group with four participants. Results suggested the need to widen the timeframe available for applicants to shortlist their preferred employers, improve the method of programme listing in the application system, and consideration of prior achievements including academic performances and placement experiences to be included in the selection methodology. Conclusions Experiences of pharmacy students on the national recruitment scheme suggest that respondents considered the selection methodology to be fair. Student engagement and satisfaction with the recruitment system can be maximised through improved listing of employers and widening the timescales for students to shortlist their preferred employers during application process. Inclusion of University achievements in the selection methodology will require consideration of evidence based approaches. Low response rate limits generalisation of findings.

Background Low and high birthweight is known to increase the risk of acute and longer‐term adverse outcomes, such as stillbirth, infant mortality, obesity, type 2 diabetes and cardiovascular diseases. Gestational dyslipidaemia is associated with a numbers of adverse birth outcomes, but evidence regarding birthweight is still inconsistent to reliably inform clinical practice and treatment recommendations. Objective The aim of this study was to explore the relationship between maternal gestational dyslipidaemia and neonatal health outcomes, namely, birthweight, metabolic factors and inflammatory parameters. Methods We searched systematically Embase, MEDLINE, PubMed, CINAHL Plus and Cochrane Library up to 1 August 2016 (with an updated search in MEDLINE at the end of July 2017) for longitudinal studies that assessed the association of maternal lipid levels during pregnancy with neonatal birthweight, or metabolic and inflammatory parameters up to 3 years old. Results Data from 46 publications including 31,402 pregnancies suggest that maternal high triglycerides and low high‐density‐lipoprotein cholesterol levels throughout pregnancy are associated with increased birthweight, higher risk of large for gestational age and macrosomia and lower risk of small‐for‐gestational age. The findings were consistent across the studied populations, but stronger associations were observed in women who were overweight or obese prior to pregnancy. Conclusions This meta‐analysis suggested that the potential under‐recognized adverse effects of intrauterine exposure to maternal dyslipidaemia may warrant further investigation into the relationship between maternal dyslipidaemia and birthweight in large prospective cohorts or in randomized trials.

ObjectivesTo estimate the current disease burden, trends and future projections for diabetes mellitus (DM) and diabetic retinopathy (DR) in the IQVIA Medical Research Data (IMRD).Participants/design/settingWe performed a cross-sectional study of patients aged 12 and above to determine the prevalence of DM and DR from the IMRD database (primary care database) in January 2017, involving a total population of 1 80 824 patients with DM. We also carried out a series of cross-sectional studies to investigate prevalence trends, and then applied a double exponential smoothing model to forecast the future burden of DM and DR in the UK.ResultsThe crude DM prevalence in 2017 was 5.2%. The DR, sight-threatening retinopathy (STR) and diabetic maculopathy prevalence figures in 2017 were 33.78%, 12.28% and 7.86%, respectively, in our IMRD cross-sectional study. There were upward trends in the prevalence of DM, DR and STR, most marked and accelerating in STR in type 1 DM but slowing in type 2 DM, and in the overall prevalence of DR.ConclusionOur results suggest differential rising trends in the prevalence of DM and DR. Preventive strategies, as well as treatment services planning, can be based on these projected prevalence estimates. Improvements that are necessary for the optimisation of care pathways, and preparations to meet demand and capacity challenges, can also be based on this information. The limitations of the study can be overcome by a future collaborative study linking DR screening and hospital eye services data.

SummaryBackground Clostridium difficile infection (CDI) is the commonest nosocomial cause of diarrhoea. Faecal microbiota transplantation (FMT) is an approved treatment for recurrent or refractory CDI but there is uncertainty about its use. Aim To evaluate the efficacy of FMT in treating recurrent and refractory CDI and investigate outcomes from modes of delivery and preparation. Methods A systematic review and meta-analysis was performed. MEDLINE, EMBASE, CINAHL, Cochrane Library, trial registers and conference proceedings were searched. Studies on FMT in recurrent and refractory CDI were included. The primary outcome was clinical resolution with subgroup analyses of modes of delivery and preparation. Random effects meta-analyses were used to combine data. Results Thirty seven studies were included; seven randomised controlled trials and 30 case series. FMT was more effective than vancomycin (RR: 0.23 95%CI 0.07-0.80) in resolving recurrent and refractory CDI. Clinical resolution across all studies was 92% (95%CI 89%-94%). A significant difference was observed between lower GI and upper GI delivery of FMT 95% (95%CI 92%-97%) vs 88% (95%CI 82%-94%) respectively (P=.02). There was no difference between fresh and frozen FMT 92% (95%CI 89%-95%) vs 93% (95%CI 87%-97%) respectively (P=.84). Administering consecutive courses of FMT following failure of first FMT resulted in an incremental effect. Donor screening was consistent but variability existed in recipient preparation and volume of FMT. Serious adverse events were uncommon. Conclusion Faecal microbiota transplantation is an effective treatment for recurrent and refractory Clostridium difficile infection, independent of preparation and route of delivery.

ObjectiveTo explore whether thyroid stimulating hormone (TSH) concentration in patients with a diagnosis of hypothyroidism is associated with increased all cause mortality and a higher risk of cardiovascular disease and fractures.DesignRetrospective cohort study.SettingThe Health Improvement Network (THIN), a database of electronic patient records from UK primary care.ParticipantsAdult patients with incident hypothyroidism from 1 January 1995 to 31 December 2017.ExposureTSH concentration in patients with hypothyroidism.Main outcome measuresIschaemic heart disease, heart failure, stroke/transient ischaemic attack, atrial fibrillation, any fractures, fragility fractures, and mortality. Longitudinal TSH measurements from diagnosis to outcomes, study end, or loss to follow-up were collected. An extended Cox proportional hazards model with TSH considered as a time varying covariate was fitted for each outcome.Results162 369 patients with hypothyroidism and 863 072 TSH measurements were included in the analysis. Compared with the reference TSH category (2-2.5 mIU/L), risk of ischaemic heart disease and heart failure increased at high TSH concentrations (>10 mIU/L) (hazard ratio 1.18 (95% confidence interval 1.02 to 1.38; P=0.03) and 1.42 (1.21 to 1.67; P10 mIU/L. An increase in the risk of fragility fractures was observed in patients in the highest TSH category (>10 mIU/L) (hazard ratio 1.15 (1.01 to 1.31; P=0.03)).ConclusionsIn patients with a diagnosis of hypothyroidism, no evidence was found to suggest a clinically meaningful difference in the pattern of long term health outcomes (all cause mortality, atrial fibrillation, ischaemic heart disease, heart failure, stroke/transient ischaemic attack, fractures) when TSH concentrations were within recommended normal limits. Evidence was found for adverse health outcomes when TSH concentration is outside this range, particularly above the upper reference value.

Objectives To investigate the association of birthweight percentile with cord blood glucose, lipids, and insulin levels. Study design Data obtained from 1522 newborns were included in the Born in Guangzhou Cohort study. The generalized additive model and multivariable linear regression model were used to explore the nonlinear and linear relationships between birthweight and cord blood metabolic measures, and to evaluate the differences of metabolic measures Z-scores among small for gestational age, appropriate for gestational age, and large for gestational age babies. Results Birthweight Z-score was linearly associated with increased cord blood insulin Z-score (adjusted β = 0.30; 95% CI, 0.22-0.37). Compared with appropriate for gestational age babies, neonates born small for gestational age had significantly higher cord blood triglycerides Z-score (adjusted mean difference [MDadj], 0.60; 95% CI, 0.40-0.79) and lower cord blood insulin (MDadj, −0.37; 95% CI, −0.57 to −0.16), high-density lipoprotein cholesterol (MDadj, −0.34; 95% CI, −0.55 to −0.13), total cholesterol (MDadj, −0.26; 95% CI, −0.47 to −0.05), and low-density lipoprotein (MDadj, −0.23; 95% CI, −0.43 to −0.02) Z-scores, and neonates born large for gestational age had higher cord blood insulin Z-score (MDadj, 0.31; 95% CI, 0.09 to 0.52). Conclusions Our findings support the hypothesis that babies born small for gestational age and large for gestational age are exposed to different intrauterine environments, which may contribute to altered fat accumulation patterns with implications for the risk of metabolic dysfunction later in life. There is a need to consider the development of tailored intervention strategies to prevent metabolic dysfunction in adult life for these babies.

Exclusive breastfeeding (EBF) rates until 6 months in most low and middle income countries (LMICs) are well below the 90% World Health Organization benchmark. This systematic review sought to provide evidence on effectiveness of various interventions on EBF until 6 months in LMICs, compared with standard care. Experimental and observational studies with concurrent comparator promoting EBF, conducted in LMICs with high country rates of breastfeeding initiation, were included. Studies were identified from a systematic review and PUBMED, Cochrane, and CABI databases. Study selection, data abstraction, and quality assessment were carried out independently and in duplicate. Relative risks (RRs) with 95% confidence intervals (CIs) were calculated for individual studies and pooled. High heterogeneity was explored through prespecified subgroup analyses for the primary outcome (EBF until 6 months) by context and by intervention for the randomized controlled trials. Prediction intervals were calculated for each effect estimate. Sixty‐seven studies with 79 comparisons from 30 LMICs were included. At 6 months, intervention group infants were more likely to be exclusively breastfed than controls (RR = 2.19, 95% CI [1.73, 2.77]; I (2) 78.4%; 25 randomized controlled trials). Larger effects were obtained from interventions delivered by a combination of professional and laypersons (RR 3.90, 95% CI [1.25, 12.21]; I (2) 46.7%), in interventions spanning antenatal and post‐natal periods (RR 2.40, 95% CI [1.70, 3.38]; I (2) 83.6%), and when intensity was between four to eight contacts/sessions (RR 3.20, 95% CI [2.30, 4.45]; I (2) 53.8%). Almost every intervention conducted in LMICs increased EBF rates; choice of intervention should therefore be driven by feasibility of delivery in the local context to reduce infant mortality.

Postpartum haemorrhage (PPH) is the leading cause of maternal mortality worldwide. Prophylactic uterotonic drugs can reduce blood loss and are routinely recommended. There are several uterotonic drugs for preventing PPH, but it is still debatable which drug or combination of drugs is the most effective.To identify the most effective and cost-effective uterotonic drug(s) to prevent PPH, and generate a ranking according to their effectiveness and side-effect profile.The Cochrane Pregnancy and Childbirth's Trials Register (1 June 2015), ClinicalTrials.gov and the World Health Organization (WHO)'s International Clinical Trials Registry Platform (ICTRP) were searched for unpublished trial reports (30 June 2015). In addition, reference lists of retrieved studies (updated October 2017) were searched for randomised trials evaluating uterotonic drugs for preventing PPH. The study estimated relative effects and rankings for preventing PPH, defined as blood loss of ≥ 500 ml and ≥ 1000 ml. Pairwise meta-analyses and network meta-analysis were performed to determine the relative effects and rankings of all available drugs and combinations thereof [ergometrine, misoprostol (CytotecFrom 137 randomised trials and 87,466 women, ergometrine plus oxytocin, carbetocin and misoprostol plus oxytocin were found to reduce the risk of PPH blood loss of ≥ 500 ml compared with the standard drug, oxytocin [ergometrine plus oxytocin: risk ratio (RR) 0.69, 95% confidence interval (CI) 0.57 to 0.83; carbetocin: RR 0.72, 95% CI 0.52 to 1.00; misoprostol plus oxytocin: RR 0.73, 95% CI 0.6 to 0.9]. Each of these three strategies had 100% cumulative probability of being ranked first, second or third most effective. Oxytocin was ranked fourth, with an almost 0% cumulative probability of being ranked in the top three. Similar rankings were noted for the reduction of PPH blood loss of ≥ 1000 ml (ergometrine plus oxytocin: RR 0.77, 95% CI 0.61 to 0.95; carbetocin: RR 0.70, 95% CI 0.38 to 1.28; misoprostol plus oxytocin: RR 0.90, 95% CI 0.72 to 1.14), and most secondary outcomes. Ergometrine plus oxytocin and misoprostol plus oxytocin had the poorest ranking for side effects. Carbetocin had a favourable side-effect profile, which was similar to oxytocin. However, the analysis was restricted to high-quality studies, carbetocin lost its ranking and was comparable to oxytocin. The relative cost-effectiveness of the alternative strategies is inconclusive, and the results are affected by both the uncertainty and inconsistency in the data reported on adverse events. For vaginal delivery, when assuming no adverse events, ergometrine plus oxytocin is less costly and more effective than all strategies except carbetocin. The strategy of carbetocin is both more effective and more costly than all other strategies. When taking adverse events into consideration, all prevention strategies, except oxytocin, are more costly and less effective than carbetocin. For delivery by caesarean section, with and without adverse events, the relative cost-effectiveness is different, again because of the uncertainty in the available data.There was considerable uncertainty in findings within the planned subgroup analyses, and subgroup effects cannot be ruled out.Ergometrine plus oxytocin, carbetocin and misoprostol plus oxytocin are more effective uterotonic drug strategies for preventing PPH than the current standard, oxytocin. Ergometrine plus oxytocin and misoprostol plus oxytocin cause significant side effects. Carbetocin has a favourable side-effect profile, which was similar to oxytocin. However, most carbetocin trials are small and of poor quality. There is a need for a large high-quality trial comparing carbetocin with oxytocin; such a trial is currently being conducted by the WHO. The relative cost-effectiveness is inconclusive, and results are affected by uncertainty and inconsistency in adverse events data.This study is registered as PROSPERO CRD42015020005; Cochrane Pregnancy and Childbirth Group (substudy) reference number 0871; PROSPERO-Cochrane (substudy) reference number CRD42015026568; and sponsor reference number ERN_13-1414 (University of Birmingham, Birmingham, UK).Funding for this study was provided by the National Institute for Health Research Health Technology Assessment programme in a research award to the University of Birmingham and supported by the UK charity Ammalife (UK-registered charity 1120236). The funders of the study had no role in study design, data collection, data synthesis, interpretation or writing of the report.Postpartum haemorrhage (PPH) is the most common reason why mothers die in childbirth worldwide. Although most healthy women can cope well with blood loss after birth, some do not, and this can pose a serious risk to their health and even life. To reduce blood loss after birth, the routine administration of a drug to contract the uterus (uterotonic) has become standard practice across the world. This research seeks to identify which is the most effective and cost-effective drug. Different drugs have been used for reducing the occurrence of PPH. They include oxytocin, misoprostol, ergometrine, carbetocin, and combinations of these drugs, each with different effectiveness and side effects. The study synthesised the available evidence to compare all of these drugs and combinations thereof. After putting the results of all available comparisons together in a network, a ranking among them was calculated, and provided robust effectiveness and side-effect profiles for each drug and their associated costs. The study included 137 randomised trials, involving a total of 87,466 women. The results suggested that ergometrine plus oxytocin, carbetocin and misoprostol plus oxytocin are the most effective strategies for preventing PPH and are more effective than the currently recommended drug, oxytocin. Each of these three strategies had almost 100% probability of being ranked first, second or third most effective. Oxytocin was ranked fourth with an almost 0% probability of being ranked in the top three. Ergometrine plus oxytocin and misoprostol plus oxytocin were the worst drug combinations for side effects, with carbetocin having the most favourable side-effect profile. Carbetocin could prevent approximately one further event of PPH out of three in comparison with oxytocin. However, existing carbetocin studies were small and of poor quality. There is need for a large high-quality study comparing carbetocin with the current standard treatment of oxytocin for the prevention of PPH. The cost analyses of the alternative drug strategies remain inconclusive.

With the increasing incidence of diabetic retinopathy and its improved detection, there is increased demand for diabetic retinopathy treatment services. Prognostic prediction models have been used to optimise services but these were intended for early detection of sight-threatening retinopathy and are mostly used in diabetic retinopathy screening services. We wanted to look into the predictive ability and applicability of the existing models for the higher-risk patients referred into hospitals. We searched MEDLINE, EMBASE, COCHRANE CENTRAL, conference abstracts and reference lists of included publications for studies of any design using search terms related to diabetes, diabetic retinopathy and prognostic models. Search results were screened for relevance to the review question. Included studies had data extracted on model characteristics, predictive ability and validation. They were assessed for quality using criteria specified by PROBAST and CHARMS checklists, independently by two reviewers. Twenty-two articles reporting on 14 prognostic models (including four updates) met the selection criteria. Eleven models had internal validation, eight had external validation and one had neither. Discriminative ability with c-statistics ranged from 0.57 to 0.91. Studies ranged from low to high risk of bias, mostly due to the need for external validation or missing data. Participants, outcomes, predictors handling and modelling methods varied. Most models focussed on lower-risk patients, the majority had high risk of bias and doubtful applicability, but three models had some applicability for higher-risk patients. However, these models will also need updating and external validation in multiple hospital settings before being implemented into clinical practice.