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Objective To describe the prevalence of and factors associated with different thyroid dysfunction phenotypes in women who are asymptomatic preconception. Design Observational cohort study. Setting A total of 49 hospitals across the United Kingdom between 2011 and 2016. Participants Women aged 16 to 41years with history of miscarriage or subfertility trying for a pregnancy. Methods Prevalences and 95% confidence intervals (CIs) were estimated using the binomial exact method. Multivariate logistic regression analyses were conducted to identify risk factors for thyroid disease. Intervention None. Main Outcome Measure Rates of thyroid dysfunction. Results Thyroid function and thyroid peroxidase antibody (TPOAb) data were available for 19213 and 19237 women, respectively. The prevalence of abnormal thyroid function was 4.8% (95% CI, 4.5-5.1); euthyroidism was defined as levels of thyroid-stimulating hormone (TSH) of 0.44 to 4.50 mIU/L and free thyroxine (fT4) of 10 to 21 pmol/L. Overt hypothyroidism (TSH > 4.50 mIU/L, fT4 < 10 pmol/L) was present in 0.2% of women (95% CI, 0.1-0.3) and overt hyperthyroidism (TSH < 0.44 mIU/L, fT4 > 21 pmol/L) was present in 0.3% (95% CI, 0.2-0.3). The prevalence of subclinical hypothyroidism (SCH) using an upper TSH concentration of 4.50 mIU/L was 2.4% (95% CI, 2.1-2.6). Lowering the upper TSH to 2.50 mIU/L resulted in higher rates of SCH, 19.9% (95% CI, 19.3-20.5). Multiple regression analyses showed increased odds of SCH (TSH > 4.50 mIU/L) with body mass index (BMI) ≥ 35.0 kg/m2 (adjusted odds ratio [aOR] 1.71; 95% CI, 1.13-2.57; P = 0.01) and Asian ethnicity (aOR 1.76; 95% CI, 1.31-2.37; P < 0.001), and increased odds of SCH (TSH ≥ 2.50 mIU/L) with subfertility (aOR 1.16; 95% CI, 1.04-1.29; P = 0.008). TPOAb positivity was prevalent in 9.5% of women (95% CI, 9.1-9.9). Conclusions The prevalence of undiagnosed overt thyroid disease is low. SCH and TPOAb are common, particularly in women with higher BMI or of Asian ethnicity. A TSH cutoff of 2.50 mIU/L to define SCH results in a significant proportion of women potentially requiring levothyroxine treatment.

ObjectiveTo evaluate whether the implementation of the FAST‐M complex intervention was feasible and improved the recognition and management of maternal sepsis in a low‐resource setting.DesignA before‐and‐after design.SettingFifteen government healthcare facilities in Malawi.PopulationWomen suspected of having maternal sepsis.MethodsThe FAST‐M complex intervention consisted of the following components: the FAST‐M maternal sepsis treatment bundle and the FAST‐M implementation programme. Performance of selected process outcomes was compared between a 2‐month baseline phase and 6‐month intervention phase with compliance used as a proxy measure of feasibility.Main outcome resultCompliance with vital sign recording and use of the FAST‐M maternal sepsis bundle.ResultsFollowing implementation of the FAST‐M intervention, women were more likely to have a complete set of vital signs taken on admission to the wards (0/163 [0%] versus 169/252 [67.1%], P P P = 0.091). In particular, women were more likely to receive antibiotics (3/12 [25.0%] versus 72/107 [67.3%], P = 0.004) within 1 hour of recognition of suspected sepsis.ConclusionImplementation of the FAST‐M complex intervention was feasible and led to the improved recognition and management of suspected maternal sepsis in a low‐resource setting such as Malawi.Tweetable AbstractImplementation of a sepsis care bundle for low‐resources improved recognition & management of maternal sepsis.

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.

Climate change affects human health; however, there have been no large-scale, systematic efforts to quantify the heat-related human health impacts that have already occurred due to climate change. Here, we use empirical data from 732 locations in 43 countries to estimate the mortality burdens associated with the additional heat exposure that has resulted from recent human-induced warming, during the period 1991–2018. Across all study countries, we find that 37.0% (range 20.5–76.3%) of warm-season heat-related deaths can be attributed to anthropogenic climate change and that increased mortality is evident on every continent. Burdens varied geographically but were of the order of dozens to hundreds of deaths per year in many locations. Our findings support the urgent need for more ambitious mitigation and adaptation strategies to minimize the public health impacts of climate change., We thank the participants of the ISIMIP Health workshop in Barcelona in November 2018 where this work was discussed for the first time. This study was supported by the Medical Research Council UK (grant no. MR/M022625/1), the Natural Environment Research Council UK (grant no. NE/R009384/1) and the European Union’s Horizon 2020 Project Exhaustion (grant no. 820655). N.S. was supported by the NIEHS-funded HERCULES Center (P30ES019776). Y.H. was supported by the Environment Research and Technology Development Fund of the Environmental Restoration and Conservation Agency, Japan (JPMEERF15S11412). J.J.J.K.J. was supported by Academy of Finland (grant no. 310372). V.H. was supported by the Spanish Ministry of Economy, Industry and Competitiveness (grant no. PCIN-2017-046) and the German Federal Ministry of Education and Research (grant no. 01LS1201A2). J.K. and A.U. were supported by the Czech Science Foundation (grant no. 20-28560S). J.M. was supported by the Fundação para a Ciência e a Tecnologia (FCT) (SFRH/BPD/115112/2016). S.R. and F.d.R. were supported by European Union’s Horizon 2020 Project EXHAUSTION (grant no. 820655). M.H. was supported by the Japan Science and Technology Agency as part of SICORP, grant no. JPMJSC20E4. Y.G. was supported by the Career Development Fellowship of the Australian National Health and Medical Research Council (APP1163693). S.L. was support by the Early Career Fellowship of the Australian National Health and Medical Research Council (APP1109193). Y.L.L.G. was supported by the Taiwan Ministry of Science and Technology (MOST110-2918-I-002-007) as a visiting academic at the University of Sydney.

BackgroundPrevious studies investigating the relationship of influenza with acute myocardial infarction (AMI) have not distinguished between AMI types 1 and 2. Influenza and cold temperature can explain the increased incidence of AMI during winter but, because they are closely related in temperate regions, their relative contribution is unknown. Methods and ResultsThe temporal relationship between incidence rates of AMI with demonstrated culprit plaque (type 1 AMI) from the regional primary angioplasty network and influenza, adjusted for ambient temperature, was studied in Madrid region (Spain) during 5 influenza seasons (from June 2013 to June 2018). A time‐series analysis with quasi‐Poisson regression models and distributed lag‐nonlinear models was used. The incidence rate of type 1 AMI according to influenza vaccination status was also explored. A total of 8240 cases of confirmed type 1 AMI were recorded. The overall risk ratio (RR) of type 1 AMI during epidemic periods, adjusted for year, month, and temperature, was 1.23 (95% CI, 1.03–1.47). An increase of weekly influenza rate of 50 cases per 100 000 inhabitants resulted in an RR for type 1 AMI of 1.16 (95% CI, 1.09–1.23) during the same week, disappearing 1 week after. When adjusted for influenza, a decrease of 1ºC in the minimum temperature resulted in an increase of 2.5% type 1 AMI. Influenza vaccination was associated with a decreased risk of type 1 AMI in subjects aged 60 to 64 years (RR, 0.58; 95% CI, 0.47–0.71) and ≥65 years (RR, 0.53; 95% CI, 0.49–0.57). ConclusionsInfluenza and cold temperature were both independently associated with an increased risk of type 1 AMI, whereas vaccination was associated with a reduced risk among older patients., This work has been partially funded by unrestricted research grants from the Fundación para la Investigación Biomédica, University Hospital “Príncipe de Asturias” (Servicio Madrileño de Salud, Madrid, Spain) (to Drs García‐Lledó and de Abajo) and funding from Sanofi‐Pasteur S.A., a manufacturer of influenza vaccines (to Dr de Abajo). The funders had no role in the study design, data collection, data analysis, data interpretation, or writing the report. Dr Tobías received support from the Japanese Society for the Promotion of Science in its invitation‐to‐research fellowship program in Japan (S18149).

Background: There is strong evidence concerning the impact of heat stress on mortality, particularly from high temperatures. However, few studies to our knowledge emphasize the importance of hot nights, which may prevent necessary nocturnal rest. Objectives: In this study, we use hot-night duration and excess to predict daily cause-specific mortality in summer, using multiple cities across Southern Europe. Methods: We fitted time series regression models to summer cause-specific mortality, including natural, respiratory, and cardiovascular causes, in 11 cities across four countries. We included a distributed lag nonlinear model with lags up to 7 days for hot night duration and excess adjusted by daily mean temperature. We summarized city-specific associations as overall-cumulative exposure-response curves at the country level using meta-analysis. Results: We found positive but generally nonlinear associations between relative risk (RR) of cause-specific mortality and duration and excess of hot nights. RR of duration associated with nonaccidental mortality in Portugal was 1.29 (95% confidence interval [CI] = 1.07, 1.54); other associations were imprecise, but we also found positive city-specific estimates for Rome and Madrid. Risk of hot-night excess ranged from 1.12 (95% CI = 1.05, 1.20) for France to 1.37 (95% CI = 1.26, 1.48) for Portugal. Risk estimates for excess were consistently higher than for duration. Conclusions: This study provides new evidence that, over a wider range of locations, hot night indices are strongly associated with cause-specific deaths. Modeling the impact of thermal characteristics during summer nights on mortality could improve decisionmaking for preventive public health strategies. D.R. was supported by a postdoctoral research fellowship of the Xunta de Galicia (Spain). R.L. was supported by a Royal Society Dorothy Hodgkin Fellowship. A.G. was supported by the Medical Research Council UK (Grant ID: MR/ M022625/1), the Natural Environment Research Council UK (Grant ID: NE/R009384/1), and the European Union’s Horizon 2020 Project Exhaustion (Grant ID: 820655) info:eu-repo/semantics/publishedVersion

BackgroundCurrent strategies for preventing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are limited to nonpharmacologic interventions. Hydroxychloroquine has been proposed as a postexposure therapy to prevent coronavirus disease 2019 (Covid-19), but definitive evidence is lacking. MethodsWe conducted an open-label, cluster-randomized trial involving asymptomatic contacts of patients with polymerase-chain-reaction (PCR)-confirmed Covid-19 in Catalonia, Spain. We randomly assigned clusters of contacts to the hydroxychloroquine group (which received the drug at a dose of 800 mg once, followed by 400 mg daily for 6 days) or to the usual-care group (which received no specific therapy). The primary outcome was PCR-confirmed, symptomatic Covid-19 within 14 days. The secondary outcome was SARS-CoV-2 infection, defined by symptoms compatible with Covid-19 or a positive PCR test regardless of symptoms. Adverse events were assessed for up to 28 days. ResultsThe analysis included 2314 healthy contacts of 672 index case patients with Covid-19 who were identified between March 17 and April 28, 2020. A total of 1116 contacts were randomly assigned to receive hydroxychloroquine and 1198 to receive usual care. Results were similar in the hydroxychloroquine and usual-care groups with respect to the incidence of PCR-confirmed, symptomatic Covid-19 (5.7% and 6.2%, respectively; risk ratio, 0.86 [95% confidence interval, 0.52 to 1.42]). In addition, hydroxychloroquine was not associated with a lower incidence of SARS-CoV-2 transmission than usual care (18.7% and 17.8%, respectively). The incidence of adverse events was higher in the hydroxychloroquine group than in the usual-care group (56.1% vs. 5.9%), but no treatment-related serious adverse events were reported. ConclusionsPostexposure therapy with hydroxychloroquine did not prevent SARS-CoV-2 infection or symptomatic Covid-19 in healthy persons exposed to a PCR-positive case patient. (Funded by the crowdfunding campaign YoMeCorono and others; BCN-PEP-CoV2 ClinicalTrials.gov number, NCT04304053.) In a trial involving asymptomatic contacts of patients with PCR-confirmed Covid-19 in Spain, the authors compared the use of hydroxychloroquine with usual care. Postexposure therapy with hydroxychloroquine did not prevent SARS-CoV-2 infection or symptomatic Covid-19 in healthy persons.

Background Epidemiological evidence on short-term association between ambient carbon monoxide (CO) and mortality is inconclusive and limited to single cities, regions, or countries. Generalisation of results from previous studies is hindered by potential publication bias and different modelling approaches. We therefore assessed the association between short-term exposure to ambient CO and daily mortality in a multicity, multicountry setting. Methods We collected daily data on air pollution, meteorology, and total mortality from 337 cities in 18 countries or regions, covering various periods from 1979 to 2016. All included cities had at least 2 years of both CO and mortality data. We estimated city-specific associations using confounder-adjusted generalised additive models with a quasi-Poisson distribution, and then pooled the estimates, accounting for their statistical uncertainty, using a random-effects multilevel meta-analytical model. We also assessed the overall shape of the exposure–response curve and evaluated the possibility of a threshold below which health is not affected. Findings Overall, a 1 mg/m3 increase in the average CO concentration of the previous day was associated with a 0·91% (95% CI 0·32–1·50) increase in daily total mortality. The pooled exposure–response curve showed a continuously elevated mortality risk with increasing CO concentrations, suggesting no threshold. The exposure–response curve was steeper at daily CO levels lower than 1 mg/m3, indicating greater risk of mortality per increment in CO exposure, and persisted at daily concentrations as low as 0·6 mg/m3 or less. The association remained similar after adjustment for ozone but was attenuated after adjustment for particulate matter or sulphur dioxide, or even reduced to null after adjustment for nitrogen dioxide. Interpretation This international study is by far the largest epidemiological investigation on short-term CO-related mortality. We found significant associations between ambient CO and daily mortality, even at levels well below current air quality guidelines. Further studies are warranted to disentangle its independent effect from other traffic-related pollutants., EU Horizon 2020, UK Medical Research Council, and Natural Environment Research Council

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®.

Acknowledgement: “This Protocol of a Cochrane Review was published in the Cochrane Database of Systematic Reviews 2020, Issue 9. Cochrane Protocols and Reviews are regularly updated as new evidence emerges and in response to feedback, and the Cochrane Database of Systematic Reviews should be consulted for the most recent version of the Protocol.'

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and associated COVID-19 have caused a global emergency that requires an engaged, integrated, interdisciplinary, and rapid response from the scientific community. Climate change, ecological change, and biodiversity loss might have played an important role in the occurrence of this zoonotic pandemic. Climatic and environmental factors, such as temperature, humidity, and air pollution, are potentially influencing the transmission, spread, and severity of SARS-CoV-2 infection. Strong scientific evidence about the contributions of these environmental determinants in the COVID-19 pandemic is needed, in combination with an understanding of the role of other important societal factors and public health interventions. This evidence will support the public health community in responding to the current crisis, and inform strategies to prevent the recurring effects of the COVID-19 pandemic and future emergencies.

IntroductionInternal temporomandibular joint (TMJ) disorders are present in approximately 80% of patients with symptomatic temporomandibular disorders. Among the minimally invasive therapies, we find the intra-articular infiltration of substances, such as corticosteroids, hyaluronic acid or platelet-rich plasma accompanied or not by an arthrocentesis. There are several studies on minimally invasive therapy for internal TMJ disorders; however, none compares the effectiveness of the different intra-articular corticosteroids to each other.The purpose of this study is to evaluate the effectiveness of the different intra-articular corticosteroids for the treatment of internal disorders of the TMJ and compare them to each other or to other minimally invasive therapies.Methods and analysisA systematic search will be carried out up to December 2019 in the electronic databases: Medline, Cochrane Library, EMBASE, SCOPUS and LILACS.Randomised clinical trials evaluating patients with internal disorders of the TMJ, with intra-articular corticosteroid therapy and comparing these to each other and/or to other minimally invasive therapy will be included. The main outcomes will be pain and range of motion measured through validated scales.Two review authors will independently screen search results, extract data from included studies and assess the risk of bias in those studies using the Revised Cochrane Risk of Bias Tool (RoB 2.0). In the case of any discrepancy and failure to reach consensus, this will be resolved by a third reviewer.A network meta-analysis will be conducted based on direct comparisons to generate indirect comparisons of the different treatments. Data will be combined in a meta-analysis using a random effects model.The principles of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system will be used to assess the overall quality of the body of evidence associated with the main results.Ethics and disseminationThis protocol will not require ethical approval. The results of this review will be disseminated through peer-reviewed publications.Trial registration numberCRD42019129014.

ObjectivesTo assess if there is any association between hyperemesis gravidarum (HG), psychological morbidity and infant bonding and to quantify any psychosocial consequences of HG.DesignTwo-point prospective case–control, multicentre survey study with antenatal and postnatal data collection.SettingThree London hospitals.ParticipantsPregnant women at ≤12 completed weeks gestation recruited consecutively over 2 years. Women with HG were recruited at the time of admission; controls recruited from a low risk antenatal clinic. 106 women were recruited to the case group and 108 to the control. Response rates at antenatal data collection were 87% and 85% in the case and control groups, respectively. Postnatally, the response rate was 90% in both groups.Primary and secondary outcome measuresPrimary outcomes were psychological morbidity in the antenatal and postnatal periods, infant bonding in the postnatal period and psychosocial implications of HG. Secondary outcomes were the effects of severity and longevity of HG and assessment of correlation between Edinburgh Postnatal Depression Scale scores and maternal-to-infant bonding scores.ResultsAntenatally, 49% of cases had probable depression compared with 6% of controls (OR 14.4 (5.29 to 39.44)). Postnatally, 29% of cases had probable depression versus 7% of controls (OR 5.2 (1.65 to 17.21)). There was no direct association between HG and infant bonding. 53% of women in the HG group reported needing four or more weeks of sick leave compared with 2% in the control group (OR 60.5 (95% CI 8.4 to 2535.6)).ConclusionsLong-lasting psychological morbidity associated with HG was evident. Significantly more women in the case group sought help for mental health symptoms in the antenatal period, however very few were diagnosed with or treated for depression in pregnancy or referred to specialist perinatal mental health services. HG did not directly affect infant bonding. Women in the case group required long periods off work, highlighting the socioeconomic impact of HG.

Background Current strategies for preventing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections are limited to non-pharmacological interventions. Hydroxychloroquine (HCQ) has been proposed as a postexposure therapy to prevent Coronavirus disease 2019 (Covid-19) but definitive evidence is lacking. Methods We conducted an open-label, cluster-randomized trial including asymptomatic contacts exposed to a PCR-positive Covid-19 case in Catalonia, Spain. Clusters were randomized to receive no specific therapy (control arm) or HCQ 800mg once, followed by 400mg daily for 6 days (intervention arm). The primary outcome was PCR-confirmed symptomatic Covid-19 within 14 days. The secondary outcome was SARS-CoV-2 infection, either symptomatically compatible or a PCR-positive result regardless of symptoms. Adverse events (AEs) were assessed up to 28 days. Results The analysis included 2,314 healthy contacts of 672 Covid-19 index cases identified between Mar 17 and Apr 28, 2020. A total of 1,198 were randomly allocated to usual care and 1,116 to HCQ therapy. There was no significant difference in the primary outcome of PCR-confirmed, symptomatic Covid-19 disease (6.2% usual care vs. 5.7% HCQ; risk ratio 0.89 [95% confidence interval 0.54-1.46]), nor evidence of beneficial effects on prevention of SARS-CoV-2 transmission (17.8% usual care vs. 18.7% HCQ). The incidence of AEs was higher in the intervention arm than in the control arm (5.9% usual care vs 51.6% HCQ), but no treatment-related serious AEs were reported. Conclusions Postexposure therapy with HCQ did not prevent SARS-CoV-2 disease and infection in healthy individuals exposed to a PCR-positive case. Our findings do not support HCQ as postexposure prophylaxis for Covid-19., This study was mainly supported by the crowdfunding campaign JoEmCorono (https://www.yomecorono.com/) with the contribution of over 72,000 citizens and corporations. The study also received financial support from Laboratorios Rubió, Gebro Pharma, Zurich Seguros, SYNLAB Barcelona, and Generalitat de Catalunya. Laboratorios Rubió also contributed to the study with the required doses of hydroxychloroquine (Dolquine®).

No effective treatments for coronavirus disease 2019 (COVID-19) exist. We aimed to determine whether early treatment with hydroxychloroquine (HCQ) would be efficacious for outpatients with COVID-19., The authors thank Gerard Carot-Sans, PhD, for providing medical writing support during the revisions of the subsequent drafts of the manuscript; the personnel from the Fights Aids and Infectious Diseases Foundation for their support in administration, human resources and supply chain management; Eric Ubals (Pierce AB) and Òscar Palao (Opentic) for website and database management; Óscar Camps and OpenArms nongovernmental organization for nursing home operations; and Anna Valentí and the Hospital Germans Trias i Pujol Human Resources Department for telephone monitoring. We thank Consorci Sanitari del Maresme, Centre Sociosanitari El Carme, l'Hospital General de Granollers and occupational hazards department of Hospital Germans Trias i Pujol for their contribution with patient enrollment. We are very grateful to Marc Clotet and Natalia Sánchez who coordinated the JoEmCorono crowd-funding campaign. We thank the Hospital Germans Trias Pujol Institutional Review Board and the Spanish Agency of Medicines and Medical Devices for their prompt action for consideration and approvals to the protocol. Financial support. This work was mainly supported by the crowd-funding campaign JoEmCorono (https://www.yomecorono.com/) with contributions from more than 72 000 citizens and corporations. The study also received financial support from Laboratorios Rubió, Laboratorios Gebro Pharma, Zurich Seguros, SYNLAB Barcelona, and Generalitat de Catalunya. Laboratorios Rubió also contributed to the study with the required doses of hydroxychloroquine (Dolquine®). Foundation Dorneur partly funded lab equipment at Irsi-Caixa.

Climate change is a severe public health challenge. Understanding to what extent fatal and non-fatal consequences of specific diseases are associated with temperature may help to improve the effectiveness of preventive public health efforts. This study examines the effects of temperature on deaths and hospital admissions by cardiovascular and respiratory diseases, empathizing the difference between mortality and morbidity., This work was partially funded by the Spanish Ministry of Science and Innovation (grant ID's: MTM2017-83850-P, PID2019-106341GB-I00).

Ship traffic emissions degrade air quality in coastal areas and contribute to climate impacts globally. The estimated health burden of exposure to shipping emissions in coastal areas may inform policy makers as they seek to reduce exposure and associated potential health impacts. This work estimates the PM2.5-attributable impacts in the form of premature mortality and cardiovascular and respiratory hospital admissions, from long-term exposure to shipping emissions. Health impact assessment (HIA) was performed in 8 Mediterranean coastal cities, using a baseline conditions from the literature and a policy case accounting for the MARPOL Annex VI rules requiring cleaner fuels in 2020. Input data were (a) shipping contributions to ambient PM2.5 concentrations based on receptor modelling studies found in the literature, (b) population and health incidence data from national statistical registries, and (c) geographically-relevant concentration-response functions from the literature. Long-term exposure to ship-sourced PM2.5 accounted for 430 (95% CI: 220–650) premature deaths per year, in the 8 cities, distributed between groups of cities: Barcelona and Athens, with >100 premature deaths/year, and Nicosia, Brindisi, Genoa, Venice, Msida and Melilla, with tens of premature deaths/year. The more stringent standards in 2020 would reduce the number of PM2.5-attributable premature deaths by 15% on average. HIA provided a comparative assessment of the health burden of shipping emissions across Mediterranean coastal cities, which may provide decision support for urban planning with a special focus on harbour areas, and in view of the reduction in sulphur content of marine fuels due to MARPOL Annex VI in 2020. © 2020 The Authors, The authors gratefully acknowledge the providers of health data and statistics: Nicosia (M. Athanasiadou, Health Monitoring Unit, Ministry of Health), Brindisi (M. Stafoggia, L. Bauleo, UOC Epidemiologia eziologica ed occupazionale, Dipartimento Epidemiologia del S.S.R. - ASL RME, Regione Lazio, Genoa-Venice (Istituto Superiore di sanità/Health Institute, http://old.iss.it/publ/ ), Misda (S. Distefano, Department for Policy in Health, Health Information and Research), Melilla ( https://pestadistico.inteligenciadegestion.mscbs.es/publicoSNS/Comun/ ), Athens (Hellenic Statistical Authority, http://www.statistics.gr/en/statistics/-/publication/SPO09/2014 ), and Barcelona (Servei Català de la Salut and the Registre de Mortalitat de Catalunya). The data provided by the Servei Català de la Salut and the Registre de Mortalitat de Catalunya, Servei de Gestió I Anàlisi de la Informació per a la Planificació Estratègica, Direcció General de Planificació en Salut, Departament de Salut were processed internally by CSIC. The authors also acknowledge fruitful technical discussions with Dr. A. Patton (Health Effects Institute, HEI). This work was partially funded by AGAUR (project 2017 SGR41 ) and by the Spanish Ministry of Science and Innovation (Project CEX2018-000794-S ). A. Karanasiou acknowledges support received through the Ramón y Cajal program (grant RYC-2014-16885 ) of the Spanish Ministry of Science, Innovation and Universities .

Background: No therapeutics have yet been proven effective for the treatment of mild-illness caused by SARS-CoV-2. We assessed the efficacy and safety of hydroxychloroquine (HCQ) alone or in combination with cobicistat-boosted darunavir (DRVc) for treating patients with mild Covid-19. Methods: We conducted a randomized, prospective, controlled, open-label trial in three health regions of Catalonia. After confirmation of a case of Covid-19 disease, we enumerated on a list a ring of the case and all their contacts and randomly assigned the ring to either control or intervention arm on a 1:1 ratio. Here we present the methods concerning eligible index cases, which involved non-hospitalized adult patients with recently confirmed SARS-CoV-2 infection and less than seven days of symptoms. Patients were assigned to receive HCQ (800 mg on day 1, followed by 400 mg once daily for six days) in combination with DRVc (800 mg/150 mg tablets, once daily for seven days) or no antiviral treatment. The protocol was adapted during the course of the trial to use HCQ alone after findings of no benefit of the protease inhibitor lopinavir-ritonavir. Study outcomes were the reduction of viral RNA load in nasopharyngeal swabs and time to clinical improvement within 28 days of follow-up in the per-protocol population. Adverse events were assessed up to 28 days. Findings: Between Mar 17 and Apr 28, 2020, 353 Covid-19 patients met the criteria for the per-protocol analysis: 165 in the control arm and 142 in the intervention arm. The median time from symptom onset to treatment start was 3 days (IQR 2–4). The per-protocol analysis revealed no significant differences in the mean reduction of viral load in nasopharyngeal swabs at day-3 compared to baseline between the control group (-1·28 Log 10 copies/mL, SD 1·68) and the intervention group (-1·47, SD 1·50); difference -0·18 [95% CI -0.59 to 0·22]. The same pattern was observed at day-7 and -14 after treatment. Time to complete alleviation of symptoms was similar in both groups (22 vs. 20·5 days, p = 0·37). Adverse events included self-limited nausea and diarrhea. Twenty patients required hospitalization, all due to Covid-19 progression. No patients died during the study. Interpretation: In patients with mild Covid-19, no benefit was observed with HCQ alone or in combination with DRVc beyond the usual care. Future testing of other agents in randomized trials may help to identify other drugs that provide a treatment benefit., Crowdfunding campaign YoMeCorono (https://www.yomecorono.com/), Laboratorios Rubió, Laboratorios Gebro Pharma, Zurich Seguros, SYNLAB Barcelona, and Generalitat de Catalunya. Laboratorios Rubió also contributed to the study with the required doses of hydroxychloroquine (Dolquine®).

Background There remains limited data on what variables affect risk of transmission of SARS-CoV-2 and developing symptomatic Covid-19 and in particular the relationship to viral load (VL). We analysed data from linked index cases and their contacts to explore factors associated with transmission of SARS-CoV-2. Methods Patients were recruited as part of a randomized control trial, conducted between March to April 2020, that aimed to assess if hydroxychloroquine reduced transmission of SARS-CoV-2. Non-hospitalised Covid-19 cases and their contacts were identified through the local surveillance system. VL, measured by quantitative PCR from a nasopharyngeal swab, was assessed at enrollment, at day 14, and whenever the participant reported Covid-19-like symptoms. Risk of transmission, developing symptomatic disease and incubation dynamics were evaluated using regression analysis. Findings We identified 314 cases, 282 of which had at least one contact (753 contacts in total). Ninety (33%) of 282 clusters had at least one transmission event. The secondary attack rate was 16% (125/753), with a variation from 12% to 24% for VL of the index case of 109 copies/mL, respectively (OR per log10 increase in VL 1.3 95%CI 1.1–1.6). Increased risk of transmission was also associated with household contact (OR 2.7; 1.4–5.06) and age of the contact (OR 1.02 per year; 1.01–1.04). The proportion of PCR positive contacts who developed symptomatic Covid-19 was 40.3% (181/449), with a variation from 25% to 60% for VL of the contact 109 copies/mL (HR log10 increase in VL 1.12; 95% CI 1.05 – 1.2). Time to onset of symptomatic disease decreased from a median of 7 days (IQR 5–10) for individuals with an initial viral load 109, respectively. Interpretation Viral load of index cases is a leading driver of SARS-CoV-2 transmission. The risk of symptomatic Covid-19 is strongly associated with viral load of contacts at baseline and shortens the incubation time in a dose-dependent manner., Crowdfunding campaign YoMeCorono (http://www.yomecorono.com/), and Generalitat de Catalunya. Support for laboratory equipment from Foundation Dormeur.

[Background] Concerns have been raised about the possibility that inhibitors of the renin–angiotensin–aldosterone system (RAAS) could predispose individuals to severe COVID-19; however, epidemiological evidence is lacking. We report the results of a case-population study done in Madrid, Spain, since the outbreak of COVID-19., [Methods] In this case-population study, we consecutively selected patients aged 18 years or older with a PCR-confirmed diagnosis of COVID-19 requiring admission to hospital from seven hospitals in Madrid, who had been admitted between March 1 and March 24, 2020. As a reference group, we randomly sampled ten patients per case, individually matched for age, sex, region (ie, Madrid), and date of admission to hospital (month and day; index date), from Base de datos para la Investigación Farmacoepidemiológica en Atención Primaria (BIFAP), a Spanish primary health-care database, in its last available year (2018). We extracted information on comorbidities and prescriptions up to the month before index date (ie, current use) from electronic clinical records of both cases and controls. The outcome of interest was admission to hospital of patients with COVID-19. To minimise confounding by indication, the main analysis focused on assessing the association between COVID-19 requiring admission to hospital and use of RAAS inhibitors compared with use of other antihypertensive drugs. We calculated odds ratios (ORs) and 95% CIs, adjusted for age, sex, and cardiovascular comorbidities and risk factors, using conditional logistic regression. The protocol of the study was registered in the EU electronic Register of Post-Authorisation Studies, EUPAS34437., [Findings] We collected data for 1139 cases and 11 390 population controls. Among cases, 444 (39·0%) were female and the mean age was 69·1 years (SD 15·4), and despite being matched on sex and age, a significantly higher proportion of cases had pre-existing cardiovascular disease (OR 1·98, 95% CI 1·62–2·41) and risk factors (1·46, 1·23–1·73) than did controls. Compared with users of other antihypertensive drugs, users of RAAS inhibitors had an adjusted OR for COVID-19 requiring admission to hospital of 0·94 (95% CI 0·77–1·15). No increased risk was observed with either angiotensin-converting enzyme inhibitors (adjusted OR 0·80, 0·64–1·00) or angiotensin-receptor blockers (1·10, 0·88–1·37). Sex, age, and background cardiovascular risk did not modify the adjusted OR between use of RAAS inhibitors and COVID-19 requiring admission to hospital, whereas a decreased risk of COVID-19 requiring admission to hospital was found among patients with diabetes who were users of RAAS inhibitors (adjusted OR 0·53, 95% CI 0·34–0·80). The adjusted ORs were similar across severity degrees of COVID-19., [Interpretation] RAAS inhibitors do not increase the risk of COVID-19 requiring admission to hospital, including fatal cases and those admitted to intensive care units, and should not be discontinued to prevent a severe case of COVID-19., This study was funded by a research grant from the Institute of Health Carlos III (COV20/00027).

Air in urban areas is usually contaminated with particle matter. High concentrations lead to a rise in the risk of cardiovascular and respiratory diseases. Some studies have reported that ultrafine particles (UFP) play a greater role in cardiovascular diseases than other particle matter, particularly regarding hypertensive crises and DBP, although in the latter such effects were described concerning clinical blood pressure (BP). In this study, we evaluate the relationship between 24-h ambulatory BP monitoring (ABPM) and atmospheric UFP concentrations in Barcelona. Methods: An observational study of individual patients’ temporal and geographical characteristics attended in Primary Care Centres and Hypertensive Units during 2009–2014 was performed. Results: The participants were 521 hypertensive patients, mean age 56.8 years (SD 14.5), 52.4% were women. Mean BMI was 28.0 kg/m2 and the most prominent cardiovascular risk factors were diabetes (N = 66, 12.7%) and smoking (N = 79, 15.2%). We describe UFP effects at short-term and up to 1 week (from lag 0 to 7). For every 10 000 particle/cm3 UFP increase measured at an urban background site, a corresponding statistically significant increase of 2.7 mmHg [95% confidence interval = (0.5–4.8)] in 24-h DBP with ABPM for the following day was observed (lag 1). Conclusion: We have observed that a rise in UFP concentrations during the day prior to ABPM is significantly associated with an increase in 24 h and diurnal DBP. It has been increasingly demonstrated that UFP play a key role in cardiovascular risk factors and, as we have demonstrated, in good BP control. Sin financiación 4.844 JCR (2020) Q2, 17/65 Peripheral Vascular Disease 1.249 SJR (2020) Q1, 70/349 Cardiology and Cardiovascular Medicine UEM

Research question What is the association of endometrial thickness with pregnancy losses and live births in IVF treatment and the optimal threshold that optimizes the IVF outcome? Design Data were analysed from 25,767 IVF cycles from centres of the CARE Fertility Group in the UK between 2007 and 2016. Transvaginal ultrasound was conducted to measure the maximum endometrial thickness during gonadotrophin stimulation. Live birth rates were per embryo transfer. Pregnancy loss rates included the combination of biochemical and clinical pregnancy losses. Results The live birth rate was 15.6% with 5 mm or less endometrial thickness and gradually increased to 33.1% with an endometrial thickness of 10 mm. On the other hand, the pregnancy loss rate was 41.7% with 5 mm or less endometrial thickness and gradually decreased to 26.5% with an endometrial thickness of 10 mm. Statistical modelling for optimal endometrial thickness threshold found 10 mm or more maximized live births and minimized pregnancy losses. This association was independent after adjusting for confounders such as age, oocyte number, number of transferred embryos, ovarian stimulation protocol and embryo quality for live births (crude RR 1.27; 95% CI 1.21 to 1.33; Adjusted RR 1.18; 95% CI 1.12 to 1.23) and pregnancy losses (crude RR 0.83; 95% CI 0.77 to 0.89; adjusted RR 0.86; 95% CI 0.8 to 0.92). Conclusions Endometrial thickness is strongly associated with pregnancy losses and live births in IVF, and the optimal endometrial thickness threshold of 10 mm or more maximized live births and minimized pregnancy losses.

Graft and patient survival outcomes following split liver transplantation (SLT), living-donor liver transplantation (LDLT) and deceased-donor liver transplantation (DDLT) were estimated using Bayesian network meta-analysis. Databases were searched for relevant articles over the previous 20 years (MEDLINE, Embase, Cochrane Library and Google Scholar). Systematic review, pairwise meta-analysis and Bayesian network meta-analysis were performed. Pairwise meta-analysis demonstrated that there were no significant differences in graft and patient survival outcomes. Consequently, Bayesian network meta-analysis demonstrated no significant differences in 1-, 3- and 5-year graft and patient survival between the three alternative liver transplantations. No discrepancies were demonstrated after comparisons of direct and indirect evidence of 1-, 3- and 5-year patient and graft survival of the three node-split models namely SLT, LDLT and DDLT. The 1-, 3- and 5-year graft and patient survival of the SLT and LDLT cohorts compared to the DDLT cohort demonstrated no significant differences. The direct and indirect evidence of this study can serve as comparator for future studies.

Objectives To analyse social inequalities in the association between ambient temperature and mortality by sex, age and educational level, in the city of Barcelona for the period 1992–2015. Methods Mortality data are represented by daily counts for natural mortality. As a measure of socioeconomic position, we used the educational level of the deceased. We also considered age group and sex. We considered, as a measure of exposure, the daily maximum temperatures. Time-series Poisson regression with distributed lag non-linear models was fitted for modelling the relationship between temperature and mortality. Results Women had higher risk of mortality by hot temperatures than men. Temperature–mortality association (heat and cold) was evident for the elderly, except for heat-related mortality in women which was present in all age groups. Men with primary education or more were more vulnerable to moderate or extreme temperatures than those without studies. Finally, women were vulnerable to heat-related mortality in all educational levels while women without studies were more vulnerable to cold temperatures. Conclusions Social and economic individual characteristics play an important role in vulnerability to high and low temperatures. It is important that decision-making groups consider identified vulnerable subgroups when redacting and implementing climate change resilience and adaptation plans., This article was partially funded by CIBER Epidemiología y Salud Pública (CIBERESP). Dr. Gasparrini was supported from a grant from Medical Research Council UK (Grant ID: MR/M022625/1). Moreover, we want to thank “Servei Meteorològic de Catalunya” (METEOCAT) for providing temperature data.

Objective: Six principal adjuvant chemotherapy treatments (ACTs) are currently available for patients with resected colorectal liver metastases. This meta-analysis was designed to determine the optimal ACT, as evaluated by 2-year disease-free survival (DFS) and 5-year overall survival (OS) rates as well as by hepatic recurrences and adverse events (AEs). Methods: A systematic literature search of the PubMed, EMBASE, Medline, Cochrane Library, and Google Scholar databases was performed. The probability of the optimal therapeutic scheme and the mean ranking were estimated for each treatment using network meta-analysis. Results: Systemic chemotherapy (SCT) had the best 2-year DFS rate (hazard ratio [HR] = 0.78, 95% confidence interval [CI] = 0.48–1.27, 95% prediction interval [PI] = 0.17–3.56, surface under the cumulative ranking area [SUCRA] = 73) and the lowest AE rate (estimated SUCRA = 65 and predicted SUCRA = 62). Hepatic arterial infusion (HAI) plus SCT had the best 5-year OS rate (HR = 0.81, 95% CI = 0.64–1.01, 95% PI = 0.50–1.29) and the lowest hepatic recurrence rate (odds ratio = 2.87, 95% CI = 1.56–5.30, 95% PI = 0.61–13.62). Conclusion: Both SCT and HAI plus SCT showed superior efficacy and safety. Clinical trials in homogeneous populations with strict selection criteria are needed to compare these two ACTs.

Recreational physical activity is an integral part of our society, and the injuries caused by sports activities are a concern for public health. We studied the effect of outdoor ambient temperature on hospital emergency department visits caused by sports injuries in Madrid, Spain, and accounted for its seasonal changes., AT was supported by the Japanese Society for the Promotion of Science (JSPS) Invitational Fellowships for Research in Japan (S18149). MC was supported by the Ministerio de Ciencia e Innovación y Ministerio de Universidades (PID2019-104830RB-I00/AEI DOI:10.13039/501100011033). This study was carried out within the ‘Cohort-Real World Data’ subprogram of CIBER of Epidemiology and Public Health (CIBERESP).

Background The increased risk of mortality during periods of high and low temperatures has been well established. However, most of the studies used daily counts of deaths or hospitalisations as health outcomes, although they are the ones at the top of the health impact pyramid reflecting only a limited proportion of patients with the most severe cases. Objectives This study evaluates the relationship between short-term exposure to the daily mean temperature and medication prescribed for the respiratory system in five Spanish cities. Methods We fitted time series regression models to cause-specific medical prescriptions, including different respiratory subgroups and age groups. We included a distributed lag non-linear model with lags up to 14 days for daily mean temperature. City-specific associations were summarised as overall-cumulative exposure-response curves. Results We found a positive association between cause-specific medical prescriptions and daily mean temperature with a non-linear inverted J- or V-shaped relationship in most cities. Between 0.3% and 0.6% of all respiratory prescriptions were attributed to cold for Madrid, Zaragoza and Pamplona, while in cities with only cold effects the attributable fractions were estimated as 19.2% for Murcia and 13.5% for Santander. Heat effects in Madrid, Zaragoza and Pamplona showed higher fractions between 8.7% and 17.2%. The estimated costs are in general higher for heat effects, showing annual values ranging between €191,905 and €311,076 for heat per 100,000 persons. Conclusions This study provides novel evidence of the effects of the thermal environment on the prescription of medication for respiratory disorders in Spain, showing that low and high temperatures lead to an increase in the number of such prescriptions. The consumption of medication can reflect exposure to the environment with a lesser degree of severity in terms of morbidity., DR was supported by a postdoctoral research followship of the Xunta de Galicia (Spain). Award number: Not aplicable.

BACKGROUND First-trimester miscarriage affects up to a quarter of women worldwide. With many competing treatment options available, there is a need for a comprehensive evidence synthesis. OBJECTIVES AND RATIONALE We conducted a systematic review and network meta-analysis to assess the effectiveness and safety of treatment options for first-trimester miscarriage: expectant management (EXP), sharp dilation and curettage (D+C), electric vacuum aspiration (EVAC), manual vacuum aspiration (MVA), misoprostol alone (MISO), mifepristone+misoprostol (MIFE+MISO) and misoprostol plus electric vacuum aspiration (MISO+EVAC). SEARCH METHODS We searched MEDLINE, Embase, CINAHL, AMED and Cochrane Library from inception till June 2018. We included randomized trials of women with first-trimester miscarriage (, The authors acknowledge the initial contribution of Arri Coomarasamy, Ioannis Gallos and Mary Eyo.

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.

This study aims to estimate the prevalence of autism spectrum disorders (ASD) in 2017 and the ASD diagnosis incidence between 2009 and 2017 in children living in Catalonia region in Spain, and their temporal and geographical variability. We used administrative data for all children aged 2–17 years who were insured in the public Catalan Health System between 2009 and 2017. We identified all ASD cases diagnosed between 2009 and 2017 (ICD-9 codes 299.0, 299.1, 299.8, and 299.9). We estimated the ASD prevalence in 2017 and the overall annual incidence between 2009 and 2017, then stratified by sex, age group, and healthcare area. We used Poisson regression models to assess temporal trends in the incidence and mixed-effects Poisson regression models to assess geographical variability. We observed an ASD prevalence of 1.23% (95% confidence interval [CI] 1.21–1.25) in 2017, with 1.95% (95% CI 1.92–1.99) for boys and 0.46% (95% CI 0.44–0.48) for girls, the highest prevalence being in 11- to 17-year-olds (1.80%, 95% CI 1.76–1.83). The ASD diagnosis incidence increased from 0.07% (95% CI 0.06–0.09) in 2009 to 0.23% (95% CI 0.21–0.24) in 2017, with a higher increase in girls, and in children aged 2–5 years at the time of diagnosis. We only observed geographical differences in prevalence in the 2017 data. We also detected a threefold increase in the diagnosis incidence overall, which was even more pronounced in girls and at early ages. In conclusion, the ASD prevalence observed in this study was 1.23% in 2017, with a sex ratio of 4.5 in favor of boys, which is consistent with previous studies. Autism Res2019. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. Lay Summary: Autism spectrum disorders (ASD) are currently well known in our society as one of the most common neurodevelopmental disorders during childhood. The results of our study showed that, in 2017 in Catalonia, slightly more than one in a 100 children had an ASD diagnosis, it was more common in boys than in girls, and also in older children. In addition, between 2009 and 2017, we observed an increase in the number of new cases diagnosed each year. The data presented in this study will assist in planning and evaluating the needs of health services in this geographical region. © 2019 The Authors. Autism Research published by International Society for Autism Research published by Wiley Periodicals, Inc., The research described in this article was conducted under contract with the Health Effects Institute (HEI), an organization funded jointly by the United States Environmental Protection Agency (EPA; Assistance Award No. R-82811201) and certain motor vehicle and engine manufacturers. The contents of this article do not necessarily reflect the views of HEI or its sponsors, nor do they necessarily reflect the views and policies of the EPA or motor vehicle and engine manufacturers. M.G. is funded by a Miguel Servet fellowship (MS13/00054, CP18/00018) from the Spanish Institute of Health Carlos III. A.P. is supported by the Medical Research Council (grant numbers MR/K501256/1, MR/N013468/1). The authors would like to express their gratitude to Joan Albert d'Escofet, from the Agency for Health Quality and Assessment of the Catalan Health Department, for providing essential data and support for this study. The research materials supporting this publication can be accessed by contacting the corresponding author on reasonable request.

Background The use of obstetric early warning systems (OEWS) are recommended as an adjunct to reduce maternal morbidity and mortality. The aim of this review was to document the variation in OEWS trigger thresholds and the quality of information included within accompanying escalation protocols. Methods A review of OEWS charts and escalation policies across consultant-led maternity units in the UK (n = 147) was conducted. OEWS charts were analysed for variation in the values of physiological parameters triggering different levels of clinical escalation. Relevant data within the escalation protocols were also searched for: urgency of clinical response; seniority of responder; frequency of on-going clinical monitoring; and clinical setting recommended for on-going care. Results The values of physiological parameters triggering specific clinical responses varied significantly between OEWS. Only 99 OEWS charts (67.3%) had an escalation protocol as part of the chart. For 29 charts (19.7%), the only escalation information included was generic, for example to “contact a doctor if triggers”. Only 76 (51.7%) charts detailed the required seniority of responder, 37 (25.2%) the frequency for on-going clinical monitoring, eight (5.4%) the urgency of clinical response and two (1.4%) the recommended clinical setting for on-going care. Conclusion The observed variations in the trigger thresholds used in OEWS charts and the quality of information included within the accompanying escalation protocols is likely to lead to suboptimal detection and response to clinical deterioration during pregnancy and the post-partum period. The development of a national OEWS and escalation protocol would help to standardise care across obstetric units.

Objective This systematic review aimed to evaluate the scientific evidence on the efficacy of desensitizing mouthwashes for the treatment of dentin hypersensitivity (DH) and root sensitivity (RS). Material and methods A thorough search in MEDLINE, PubMed and Cochrane Plus Library was conducted up to February 2015. Randomized clinical trials, parallel, double-blinded and placebo-controlled, with a follow-up of at least 6 weeks, reporting changes on response to tactile stimuli, thermal/evaporative stimuli or patients’ subjective assessment of the pain experienced during their daily life after the home use of desensitizing mouthwashes were considered for inclusion. Results The screening of titles and abstracts resulted in seven publications meeting the eligibility criteria. The desensitizing agents evaluated were potassium nitrate (n = 5), aluminium lactate (n = 1) and sodium fluoride (n = 1). A meta-analysis for each of the hypersensitivity stimuli was performed. Results demonstrated statistically significant reduction in sensitivity scores favouring test group when DH was assessed by means of patients’ self-reported pain experience (SMD at 8 weeks = 0.77; 95% CI [0.23; 1.31]; P = 0.005). No significant effects were detected in response to tactile or thermal/evaporative stimuli. Meta-regression analysis demonstrated a tendency towards an increased effect favouring test group for the patients’ subjective perception, whereas tactile and thermal/evaporative stimuli showed a slight tendency towards a reduction in the efficacy of the test mouthwash. Conclusions There exists a tendency towards a decrease in DH or RS scores with time in both treatment groups, with significant differences in favour of test group when sensitivity is evaluated in terms of patients’ self-reported sensitivity symptoms.

Objective: To determine the effectiveness of the Phosphodiesterase 5 (PDE5) Inhibitors for the treatment of erectile dysfunction in patients with spinal trauma. Methods: A systematic review and meta-analysis comparing PDE5 inhibitors versus placebo were carried out for clinical trials conducted between 1980 and 2014 that evaluated male patients older than 18 years, diagnosed with spinal cord trauma and erectile dysfunction. We designed a search strategy for Medline, CENTRAL, EMBASE and other electronic sources. Two investigators independently and blindly screened the studies for inclusion. A random effect meta-analysis was performed. Results: Six studies involving 963 patients were included. Male patients over 18 years with ED attributable or subsequent to traumatic spinal cord injury (SCI) were included from these studies. In 4 of these studies, patients were randomized to the treatment group receiving sildenafil and the comparison group was placebo. Out of the remaining 2 trials, one compared tadalafil against the placebo and the other vardenafil versus placebo. The improvement on SCIs with PDE5 inhibitors was found to be large (standardized mean difference 0.71; 95% CI 0.39-1.03), with a high heterogeneity (I2 = 74.4%). Conclusions: PDE5 inhibitors are effective for the treatment of erectile dysfunction secondary to SCI. © 2016 S. Karger AG, Basel.

Background: The evidence and method are limited for the associations between mortality and temperature variability (TV) within or between days. Objectives: We developed a novel method to calculate TV and investigated TV-mortality associations using a large multicountry data set. Methods: We collected daily data for temperature and mortality from 372 locations in 12 countries/regions (Australia, Brazil, Canada, China, Japan, Moldova, South Korea, Spain, Taiwan, Thailand, the United Kingdom, and the United States). We calculated TV from the standard deviation of the minimum and maximum temperatures during the exposure days. Two-stage analyses were used to assess the relationship between TV and mortality. In the first stage, a Poisson regression model allowing over-dispersion was used to estimate the community-specific TV-mortality relationship, after controlling for potential confounders. In the second stage, a meta-analysis was used to pool the effect estimates within each country. Results: There was a significant association between TV and mortality in all countries, even after controlling for the effects of daily mean temperature. In stratified analyses, TV was still significantly associated with mortality in cold, hot, and moderate seasons. Mortality risks related to TV were higher in hot areas than in cold areas when using short TV exposures (0–1 days), whereas TV-related mortality risks were higher in moderate areas than in cold and hot areas when using longer TV exposures (0–7 days). Conclusions: The results indicate that more attention should be paid to unstable weather conditions in order to protect health. These findings may have implications for developing public health policies to manage health risks of climate change. © 2016, Public Health Services, US Dept of Health and Human Services. All rights reserved., This work was supported by the University of Queensland (Australia) (Y.G.); the National Health and Medical Research Council (Australia) (grant 553043) (S.T.); the Australian Research Council (Australia) (grant DP110100651) (S.T.); the Medical Research Council-UK (grant G1002296) (A.G.); the Ministry of Education, Spain (grant PRX12/00515) (A.T.); the Ministry of the Environment, Japan (M.H. and Y.H.); and the National Research Foundation of Korea (grant K21004000001-10A0500-00710) (H.K.).

Background/AimLow and high temperatures have been associated with mortality risk. In addition, the temperature-mortality relationship is different across geographic locations and specific causes. T...

Background Postpartum haemorrhage (PPH) is the leading cause of maternal mortality worldwide. Prophylactic uterotonic agents can prevent PPH, and are routinely recommended. The current World Health Organization (WHO) recommendation for preventing PPH is 10 IU (international units) of intramuscular or intravenous oxytocin. There are several uterotonic agents for preventing PPH but there is still uncertainty about which agent is most effective with the least side effects. This is an update of a Cochrane Review which was first published in April 2018 and was updated to incorporate results from a recent large WHO trial. Objectives To identify the most effective uterotonic agent(s) to prevent PPH with the least side effects, and generate a ranking according to their effectiveness and side-effect profile. Search methods We searched the Cochrane Pregnancy and Childbirth’s Trials Register, ClinicalTrials.gov, the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (24 May 2018), and reference lists of retrieved studies. Selection criteria All randomised controlled trials or cluster-randomised trials comparing the effectiveness and side effects of uterotonic agents with other uterotonic agents, placebo or no treatment for preventing PPH were eligible for inclusion. Quasi-randomised trials were excluded. Randomised trials published only as abstracts were eligible if sufficient information could be retrieved. Data collection and analysis At least three review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. We estimated the relative effects and rankings for preventing PPH ≥ 500 mL and PPH ≥ 1000 mL as primary outcomes. Secondary outcomes included blood loss and related outcomes, morbidity outcomes, maternal well-being and satisfaction and side effects. Primary outcomes were also reported for pre-specified subgroups, stratifying by mode of birth, prior risk of PPH, healthcare setting, dosage, regimen and route of administration. We performed pairwise meta-analyses and network meta-analysis to determine the relative effects and rankings of all available agents. Main results The network meta-analysis included 196 trials (135,559 women) involving seven uterotonic agents and placebo or no treatment, conducted across 53 countries (including high-, middle- and low-income countries). Most trials were performed in a hospital setting (187/196, 95.4%) with women undergoing a vaginal birth (71.5%, 140/196). Relative effects from the network meta-analysis suggested that all agents were effective for preventing PPH ≥ 500 mL when compared with placebo or no treatment. The three highest ranked uterotonic agents for prevention of PPH ≥ 500 mL were ergometrine plus oxytocin combination, misoprostol plus oxytocin combination and carbetocin. There is evidence that ergometrine plus oxytocin (RR 0.70, 95% CI 0.59 to 0.84, moderate certainty), carbetocin (RR 0.72, 95% CI 0.56 to 0.93, moderate certainty) and misoprostol plus oxytocin (RR 0.70, 95% CI 0.58 to 0.86, low certainty) may reduce PPH ≥ 500 mL compared with oxytocin. Low-certainty evidence suggests that misoprostol, injectable prostaglandins, and ergometrine may make little or no difference to this outcome compared with oxytocin. All agents except ergometrine and injectable prostaglandins were effective for preventing PPH ≥ 1000 mL when compared with placebo or no treatment. High-certainty evidence suggests that ergometrine plus oxytocin (RR 0.83, 95% CI 0.66 to 1.03) and misoprostol plus oxytocin (RR 0.88, 95% CI 0.70 to 1.11) make little or no difference in the outcome of PPH ≥ 1000 mL compared with oxytocin. Low-certainty evidence suggests that ergometrine may make little or no difference to this outcome compared with oxytocin meanwhile the evidence on carbetocin was of very low certainty. High-certainty evidence suggests that misoprostol is less effective in preventing PPH ≥ 1000 mL when compared with oxytocin (RR 1.19, 95% CI 1.01 to 1.42). Despite the comparable relative treatment effects between all uterotonics (except misoprostol) and oxytocin, ergometrine plus oxytocin, misoprostol plus oxytocin combinations and carbetocin were the highest ranked agents for PPH ≥ 1000 mL. Misoprostol plus oxytocin reduces the use of additional uterotonics (RR 0.56, 95% CI 0.42 to 0.73, high certainty) and probably also reduces the risk of blood transfusion (RR 0.51, 95% CI 0.37 to 0.70, moderate certainty) when compared with oxytocin. Carbetocin, injectable prostaglandins and ergometrine plus oxytocin may also reduce the use of additional uterotonics but the certainty of the evidence is low. No meaningful differences could be detected between all agents for maternal deaths or severe morbidity as these outcomes were rare in the included randomised trials where they were reported. The two combination regimens were associated with important side effects. When compared with oxytocin, misoprostol plus oxytocin combination increases the likelihood of vomiting (RR 2.11, 95% CI 1.39 to 3.18, high certainty) and fever (RR 3.14, 95% CI 2.20 to 4.49, moderate certainty). Ergometrine plus oxytocin increases the likelihood of vomiting (RR 2.93, 95% CI 2.08 to 4.13, moderate certainty) and may make little or no difference to the risk of hypertension, however absolute effects varied considerably and the certainty of the evidence was low for this outcome. Subgroup analyses did not reveal important subgroup differences by mode of birth (caesarean versus vaginal birth), setting (hospital versus community), risk of PPH (high versus low risk for PPH), dose of misoprostol (≥ 600 mcg versus < 600 mcg) and regimen of oxytocin (bolus versus bolus plus infusion versus infusion only). Authors' conclusions All agents were generally effective for preventing PPH when compared with placebo or no treatment. Ergometrine plus oxytocin combination, carbetocin, and misoprostol plus oxytocin combination may have some additional desirable effects compared with the current standard oxytocin. The two combination regimens, however, are associated with significant side effects. Carbetocin may be more effective than oxytocin for some outcomes without an increase in side effects. Which drug is best for reducing excessive blood loss after birth? What is the issue? The aim of this Cochrane Review was to find out which drug is most effective in preventing excessive blood loss at childbirth and has the least side effects. We collected and analysed all the relevant studies to answer this question (date of search: 24 May 2018). Why is this important? Excessive bleeding after birth is the most common reason why mothers die in childbirth worldwide. Although most women will have moderate bleeding at birth, others may bleed excessively, and this can pose a serious risk to their health and life. To reduce excessive bleeding at birth, the routine administration of a drug to contract the uterus (uterotonic) has become standard practice across the world. Different drugs given routinely at birth have been used for reducing excessive bleeding. They include oxytocin, misoprostol, ergometrine, carbetocin, injectable prostaglandins and combinations of these drugs, each with different effectiveness and side effects. Some of the side effects identified include: vomiting, high blood pressure and fever. Currently, oxytocin is recommended as the standard drug to reduce excessive bleeding. We analysed all the available evidence to compare the effectiveness and side-effect profiles for each drug. What evidence did we find? We found 196 studies involving 135,559 women. We compared seven uterotonic agents against each other and against women receiving no uterotonic. Studies were conducted across 53 countries. In most studies women were giving birth normally and in a hospital. The analysis suggests that all drugs are effective for preventing blood loss that equals or exceeds 500 mL when compared with no routine uterotonic treatment. Compared with oxytocin (the standard recommended drug), the three best drugs for this outcome were a combination of ergometrine plus oxytocin, carbetocin, and a combination of misoprostol plus oxytocin. We found the other drugs misoprostol, injectable prostaglandins, and ergometrine may make little or no difference to this outcome compared with oxytocin. All drugs except ergometrine and injectable prostaglandins are effective for preventing blood loss that equals or exceeds 1000 mL when compared with no treatment. Ergometrine plus oxytocin and misoprostol plus oxytocin make little or no difference in this outcome compared with oxytocin. It is uncertain whether carbetocin and ergometrine alone make any difference to this outcome. However, misoprostol is less effective in preventing blood loss that equals or exceeds 1000 mL compared with oxytocin. Misoprostol plus oxytocin reduces the use of additional uterotonics and probably also reduces the risk of blood transfusion when compared with oxytocin. Carbetocin, injectable prostaglandins and ergometrine plus oxytocin may also reduce the use of additional uterotonics but the certainty of the evidence is low. No meaningful differences could be detected between all agents for maternal deaths or severe birth complication as these are rare in such studies. The two combinations of drugs were associated with important side effects. When compared with oxytocin, women receiving misoprostol plus oxytocin combination are more likely to suffer vomiting and fever. Women receiving ergometrine plus oxytocin are also more likely to suffer vomiting and may make little or no difference to the risk of hypertension, however the certainty of the evidence was low for this outcome. The analyses gave similar results irrespective of whether women were giving birth normally or by caesarean, in a hospital or in the community, were at high or low risk for bleeding excessively after birth, whether they received a high or a low dose of misoprostol and whether they received a bolus or an infusion of oxytocin or both. What does this mean? All agents were generally effective for preventing excessive bleeding when compared with no uterotonic drug treatment. Ergometrine plus oxytocin combination, carbetocin, and misoprostol plus oxytocin combination may have some additional benefits compared with the current standard oxytocin. The two combination drugs, however, are associated with significant side effects that women might find disturbing compared with oxytocin. Carbetocin may have some additional benefits compared with oxytocin and appears to be without an increase in side effects.

Objective To estimate the incidence of caesarean scar pregnancy (CSP) and to describe the management outcomes associated with this condition. Design A national cohort study using the UK Early Pregnancy Surveillance Service (UKEPSS). Setting 86 participating Early Pregnancy Units. Population All women diagnosed in the participating units with CSP between November 2013 and January 2015. Methods Cohort study of women identified through the UKEPSS monthly mailing system. Main outcome measures Incidence, clinical outcomes and complications. Results 102 cases of CSP were reported, with an estimated incidence of 1.5 per 10 000 (95% CI 1.1-1.9) maternities. Full outcome data were available for 92 women. Management was expectant in 21/92 (23%), medical in 15/92 (16%) and surgical in 56/92 (61%). The success rates of expectant, medical and surgical management were 43% (9/21), 46% (7/15) and 96% (54/56), respectively. The complication rates were 15/21 (71%) with expectant, 9/15 (60%) with medical and 20/56 (36%) with surgical management. Discharge from care (median number of days) was 82 (range 37-174) with expectant, 21 (range 10-31) with medical and 11 (range 4-49) with surgical management. Conclusions Surgical management appears to be associated with a high success rate, low complication rate and short post-treatment follow up. Tweetable abstract Surgery for CSP appears to be successful, with low complication rates and short post-treatment follow up.

STUDY QUESTION Is serum vitamin D associated with live birth rates in women undergoing ART? SUMMARY ANSWER Women undergoing ART who are replete in vitamin D have a higher live birth rate than women who are vitamin D deficient or insufficient. WHAT IS KNOWN ALREADY Vitamin D deficiency has been associated with an increased risk of abnormal pregnancy implantation as well as obstetric complications such as pre-eclampsia and fetal growth restriction. However, the effect of vitamin D on conception and early pregnancy outcomes in couples undergoing ART is poorly understood. STUDY DESIGN, SIZE, DURATION A systematic review and meta-analysis of 11 published cohort studies (including 2700 women) investigating the association between vitamin D and ART outcomes. PARTICIPANTS/MATERIALS, SETTINGS, METHODS Literature searches were conducted to retrieve studies which reported on the association between vitamin D and ART outcomes. Databases searched included MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials and CINAHL. Eleven studies matched the inclusion criteria. MAIN RESULTS AND THE ROLE OF CHANCE Live birth was reported in seven of the included studies (including 2026 patients). Live birth was found to be more likely in women replete in vitamin D when compared to women with deficient or insufficient vitamin D status (OR 1.33 [1.08-1.65]). Five studies (including 1700 patients) found that women replete in vitamin D were more likely to achieve a positive pregnancy test than women deficient or insufficient in vitamin D (OR 1.34 ([1.04-1.73]). All 11 of the included studies (including 2700 patients) reported clinical pregnancy as an outcome. Clinical pregnancy was found to be more likely in women replete in vitamin D (OR 1.46 [1.05-2.02]). Six studies (including 1635 patients) reported miscarriage by vitamin D concentrations. There was no association found between miscarriage and vitamin D concentrations (OR 1.12 [0.81-1.54]. The included studies scored well on the Newcastle-Ottawa quality assessment scale. LIMITATIONS REASONS FOR CAUTION Although strict inclusion criteria were used in the conduct of the systematic review, the included studies are heterogeneous in population characteristics and fertility treatment protocols. WIDER IMPLICATIONS OF THE FINDINGS The findings of this systematic review show that there is an association between vitamin D status and reproductive treatment outcomes achieved in women undergoing ART. Our results show that vitamin D deficiency and insufficiency could be important conditions to treat in women considering ARTs. A randomized controlled trial to investigate the benefits of vitamin D deficiency treatment should be considered to test this hypothesis. STUDY FUNDING/COMPETING INTERESTS No external funding was either sought or obtained for this study. The authors have no competing interests to declare. REGISTRATION NUMBER N/A.

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: Primary To assess the relative effectiveness and produce a clinically meaningful hierarchy of first-line uterotonic drugs for the treatment of postpartum haemorrhage (PPH). Secondary To assess the relative risks and produce side effect hierarchies of first-line uterotonic drugs for the treatment of PPH.

Background and aims Most studies show that probiotics are effective in preventing morbidity and mortality in preterm infants. Using network meta-analysis (NMA) we aim to rank treatments’ efficacy and identify the most effective strain, formulation and dose. Methods Databases searched: CENTRAL, Ovid MEDLINE EMBASE, LILACS and the Cochrane Database of Systematic Reviews. Clinicaltrials.gov; controlled-trials.com; and WHO’s ICTRP were searched for any ongoing studies. Searches completed up to November 2016 without language restriction. Reference checking, citation searching and contact with study authors were done to identify additional studies. Randomised controlled trials evaluating probiotics interventions and combinations of probiotics/strains of the same probiotic of all durations were included. 2 independent, unblinded review authors assessed the trials for inclusion and extracted data. We used standard methodology as per The Cochrane Collaboration. The protocol was registered – Cochrane Database CD012303, PROSPERO CRD42016047640. Main results 53 included trials reported outcomes on 13 630 infants. The period of studies was Jan 1986-Oct 2016. All studies enrolled infants Our preliminary results from 35 studies (10 063 patients) show evidence of significant reduction in global mortality in probiotics group (10 063 patients, RR 0.77, 95% CI 0.66 to 0.91, I2=0%). Data from 38 studies provide information on severe necrotising enterocolitis (NEC), stage 2 or 3, with a significant reduction in the incidence of NEC with prophylactic administration of probiotics (9455 patients, RR 0.52, 95% CI 0.40 to 0.68, I2=22%). And, data from 35 studies with 10 565 patients informed about any culture proven sepsis, showed a significant reduction in rates of confirmed sepsis (RR 0.82, 95% CI 0.74 to 0.92, I2=33%). Conclusion Based on our preliminary results, It seems (moderate quality of evidence) that administration of probiotics in preterm infants could reduce NEC, culture proven sepsis and even global mortality. We are currently analysing the most effective strain of probiotic. Further clinical trials of probiotics head to head will be needed to confirm our data.

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: We aim to assess the clinical effectiveness and safety profile of currently applied controlled ovarian stimulation (COS) protocols, and to generate a clinically-useful ranking of these protocols.

Objectives: To evaluate the impact of road safety interventions, including the penalty point system (PPS) and the reformed Spanish penal code (RPC), on traffic-related occupational injuries in Spain. Methods: The study design was an interrupted time-series with a comparison group. The study group had traffic-related, occupational injuries incurred during working and commuting hours; the comparison group had non-traffic-related injuries incurred at the work site. A negative binomial regression model was used to determine the relative risk (RR) of sustaining occupational injuries for the post-intervention periods compared to the non-intervention period. Results: Non-fatal, traffic-related injuries did not significantly change after the PPS and RPC implementations, except for those occurred in commuting hours, which increased significantly after the PPS. On the other hand, after the RPC, fatal, traffic-related injuries decreased significantly during working hours (0.79; 95%CI 0.65 to 0.97) and commuting hours (RR: 0.63; 95%CI:0,56 to 0.72), although fatal, non-traffic-related injuries also decreased at the work site. Conclusions: Road safety interventions did not clearly affect traffic-related occupational injuries in Spain. Specific occupational risk factors could influence the occurrence of those injuries. (C) 2014 Elsevier Ltd. All rights reserved.

Introduction Desert dust concentrations raise concerns about adverse effects on human health. During the last decade, special attention has been given to mineral dust particles from desert dust and sand storms. However, evidence from previous reviews reported inconclusive results on their health effects and the biological mechanism remains unclear. We aim to systematically synthesise evidence on the health effects of desert dust and sand storms accounting for the relevant desert dust patterns from source areas and emissions, transport and composition. Methods an analysis We will conduct a systematic review that investigated the health effects of desert dust and sand storms in any population. The search will be performed for any eligible studies from previous reviews and selected electronic databases until 2018. Study selection and reporting will follow the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Data from individual studies will be extracted using a standardised data extraction form. Quality of the studies will be assessed using a risk of bias tool for environmental exposures developed by experts convened by the WHO. A meta-analysis will be performed by calculating the appropriate effect measures of association for binary and continuous outcomes from individual studies. Subgroup analyses will be performed by geographical areas to account for desert dust patterns. Ethics and dissemination No primary data will be collected. For this reason, no formal ethical approval is required. This systematic review will help to fill the research gaps in the knowledge of desert dust on human health. The results will be disseminated through a WHO peer-reviewed publication and a conference presentation. © 2019 Author(s) (or their employer(s)). Re-use permitted under CC BY. Published by BMJ., Funding The World Health Organization, supported by the Ministry of Foreign Affairs of Norway, has funded this systematic review.

Purpose Atomoxetine is a non-stimulant drug that could be an alternative to methylphenidate, whose benefit:risk balance for the treatment of adults with attention deficit hyperactivity disorder (ADHD) has recently been shown to be unclear. This study aimed to compare all-cause discontinuation rate between atomoxetine and placebo in adults with ADHD. Secondarily, efficacy and safety were investigated. Methods Systematic review and meta-analysis of randomized controlled trials comparing atomoxetine with placebo in adults with ADHD were performed. All-cause treatment discontinuation was the primary endpoint. Efficacy in reducing ADHD symptoms and safety were the secondary endpoints. Odds ratio (OR) and the standardized mean difference (SMD) were calculated for dichotomous and continuous outcomes, respectively. Data were pooled using the fixed and random effects model. The influence of study design-related, intervention-related and patient-related co-variables over the primary endpoint was investigated by means of meta-regression. This study is registered with the international prospective register of systematic reviews (PROSPERO): CRD 42012002042. Results Twelve studies (3375 patients) were included. Treatment discontinuation was larger with atomoxetine than with placebo (OR= 1.39). No co-variable was found to modify the effect of atomoxetine over treatment discontinuation. Atomoxetine showed modest efficacy in reducing ADHD symptoms irrespective of the assessor: patient (SMD=0.33); clinician (SMD=0.40). The rate of adverse events-induced discontinuation was higher with atomoxetine than with placebo (OR=2.57). Conclusion This study suggests that atomoxetine has a poor benefit–risk balance for the treatment of adults with ADHD. The recommendation of atomoxetine use in this population is weak. Copyright © 2013 John Wiley & Sons, Ltd. key words—attention deficit hyperactivity disorder; atomoxetine; discontinuation; efficacy; safety; meta-analysis; meta-regression; pharmacoepidemiology

BACKGROUND: The risk-benefit balance of pharmacological treatment for children and adolescents with ADHD and the factors that moderate this relationship are unclear. METHODS: A systematic review and meta-analysis of randomised, placebo-controlled clinical trials (RPCCTs) investigating the efficacy of pharmacological treatment in children or adolescents with ADHD was carried out. Meta-analysis of treatment discontinuation, clinician-, parent- and teacher-rated efficacy and adverse events was performed. The effect of covariates was studied. RESULTS: Sixty-three studies were included. Ten drugs were investigated, with atomoxetine and methylphenidate the most frequently studied. RPCCTs had mostly a short duration (7.9 weeks). All-cause treatment discontinuation was lower with pharmacological treatment than placebo (OR = 0.68). Pharmacological treatment was more efficacious than placebo independently of the rater (clinician, standardised mean difference (SMD) 0.74; parent, SMD = 0.63; or teacher, SMD = 0.75). Evidence of publication bias was found for clinician-rated efficacy, especially in industry-sponsored RPCCT. Psychostimulants showed a higher efficacy and were associated with a better outcome on treatment discontinuation than non-stimulant drugs. Efficacy was smaller in RPCCTs for which a psychiatric comorbid disorder was an inclusion criterion, was larger in studies with a commercial sponsorship and showed a negative association with treatment length. CONCLUSIONS: In the short term, pharmacological treatment provides moderate-high symptom relief, is safe and shows lower treatment discontinuation than placebo, suggesting a suitable risk-benefit balance, particularly with psychostimulants. The efficacy is lower in patients with a comorbid psychiatric disorder and should be assessed periodically, as it appears to reduce over time. Publication bias of clinician-rated efficacy in studies with a commercial sponsor is suggested.

Epidemiological evidence on the associations between exposure to ultrafine particles (UFP), with aerodynamic electrical mobility diameters, We thank the Consorci Sanitari de Barcelona (Cat-Salut) for providing hospitalisation data for Barcelona and the Agencia Estatal de Meteorologia (Ministerio de Agricultura, Alimentación y Medio Ambiente) for providing the weather data for Spain. We thank the Finnish Meteorological Institute for providing the weather data for Finland and Helsinki Region Environmental Services Authority HSY for providing the air pollution (other than UFP) data for Helsinki, Finland. The study has been conducted as a collaborative effort of the UF&HEALTH Study Group. UF&HEALTH Study Group: S. Breitner, J. Cyrys, R. Hampel, F. Hennig, B. Hoffmann, T. Kuhlbusch; S. Lanzinger, A. Peters, U. Quass, A. Schneider, K. Wolf (Germany); E. Diapouli, K. Elefteriadis, K. Katsouyanni, E. Samoli, S. Vratolis (Greece); T. Ellermann, Z. Ivanovic-Andersen, S. Loft, A. Massling, C. Nordstrøm (Denmark); P.P. Aalto, M. Kulmala, T. Lanki, J. Pekkanen, P. Tiittanen, T. Yli-Tuomi (Finland); G. Cattani, A. Faustini, F. Forastiere, M. Inglessis, M. Renzi, M. Stafoggia (Italy); D. Agis, X. Basagaña, B. Jacquemin, N. Perez, J. Sunyer, A. Tobias (Spain); G. Bero-Bedada, T. Bellander (Sweden).