Summary Background Causes of mortality are a crucial input for health systems for identifying appropriate interventions for child survival. We present an updated series of cause-specific mortality for neonates and children younger than 5 years from 2000 to 2019. Methods We updated cause-specific mortality estimates for neonates and children aged 1–59 months, stratified by level (low, moderate, or high) of mortality. We made a substantial change in the statistical methods used for previous estimates, transitioning to a Bayesian framework that includes a structure to account for unreported causes in verbal autopsy studies. We also used systematic covariate selection in the multinomial framework, gave more weight to nationally representative verbal autopsy studies using a random effects model, and included mortality due to tuberculosis. Findings In 2019, there were 5·30 million deaths (95% uncertainty range 4·92–5·68) among children younger than 5 years, primarily due to preterm birth complications (17·7%, 16·1–19·5), lower respiratory infections (13·9%, 12·0–15·1), intrapartum-related events (11·6%, 10·6–12·5), and diarrhoea (9·1%, 7·9–9·9), with 49·2% (47·3–51·9) due to infectious causes. Vaccine-preventable deaths, such as for lower respiratory infections, meningitis, and measles, constituted 21·7% (20·4–25·6) of under-5 deaths, and many other causes, such as diarrhoea, were preventable with low-cost interventions. Under-5 mortality has declined substantially since 2000, primarily because of a decrease in mortality due to lower respiratory infections, diarrhoea, preterm birth complications, intrapartum-related events, malaria, and measles. There is considerable variation in the extent and trends in cause-specific mortality across regions and for different strata of all-cause under-5 mortality. Interpretation Progress is needed to improve child health and end preventable deaths among children younger than 5 years. Countries should strategize how to reduce mortality among this age group using interventions that are relevant to their specific causes of death. Funding Bill & Melinda Gates Foundation; WHO.

SummaryBackgroundAntifibrinolytics reduce death from bleeding in trauma and post-partum haemorrhage. We examined the effect of treatment delay on the effectiveness of antifibrinolytics.MethodsWe did an individual patient-level data meta-analysis of randomised trials done with more than 1000 patients that assessed antifibrinolytics in acute severe bleeding. We identified trials done between Jan 1, 1946, and April 7, 2017, from MEDLINE, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science, PubMed, Popline, and the WHO International Clinical Trials Registry Platform. The primary measure of treatment benefit was absence of death from bleeding. We examined the effect of treatment delay on treatment effectiveness using logistic regression models. We investigated the effect of measurement error (misclassification) in sensitivity analyses. This study is registered with PROSPERO, number 42016052155.FindingsWe obtained data for 40 138 patients from two randomised trials of tranexamic acid in acute severe bleeding (traumatic and post-partum haemorrhage). Overall, there were 3558 deaths, of which 1408 (40%) were from bleeding. Most (884 [63%] of 1408) bleeding deaths occurred within 12 h of onset. Deaths from post-partum haemorrhage peaked 2–3 h after childbirth. Tranexamic acid significantly increased overall survival from bleeding (odds ratio [OR] 1·20, 95% CI 1·08–1·33; p=0·001), with no heterogeneity by site of bleeding (interaction p=0·7243). Treatment delay reduced the treatment benefit (p<0·0001). Immediate treatment improved survival by more than 70% (OR 1·72, 95% CI 1·42–2·10; p<0·0001). Thereafter, the survival benefit decreased by 10% for every 15 min of treatment delay until 3 h, after which there was no benefit. There was no increase in vascular occlusive events with tranexamic acid, with no heterogeneity by site of bleeding (p=0·5956). Treatment delay did not modify the effect of tranexamic acid on vascular occlusive events.InterpretationDeath from bleeding occurs soon after onset and even a short delay in treatment reduces the benefit of tranexamic acid administration. Patients must be treated immediately. Further research is needed to deepen our understanding of the mechanism of action of tranexamic acid.FundingUK NIHR Health Technology Assessment programme, Pfizer, BUPA Foundation, and J P Moulton Charitable Foundation (CRASH-2 trial). London School of Hygiene & Tropical Medicine, Pfizer, UK Department of Health, Wellcome Trust, and Bill & Melinda Gates Foundation (WOMAN trial).

Background: The associations between pregnancy hypertensive disorders and common cardiovascular disorders have not been investigated at scale in a contemporaneous population. We aimed to investigate the association between preeclampsia, hypertensive disorders of pregnancy, and subsequent diagnosis of 12 different cardiovascular disorders. Methods: We used linked electronic health records from 1997 to 2016 to recreate a UK population-based cohort of 1.3 million women, mean age at delivery 28 years, with nearly 1.9 million completed pregnancies. We used multivariable Cox models to determine the associations between hypertensive disorders of pregnancy, and preeclampsia alone (term and preterm), with 12 cardiovascular disorders in addition to chronic hypertension. We estimated the cumulative incidence of a composite end point of any cardiovascular disorder according to preeclampsia exposure. Results: During the 20-year study period, 18 624 incident cardiovascular disorders were observed, 65% of which had occurred in women under 40 years. Compared to women without hypertension in pregnancy, women who had 1 or more pregnancies affected by preeclampsia had a hazard ratio of 1.9 (95% confidence interval 1.53–2.35) for any stroke, 1.67 (1.54–1.81) for cardiac atherosclerotic events, 1.82 (1.34–2.46) for peripheral events, 2.13 (1.64–2.76) for heart failure, 1.73 (1.38–2.16) for atrial fibrillation, 2.12 (1.49–2.99) for cardiovascular deaths, and 4.47 (4.32–4.62) for chronic hypertension. Differences in cumulative incidence curves, according to preeclampsia status, were apparent within 1 year of the first index pregnancy. Similar patterns of association were observed for hypertensive disorders of pregnancy, while preterm preeclampsia conferred slightly further elevated risks. Conclusions: Hypertensive disorders of pregnancy, including preeclampsia, have a similar pattern of increased risk across all 12 cardiovascular disorders and chronic hypertension, and the impact was evident soon after pregnancy. Hypertensive disorders of pregnancy should be considered as a natural screening tool for cardiovascular events, enabling cardiovascular risk prevention through national initiatives.

IMPORTANCE Oral intake of new probiotic formulations may improve the course of atopic dermatitis (AD) in a young population.OBJECTIVE To determine whether a mixture of oral probiotics is safe and effective in the treatment of AD symptoms and to evaluate its influence on the use of topical steroids in a young population. DESIGN, SETTING, AND PARTICIPANTSA 12-week randomized, double-blind, placebo-controlled intervention trial, from March to June 2016, at the outpatient hospital Centro Dermatológico Estético de Alicante, Alicante, Spain. Observers were blinded to patient groupings. Participants were children aged 4 to 17 years with moderate atopic dermatitis. The groups were stratified and block randomized according to sex, age, and age of onset. Patients were ineligible if they had used systemic immunosuppressive drugs in the previous 3 months or antibiotics in the previous 2 weeks or had a concomitant diagnosis of intestinal bowel disease or signs of bacterial infection.INTERVENTIONS Twelve weeks with a daily capsule containing freeze-dried powder with 10 9 total colony-forming units of the probiotic strains Bifidobacterium lactis CECT 8145, B longum CECT 7347, and Lactobacillus casei CECT 9104 and maltodextrin as a carrier, or placebo (maltodextrin-only capsules).MAIN OUTCOMES AND MEASURES SCORAD index score and days of topical steroid use were analyzed.RESULTS Fifty children (26 [50%] female; mean [SD] age, 9.2 [3.7] years) participated. After 12 weeks of follow-up, the mean reduction in the SCORAD index in the probiotic group was 19.2 points greater than in the control group (mean difference, −19.2; 95% CI, −15.0 to −23.4). In relative terms, we observed a change of −83% (95% CI, −95% to −70%) in the probiotic group and −24% (95% CI, −36% to −11%) in the placebo group (P < .001). We found a significant reduction in the use of topical steroids to treat flares in the probiotic arm (161 of 2084 patient-days [7.7%]) compared with the control arm (220 of 2032 patient-days [10.8%]; odds ratio, 0.63; 95% CI, 0.51 to 0.78). CONCLUSIONS AND RELEVANCEThe mixture of probiotics was effective in reducing SCORAD index and reducing the use of topical steroids in patients with moderate AD. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT02585986

Background Atopic eczema is a common inflammatory skin disease. Various inflammatory conditions have been linked to cardiovascular disease, a major cause of global mortality and morbidity. Objective We sought to systematically review and meta-analyze population-based studies assessing associations between atopic eczema and specific cardiovascular outcomes. Methods MEDLINE, Embase, and Global Health were searched from inception to December 2017. We obtained pooled estimates using random-effects meta-analyses. We used a multivariate Bayesian meta-regression model to estimate the slope of effect of increasing atopic eczema severity on cardiovascular outcomes. Results Nineteen relevant studies were included. The effects of atopic eczema reported in cross-sectional studies were heterogeneous, with no evidence for pooled associations with angina, myocardial infarction, heart failure, or stroke. In cohort studies atopic eczema was associated with increased risk of myocardial infarction (n = 4; relative risk [RR], 1.12; 95% CI, 1.00-1.25), stroke (n = 4; RR, 1.10; 95% CI, 1.03-1.17), ischemic stroke n = 4; RR, 1.17; 95% CI, 1.14-1.20), angina (n = 2; RR, 1.18; 95% CI, 1.13-1.24), and heart failure (n = 2; RR, 1.26; 95% CI, 1.05-1.51). Prediction intervals were wide for myocardial infarction and stroke. The risk of cardiovascular outcomes appeared to increase with increasing severity (mean RR increase between severity categories, 1.15; 95% credibility interval, 1.09-1.21; uncertainty interval, 1.04-1.28). Conclusion Significant associations with cardiovascular outcomes were more common in cohort studies but with considerable between-study heterogeneity. Increasing atopic eczema severity was associated with increased risk of cardiovascular outcomes. Improved awareness among stakeholders regarding this small but significant association is warranted.

Objectives To examine whether the effect of tranexamic acid on the risk of death and thrombotic events in patients with traumatic bleeding varies according to baseline risk of death. To assess the extent to which current protocols for treatment with tranexamic acid maximise benefits to patients.Design Prespecified stratified analysis of data from an international multicentre randomised controlled trial (the CRASH-2 trial) with an estimation of the proportion of premature deaths that could potentially be averted through the administration of tranexamic acid.Participants 13 273 trauma patients in the CRASH-2 trial who were treated with tranexamic acid or placebo within three hours of injury and trauma patients enrolled in UK Trauma and Audit Research Network, stratified by risk of death at baseline (<6%, 6-20%, 21-50%, >50%).Intervention Tranexamic acid (1 g over 10 minutes followed by 1 g over eight hours) or matching placebo.Main outcome measure Odds ratios and 95% confidence intervals for death in hospital within four weeks of injury, deaths from bleeding, and fatal and non-fatal thrombotic events associated with the use of tranexamic acid according to baseline risk of death. Unless there was strong evidence against the null hypothesis of homogeneity of effects (P<0.001), the overall odds ratio was used as the most reliable guide to the odds ratios in all strata.Results Tranexamic acid was associated with a significant reduction in all cause mortality and deaths from bleeding. In each stratum of baseline risk, there were fewer deaths among patients treated with tranexamic acid. There was no evidence of heterogeneity in the effect of tranexamic acid on all cause mortality (P=0.96 for interaction) or deaths from bleeding (P=0.98) by baseline risk of death. In those treated with tranexamic acid there was a significant reduction in the odds of fatal and non-fatal thrombotic events (odds ratio 0.69, 95% confidence interval 0.53 to 0.89; P=0.005) and a significant reduction in arterial thrombotic events (0.58, 0.40 to 0.83; P=0.003) but no significant reduction in venous thrombotic events (0.83, 0.59 to 1.17; P=0.295). There was no evidence of heterogeneity in the effect of tranexamic acid on the risk of thrombotic events (P=0.74). If the effect of tranexamic acid is assumed to be the same in all risk strata (<6%, 6-20%, 21-50%, >50% risk of death at baseline), the percentage of deaths that could be averted by administration of tranexamic acid within three hours of injury in each group is 17%, 36%, 30%, and 17%, respectively.Conclusions Tranexamic acid can be administered safely to a wide spectrum of patients with traumatic bleeding and should not be restricted to the most severely injured.Trial registration ISRCTN86750102.

This clinical trial evaluated the effect of a probiotic mixture as coadjutant treatment together with topical steroids in 90 patients with plaque psoriasis. The results showed a larger reduction in the score of severity indexes in the probiotic group compared with the placebo group. Gut microbiota analysis demonstrated the efficacy of the probiotic in modulation of the composition of the microbiota. After the end of the probiotic or placebo intake, patients were followedup for 6 months. The results showed a lower risk of relapse in patients in the probiotic group. The aim of this 12-week randomized, double-blind, placebo-controlled trial was to determine the efficacy and safety of a probiotic mixture in the reduction of psoriasis severity. Ninety 18-70-year-old adults with plaque psoriasis were randomized into probiotic and placebo groups. At 12-week follow-up, 66.7% of patients in the probiotic group and 41.9% in the placebo group showed a reduction in Psoriasis Area and Severity Index of at least 75% (p < 0.05). A clinically relevant difference was observed in Physician Global Assessment index: 48.9% in the probiotic group achieved a score of 0 or 1, compared with 30.2% in the placebo group. The results of follow-up 6 months after the end of the study showed a lower risk of relapse after the intake of the probiotic mixture. Analysis of gut microbiota confirmed the efficacy of the probiotic in modulation of the microbiota composition.

Background: The burden of noncommunicable diseases and their risk factors has rapidly increased worldwide, including in India. Innovative management strategies with electronic decision support and task sharing have been assessed for hypertension, diabetes mellitus, and depression individually, but an integrated package for multiple chronic condition management in primary care has not been evaluated. Methods: In a prospective, multicenter, open-label, cluster-randomized controlled trial involving 40 community health centers, using hypertension and diabetes mellitus as entry points, we evaluated the effectiveness of mWellcare, an mHealth system consisting of electronic health record storage and an electronic decision support for the integrated management of 5 chronic conditions (hypertension, diabetes mellitus, current tobacco and alcohol use, and depression) versus enhanced usual care among patients with hypertension and diabetes mellitus in India. At trial end (12-month follow-up), using intention-to-treat analysis, we examined the mean difference between arms in change in systolic blood pressure and glycated hemoglobin as primary outcomes and fasting blood glucose, total cholesterol, predicted 10-year risk of cardiovascular disease, depression score, and proportions reporting tobacco and alcohol use as secondary outcomes. Mixed-effects regression models were used to account for clustering and other confounding variables. Results: Among 3698 enrolled participants across 40 clusters (mean age, 55.1 years; SD, 11 years; 55.2% men), 3324 completed the trial. There was no evidence of difference between the 2 arms for systolic blood pressure (Δ=−0.98; 95% CI, −4.64 to 2.67) and glycated hemoglobin (Δ=0.11; 95% CI, −0.24 to 0.45) even after adjustment of several key variables (adjusted differences for systolic blood pressure: – 0.31 [95% CI, −3.91 to 3.29]; for glycated hemoglobin: 0.08 [95% CI, −0.27 to 0.44]). The mean within-group changes in systolic blood pressure in mWellcare and enhanced usual care were −13.65 mm Hg versus −12.66 mm Hg, respectively, and for glycated hemoglobin were −0.48% and −0.58%, respectively. Similarly, there were no differences in the changes between the 2 groups for tobacco and alcohol use or other secondary outcomes. Conclusions: We did not find an incremental benefit of mWellcare over enhanced usual care in the management of the chronic conditions studied. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02480062.