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Background Master protocols, classified as basket trials, umbrella trials, and platform trials, are novel designs that investigate multiple hypotheses through concurrent sub-studies (e.g., multiple treatments or populations or that allow adding/removing arms during the trial), offering enhanced efficiency and a more ethical approach to trial evaluation. Despite the many advantages of these designs, they are infrequently used. Methods We conducted a landscape analysis of master protocols using a systematic literature search to determine what trials have been conducted and proposed for an overall goal of improving the literacy in this emerging concept. On July 8, 2019, English-language studies were identified from MEDLINE, EMBASE, and CENTRAL databases and hand searches of published reviews and registries. Results We identified 83 master protocols (49 basket, 18 umbrella, and 16 platform trials). The number of master protocols has increased rapidly over the last five years. Most have been conducted in the US ( n = 44/83) and investigated experimental drugs ( n = 82/83) in the field of oncology ( n = 76/83). The majority of basket trials were exploratory (i.e., phase I/II; n = 47/49) and not randomized ( n = 44/49), and more than half ( n = 28/48) investigated only a single intervention. The median sample size of basket trials was 205 participants (interquartile range, Q3-Q1 [IQR]: 500–90 = 410), and the median study duration was 22.3 (IQR: 74.1–42.9 = 31.1) months. Similar to basket trials, most umbrella trials were exploratory ( n = 16/18), but the use of randomization was more common ( n = 8/18). The median sample size of umbrella trials was 346 participants (IQR: 565–252 = 313), and the median study duration was 60.9 (IQR: 81.3–46.9 = 34.4) months. The median number of interventions investigated in umbrella trials was 5 (IQR: 6–4 = 2). The majority of platform trials were randomized ( n = 15/16), and phase III investigation ( n = 7/15; one did not report information on phase) was more common in platform trials with four of them using seamless II/III design. The median sample size was 892 (IQR: 1835–255 = 1580), and the median study duration was 58.9 (IQR: 101.3–36.9 = 64.4) months. Conclusions We anticipate that the number of master protocols will continue to increase at a rapid pace over the upcoming decades. More efforts to improve awareness and training are needed to apply these innovative trial design methods to fields outside of oncology.

In this trial comparing less-tight control of hypertension (target diastolic blood pressure, 100 mm Hg) with tight control (85 mm Hg) among pregnant women, rates of pregnancy loss, high-level neonatal care, and serious maternal complications were similar between groups. Almost 10% of pregnant women have hypertension; hypertension is preexisting in 1%, gestational hypertension without proteinuria develops in 5 to 6%, and preeclampsia develops in 2%. 1 Preexisting hypertension and gestational hypertension before 34 weeks are associated with an increased risk of perinatal and maternal complications. 2 – 4 Blood-pressure targets for women with nonsevere hypertension during pregnancy are much debated. Relevant randomized, controlled trials have been small and of moderate or poor quality; tight control (the use of antihypertensive therapy to normalize blood pressure) has been associated with maternal benefits (e.g., a decrease in the frequency of severe hypertension and possibly in . . .

Type 2 diabetes can be treated, and sometimes reversed, with dietary interventions; however, strategies to implement these interventions while addressing medication changes are lacking. We conducted a 12-week pragmatic, community-based parallel-group randomized controlled trial (ClinicalTrials.gov: NCT03181165) evaluating the effect of a low-carbohydrate (<50 g), energy-restricted diet (~850-1100 kcal/day; Pharm-TCR; n = 98) compared to treatment-as-usual (TAU; n = 90), delivered by community pharmacists, on glucose-lowering medication use, cardiometabolic health, and health-related quality of life. The Pharm-TCR intervention was effective in reducing the need for glucose-lowering medications through complete discontinuation of medications (35.7%; n = 35 vs. 0%; n = 0 in TAU; p < 0.0001) and reduced medication effect score compared to TAU. These reductions occurred concurrently with clinically meaningful improvements in hemoglobin A1C, anthropometrics, blood pressure, and triglycerides (all p < 0.0001). These data indicate community pharmacists are a viable and innovative option for implementing short-term nutritional interventions for people with type 2 diabetes, particularly when medication management is a safety concern. Community pharmacists are accessible healthcare providers with expertise in medication management. Here the authors show that a low-carbohydrate, low-energy diet implemented by community pharmacists reduced diabetes medication use and improved glucose control in people with type 2 diabetes.

This study tested progesterone for perimenopausal hot flush ± night sweat (vasomotor symptom, VMS) treatment. It was a double-blind, randomized trial of 300 mg oral micronized progesterone@bedtime versus placebo for 3-months (m) after a 1-m untreated baseline during 2012/1–2017/4. We randomized untreated, non-depressed, screen- and baseline-eligible by VMS, perimenopausal women (with flow within 1-year), ages 35–58 (n = 189). Participants aged 50 (± SD = 4.6) were mostly White, educated, minimally overweight with 63% in late perimenopause; 93% participated remotely. The 1° outcome was 3rd-m VMS Score difference. Participants recorded VMS number and intensity (0–4 scale)/24 h on a VMS Calendar. Randomization required VMS (intensity 2–4/4) of sufficient frequency and/or ≥ 2/week night sweat awakenings. Baseline total VMS Score (SD) was 12.2 (11.3) without assignment difference. Third-m VMS Score did not differ by therapy (Rate Difference − 1.51). However, the 95% CI [− 3.97, 0.95] P  = 0.222, did not exclude 3, a minimal clinically important difference. Women perceived progesterone caused decreased night sweats ( P  = 0.023) and improved sleep quality (P = 0.005); it decreased perimenopause-related life interference ( P  = 0.017) without increased depression. No serious adverse events occurred. Perimenopausal night sweats ± hot flushes are variable; this RCT was underpowered but could not exclude a minimal clinically important VMS benefit. Perceived night sweats and sleep quality significantly improved.

[This corrects the article DOI: 10.1371/journal.pone.0308926.].

Pelvic organ prolapse (POP) increases in incidence and severity with aging. At least 1 in 4 women seek pelvic floor care and many more suffer with concurrent symptoms of bowel, bladder and sexual dysfunction, which can have a large impact on quality of life. It is estimated that 1 in 5 women will undergo surgery for POP. POP is difficult to cure with existing surgeries and therefore treatment failure and reoperations are common. Surgical innovation in this area is urgently needed and we have developed a novel technique of bilateral sacrospinous vaginal vault fixation with synthetic mesh arms (BSSVF-M). Based on preliminary studies it may be more successful, durable and cost-effective than standard sacrospinous ligament suspension with sutures (SSLS). Preliminary development and exploration studies showed safety and efficacy of BSSVF-M. Following an established framework for research in surgical innovations, we now wish to conduct a randomized comparative effectiveness trial for assessment of this novel technique. This is a multi-center randomized controlled trial in Canada comparing the surgical techniques of BSSVF-M vs. SSLS to address apical prolapse. In total, 358 women with symptomatic POP at five centers will be randomized with 80% power to detect a 15% difference in primary composite outcome and accounting for a 15% loss to follow-up over 2 years. The primary objective is to investigate BSSVF-M vs. SSLS using an established composite of 3 objective signs and 1 subjective symptom of POP measured 2 years postoperatively. Secondary objectives: 1) To determine changes in condition-specific pelvic symptoms, quality of life, pain and condition-specific body image post BSSVF-M vs. SSLS using validated questionnaires; 2) To determine changes in sexuality post BSSVF-M vs. SSLS; 3) To determine global impression of improvement, adverse events (validated classification scheme), reoperations and health utility post BSSVF-M vs. SSLS; 4) To determine the cost-effectiveness of BSSVF-M vs SSLS. Study Registration at clinicaltrials.gov (NCT02965313). There is a need for innovation to improve the surgical approach to vaginal apical suspension. Despite controversies with mesh, it has been shown to be safe when used appropriately and to have higher durability when compared with sutures. As well, the importance of restoring anatomy and tension-free surgical approach in pelvic reconstructive surgery has led to better long-term outcomes and fewer side effects. These principles have been applied when developing the novel BSSVF-M technique. Anticipated challenges of this trial include recruitment, compliance problems and loss to follow up However, the robust methodology will provide evidence on the best surgical approach to correct POP, a common condition among aging women.

Cystic fibrosis (CF) is a progressive multi-organ disease with significant morbidity placing extensive demands on the healthcare system. Little is known about those individuals with CF who continually incur high costs over multiple years. Understanding their characteristics may help inform opportunities to improve management and care, and potentially reduce costs. The purpose of this study was to identify and understand the clinical and demographic attributes of frequent high-costing CF individuals and characterize their healthcare utilization and costs over time. A longitudinal study of retrospective data was completed in British Columbia, Canada by linking the Canadian CF Registry with provincial healthcare administrative databases for the period between 2009 and 2017. Multivariable Cox regression models were employed to identify baseline factors associated with becoming a frequent high-cost CF user (vs. not a frequent high-cost CF user) in the follow-up period. We found that severe lung impairment (Hazard Ratio [HR]: 3.71, 95% confidence interval [CI], 1.49–9.21), lung transplantation (HR: 4.23, 95% CI, 1.68–10.69), liver cirrhosis with portal hypertension (HR: 10.96, 95% CI: 3.85–31.20) and female sex (HR: 1.97, 95% CI: 1.13–3.44) were associated with becoming a frequent high-cost CF user. Fifty-nine (17% of cohort) frequent high-cost CF users accounted for more than one-third of the overall total healthcare costs, largely due to inpatient hospitalization and outpatient medication costs.

Chronic or gestational hypertension complicates approximately 7% of pregnancies, half of which reach 37 weeks' gestation. Early term birth (at 37 to 38 weeks) may reduce maternal complications, cesareans, stillbirths, and costs but may increase neonatal morbidity. In the WILL Trial (When to Induce Labour to Limit risk in pregnancy hypertension), we aimed to establish optimal timing of birth for women with chronic or gestational hypertension who reach term and remain well. This 50-centre, open-label, randomised trial in the United Kingdom included an economic analysis. WILL randomised women with chronic or gestational hypertension at 36 to 37 weeks and a singleton fetus, and who provided documented informed consent to \"Planned early term birth at 38+0-3 weeks\" (intervention) or \"usual care at term\" (control). The coprimary outcomes were \"poor maternal outcome\" (composite of severe hypertension, maternal death, or maternal morbidity; superiority hypothesis) and \"neonatal care unit admission for ≥4 hours\" (noninferiority hypothesis). The key secondary was cesarean. Follow-up was to 6 weeks postpartum. The planned sample size was 540/group. Analysis was by intention-to-treat. A total of 403 participants (37.3% of target) were randomised to the intervention (n = 201) or control group (n = 202), from 3 June 2019 to 19 December 2022, when the funder stopped the trial for delayed recruitment. In the intervention (versus control) group, losses to follow-up were 18/201 (9%) versus 15/202 (7%). In each group, maternal age was about 30 years, about one-fifth of women were from ethnic minorities, over half had obesity, approximately half had chronic hypertension, and most were on antihypertensives with normal blood pressure. In the intervention (versus control) group, birth was a median of 0.9 weeks earlier (38.4 [38.3 to 38.6] versus 39.3 [38.7 to 39.9] weeks). There was no evidence of a difference in \"poor maternal outcome\" (27/201 [13%] versus 24/202 [12%], respectively; adjusted risk ratio [aRR] 1.16, 95% confidence interval [CI] 0.72 to 1.87). For \"neonatal care unit admission for ≥4 hours,\" the intervention was considered noninferior to the control as the adjusted risk difference (aRD) 95% CI upper bound did not cross the 8% prespecified noninferiority margin (14/201 [7%] versus 14/202 [7%], respectively; aRD 0.003, 95% CI -0.05 to +0.06), although event rates were lower-than-estimated. The intervention (versus control) was associated with no difference in cesarean (58/201 [29%] versus 72/202 [36%], respectively; aRR 0.81, 95% CI 0.61 to 1.08. There were no serious adverse events. Limitations include our smaller-than-planned sample size, and lower-than-anticipated event rates, so the findings may not be generalisable to where hypertension is not treated with antihypertensive therapy. In this study, we observed that most women with chronic or gestational hypertension required labour induction, and planned birth at 38+0-3 weeks (versus usual care) resulted in birth an average of 6 days earlier, and no differences in poor maternal outcome or neonatal morbidity. Our findings provide reassurance about planned birth at 38+0-3 weeks as a clinical option for these women. isrctn.com ISRCTN77258279.

Mortality following hospital discharge is an important and under-recognized contributor to overall child mortality in developing countries. The primary objective of this systematic review was to identify all studies reporting post-discharge mortality in children, estimate likelihood of death, and determine the most important risk factors for death. MEDLINE and EMBASE were systematically searched using MeSH terms and keywords from the inception date to October, 2012. Key word searches using Google Scholar™ and hand searching of references of retrieved articles was also performed. Studies from developing countries reporting mortality following hospital discharge among a pediatric population were considered for inclusion. Thirteen studies that reported mortality rates following discharge were identified. Studies varied significantly according to design, underlying characteristics of study population and duration of follow-up. Mortality rates following discharge varied significantly between studies (1%-18%). When reported, post-discharge mortality rates often exceeded in-hospital mortality rates. The most important baseline variables associated with post-discharge mortality were young age, malnutrition, multiple previous hospitalizations, HIV infection and pneumonia. Most post-discharge deaths occurred early during the post-discharge period. Follow-up care was examined in only one study examining malaria prophylaxis in children discharged following an admission secondary to malaria, which showed no significant benefit on post-discharge mortality. The months following hospital discharge carry significant risk for morbidity and mortality. While several characteristics are strongly associated with post-discharge mortality, no validated tools are available to aid health workers or policy makers in the systematic identification of children at high risk of post-discharge mortality. Future research must focus on both the creation of tools to aid in defining groups of children most likely to benefit from post-discharge interventions, and formal assessment of the effectiveness of such interventions in reducing morbidity and mortality in the first few months following hospital discharge.