The Tibetan Uterotonic Zhi Byed 11: Mechanisms of Action, Efficacy, and Historical Use for Postpartum Hemorrhage

Objective. To explore evidence for the traditional Tibetan medicine, Zhi Byed 11 (ZB11), for use as a uterotonic. Methods. The eleven ingredients in ZB11 were chemically analyzed by mass spectroscopy. A review was conducted of Western allopathic literature for scientific studies on ZB11's individual components. Literature from Tibetan and other traditional paradigms were reviewed. Results. Potential mechanisms of action for ZB11 as a uterotonic include laxative effects, a dose-dependant increase in smooth muscle tissue peristalsis that may also affect the uterus smooth muscle, and chemical components that are prostaglandin precursors and/or increase prostaglandin synthesis. A recent RCT demonstrated comparable efficacy to misoprostol in reducing severe postpartum hemorrhage (PPH) (>1000 mL) and greater effect than placebo. Historical and anecdotal evidence for ZB11 and its ingredients for childbirth provide further support. Discussion. ZB11 and its ingredients are candidates for potentially effective uterotonics, especially in low-resource settings. Further research is warranted to understand the mechanisms of action and synergy between ingredients

The Effects of Leadership Curricula With and Without Implicit Bias Training on Graduate Medical Education: A Multicenter Randomized Trial

Purpose: To determine whether a brief leadership curriculum including high-fidelity simulation can improve leadership skills among resident physicians. Method: This was a double-blind randomized controlled trial among obstetrics and gynecology (OB/GYN) and emergency medicine (EM) residents across 5 academic medical centers from different geographic areas of the United States, 2015–2017. Participants were assigned to 1 of 3 study arms: the LEADS (Leadership Education Advanced During Simulation) curriculum, a shortened TeamSTEPPS (Team Strategies and Tools to Enhance Performance and Patient Safety) curriculum, or as active controls (no leadership curriculum). Active controls were recruited from a separate site and not randomized in order to limit any unintentional introduction of materials from the leadership curricula. The LEADS curriculum was developed in partnership with the Council on Resident Education in Obstetrics and Gynecology and Council of Residency Directors in Emergency Medicine as a novel way to provide a leadership toolkit. Both LEADS and the abbreviated TeamSTEPPS were designed as six 10-minute interactive web-based modules. The primary outcome of interest was the leadership performance score from the validated Clinical Teamwork Scale instrument measured during standardized high-fidelity simulation scenarios. Secondary outcomes were 9 key components of leadership from the detailed leadership evaluation measured on 5-point Likert scales. Both outcomes were rated by a blinded clinical video reviewer. Results: One hundred and ten OB/GYN and EM residents participated in this 2-year trial. Participants in both LEADS and TeamSTEPPS had statistically significant improvement in leadership scores from “average” to “good” ranges both immediately and at the 6-month follow-up, while controls remained unchanged in the “average” category throughout the study. There were no differences between the LEADS and TeamSTEPPS curricula with respect to the primary outcome. Conclusions: Residents who participated in a brief structured leadership training intervention had improved leadership skills that were maintained at 6-month follow-up

Risk factors for poor virological outcome at 12 months in a workplace-based antiretroviral therapy programme in South Africa: A cohort study

<p>Abstract</p> <p>Background</p> <p>Reasons for the variation in reported treatment outcomes from antiretroviral therapy (ART) programmes in developing countries are not clearly defined.</p> <p>Methods</p> <p>Among ART-naïve individuals in a workplace ART programme in South Africa we determined virological outcomes at 12 months, and risk factors for suboptimal virological outcome, defined as plasma HIV-1 viral load >= 400 copies/ml.</p> <p>Results</p> <p>Among 1760 individuals starting ART before July 2004, 1172 were in follow-up at 12 months of whom 953 (81%) had a viral load measurement (median age 41 yrs, 96% male, median baseline CD4 count 156 × 10⁶/l). 71% (681/953) had viral load < 400 copies/ml at 12 months. In a multivariable analysis, independent predictors of suboptimal virological outcome at 12 months were <1 log decrease in viral load at six weeks (odds ratio [OR] 4.71, 95% confidence interval [CI] 2.56–8.68), viral load at baseline (OR 3.63 [95% CI 1.88–7.00] and OR 3.54 [95% CI 1.79–7.00] for 10,001–100,000 and >100,000 compared to <= 10,000 copies/ml, respectively), adherence at six weeks (OR 3.50 [95% CI 1.92–6.35]), WHO stage (OR 2.08 [95% CI 1.28–3.34] and OR 2.03 [95% CI 1.14–3.62] for stage 3 and 4 compared to stage 1–2, respectively) and site of ART delivery. Site of delivery remained an independent risk factor even after adjustment for individual level factors. At 6 weeks, of 719 patients with self-reported adherence and viral load, 72 (10%) reported 100% adherence but had <1 log decrease in viral load; conversely, 60 (8%) reported <100% adherence but had >= 1 log decrease in viral load.</p> <p>Conclusion</p> <p>Virological response at six weeks after ART start was the strongest predictor of suboptimal virological outcome at 12 months, and may identify individuals who need interventions such as additional adherence support. Self reported adherence was less strongly associated but identified different patients compared with viral load at 6 weeks. Site of delivery had an important influence on virological outcomes; factors at the health system level which influence outcome need further investigation to guide development of effective ART programmes.</p

Clinical trials in amyotrophic lateral sclerosis:a systematic review and perspective

Amyotrophic lateral sclerosis is a progressive and devastating neurodegenerative disease. Despite decades of clinical trials, effective disease modifying drugs remain scarce. To understand the challenges of trial design and delivery, we performed a systematic review of phase II, phase II/III and phase III amyotrophic lateral sclerosis clinical drug trials on trial registries and PubMed between 2008 and 2019. We identified 125 trials, investigating 76 drugs and recruiting more than 15000 people with amyotrophic lateral sclerosis. 90% of trials used traditional fixed designs. The limitations in understanding of disease biology, outcome measures, resources and barriers to trial participation in a rapidly progressive, disabling and heterogenous disease hindered timely and definitive evaluation of drugs in two-arm trials. Innovative trial designs, especially adaptive platform trials may offer significant efficiency gains to this end. We propose a flexible and scalable multi-arm, multi-stage trial platform where opportunities to participate in a clinical trial can become the default for people with amyotrophic lateral sclerosis

Predictors and outcome of surgical repair of obstetric fistula at a regional referral hospital, Mbarara, western Uganda

<p>Abstract</p> <p>Background</p> <p>Obstetric fistula although virtually eliminated in high income countries, still remains a prevalent and debilitating condition in many parts of the developing world. It occurs in areas where access to care at childbirth is limited, or of poor quality and where few hospitals offer the necessary corrective surgery.</p> <p>Methods</p> <p>This was a prospective observational study where all women who attended Mbarara Regional Referral Hospital in western Uganda with obstetric fistula during the study period were assessed pre-operatively for social demographics, fistula characteristics, classification and outcomes after surgery. Assessment for fistula closure and stress incontinence after surgery was done using a dye test before discharge</p> <p>Results</p> <p>Of the 77 women who were recruited in this study, 60 (77.9%) had successful closure of their fistulae. Unsuccessful fistula closure was significantly associated with large fistula size (Odds Ratio 6 95% Confidential interval 1.46-24.63), circumferential fistulae (Odds ratio 9.33 95% Confidential interval 2.23-39.12) and moderate to severe vaginal scarring (Odds ratio 12.24 95% Confidential interval 1.52-98.30). Vaginal scarring was the only factor independently associated with unsuccessful fistula repair (Odds ratio 10 95% confidential interval 1.12-100.57). Residual stress incontinence after successful fistula closure was associated with type IIb fistulae (Odds ratio 5.56 95% Confidential interval 1.34-23.02), circumferential fistulae (Odds ratio 10.5 95% Confidential interval 1.39-79.13) and previous unsuccessful fistula repair (Odds ratio 4.8 95% Confidential interval 1.27-18.11). Independent predictors for residual stress incontinence after successful fistula closure were urethral involvement (Odds Ratio 4.024 95% Confidential interval 2.77-5.83) and previous unsuccessful fistula repair (Odds ratio 38.69 95% Confidential interval 2.13-703.88).</p> <p>Conclusions</p> <p>This study demonstrated that large fistula size, circumferential fistulae and marked vaginal scarring are predictors for unsuccessful fistula repair while predictors for residual stress incontinence after successful fistula closure were urethral involvement, circumferential fistulae and previous unsuccessful fistula repair.</p

Differentiation of embryonic stem cells into fibroblast-like cells in three-dimensional type I collagen gel cultures

Fibroblasts are heterogeneous mesenchymal cells that play important roles in the production and maintenance of extracellular matrix. Although their heterogeneity is recognized, progenitor progeny relationships among fibroblasts and the factors that control fibroblast differentiation are poorly defined. The current study was designed to develop a reliable method that would permit in vitro differentiation of fibroblast-like cells from human and murine embryonic stem cells (ESCs). Undifferentiated ESCs were differentiated into embryoid bodies (EBs) with differentiation media. EBs were then cast into type I collagen gels and cultured for 21 d with basal media. The spindle-shaped cells that subsequently grew from the EBs were released from the gels and subsequently cultured as monolayers in basal media supplemented with serum. Differentiated cells showed a characteristic spindle-shaped morphology and had ultrastructural features consistent with fibroblasts. Immunocytochemistry showed positive staining for vimentin and alpha-smooth muscle actin but was negative for stage-specific embryonic antigens and cytokeratins. Assays of fibroblast function, including proliferation, chemotaxis, and contraction of collagen gels demonstrated that the differentiated cells, derived from both human and murine ESCs, responded to transforming growth factor-β1 and prostaglandin E2 as would be expected of fibroblasts, functions not expected of endothelial or epithelial cells. The current study demonstrates that cells with the morphologic and functional features of fibroblasts can be reliably derived from human and murine ESCs. This methodology provides a means to investigate and define the mechanisms that regulate fibroblast differentiation

Insights into hominid evolution from the gorilla genome sequence.

Gorillas are humans' closest living relatives after chimpanzees, and are of comparable importance for the study of human origins and evolution. Here we present the assembly and analysis of a genome sequence for the western lowland gorilla, and compare the whole genomes of all extant great ape genera. We propose a synthesis of genetic and fossil evidence consistent with placing the human-chimpanzee and human-chimpanzee-gorilla speciation events at approximately 6 and 10 million years ago. In 30% of the genome, gorilla is closer to human or chimpanzee than the latter are to each other; this is rarer around coding genes, indicating pervasive selection throughout great ape evolution, and has functional consequences in gene expression. A comparison of protein coding genes reveals approximately 500 genes showing accelerated evolution on each of the gorilla, human and chimpanzee lineages, and evidence for parallel acceleration, particularly of genes involved in hearing. We also compare the western and eastern gorilla species, estimating an average sequence divergence time 1.75 million years ago, but with evidence for more recent genetic exchange and a population bottleneck in the eastern species. The use of the genome sequence in these and future analyses will promote a deeper understanding of great ape biology and evolution