Treatment of critical bleeding events in patients with immune thrombocytopenia: a protocol for a systematic review and meta-analysis.

BACKGROUND: Critical bleeding events in adults and children with ITP are medical emergencies; however, evidence-based treatment protocols are lacking. Due to the severe thrombocytopenia, (typically platelet count less than 20 × 109/L), a critical bleed portends a high risk of death or disability. We plan to perform a systematic review and meta-analysis of treatments for critical bleeding in patients with ITP that will inform evidence-based recommendations. METHODS: Literature searches will be conducted in four electronic databases: Ovid MEDLINE, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and PubMed. Eligible studies will be randomized controlled trials or observational studies that enrolled patients with ITP describing one or more interventions for the management of critical bleeding. Title and abstract screening, full-text screening, data extraction, and risk of bias evaluation will be conducted independently and in duplicate using Covidence and Excel. Outcomes will be pooled for meta-analysis where appropriate or summarized descriptively. Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology will be used to evaluate the certainty of the evidence. Primary outcomes of interest will include frequency of critical bleeds, mortality and bleeding-related mortality, bleeding resolution, platelet count, and disability. DISCUSSION: Evidence-based treatments for critical bleeding in patients with ITP are needed to improve patient outcomes and standardize care in the emergency setting. SYSTEMATIC REVIEW REGISTRATION: CRD42020161206.

Signal transduction at GPCRs: Allosteric activation of the ERK MAPK by ß-arrestin.

ß-arrestins are multivalent adaptor proteins that bind active phosphorylated G protein-coupled receptors (GPCRs) to inhibit G protein signaling, mediate receptor internalization, and initiate alternative signaling events. ß-arrestins link agonist-stimulated GPCRs to downstream signaling partners, such as the c-Raf-MEK1-ERK1/2 cascade leading to ERK1/2 activation. ß-arrestins have been thought to transduce signals solely via passive scaffolding by facilitating the assembly of multiprotein signaling complexes. Recently, however, ß-arrestin 1 and 2 were shown to activate two downstream signaling effectors, c-Src and c-Raf, allosterically. Over the last two decades, ERK1/2 have been the most intensely studied signaling proteins scaffolded by ß-arrestins. Here, we demonstrate that ß-arrestins play an active role in allosterically modulating ERK kinase activity in vitro and within intact cells. Specifically, we show that ß-arrestins and their GPCR-mediated active states allosterically enhance ERK2 autophosphorylation and phosphorylation of a downstream ERK2 substrate, and we elucidate the mechanism by which ß-arrestins do so. Furthermore, we find that allosteric stimulation of dually phosphorylated ERK2 by active-state ß-arrestin 2 is more robust than by active-state ß-arrestin 1, highlighting differential capacities of ß-arrestin isoforms to regulate effector signaling pathways downstream of GPCRs. In summary, our study provides strong evidence for a new paradigm in which ß-arrestins function as active "catalytic" scaffolds to allosterically unlock the enzymatic activity of signaling components downstream of GPCR activation.

Outcomes of an Online Virtual Boot Camp to Prepare Fourth-Year Medical Students for a Successful Transition to Internship.

Introduction Changes in medical education and health care delivery have limited the ability of fourth-year medical students to perform the role of an intern prior to graduating from medical school. To address this issue, many schools have instituted residency preparation courses (sometimes referred to as boot camps) particularly for students entering surgical fields. Courses for students entering nonprocedural fields are less common and most assess increases in self-reported confidence without providing objective evidence of a gain in knowledge or skills improvement. Materials and Methods We used a Plan, Do, Study, Act (PDSA) model to develop and pilot cycle 1 of a nonprocedural internship preparation elective in 2019. Feedback was used to refine the course and map sessions to core competencies outlined by the Accreditation Council of Graduate Medical Education (ACGME) for PDSA cycle 2. The curriculum was adapted for remote synchronous delivery due to the coronavirus pandemic in spring 2020 using a combination of didactic lectures containing embedded polls and case-based role play responses using a chat box. Students completed anonymous surveys assessing self-perceived levels of confidence, as well as an objective comprehensive assessment after course completion. Results A total of 89 students participated in the course. Pre-session confidence was lowest for transfusion medicine, handling pages from nursing while on call, and knowledge of the role of a chief resident. A statistically significant increase in median scores for self-reported knowledge or confidence was seen in all sessions. The percentage of students reporting that they were either confident or extremely confident also increased significantly after each session (p<0.001 for all). All sessions analyzed were rated as useful or extremely useful by more than half of the students, and 94% of the students scored 70% or higher on the comprehensive course assessment. Conclusions An online virtual synchronous boot camp increased students' confidence in handling common topics encountered during residency and demonstrated an appropriate gain in knowledge using a comprehensive assessment. We were able to adapt our curriculum to a remote model and will likely keep several sessions in an online format in the future.

Prevalence and intensity of persistent post-surgical pain following breast cancer surgery: a systematic review and meta-analysis of observational studies.

BACKGROUND: The prevalence and intensity of persistent post-surgical pain (PPSP) after breast cancer surgery are uncertain. We conducted a systematic review and meta-analysis to further elucidate this issue. METHODS: We searched MEDLINE, Embase, CINAHL, and PsycINFO, from inception to November 2018, for observational studies reporting persistent pain (≥3 months) after breast cancer surgery. We used random-effects meta-analysis and the Grading of Recommendations, Assessment, Development and Evaluations approach to rate quality of evidence. RESULTS: We included 187 observational studies with 297 612 breast cancer patients. The prevalence of PPSP ranged from 2% to 78%, median 37% (inter-quartile range: 22-48%); the pooled prevalence was 35% (95% confidence interval [CI]: 32-39%). The pooled pain intensity was 3.9 cm on a 10 cm visual analogue scale (95% CI: 3.6-4.2 cm). Moderate-quality evidence supported the subgroup effects of PPSP prevalence for localized pain vs any pain (29% vs 44%), moderate or greater vs any pain (26% vs 44%), clinician-assessed vs patient-reported pain (23% vs 36%), and whether patients underwent sentinel lymph node biopsy vs axillary lymph node dissection (26% vs 43%). The adjusted analysis found that the prevalence of patient-reported PPSP (any severity/location) was 46% (95% CI: 36-56%), and the prevalence of patient-reported moderate-to-severe PPSP at any location was 27% (95% CI: 10-43%). CONCLUSIONS: Moderate-quality evidence suggests that almost half of all women undergoing breast cancer surgery develop persistent post-surgical pain, and about one in four develop moderate-to-severe persistent post-surgical pain; the higher prevalence was associated with axillary lymph node dissection. Future studies should explore whether nerve sparing for axillary procedures reduces persistent post-surgical pain after breast cancer surgery.

Comparison of dietary macronutrient patterns of 14 popular named dietary programmes for weight and cardiovascular risk factor reduction in adults: systematic review and network meta-analysis of randomised trials.

OBJECTIVE: To determine the relative effectiveness of dietary macronutrient patterns and popular named diet programmes for weight loss and cardiovascular risk factor improvement among adults who are overweight or obese. DESIGN: Systematic review and network meta-analysis of randomised trials. DATA SOURCES: Medline, Embase, CINAHL, AMED, and CENTRAL from database inception until September 2018, reference lists of eligible trials, and related reviews. STUDY SELECTION: Randomised trials that enrolled adults (≥18 years) who were overweight (body mass index 25-29) or obese (≥30) to a popular named diet or an alternative diet. OUTCOMES AND MEASURES: Change in body weight, low density lipoprotein (LDL) cholesterol, high density lipoprotein (HDL) cholesterol, systolic blood pressure, diastolic blood pressure, and C reactive protein at the six and 12 month follow-up. REVIEW METHODS: Two reviewers independently extracted data on study participants, interventions, and outcomes and assessed risk of bias, and the certainty of evidence using the GRADE (grading of recommendations, assessment, development, and evaluation) approach. A bayesian framework informed a series of random effects network meta-analyses to estimate the relative effectiveness of the diets. RESULTS: 121 eligible trials with 21 942 patients were included and reported on 14 named diets and three control diets. Compared with usual diet, low carbohydrate and low fat diets had a similar effect at six months on weight loss (4.63 v 4.37 kg, both moderate certainty) and reduction in systolic blood pressure (5.14 mm Hg, moderate certainty v 5.05 mm Hg, low certainty) and diastolic blood pressure (3.21 v 2.85 mm Hg, both low certainty). Moderate macronutrient diets resulted in slightly less weight loss and blood pressure reductions. Low carbohydrate diets had less effect than low fat diets and moderate macronutrient diets on reduction in LDL cholesterol (1.01 mg/dL, low certainty v 7.08 mg/dL, moderate certainty v 5.22 mg/dL, moderate certainty, respectively) but an increase in HDL cholesterol (2.31 mg/dL, low certainty), whereas low fat (-1.88 mg/dL, moderate certainty) and moderate macronutrient (-0.89 mg/dL, moderate certainty) did not. Among popular named diets, those with the largest effect on weight reduction and blood pressure in comparison with usual diet were Atkins (weight 5.5 kg, systolic blood pressure 5.1 mm Hg, diastolic blood pressure 3.3 mm Hg), DASH (3.6 kg, 4.7 mm Hg, 2.9 mm Hg, respectively), and Zone (4.1 kg, 3.5 mm Hg, 2.3 mm Hg, respectively) at six months (all moderate certainty). No diets significantly improved levels of HDL cholesterol or C reactive protein at six months. Overall, weight loss diminished at 12 months among all macronutrient patterns and popular named diets, while the benefits for cardiovascular risk factors of all interventions, except the Mediterranean diet, essentially disappeared. CONCLUSIONS: Moderate certainty evidence shows that most macronutrient diets, over six months, result in modest weight loss and substantial improvements in cardiovascular risk factors, particularly blood pressure. At 12 months the effects on weight reduction and improvements in cardiovascular risk factors largely disappear. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42015027929.

Anti-Ebola therapy for patients with Ebola virus disease: a systematic review.

BACKGROUND: Management of Ebola virus disease (EVD) has historically focused on infection prevention, case detection and supportive care. Several specific anti-Ebola therapies have been investigated, including during the 2014-2016 West African outbreak. Our objective was to conduct a systematic review of the effect of anti-Ebola virus therapies on clinical outcomes to guide their potential use and future evaluation. METHODS: We searched PubMed, EMBASE, Global Health, Cochrane Library, African Index Medicus, WHOLIS (inception-9 April 2018), and trial registries for observational studies or clinical trials, in any language, that enrolled patients with confirmed EVD who received therapy targeting Ebola virus and reported on mortality, symptom duration, or adverse effects. RESULTS: From 11,257 citations and registered trials, we reviewed 55 full-text citations, of which 35 met eligibility criteria (1 randomized clinical trial (RCT), 8 non-randomized comparative studies, 9 case series and 17 case reports) and collectively examined 21 anti-Ebola virus agents. The 31 studies performed during the West African outbreak reported on 4.8% (1377/28616) of all patients with Ebola. The only RCT enrolled 72 patients (0.25% of all patients with Ebola) and compared the monoclonal antibody ZMapp vs. standard care (mortality, 22% vs. 37%; 95% confidence interval for risk difference, - 36 to 7%). Studies of convalescent plasma, interferon-ß-1a, favipiravir, brincidofovir, artesunate-amodiaquine and TKM-130803 were associated with at least moderate risk of bias. CONCLUSIONS: Research evaluating anti-Ebola virus agents has reached very few patients with EVD, and inferences are limited by non-randomized study designs. ZMapp has the most promising treatment signal.

Predictors of Unemployment After Breast Cancer Surgery: A Systematic Review and Meta-Analysis of Observational Studies.

Purpose Breast cancer surgery is associated with unemployment. Identifying high-risk patients could help inform strategies to promote return to work. We systematically reviewed observational studies to explore factors associated with unemployment after breast cancer surgery. Methods We searched MEDLINE, EMBASE, CINAHL, and PsycINFO to identify studies that explored risk factors for unemployment after breast cancer surgery. When possible, we pooled estimates of association for all independent variables reported by more than one study. Results Twenty-six studies (46,927 patients) reported the association of 127 variables with unemployment after breast cancer surgery. Access to universal health care was associated with higher rates of unemployment (26.6% v 15.4%; test of interaction P = .05). High-quality evidence showed that unemployment after breast cancer surgery was associated with high psychological job demands (odds ratio [OR], 4.26; 95% CI, 2.27 to 7.97), childlessness (OR, 1.30; 95% CI, 1.11 to 1.53), lower education level (OR, 1.15; 95% CI, 1.05 to 1.25), lower income level (OR, 1.46; 95% CI, 1.24 to 1.73), cancer stage II, III or IV (OR, 1.43; 95% CI, 1.13 to 1.82), and mastectomy versus breast-conserving surgery (OR, 1.18; 95% CI, 1.07 to 1.30). Moderate-quality evidence suggested an association with high physical job demands (OR, 2.11; 95%CI, 1.52 to 2.93), African-American ethnicity (OR, 1.89; 95% CI, 1.21 to 2.96), and receipt of chemotherapy (OR, 1.95; 95% CI, 1.36 to 2.79). High-quality evidence demonstrated no significant association with part-time hours, blue-collar work, tumor size, positive lymph nodes, or receipt of radiotherapy or endocrine therapy; moderate-quality evidence suggested no association with age, marital status, or axillary lymph node dissection. Conclusion Addressing high physical and psychological job demands may be important in reducing unemployment after breast cancer surgery.

Predictors of persistent pain after breast cancer surgery: a systematic review and meta-analysis of observational studies.

BACKGROUND: Persistent pain after breast cancer surgery affects up to 60% of patients. Early identification of those at higher risk could help inform optimal management. We conducted a systematic review and meta-analysis of observational studies to explore factors associated with persistent pain among women who have undergone surgery for breast cancer. METHODS: We searched the MEDLINE, Embase, CINAHL and PsycINFO databases from inception to Mar. 12, 2015, to identify cohort or case-control studies that explored the association between risk factors and persistent pain (lasting ≥ 2 mo) after breast cancer surgery. We pooled estimates of association using random-effects models, when possible, for all independent variables reported by more than 1 study. We reported relative measures of association as pooled odds ratios (ORs) and absolute measures of association as the absolute risk increase. RESULTS: Thirty studies, involving a total of 19 813 patients, reported the association of 77 independent variables with persistent pain. High-quality evidence showed increased odds of persistent pain with younger age (OR for every 10-yr decrement 1.36, 95% confidence interval [CI] 1.24-1.48), radiotherapy (OR 1.35, 95% CI 1.16-1.57), axillary lymph node dissection (OR 2.41, 95% CI 1.73-3.35) and greater acute postoperative pain (OR for every 1 cm on a 10-cm visual analogue scale 1.16, 95% CI 1.03-1.30). Moderate-quality evidence suggested an association with the presence of preoperative pain (OR 1.29, 95% CI 1.01-1.64). Given the 30% risk of pain in the absence of risk factors, the absolute risk increase corresponding to these ORs ranged from 3% (acute postoperative pain) to 21% (axillary lymph node dissection). High-quality evidence showed no association with body mass index, type of breast surgery, chemotherapy or endocrine therapy. INTERPRETATION: Development of persistent pain after breast cancer surgery was associated with younger age, radiotherapy, axillary lymph node dissection, greater acute postoperative pain and preoperative pain. Axillary lymph node dissection provides the only high-yield target for a modifiable risk factor to prevent the development of persistent pain after breast cancer surgery.