Platelets in Early Antibody-Mediated Rejection of Renal Transplants

Antibody-mediated rejection is a major complication in renal transplantation. The pathologic manifestations of acute antibody-mediated rejection that has progressed to functional impairment of a renal transplant have been defined in clinical biopsy specimens. However, the initial stages of the process are difficult to resolve with the unavoidable variables of clinical studies. We devised a model of renal transplantation to elucidate the initial stages of humoral rejection. Kidneys were orthotopically allografted to immunodeficient mice. After perioperative inflammation subsided, donor-specific alloantibodies were passively transferred to the recipient. Within 1 hour after a single transfer of antibodies, C4d was deposited diffusely on capillaries, and von Willebrand factor released from endothelial cells coated intravascular platelet aggregates. Platelet-transported inflammatory mediators platelet factor 4 and serotonin accumulated in the graft at 100- to 1000-fold higher concentrations compared with other platelet-transported chemokines. Activated platelets that expressed P-selectin attached to vascular endothelium and macrophages. These intragraft inflammatory changes were accompanied by evidence of acute endothelial injury. Repeated transfers of alloantibodies over 1 week sustained high levels of platelet factor 4 and serotonin. Platelet depletion decreased platelet mediators and altered the accumulation of macrophages. These data indicate that platelets augment early inflammation in response to donor-specific antibodies and that platelet-derived mediators may be markers of evolving alloantibody responses.     

Comparison of outcomes between minimally invasive and median sternotomy for double and triple valve surgery: A meta-analysis

Background

Limited data exists demonstrating the efficacy of minimally invasive surgery (MIS) compared to median sternotomy (MS) for multiple valvular disease (MVD). This systematic review and meta-analysis aims to compare operative and peri-operative outcomes of MIS vs MS in MVD.

Methods

PubMed, Ovid, and Embase were searched from inception until August 2019 for randomized and observational studies comparing MIS and MS in patients with MVD. Clinical outcomes of intra- and postoperative times, reoperation for bleeding and surgical site infection were evaluated.

Results

Five observational studies comparing 340 MIS vs 414 MS patients were eligible for qualitative and quantitative review. The quality of evidence assessed using the Newcastle-Ottawa scale was good for all included studies. Meta-analysis demonstrated increased cardiopulmonary bypass time for MIS patients (weighted mean difference [WMD], 0.487; 95% confidence interval [CI], 0.365-0.608; P < .0001). Similarly, aortic cross-clamp time was longer in patients undergoing MIS (WMD, 0.632; 95% CI, 0.509-0.755; P < .0001). No differences were found in operative mortality, reoperation for bleeding, surgical site infection, or hospital stay.

Conclusions

MIS for MVD have similar short-term outcomes compared to MS. This adds value to the use of minimally invasive methods for multivalvular surgery, despite conferring longer operative times. However, the paucity in literature and learning curve associated with MIS warrants further evidence, ideally randomized control trials, to support these findings.

     

Development of a Simulation-Based Mastery Learning Curriculum for Breaking Bad News

Introduction

Physician communication impacts patient outcomes. However, communication skills, especially around difficult conversations, remain suboptimal, and there is no clear way to determine the validity of entrustment decisions. The aims of this study were to 1) describe the development of a simulation-based mastery learning (SBML) curriculum for breaking bad news (BBN) conversation skills and 2) set a defensible minimum passing standard (MPS) to ensure uniform skill acquisition among learners.

Early intervention in myelofibrosis and impact on outcomes: A pooled analysis of the COMFORT-I and COMFORT-II studies

Background

In a pooled analysis of the phase 3 Controlled Myelofibrosis Study With Oral JAK Inhibitor Treatment I (COMFORT-I) and COMFORT-II clinical trials, adult patients with intermediate-2 or high-risk myelofibrosis who received oral ruxolitinib at randomization or after crossover from placebo or best available therapy (BAT) had improved overall survival (OS).

Methods

This post hoc analysis of pooled COMFORT data examined relevant disease outcomes based on the disease duration (≤12 or >12 months from diagnosis) before ruxolitinib initiation.

Results

The analysis included 525 patients (ruxolitinib: ≤12 months, n = 84; >12 months, n = 216; placebo/BAT: ≤12 months, n = 66; >12 months, n = 159); the median age was 65.0–70.0 years. Fewer thrombocytopenia and anemia events were observed among patients who initiated ruxolitinib treatment earlier. At Weeks 24 and 48, the spleen volume response (SVR) was higher for patients who initiated ruxolitinib earlier (47.6% vs. 32.9% at Week 24, p = .0610; 44.0% vs. 26.9% at Week 48, p = .0149). In a multivariable analysis of factors associated with spleen volume reduction, a logistic regression model that controlled for confounding factors found that a significantly greater binary reduction was observed among patients with shorter versus longer disease duration (p = .022). At Week 240, OS was significantly improved among patients who initiated ruxolitinib earlier (63% [95% CI, 51%‒73%] vs. 57% [95% CI, 49%‒64%]; hazard ratio, 1.53; 95% CI, 1.01‒2.31; p = .0430). Regardless of disease duration, a longer OS was observed for patients who received ruxolitinib versus those who received placebo/BAT.

Conclusions

These findings suggest that earlier ruxolitinib initiation for adult patients with intermediate-2 and high-risk myelofibrosis may improve clinical outcomes, including fewer cytopenia events, durable SVR, and prolonged OS.

Plain Language Summary

• Patients with myelofibrosis, a bone marrow cancer, often do not live as long as the general population. These patients may also have an enlarged spleen and difficult symptoms such as fatigue.
• Two large clinical trials showed that patients treated with the drug ruxolitinib lived longer and had improved symptoms compared to those treated with placebo or other standard treatments.
• Here it was examined whether starting treatment with ruxolitinib earlier (i.e., within a year of diagnosis) provided benefits versus delaying treatment.
• Patients who received ruxolitinib within a year of diagnosis lived longer and experienced fewer disease symptoms than those whose treatment was delayed.

     

South African abortion attitudes from 2007-2016: the roles of religiosity and attitudes toward sexuality and gender equality

ABSTRACT

Abortion is legal in South Africa, but negative abortion attitudes remain common and are poorly understood. We used nationally representative South African Social Attitudes Survey data to analyze abortion attitudes in the case of fetal anomaly and in the case of poverty from 2007 to 2016 (n = 20,711; ages = 16+). We measured correlations between abortion attitudes and these important predictors: religiosity, attitudes about premarital sex, attitudes about preferential hiring and promotion of women, and attitudes toward family gender roles. Abortion acceptability for poverty increased over time (b = 0.05, p < .001), but not for fetal anomaly (b = ?0.008, p = .284). Highly religious South Africans reported lower abortion acceptability in both cases (Odds Ratio (OR)_anomaly = 0.85, p = .015; OR_poverty = 0.84, p = .02). Premarital sex acceptability strongly and positively predicted abortion acceptability (OR_anomaly = 2.63, p < .001; OR_poverty = 2.46, p < .001). Attitudes about preferential hiring and promotion of women were not associated with abortion attitudes, but favorable attitudes about working mothers were positively associated with abortion acceptability for fetal anomaly ((OR_anomaly = 1.09, p = .01; OR_poverty = 1.02, p = .641)). Results suggest negative abortion attitudes remain common in South Africa and are closely tied to religiosity, traditional ideologies about sexuality, and gender role expectations about motherhood.