Citations

Abstract TNF-related apoptosis-inducing ligand (TRAIL) was initially described to induce apoptosis of tumor cells and/or virally infected cells, although sparing normal cells, and has been implicated in the pathogenesis of HIV disease. We previously identified TRAILshort, a TRAIL splice variant, in HIV-infected patients and characterized it as being a dominant negative ligand to subvert TRAIL-mediated killing. Herein, using single-cell genomics we demonstrate that TRAILshort is produced by HIV-infected cells, as well as by uninfected bystander cells, and that the dominant stimulus which induces TRAILshort production are type I IFNs and TLR7, TLR8, and TLR9 agonists. TRAILshort has a short t1/2 by virtue of containing a PEST domain, which targets the protein toward the ubiquitin proteasome pathway for degradation. Further we show that TRAILshort binds preferentially to TRAIL receptors 1 and 2 with significantly reduced interaction with the decoy TRAIL receptors 3 and 4. Recombinant TRAILshort is sufficient to protect cells against TRAIL-induced killing, whereas immunodepletion of TRAILshort with a specific Ab restores TRAIL sensitivity. Importantly we show that TRAILshort is shed in microvesicles into the cellular microenvironment and therefore confers TRAIL resistance not only on the cell which produces it, but also upon neighboring bystander cells. These results establish a novel paradigm for understanding and overcoming TRAIL resistance, in particular how HIV-infected cells escape immune elimination by the TRAIL:TRAILshort receptor axis.

SummaryBackgroundUp to 80% of patients with Crohn's disease require an abdominal operation in their lifetime. As the use of vedolizumab is increasing for the treatment of Crohn's disease, it is important to understand its potential association with post‐operative complications.AimWe sought to compare 30‐day postoperative infectious complication rate among vedolizumab‐treated Crohn's disease patients vs those who had received TNFα inhibitors or no biologic therapy.MethodsA retrospective review of all Crohn's disease patients who received vedolizumab within 12 weeks of a major abdominal or pelvic operation was performed. Two control cohorts consisted of Crohn's disease patients treated with TNFα inhibitors or no biologic therapy.ResultsOne hundred Crohn's disease patients received vedolizumab within 12 weeks of an abdominal operation. Vedolizumab‐treated patients underwent an equivalent rate of laparoscopic surgery (P = .25), had fewer anastomoses performed (P = .0002), and had equally frequent diversion in the setting of anastomoses (P = .47). Thirty‐two vedolizumab‐treated patients experienced postoperative infectious complications (32%), 26 of which were surgical site infections (26%). The vedolizumab‐treated group experienced no difference in nonsurgical site infections (6% vs 5% anti‐TNFα and 2% nonbiologic; P = .34), but significantly higher rates of surgical site infections (26% vs 8% and 11%; P < .001). On univariate and multivariate analysis, exposure to vedolizumab remained a significant predictor of postoperative surgical site infection (P < .001 and P = .002).ConclusionsTwenty‐six per cent of Crohn's disease patients who received vedolizumab within 12 weeks prior to a major abdominal operation experienced a 30‐day postoperative surgical site infection, significantly higher than that of patients receiving TNFα inhibitors or no biologic therapy. Vedolizumab within 12 weeks of surgery remained a predictor of 30‐day postoperative surgical site infection on multivariable analysis. While vedolizumab‐treated Crohn's disease patients may be a sicker cohort of patients, it is important to consider these findings with regard to preoperative counselling, operative timing and primary closure of wounds.

ABSTRACT Background Physician well-being is garnering increasing attention. In 2016, the Journal of Graduate Medical Education (JGME) published a review by Kristin Raj, MD, entitled “Well-Being in Residency: A Systematic Review.” There is benefit in contextualizing the literature on resident well-being through an academic journal club. Objective We summarized an asynchronous, online journal club discussion about this systematic review and highlighted themes that were identified in the review. Methods In January 2017, JGME and the Academic Life in Emergency Medicine (ALiEM) blog facilitated an open-access, online, weeklong journal club on the featured JGME article. Online discussions and interactions were facilitated via blog posts and comments, a video discussion on Google Hangouts on Air, and Twitter. We performed a thematic analysis of the discussion and captured web analytics. Results Over the first 14 days, the blog post was viewed 1070 unique times across 52 different countries. A total of 130 unique participants on Twitter posted 480 tweets using the hashtag #JGMEscholar. Thematic analysis revealed 5 major domains: the multidimensional nature of well-being, measurement of well-being, description of wellness programs and interventions, creation of a culture of wellness, and critique of the methodology of the review. Conclusions Our online journal club highlighted several gaps in the current understanding of resident well-being, including the need for consensus on the operational definition, the need for effective instruments to evaluate wellness programs and identify residents in distress, and a national research collaboration to assess wellness programs and their impact on resident well-being.

OBJECTIVEThe use of nerve transfers versus nerve grafting for neonatal brachial plexus palsy (NBPP) remains controversial. In adult brachial plexus injury, transfer of an ulnar fascicle to the biceps branch of the musculocutaneous nerve (Oberlin transfer) is reportedly superior to nerve grafting for restoration of elbow flexion. In pediatric patients with NBPP, recovery of elbow flexion and forearm supination is an indicator of resolved NBPP. Currently, limited evidence exists of outcomes for flexion and supination when comparing nerve transfer and nerve grafting for NBPP. Therefore, the authors compared 1-year postoperative outcomes for infants with NBPP who underwent Oberlin transfer versus nerve grafting.METHODSThis retrospective cohort study reviewed patients with NBPP who underwent Oberlin transfer (n = 19) and nerve grafting (n = 31) at a single institution between 2005 and 2015. A single surgeon conducted intraoperative exploration of the brachial plexus and determined the surgical nerve reconstruction strategy undertaken. Active range of motion was evaluated preoperatively and postoperatively at 1 year.RESULTSNo significant difference between treatment groups was observed with respect to the mean change (pre- to postoperatively) in elbow flexion in adduction and abduction and biceps strength. The Oberlin transfer group gained significantly more supination (100° vs 19°; p < 0.0001). Forearm pronation was maintained at 90° in the Oberlin transfer group whereas it was slightly improved in the grafting group (0° vs 32°; p = 0.02). Shoulder, wrist, and hand functions were comparable between treatment groups.CONCLUSIONSThe preliminary data from this study demonstrate that the Oberlin transfer confers an advantageous early recovery of forearm supination over grafting, with equivalent elbow flexion recovery. Further studies that monitor real-world arm usage will provide more insight into the most appropriate surgical strategy for NBPP.

The hereditary spastic paraplegias (HSPs) are a heterogeneous group of disorders characterized by degeneration of the corticospinal and spinocerebellar tracts leading to progressive spasticity. One subtype, spastic paraplegia type 47 (SPG47 or HSP‐AP4B1), is due to bi‐allelic loss‐of‐function mutations in the AP4B1 gene. AP4B1 is a subunit of the adapter protein complex 4 (AP‐4), a heterotetrameric protein complex that regulates the transport of membrane proteins. Since 2011, 11 individuals from six families with AP4B1 mutations have been reported, nine of whom had homozygous mutations and were from consanguineous families. Here we report eight patients with AP4B1‐associated SPG47, the majority born to non‐consanguineous parents and carrying compound heterozygous mutations. Core clinical features in this cohort and previously published patients include neonatal hypotonia that progresses to spasticity, early onset developmental delay with prominent motor delay and severely impaired or absent speech development, episodes of stereotypic laughter, seizures including frequent febrile seizures, thinning of the corpus callosum, and delayed myelination/white matter loss. Given that some of the features of AP‐4 deficiency overlap with those of cerebral palsy, and the discovery of the disorder in non‐consanguineous populations, we believe that AP‐4 deficiency may be more common than previously appreciated.

Objectives: Low serum albumin levels (hypoalbuminemia) have classically been used to identify malnutrition. The effect of increasing severity of malnutrition on postoperative outcomes in patients undergoing hip fracture surgery has not been well delineated on a large scale. Design: Retrospective. Setting: Multicenter. Patient/Participants: A total of 12,373 patients undergoing hip fracture surgery from 2006 to 2013 National Surgery Quality Improvement Project data were identified. Intervention: Patient demographic, comorbidity, and preoperative laboratory data and complication, reoperation, and readmission data were collected. Main Outcome Measurements: Multivariate logistic regression was used to determine the effect of increasing severity of malnutrition on rates of 30-day postoperative complications, readmissions, and reoperations. Results: A total of 12,373 hip fractures met inclusion criteria. A total of 6506 (52.6%) patients had normal albumin levels (albumin ≥3.5 g/dL), 3205 (25.9%) patients were mildly malnourished (albumin 3.1–3.49 g/dL), 2265 (18.3%) were moderately malnourished (albumin 2.4–3.1 g/dL), and 397 (3.2%) patients were severely malnourished (albumin <2.4 g/dL). Mean age was similar between the 4 cohorts (P < 0.001). Severe malnutrition was associated with a 2-fold increase in the odds of postoperative complications and mortality when compared with mild malnutrition (P < 0.001). Increasing severity of malnutrition was associated with significantly longer lengths of stay and higher odds of experiencing a related readmission (P < 0.001). Conclusions: Increasing severity of hypoalbuminemia is independently associated with poorer outcomes in the 30 days after hip fracture surgery. Level of Evidence: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Study Design: Retrospective cohort study. Objectives: Epidemiologic studies suggest that the prevalence of moderate to severe obstructive sleep apnea (OSA) is increasing. OSA has been linked to increased rates of postoperative complications following surgery. Large studies, however, regarding surgical outcomes in this patient population, particularly in the spine literature, are limited. Consequently, the purpose of this study was to assess the prevalence of and postoperative risks conferred by OSA in the elective spine population. Methods: Using data from the National Inpatient Sample from 2008 to 2012, an estimated 56 372 (5.1%) patients with OSA undergoing elective cervical and thoracolumbar spine surgery were selected and compared to 1 052 837 patients without OSA undergoing the same procedures. Our primary outcome measures included postoperative complication rates, inpatient mortality, length of stay, and total hospital charges. Results: Patients with OSA were, on average 2.6 years older than those without OSA ( P < .001) and had a higher comorbidity burden. The prevalence of OSA increased between 2008 and 2012 from 3.5% to 6.8%; P < .001. OSA was associated with a 3-fold increase in major complications ( P < .001) and was confirmed as an independent risk factor for major complications based on multivariate analysis (odds ratio [OR] = 2.82; 95% CI = 2.59-2.79; P < .001). Rates of deep venous thrombosis were doubled in patients with OSA. OSA was determined to be an independent predictor of pulmonary complications (OR = 2.69; 95% CI = 2.59-2.79; P < .001). OSA did not increase the risk of postoperative mortality. Conclusions: Patients with OSA often have multiple concomitant comorbidities and consequently are at increased risk of experiencing a more difficult postoperative course following elective spine surgery. Specifically, increased risks of pulmonary complications and deep venous thrombosis should be anticipated.