Citations

ABSTRACT Replication of negative-strand RNA viruses occurs in association with discrete cytoplasmic foci called inclusion bodies. Whereas inclusion bodies represent a prominent subcellular structure induced by viral infection, our knowledge of the cellular protein components involved in inclusion body formation and function is limited. Using measles virus-infected HeLa cells, we found that the WD repeat-containing protein 5 (WDR5), a subunit of histone H3 lysine 4 methyltransferases, was selectively recruited to virus-induced inclusion bodies. Furthermore, WDR5 was found in complexes containing viral proteins associated with RNA replication. WDR5 was not detected with mitochondria, stress granules, or other known secretory or endocytic compartments of infected cells. WDR5 deficiency decreased both viral protein production and infectious virus yields. Interferon production was modestly increased in WDR5-deficient cells. Thus, our study identifies WDR5 as a novel viral inclusion body-associated cellular protein and suggests a role for WDR5 in promoting viral replication. IMPORTANCE Measles virus is a human pathogen that remains a global concern, with more than 100,000 measles-related deaths annually despite the availability of an effective vaccine. As measles continues to cause significant morbidity and mortality, understanding the virus-host interactions at the molecular level that affect virus replication efficiency is important for development and optimization of treatment procedures. Measles virus is an RNA virus that encodes six genes and replicates in the cytoplasm of infected cells in discrete cytoplasmic replication bodies, though little is known of the biochemical nature of these structures. Here, we show that the cellular protein WDR5 is enriched in the cytoplasmic viral replication factories and enhances virus growth. WDR5-containing protein complex includes viral proteins responsible for viral RNA replication. Thus, we have identified WDR5 as a host factor that enhances the replication of measles virus.

AbstractBackgroundPatients at low risk for acute coronary syndrome are frequently admitted for observation and cardiac testing, resulting in substantial burden and cost to the patient and the health care system.ObjectivesThe purpose of this investigation was to measure the effect of the Chest Pain Choice (CPC) decision aid on overall health care utilization as well as utilization of specific services both during the index emergency department (ED) visit and in the subsequent 45 days.MethodsThis was a planned secondary analysis of data from a pragmatic multicenter randomized trial of shared decision making in adults presenting to the ED with chest pain who were being considered for observation unit admission for cardiac stress testing or coronary computed tomography angiography. The trial compared an intervention group engaged in shared decision making facilitated by the CPC decision aid to a control group receiving usual care. Hospital‐level billing data were used to measure utilization for the index ED visit and during the following 45 days. Patients in both groups also were asked to keep a diary recording health care utilization over the same 45‐day period. Outcomes assessed included length of time in the ED and observation, ED visits, office visits, hospitalizations, testing, imaging, and procedures.ResultsOf the 898 patients included in the original trial, we were able to contact 834 (92.9%) patients for 45‐day health care diary review. There was no difference in patient‐reported health care utilization between the study arms. Hospital‐level billing data were obtained for all 898 (100%) patients. During the initial ED visit the length of stay (LOS) was similar, and there was no difference in the frequency of observation unit admission between study arms. However, the mean observation unit LOS was 95 minutes (95% confidence interval [CI] = 40.8–149.8) shorter in the CPC arm and the mean number of tests was lower in the CPC arm (decrease in 19.4 imaging studies per 100 patients, 95% CI = 15.5–23.3). When evaluating the entire encounter and follow‐up period, the intervention arm underwent fewer tests (decrease in 125.6 tests per 100 patients, 95% CI = 29.3–221.6). More specifically, there were fewer advanced cardiac imaging tests completed (25.8 fewer per 100 patients, 95% CI = 3.74–47.9) in the intervention arm.ConclusionsShared decision making in low‐risk chest pain can lead to decreased diagnostic testing without worsening outcomes measured over 45 days.

Purpose Self-directed learning (SDL) is part of residency training, which residents desire guidance in implementing. To characterize SDL within the clinical context, this study explored residents’ perceptions of faculty members’ role in promoting and supporting resident SDL. Method Using a constructivist grounded theory approach, the authors conducted seven focus groups with 46 internal medicine residents at the Mayo Clinic Internal Medicine Residency Program from October 2014 to January 2015. Focus group transcripts were deidentified and processed through open coding and analytic memo writing. Guided by a previously developed SDL model, data were analyzed regarding faculty member involvement in resident SDL. Themes were organized and patterns were discussed at team meetings, with constant comparison with new data. Trustworthiness was established using two member-check sessions. Results The authors identified themes within the categories of faculty guidance for SDL, SDL versus other-directed learning (ODL), and faculty archetypes for supporting SDL. Clinical teachers play a key role in facilitating resident SDL and can provide guidance at each step in the SDL process. Residents discussed the distinction between SDL and ODL, highlighting the integrated nature of learning and interplay between the two approaches to learning. Residents identified themes relating to three archetypal approaches faculty implement to support resident SDL in the clinical environment (directed, collaborative, and role model SDL), with benefits and challenges of each approach. Conclusions This study underscores the importance of external guidance for resident SDL and expands on approaches faculty members can use to support SDL in the clinical context.

Mechanical forces are increasingly recognized to regulate morphogenesis, but how this is accomplished in the context of the multiple tissue types present within a developing organ remains unclear. Here we use bioengineered “microfluidic chest cavities” to precisely control the mechanical environment of the fetal lung. We show that transmural pressure controls airway branching morphogenesis, the frequency of airway smooth muscle contraction, and the rate of developmental maturation of the lungs, as assessed by transcriptional analyses. Timelapse imaging reveals that branching events are synchronized across distant locations within the lung, and are preceded by long-duration waves of airway smooth muscle contraction. Higher transmural pressure decreases the interval between systemic smooth muscle contractions and increases the rate of morphogenesis of the airway epithelium. These data reveal that the mechanical properties of the microenvironment instruct crosstalk between different tissues to control the development of the embryonic lung.

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.

Abstract The University at Buffalo's neuroendovascular fellowship is one of the longest running fellowship programs in North America. The burgeoning neurointerventional workforce and the rapid growth in the neurointerventional space on the heels of groundbreaking clinical trials prompted us to assess the fellowship's academic impact and its graduates’ perceptions and productivity. An anonymized web-based survey was sent to all former neuroendovascular fellows with specific questions pertaining to current practice, research and funding, and perceptions about the fellowship's impact on their skills, competitiveness, and compensation. Additionally, the h -index was calculated to assess the academic productivity of each graduated fellow. Among 50 former fellows, 42 (84%) completed the survey. The fellows came from various countries, ethnic backgrounds, and specialties including neurosurgery (n = 39, 93%), neurology (n = 2, 5%), and neuroradiology (n = 1, 2%). Twenty (48%) respondents were currently chairs or directors of their practice. Most (n = 30, 71%) spent at least 10% of their time on research activities, with 27 (64%) receiving research funding. The median h -index of all 50 former fellows was 14. The biggest gains from the fellowship were reported to be improvement in endovascular skills (median = 10 on a scale of 0-10 [highest]) and increase in competitiveness for jobs in vascular neurosurgery (median = 10), followed by increase in academic productivity (median = 8), and knowledge of vascular disease (median = 8). In an era with open calls for moratoriums on endovascular fellowships, concerns over market saturation, and pleas to improve training, fellowship programs perhaps merit a more objective assessment. The effectiveness of a fellowship program may best be measured by the academic impact and leadership roles of former fellows.

The Institute of Medicine and US Food and Drug Administration (FDA) recognize that activating clinical trials in the United States is lengthy and inefficient. Downstream consequences include increased expense, suboptimal accrual, move of clinical trials overseas, and delayed availability of treatments for patients. An in‐tandem processing initiative is here highlighted that transformed the activation of clinical trials (TACT), reduced the activation time by 70%, and offers a paradigm for enhanced translational readiness.