Evolution of a functionally intact but antigenically distinct DENV fusion loop

A hallmark of dengue virus (DENV) pathogenesis is the potential for antibody-dependent enhancement, which is associated with deadly DENV secondary infection, complicates the identification of correlates of protection, and negatively impacts the safety and efficacy of DENV vaccines. Antibody-dependent enhancement is linked to antibodies targeting the fusion loop (FL) motif of the envelope protein, which is completely conserved in mosquito-borne flaviviruses and required for viral entry and fusion. In the current study, we utilized saturation mutagenesis and directed evolution to engineer a functional variant with a mutated FL (D2-FL), which is not neutralized by FL-targeting monoclonal antibodies. The FL mutations were combined with our previously evolved prM cleavage site to create a mature version of D2-FL (D2-FLM), which evades both prM- and FL-Abs but retains sensitivity to other type-specific and quaternary cross-reactive (CR) Abs. CR serum from heterotypic (DENV4)-infected non-human primates (NHP) showed lower neutralization titers against D2-FL and D2-FLM than isogenic wildtype DENV2 while similar neutralization titers were observed in serum from homotypic (DENV2)-infected NHP. We propose D2-FL and D2-FLM as valuable tools to delineate CR Ab subtypes in serum as well as an exciting platform for safer live-attenuated DENV vaccines suitable for naïve individuals and children

The Geographic Movement Patterns and Career and Personal Interests of Orthopaedic Surgery Residents in the United States

BACKGROUND: Orthopaedic surgery continues to be a highly desired residency specialty for graduating medical students in the United States. The geographic preferences and trajectories of orthopaedic surgery applicants are not well understood. OBJECTIVE: The primary objective of this study was to determine the geographic movement patterns of orthopaedic residents from university through residency. A secondary objective was to trend the career and personal interests of orthopaedic residents. METHODS: One hundred eighty-seven orthopaedic surgery programs and 3672 residents were identified through the Electronic Residency Application Service website and Google searches and included for study. Program provided information, including the residents' medical school, undergraduate institution, career interests, and personal interests was then gathered. All data were recorded between the dates of March 25, 2020, and April 2, 2020. RESULTS: A minority of orthopaedic residents (46.2%; n = 1,569/3,398) were training in the same geographic region of their medical school; however, analysis revealed a statistically significant strength of association for home region over a different US census bureau region (χ2 = 127.4, df = 8, Cramer's V = 0.2, P < 0.001). The average distance between orthopaedic residents' medical school and residency program was 666 miles. Male residents were more interested in arthroplasty, spine, and sports, whereas female residents were more interested in hand and pediatrics. The residents leading interests were in arthroplasty (24.4%), sports (21.7%), and trauma (21.3%). CONCLUSION: Orthopaedic surgery residents are more likely to train in a geographical region that is different from their medical school or undergraduate institution. The reported career interests of male and female orthopaedic residents showed significant differences, but personal interests seem to be similar between genders. Copyright © 2021 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Orthopaedic Surgeons.Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Prevalence of urinary schistosomiasis in Nigeria, 1994–2015: Systematic review and meta-analysis

Introduction: The Global significance of schistosomiasis started waning over the years owing to its eradication in most developed societies, until the reawaking of global attention and it now occupies a prominent place amongst the neglected tropical diseases (NTD). The aim of our study was to accurately estimate the prevalence of schistosomiasis in Nigeria, and its six geo-political zones. Subjects and methods: We utilized electronic databases to search and select studies on prevalence across the geographical zones between 1994 and 2015. STATA 10 Random effects meta-analysis of observational studies was used to generate our estimates. Result: Sixty-seven studies met the inclusion criteria. The unified pooled population studied was 47,440 (n = 14,888 persons). The pooled prevalence]) of Schistosoma haematobium infestation was, for all regions = 34.7% (31.0–38.5) (95% confidence interval [CI)). Conclusion: Schistosomal infestations remain hyperendemic in Nigeria. Nigeria must, therefore, expedite the execution of resolution WHA66.12 adopted by the World Health Assembly on NTD

Colorectal Endoscopic Stenting Trial (CReST) for obstructing left-sided colorectal cancer: randomized clinical trial

Background Colorectal cancer often presents with obstruction needing urgent, potentially life-saving decompression. The comparative efficacy and safety of endoluminal stenting versus emergency surgery as initial treatment for such patients is uncertain. Methods Patients with left-sided colonic obstruction and radiological features of carcinoma were randomized to endoluminal stenting using a combined endoscopic/fluoroscopic technique followed by elective surgery 1–4 weeks later, or surgical decompression with or without tumour resection. Treatment allocation was via a central randomization service using a minimization procedure stratified by curative intent, primary tumour site, and severity score (Acute Physiology And Chronic Health Evaluation). Co-primary outcome measures were duration of hospital stay and 30-day mortality. Secondary outcomes were stoma formation, stenting completion and complication rates, perioperative morbidity, 6-month survival, 3-year recurrence, resource use, adherence to chemotherapy, and quality of life. Analyses were undertaken by intention to treat. Results Between 23 April 2009 and 22 December 2014, 245 patients from 39 hospitals were randomized. Stenting was attempted in 119 of 123 allocated patients (96.7 per cent), achieving relief of obstruction in 98 of 119 (82.4 per cent). For the 89 per cent treated with curative intent, there were no significant differences in 30-day postoperative mortality (3.6 per cent (4 of 110) versus 5.6 per cent (6 of 107); P = 0.48), or duration of hospital stay (median 19 (i.q.r. 11–34) versus 18 (10–28) days; P = 0.94) between stenting followed by delayed elective surgery and emergency surgery. Among patients undergoing potentially curative treatment, stoma formation occurred less frequently in those allocated to stenting than those allocated to immediate surgery (47 of 99 (47.5 per cent) versus 72 of 106 (67.9 per cent); P = 0.003). There were no significant differences in perioperative morbidity, critical care use, quality of life, 3-year recurrence or mortality between treatment groups. Conclusion Stenting as a bridge to surgery reduces stoma formation without detrimental effects. Registration number: ISRCTN13846816 (http://www.controlled-trials.com)