Evaluation of Standard- and High-Dose Daptomycin versus Linezolid against Vancomycin-Resistant Enterococcus Isolates in an In Vitro Pharmacokinetic/Pharmacodynamic Model with Simulated Endocardial Vegetations

Daptomycin MICs for enterococci are typically 1- to 2-fold higher than those for Staphylococcus aureus, and there is an imminent need to establish the optimal dose for appropriate treatment of enterococcal infections. We investigated the bactericidal activity of daptomycin at various dose exposures compared to that of linezolid against vancomycin-resistant enterococcus (VRE) in an in vitro pharmacokinetic/pharmacodynamic model utilizing simulated endocardial vegetations over 96 h. Daptomycin at doses of 6, 8, 10, and 12 mg/kg of body weight/day and linezolid at a dose of 600 mg every 12 h were evaluated against two clinical vancomycin-resistant Enterococcus faecium strains (EFm11499 and 09-184D1051), one of which was linezolid resistant (09-184D1051), and one clinical vancomycin-resistant Enterococcus faecalis strain (EFs11496). Daptomycin MICs were 4, 2, and 0.5 μg/ml for EFm11499, 09-184D1051, and EFs11496, respectively. Bactericidal activity, defined as a ≥3 log10 CFU/g reduction from the initial colony count, was demonstrated against all three isolates with all doses of daptomycin; however, bactericidal activity was not sustained with the daptomycin 6- and 8-mg/kg/day regimens. Linezolid was bacteriostatic against EFm11499 and displayed no appreciable activity against 09-184D1051 or EFs11496. Concentration-dependent killing was displayed with more sustained reduction in colony count (3.58 to 6.46 and 5.89 to 6.56 log10 CFU/g) at 96 h for the simulated regimen of daptomycin at doses of 10 and 12 mg/kg/day, respectively (P ≤ 0.012). No E. faecium mutants with reduced susceptibility were recovered at any dosage regimen; however, the E. faecalis strain developed reduced daptomycin susceptibility with daptomycin at 6, 8, and 10 but not at 12 mg/kg/day. Daptomycin displayed a dose-dependent response against three VRE isolates, with high-dose daptomycin producing sustained bactericidal activity. Further research is warranted.This investigator-initiated study was funded by a research grant from Cubist Pharmaceuticals. We are grateful to Audrey Wanger for providing isolate 09-184D1051 and to Marcus Zervos for providing isolates SF11496 and SF11499. M.J.R. has received grant support, has served as a consultant, or has participated as a speaker for Astellas, Cubist, Forest Laboratories, Pfizer, Rib-X, and Novartis and is supported in part by grant R21AI092055 from the NIAID. C.A.A. has received lecture fees, research support, and consulting fees from Pfizer, Inc., and Cubist and has served as a speaker for Novartis. C.A.A. is supported in part by NIH grants R00 AI72961 and R01 AI093749 from the NIAID. B.E.M. has received grant support from Johnson & Johnson, Astellas, Palumed, Intercell, and Cubist, has served as a consultant for Astellas, Cubist, The Medicines Company, Pfizer, Rib-X, AstraZeneca, and Duranta Therapeutics, and was supported in part by NIH grant R01 AI72961

Eff ectiveness of reactive oral cholera vaccination in rural Haiti: a case-control study and bias-indicator analysis

Background Between April and June, 2012, a reactive cholera vaccination campaign was done in Haiti with an oral inactivated bivalent whole-cell vaccine. We aimed to assess the eff ectiveness of the vaccine in a case-control study and to assess the likelihood of bias in that study in a bias-indicator study. Methods Residents of Bocozel or Grand Saline who were eligible for the vaccination campaign (ie, age ≥12 months, not pregnant, and living in the region at the time of the vaccine campaign) were included. In the primary case-control study, cases had acute watery diarrhoea, sought treatment at one of three participating cholera treatment units, and had a stool sample positive for cholera by culture. For each case, four control individuals who did not seek treatment for acute watery diarrhoea were matched by location of residence, enrolment time (within 2 weeks of the case), and age (1–4 years, 5–15 years, and >15 years). Cases in the bias-indicator study were individuals with acute watery diarrhoea with a negative stool sample for cholera. Controls were selected in the same manner as in the primary case-control study. Trained staff used standard laboratory procedures to do rapid tests and stool cultures from study cases. Participants were interviewed to collect data on sociodemographic characteristics, risk factors for cholera, and self-reported vaccination. Data were analysed by conditional logistic regression, adjusting for matching factors. Findings From Oct 24, 2012, to March 9, 2014, 114 eligible individuals presented with acute watery diarrhoea and were enrolled, 25 of whom were subsequently excluded. 47 participants were analysed as cases in the vaccine eff ectiveness case-control study and 42 as cases in the bias-indicator study. 33 (70%) of 47 cholera cases self-reported vaccination versus 167 (89%) of 188 controls (vaccine eff ectiveness 63%, 95% CI 8–85). 27 (57%) of 47 cases had certifi ed vaccination versus 147 (78%) of 188 controls (vaccine eff ectiveness 58%, 13–80). Neither self-reported nor verifi ed vaccination was signifi cantly associated with non-cholera diarrhoea (vaccine eff ectiveness 18%, 95% CI –208 to 78 by self-report and –21%, –238 to 57 by verifi ed vaccination). Interpretation Bivalent whole-cell oral cholera vaccine eff ectively protected against cholera in Haiti from 4 months to 24 months after vaccination. Vaccination is an important component of eff orts to control cholera epidemics

Trying Cases in the Media: Legal Ethics, Fair Trials and Free Press

The 2000 symposium consisted of a panel discussion which used role-playing and a mock trial to highlight the issues of lawyer/litigant comments to the press before and during trial and the dilemma of journalists confronted by court demands for documents, testimony, or sources of information obtained in the course of gathering news on pending trials. Participants included: As United States Attorney for the Eastern District of Freedonia: John Douglas, Associate Professor of Law at the University of Richmond. As Freedonia criminal defense lawyer: Gerald Zerkin, Private Defense Attorney. As investigative journalist: Steve Nash, Associate Professor of Journalism at the University of Richmond. As federal judge: Judge Margaret P. Spencer, Virginia Circuit Court Judge. As media attorney: Craig Thomas Merritt, Attorney. As first amendment attorney: J. Joshua Wheeler, Attorney and Director of Programs for the Thomas Jefferson Center for the Protection of Free Expression, and adjunct professor at University of Virginia. As Chief Justice: Paul D. Carrington, The Chadwick Professor of Law at Duke University. As Associate Justices of the United States Supreme Court: C. Thomas Dienes, Patricia Roberts Harris Professor of Law at George Washington University\u27s Law School; John E. Nowak, David C. Baum Professor of Law at the University of Illinois; Molly Delea, third-year law student, University of Richmond School of Law; Kate Murray, third-year law student, University of Richmond School of Law; Thomas Queen, third-year law student, University of Richmond School of Law; and Courtney Sydnor, third-year law student, University of Richmond School of Law

Body mass index trajectories in the first 5 years and associated antenatal factors

Background: The increasing prevalence of childhood obesity is an important public health issue and the development of obesity in early life and associated risk factors need to be better understood. The aim of this study was to identify distinct body mass index trajectories in the first 5 years of life and to examine their associations with factors identified in pregnancy, including metabolic parameters. Methods: BMI measurements from 2,172 children in Ireland enrolled in the BASELINE cohort study with BMI assessments at birth, 2, 6, and 12 months, and 2 and 5 years were analyzed. Growth mixture modeling was used to identify distinct BMI trajectories, and multivariate multinomial logistic regression was used to assess the association between these trajectories and antenatal factors. Results: Three distinct BMI trajectories were identified: normal (89.6%); rapid gain in the first 6 months (7.8%); and rapid BMI after 12 months (2.6%). Male sex and higher maternal age increased the likelihood of belonging to the rapid gain in the first 6 months trajectory. Raised maternal BMI at 15 weeks of pregnancy and lower cord blood IGF-2 were associated with rapid gain after 1 year. Conclusion: Sex, maternal age and BMI, and IGF-2 levels were found to be associated with BMI trajectories in early childhood departing from normal growth. Further research and extended follow-up to examine the effects of childhood growth patterns are required to understand their relationship with health outcomes

Global, regional, and national sex differences in the global burden of tuberculosis by HIV status, 1990–2019: results from the Global Burden of Disease Study 2019

Tuberculosis is a major contributor to the global burden of disease, causing more than a million deaths annually. Given an emphasis on equity in access to diagnosis and treatment of tuberculosis in global health targets, evaluations of differences in tuberculosis burden by sex are crucial. We aimed to assess the levels and trends of the global burden of tuberculosis, with an emphasis on investigating differences in sex by HIV status for 204 countries and territories from 1990 to 2019.publishedVersio

Benefits and barriers among volunteer teaching faculty: comparison between those who precept and those who do not in the core pediatrics clerkship

Background: Community-based outpatient experiences are a core component of the clinical years in medical school. Central to the success of this experience is the recruitment and retention of volunteer faculty from the community. Prior studies have identified reasons why some preceptors volunteer their time however, there is a paucity of data comparing those who volunteer from those who do not. Methods: A survey was developed following a review of previous studies addressing perceptions of community-based preceptors. A non-parametric, Mann–Whitney U test was used to compare active preceptors (APs) and inactive preceptors (IPs) and all data were analyzed in SPSS 20.0. Results: There was a 28% response rate. Preceptors showed similar demographic characteristics, valued intrinsic over extrinsic benefits, and appreciated Continuing Medical Education (CME)/Maintenance of Certification (MOC) opportunities as the highest extrinsic reward. APs were more likely to also precept at the M1/M2 level and value recognition and faculty development opportunities (p<0.05). IPs denoted time as the most significant barrier and, in comparison to APs, rated financial compensation as more important (p<0.05). Conclusions: Community preceptors are motivated by intrinsic benefits of teaching. Efforts to recruit should initially focus on promoting awareness of teaching opportunities and offering CME/MOC opportunities. Increasing the pool of preceptors may require financial compensation

Clinically Actionable Hypercholesterolemia and Hypertriglyceridemia in Children with Nonalcoholic Fatty Liver Disease

OBJECTIVE: To determine the percentage of children with nonalcoholic fatty liver disease (NAFLD) in whom intervention for low-density lipoprotein cholesterol or triglycerides was indicated based on National Heart, Lung, and Blood Institute guidelines. STUDY DESIGN: This multicenter, longitudinal cohort study included children with NAFLD enrolled in the National Institute of Diabetes and Digestive and Kidney Diseases Nonalcoholic Steatohepatitis Clinical Research Network. Fasting lipid profiles were obtained at diagnosis. Standardized dietary recommendations were provided. After 1 year, lipid profiles were repeated and interpreted according to National Heart, Lung, and Blood Institute Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction. Main outcomes were meeting criteria for clinically actionable dyslipidemia at baseline, and either achieving lipid goal at follow-up or meeting criteria for ongoing intervention. RESULTS: There were 585 participants, with a mean age of 12.8 years. The prevalence of children warranting intervention for low-density lipoprotein cholesterol at baseline was 14%. After 1 year of recommended dietary changes, 51% achieved goal low-density lipoprotein cholesterol, 27% qualified for enhanced dietary and lifestyle modifications, and 22% met criteria for pharmacologic intervention. Elevated triglycerides were more prevalent, with 51% meeting criteria for intervention. At 1 year, 25% achieved goal triglycerides with diet and lifestyle changes, 38% met criteria for advanced dietary modifications, and 37% qualified for antihyperlipidemic medications. CONCLUSIONS: More than one-half of children with NAFLD met intervention thresholds for dyslipidemia. Based on the burden of clinically relevant dyslipidemia, lipid screening in children with NAFLD is warranted. Clinicians caring for children with NAFLD should be familiar with lipid management

Effectiveness of Early Antiretroviral Therapy Initiation to Improve Survival among HIV-Infected Adults with Tuberculosis: A Retrospective Cohort Study

Molly Franke, Megan Murray, and colleagues report that early cART reduces mortality among HIV-infected adults with tuberculosis and improves retention in care, regardless of CD4 count

SFRP1 reduction results in an increased sensitivity to TGF-β signaling

Background Transforming growth factor (TGF)-β plays a dual role during mammary gland development and tumorigenesis and has been shown to stimulate epithelial-mesenchymal transition (EMT) as well as cellular migration. The Wnt/β-catenin pathway is also implicated in EMT and inappropriate activation of the Wnt/β-catenin signaling pathway leads to the development of several human cancers, including breast cancer. Secreted frizzled-related protein 1 (SFRP1) antagonizes this pathway and loss of SFRP1 expression is frequently observed in breast tumors and breast cancer cell lines. We previously showed that when SFRP1 is knocked down in immortalized non-malignant mammary epithelial cells, the cells (TERT-siSFRP1) acquire characteristics associated with breast tumor initiating cells. The phenotypic and genotypic changes that occur in response to SFRP1 loss are consistent with EMT, including a substantial increase in the expression of ZEB2. Considering that ZEB2 has been shown to interact with mediators of TGF-β signaling, we sought to determine whether TGF-β signaling is altered in TERT-siSFRP1 cells. Methods Luciferase reporter assays and real-time PCR analysis were employed to measure TGF-β transcriptional targets. Western blot analysis was used to evaluate TGF-β-mediated ERK1/2 phosphorylation. Migration chamber assays were utilized to quantify cellular migration. TERT-siSFRP1 cells were transfected with Stealth RNAi™ siRNA in order to knock-down the expression of ZEB2. Results TERT-siSFRP1 cells exhibit a significant increase in both TGF-β-mediated luciferase activity as well as TGF-β transcriptional targets, including Integrin β3 and PAI-1. Phosphorylation of ERK1/2 is increased in TERT-siSFRP1 cells in response to enhanced TGF-β signaling. Furthermore, when the TGF-β pathway is blocked with a TGF-βR antagonist (LY364947), cellular migration is significantly hindered. Finally, we found that when ZEB2 is knocked-down, there is a significant reduction in the expression of exogeneous and endogenous TGF-β transcriptional targets and cellular migration is impeded. Conclusions We demonstrate that down-regulation of SFRP1 renders mammary epithelial cells more sensitive to TGF-β signaling which can be partially ameliorated by blocking the expression of ZEB2

Diverse perspectives on interdisciplinarity from the Members of the College of the Royal Society of Canada

Various multiple-disciplinary terms and concepts (although most commonly “interdisciplinarity”, which is used herein) are used to frame education, scholarship, research, and interactions within and outside academia. In principle, the premise of interdisciplinarity may appear to have many strengths; yet, the extent to which interdisciplinarity is embraced by the current generation of academics, the benefits and risks for doing so, and the barriers and facilitators to achieving interdisciplinarity represent inherent challenges. Much has been written on the topic of interdisciplinarity, but to our knowledge there have been few attempts to consider and present diverse perspectives from scholars, artists, and scientists in a cohesive manner. As a team of 57 members from the Canadian College of New Scholars, Artists, and Scientists of the Royal Society of Canada (the College) who self-identify as being engaged or interested in interdisciplinarity, we provide diverse intellectual, cultural, and social perspectives. The goal of this paper is to share our collective wisdom on this topic with the broader community and to stimulate discourse and debate on the merits and challenges associated with interdisciplinarity. Perhaps the clearest message emerging from this exercise is that working across established boundaries of scholarly communities is rewarding, necessary, and is more likely to result in impact. However, there are barriers that limit the ease with which this can occur (e.g., lack of institutional structures and funding to facilitate cross-disciplinary exploration). Occasionally, there can be significant risk associated with doing interdisciplinary work (e.g., lack of adequate measurement or recognition of work by disciplinary peers). Solving many of the world’s complex and pressing problems (e.g., climate change, sustainable agriculture, the burden of chronic disease, and aging populations) demand thinking and working across long-standing, but in some ways restrictive, academic boundaries. Academic institutions and key support structures, especially funding bodies, will play an important role in helping to realize what is readily apparent to all who contributed to this paper—that interdisciplinarity is essential for solving complex problems; it is the new norm. Failure to empower and encourage those doing this research will serve as a great impediment to training, knowledge, and addressing societal issues