Impact of Small Body Weight on Tenofovir-Associated Renal Dysfunction in HIV-Infected Patients: A Retrospective Cohort Study of Japanese Patients

BACKGROUND: Treatment with tenofovir is sometimes associated with renal dysfunction. Limited information is available on this side effect in patients with small body weight, although the use of tenofovir will spread rapidly in Asia and Africa, where patients are likely to be of smaller body weight. METHODS: In a single-center cohort, Japanese patients with HIV infection who started tenofovir-containing antiretroviral therapy were retrospectively analyzed. The incidence of tenofovir-associated renal dysfunction, defined as more than 25% decrement of estimated glomerular filtration rate (eGFR) from the baseline, was determined. The effects of small body weight and body mass index (BMI) on tenofovir-associated renal dysfunction, respectively, were estimated in univariate and multivariate Cox hazards models as the primary exposure. Other possible risk factors were evaluated by univariate analysis and those found significant were entered into the multivariate analysis. RESULTS: The median weight of 495 patients was 63 kg. Tenofovir-related renal dysfunction occurred in 97 (19.6%) patients (incidence: 10.5 per 100 person-years). Univariate analysis showed that the incidence of tenofovir-related renal dysfunction was significantly associated with smaller body weight and BMI, respectively (per 5 kg decrement, HR = 1.23; 95% CI, 1.10-1.37; p<0.001)(per 1 kg/m(2) decrement, HR = 1.14; 95% CI, 1.05-1.23; p = 0.001). Old age, high baseline eGFR, low serum creatinine, low CD4 count, high HIV viral load, concurrent nephrotoxic drugs, hepatitis C infection, and current smoking were also associated with tenofovir-related renal dysfunction. Multivariate analysis identified small body weight as a significant risk (adjusted HR = 1.13; 95% CI, 1.01-1.27; p = 0.039), while small BMI had marginal significance (adjusted HR = 1.07; 95% CI 1.00-1.16; p = 0.058). CONCLUSION: The incidence of tenofovir-associated renal dysfunction in Japanese patients was high. Small body weight was identified as an independent risk factor for tenofovir-associated renal dysfunction. Close monitoring of renal function is advocated for patients with small body weight treated with tenofovir

Varespladib and cardiovascular events in patients with an acute coronary syndrome: the VISTA-16 randomized clinical trial

IMPORTANCE: Secretory phospholipase A2(sPLA2) generates bioactive phospholipid products implicated in atherosclerosis. The sPLA2inhibitor varespladib has favorable effects on lipid and inflammatory markers; however, its effect on cardiovascular outcomes is unknown. OBJECTIVE: To determine the effects of sPLA2inhibition with varespladib on cardiovascular outcomes. DESIGN, SETTING, AND PARTICIPANTS: A double-blind, randomized, multicenter trial at 362 academic and community hospitals in Europe, Australia, New Zealand, India, and North America of 5145 patients randomized within 96 hours of presentation of an acute coronary syndrome (ACS) to either varespladib (n = 2572) or placebo (n = 2573) with enrollment between June 1, 2010, and March 7, 2012 (study termination on March 9, 2012). INTERVENTIONS: Participants were randomized to receive varespladib (500 mg) or placebo daily for 16 weeks, in addition to atorvastatin and other established therapies. MAIN OUTCOMES AND MEASURES: The primary efficacy measurewas a composite of cardiovascular mortality, nonfatal myocardial infarction (MI), nonfatal stroke, or unstable angina with evidence of ischemia requiring hospitalization at 16 weeks. Six-month survival status was also evaluated. RESULTS: At a prespecified interim analysis, including 212 primary end point events, the independent data and safety monitoring board recommended termination of the trial for futility and possible harm. The primary end point occurred in 136 patients (6.1%) treated with varespladib compared with 109 patients (5.1%) treated with placebo (hazard ratio [HR], 1.25; 95%CI, 0.97-1.61; log-rank P = .08). Varespladib was associated with a greater risk of MI (78 [3.4%] vs 47 [2.2%]; HR, 1.66; 95%CI, 1.16-2.39; log-rank P = .005). The composite secondary end point of cardiovascular mortality, MI, and stroke was observed in 107 patients (4.6%) in the varespladib group and 79 patients (3.8%) in the placebo group (HR, 1.36; 95% CI, 1.02-1.82; P = .04). CONCLUSIONS AND RELEVANCE: In patients with recent ACS, varespladib did not reduce the risk of recurrent cardiovascular events and significantly increased the risk of MI. The sPLA2inhibition with varespladib may be harmful and is not a useful strategy to reduce adverse cardiovascular outcomes after ACS. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01130246. Copyright 2014 American Medical Association. All rights reserved

Systematic review of reduced therapy regimens for children with low risk febrile neutropenia

PURPOSE: Reduced intensity therapy for children with low-risk febrile neutropenia may provide benefits to both patients and the health service. We have explored the safety of these regimens and the effect of timing of discharge. METHODS: Multiple electronic databases, conference abstracts and reference lists were searched. Randomised controlled trials (RCT) and prospective observational cohorts examining the location of therapy and/or the route of administration of antibiotics in people younger than 18 years who developed low-risk febrile neutropenia following treatment for cancer were included. Meta-analysis using a random effects model was conducted. I (2) assessed statistical heterogeneity not due to chance. Registration: PROSPERO (CRD42014005817). RESULTS: Thirty-seven studies involving 3205 episodes of febrile neutropenia were included; 13 RCTs and 24 prospective observational cohorts. Four safety events (two deaths, two intensive care admissions) occurred. In the RCTs, the odds ratio for treatment failure (persistence, worsening or recurrence of fever/infecting organisms, antibiotic modification, new infections, re-admission, admission to critical care or death) with outpatient treatment was 0.98 (95% confidence interval (95%CI) 0.44-2.19, I (2) = 0 %) and with oral treatment was 1.05 (95%CI 0.74-1.48, I (2) = 0 %). The estimated risk of failure using outpatient therapy from all prospective data pooled was 11.2 % (95%CI 9.7-12.8 %, I (2) = 77.2 %) and using oral antibiotics was 10.5 % (95%CI 8.9-12.3 %, I (2) = 78.3 %). The risk of failure was higher when reduced intensity therapies were used immediately after assessment, with lower rates when these were introduced after 48 hours. CONCLUSIONS: Reduced intensity therapy for specified groups is safe with low rates of treatment failure. Services should consider how these can be acceptably implemented

Characterization of the astrophysical diffuse neutrino flux using starting track events in IceCube

A measurement of the diffuse astrophysical neutrino spectrum is presented using IceCube data collected from 2011-2022 (10.3 years). We developed novel detection techniques to search for events with a contained vertex and exiting track induced by muon neutrinos undergoing a charged-current interaction. Searching for these starting track events allows us to not only more effectively reject atmospheric muons but also atmospheric neutrino backgrounds in the southern sky, opening a new window to the sub-100 TeV astrophysical neutrino sky. The event selection is constructed using a dynamic starting track veto and machine learning algorithms. We use this data to measure the astrophysical diffuse flux as a single power law flux (SPL) with a best-fit spectral index of γ=2.58-0.09+0.10 and per-flavor normalization of φper-flavorAstro=1.68-0.22+0.19×10-18×GeV-1 cm-2 s-1 sr-1 (at 100 TeV). The sensitive energy range for this dataset is 3-550 TeV under the SPL assumption. This data was also used to measure the flux under a broken power law, however we did not find any evidence of a low energy cutoff

The Notch pathway in ovarian carcinomas and adenomas

Elements of the Notch pathway regulate differentiation; we investigated the expression of such elements in epithelial ovarian tumours. A total of 32 ovarian tumour samples (17 adenocarcinomas, three borderline tumours, 12 adenomas), two human ovarian cancer (A2780, OVCAR3), and one ovarian surface (IOSE 144) cell lines were analysed. The expression of Notch pathway elements was assessed by RT–PCR, real-time PCR (Notch 1), and by immunoblots (Notch 1 extracellular domain (EC), HES1). The proliferation and colony formation of A2780 cells were measured after stable transfection with activated Notch 1 (intracellular domain). Jagged 2, Delta-like-1, Manic Fringe, and TSL1 were expressed more frequently in adenocarcinomas whereas Deltex, Mastermind, and Radical Fringe were more frequent in adenomas. Quantitative PCR revealed decreased Notch 1 mRNA in ovarian adenocarcinomas compared with adenomas. The expression of Notch 1-EC protein was similar in benign and malignant tumours. HES1 protein was strongly expressed in 18/19 ovarian cancers and borderline tumours but not in adenomas. Transfecting A2780 cells with active Notch 1-IC resulted in a proliferative and colony formation advantage compared to mock transfected cells. Thus, Notch pathway elements are expressed in ovarian epithelial tumours and some of them are differentially expressed between adenomas and carcinomas. The Notch pathway could be a target for the development of therapies for ovarian cancer

KSHV Manipulates Notch Signaling by DLL4 and JAG1 to Alter Cell Cycle Genes in Lymphatic Endothelia

Increased expression of Notch signaling pathway components is observed in Kaposi sarcoma (KS), but the mechanism underlying the manipulation of the canonical Notch pathway by the causative agent of KS, Kaposi sarcoma herpesvirus (KSHV), has not been fully elucidated. Here, we describe the mechanism through which KSHV directly modulates the expression of the Notch ligands JAG1 and DLL4 in lymphatic endothelial cells. Expression of KSHV-encoded vFLIP induces JAG1 through an NF kappa B-dependent mechanism, while vGPCR upregulates DLL4 through a mechanism dependent on ERK. Both vFLIP and vGPCR instigate functional Notch signalling through NOTCH4. Gene expression profiling showed that JAG1- or DLL4-stimulated signaling results in the suppression of genes associated with the cell cycle in adjacent lymphatic endothelial cells, indicating a role for Notch signaling in inducing cellular quiescence in these cells. Upregulation of JAG1 and DLL4 by KSHV could therefore alter the expression of cell cycle components in neighbouring uninfected cells during latent and lytic phases of viral infection, influencing cellular quiescence and plasticity. In addition, differences in signaling potency between these ligands suggest a possible complementary role for JAG1 and DLL4 in the context of KS