Dengue Virus Infection Perturbs Lipid Homeostasis in Infected Mosquito Cells

Dengue virus causes ∼50–100 million infections per year and thus is considered one of the most aggressive arthropod-borne human pathogen worldwide. During its replication, dengue virus induces dramatic alterations in the intracellular membranes of infected cells. This phenomenon is observed both in human and vector-derived cells. Using high-resolution mass spectrometry of mosquito cells, we show that this membrane remodeling is directly linked to a unique lipid repertoire induced by dengue virus infection. Specifically, 15% of the metabolites detected were significantly different between DENV infected and uninfected cells while 85% of the metabolites detected were significantly different in isolated replication complex membranes. Furthermore, we demonstrate that intracellular lipid redistribution induced by the inhibition of fatty acid synthase, the rate-limiting enzyme in lipid biosynthesis, is sufficient for cell survival but is inhibitory to dengue virus replication. Lipids that have the capacity to destabilize and change the curvature of membranes as well as lipids that change the permeability of membranes are enriched in dengue virus infected cells. Several sphingolipids and other bioactive signaling molecules that are involved in controlling membrane fusion, fission, and trafficking as well as molecules that influence cytoskeletal reorganization are also up regulated during dengue infection. These observations shed light on the emerging role of lipids in shaping the membrane and protein environments during viral infections and suggest membrane-organizing principles that may influence virus-induced intracellular membrane architecture

Bezlotoxumab for Prevention of Recurrent Clostridium difficile Infection

BACKGROUND Clostridium difficile is the most common cause of infectious diarrhea in hospitalized patients. Recurrences are common after antibiotic therapy. Actoxumab and bezlotoxumab are human monoclonal antibodies against C. difficile toxins A and B, respectively. METHODS We conducted two double-blind, randomized, placebo-controlled, phase 3 trials, MODIFY I and MODIFY II, involving 2655 adults receiving oral standard-of-care antibiotics for primary or recurrent C. difficile infection. Participants received an infusion of bezlotoxumab (10 mg per kilogram of body weight), actoxumab plus bezlotoxumab (10 mg per kilogram each), or placebo; actoxumab alone (10 mg per kilogram) was given in MODIFY I but discontinued after a planned interim analysis. The primary end point was recurrent infection (new episode after initial clinical cure) within 12 weeks after infusion in the modified intention-to-treat population. RESULTS In both trials, the rate of recurrent C. difficile infection was significantly lower with bezlotoxumab alone than with placebo (MODIFY I: 17% [67 of 386] vs. 28% [109 of 395]; adjusted difference, −10.1 percentage points; 95% confidence interval [CI], −15.9 to −4.3; P<0.001; MODIFY II: 16% [62 of 395] vs. 26% [97 of 378]; adjusted difference, −9.9 percentage points; 95% CI, −15.5 to −4.3; P<0.001) and was significantly lower with actoxumab plus bezlotoxumab than with placebo (MODIFY I: 16% [61 of 383] vs. 28% [109 of 395]; adjusted difference, −11.6 percentage points; 95% CI, −17.4 to −5.9; P<0.001; MODIFY II: 15% [58 of 390] vs. 26% [97 of 378]; adjusted difference, −10.7 percentage points; 95% CI, −16.4 to −5.1; P<0.001). In prespecified subgroup analyses (combined data set), rates of recurrent infection were lower in both groups that received bezlotoxumab than in the placebo group in subpopulations at high risk for recurrent infection or for an adverse outcome. The rates of initial clinical cure were 80% with bezlotoxumab alone, 73% with actoxumab plus bezlotoxumab, and 80% with placebo; the rates of sustained cure (initial clinical cure without recurrent infection in 12 weeks) were 64%, 58%, and 54%, respectively. The rates of adverse events were similar among these groups; the most common events were diarrhea and nausea. CONCLUSIONS Among participants receiving antibiotic treatment for primary or recurrent C. difficile infection, bezlotoxumab was associated with a substantially lower rate of recurrent infection than placebo and had a safety profile similar to that of placebo. The addition of actoxumab did not improve efficacy. (Funded by Merck; MODIFY I and MODIFY II ClinicalTrials.gov numbers, NCT01241552 and NCT01513239.

Improving policy coherence for food security and nutrition in South Africa: a qualitative policy analysis

Like most other low and middle-income countries, South Africa must address a rising burden of diet-related chronic disease in a situation of persistent food insecurity and undernutrition. Supply-side policy interventions are a critical component of action to address the double burden of malnutrition. However, the food supply is governed by a number of different policy sectors, and policy incoherence can occur between government action to promote a healthy food supply and objectives for economic liberalization. We analysed the coherence of food supply policy content with respect to nutrition and food security in South Africa, and conducted 14 in-depth interviews with 22 public and private sector actors to identify opportunities to improve policy coherence across sectors governing the food supply. Drawing on Sabatier’s conceptualization of actors as influential in shaping policy outcomes, we identified three coalitions of actors related to food security and nutrition in South Africa: the dominant Economic Growth coalition, the Food Security coalition, and the Health coalition. Understanding the frames, beliefs and resources held by these coalitions offers insights into the policy tensions faced by the Government of South Africa with respect to the food supply. The analysis indicates that the current reconsideration of economic policy agendas favouring liberalization in SouthAfrica, including the termination of most bilateral investment treaties, may present an opportunity for increased recognition of food security and nutrition priorities in food supply policy making. Opportunities to strengthen policy coherence across the food supply for food security and nutrition include: specific changes to economic policy relating to the food supply that achieve both food security/nutrition and economic objectives; creating links between producers and consumers, through markets and fiscal incentives that make healthy / fresh foods more accessible and affordable; increasing formal avenues for engagement by Civil Society in nutrition and food security policy making; and including consideration of the nutritional quality of the food supply in policy objectives across sectors, to create a framework for policy coherence across sectors relating to the food supply

"It's a balance of just getting things right"

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. This study was funded by NHS Grampian. FD, LC, JC, and GMcN receive personal support from the RESAS programme of the Scottish Government Nutrition and Health. We would also like to thank Caroline Comerford of NHS Grampian and other members of the research steering group for their advice during the study; the parents for their time and input; the nursery school staff for distributing study packs for parents; Andrea Gilmartin for organising the focus groups and Dr Sandra Carlisle for the helpful comments on earlier drafts of the manuscript.Peer reviewedPublisher PD

Transition from high- to low-NOx control of night-time oxidation in the southeastern US

The influence of nitrogen oxides (NOx) on daytime atmospheric oxidation cycles is well known, with clearly defined high- and low-NOx regimes. During the day, oxidation reactions—which contribute to the formation of secondary pollutants such as ozone—are proportional to NOx at low levels, and inversely proportional to NOx at high levels. Night-time oxidation of volatile organic compounds also influences secondary pollutants but lacks a similar clear definition of high- and low-NOx regimes, even though such regimes exist. Decreases in anthropogenic NOx emissions in the US and Europe coincided with increases in Asia over the last 10 to 20 years, and have altered both daytime and nocturnal oxidation cycles. Here we present measurements of chemical species in the lower atmosphere from day- and night-time research flights over the southeast US in 1999 and 2013, supplemented by atmospheric chemistry simulations. We find that night-time oxidation of biogenic volatile organic compounds (BVOC) is NOx-limited when the ratio of NOx to BVOC is below approximately 0.5, and becomes independent of NOx at higher ratios. The night-time ratio of NOx to BVOC in 2013 averaged 0.6 aloft. We suggest that night-time oxidation in the southeast US is in transition between NOx-dominated and ozone-dominated