The neuropeptide NMU amplifies ILC2-driven allergic lung inflammation

Type 2 innate lymphoid cells (ILC2s) both contribute to mucosal homeostasis and initiate pathologic inflammation in allergic asthma. However, the signals that direct ILC2s to promote homeostasis versus inflammation are unclear. To identify such molecular cues, we profiled mouse lung-resident ILCs using single-cell RNA sequencing at steady state and after in vivo stimulation with the alarmin cytokines IL-25 and IL-33. ILC2s were transcriptionally heterogeneous after activation, with subpopulations distinguished by expression of proliferative, homeostatic and effector genes. The neuropeptide receptor Nmur1 was preferentially expressed by ILC2s at steady state and after IL-25 stimulation. Neuromedin U (NMU), the ligand of NMUR1, activated ILC2s in vitro, and in vivo co-administration of NMU with IL-25 strongly amplified allergic inflammation. Loss of NMU-NMUR1 signalling reduced ILC2 frequency and effector function, and altered transcriptional programs following allergen challenge in vivo. Thus, NMUR1 signalling promotes inflammatory ILC2 responses, highlighting the importance of neuro-immune crosstalk in allergic inflammation at mucosal surfaces

Managing Carbon

Storing carbon (C) and offsetting carbon dioxide (CO2) emissions with the use of wood for energy, both of which slow emissions of CO2 into the atmosphere, present significant challenges for forest management (IPCC 2001). In the United States, there has been a net increase in C in forests and in harvested wood products stocks (Tables 7.1 and 7.2), a result of historical and recent ecological conditions, management practices, and use of forest products (Birdsey et al. 2006). However, recent projections for the forest sector suggest that annual C storage could begin to decline, and U.S. forests could become a net C emitter of tens to hundreds of Tg C year ¹ within a few decades (USDA FS 2012a). It is therefore urgent to identify effective C management strategies, given the complexity of factors that drive the forest C cycle and the multiple objectives for which forests are managed. An ideal C management activity contributes benefits beyond increasing C storage by achieving other management objectives and providing ecosystem services in a sustainable manner. Strategies for effectively managing forest C stocks and offsetting C emissions requires a thorough understanding of biophysical and social influences on the forest C cycle (Birdsey et al. 1993). Successful policies and incentives may be chosen to support strategies if sufficient knowledge of social processes (e.g., landowner or wood-user response to incentives and markets) is available. For example, if C stocks are expected to decrease owing to decreasing forest land area caused by exurban development, policies or incentives to avoid deforestation in those areas may be effective. If C stocks are expected to decrease owing to the effects of a warmer climate, reducing stand densities may retain C over the long term by increasing resilience to drought and other stressors and by reducing crown fire hazard (Jackson et al. 2005; Reinhardt et al. 2008). Protecting old forests and other forests that have high C stocks may be more effective than seeking C offsets associated with wood use, especially if those forests would recover C more slowly in an altered climate. If climate change increases productivity in a given area over a long period of time, increasing forest C stocks through intensive management and forest products, including biomass energy, may be especially effective. It is equally important to know which strategies might make some management practices unacceptable (e.g., reducing biodiversity). However, no standard evaluation framework exists to aid decision making on alternative management strategies for maximizing C storage while minimizing risks and tradeoffs. Here we discuss (1) where forest C is stored in the United States, (2) how to measure forest C through space and time, (3) effectiveness of various management strategies in reducing atmospheric greenhouse gases (GHG), and (4) effectiveness of incentives, regulations, and institutional arrangements for implementing C management. Understanding of biophysical and social influences on the forest C cycle (Birdsey et al. 1993). Successful policies and incentives may be chosen to support strategies if sufficient knowledge of social processes (e.g., landowner or wood-user response to incentives and markets) is available. For example, if C stocks are expected to decrease owing to decreasing forest land area caused by exurban development, policies or incentives to avoid deforestation in those areas may be effective. If C stocks are expected to decrease owing to the effects of a warmer climate, reducing stand densities may retain C over the long term by increasing resilience to drought and other stressors and by reducing crown fire hazard (Jackson et al. 2005; Reinhardt et al. 2008). Protecting old forests and other forests that have high C stocks may be more effective than seeking C offsets associated with wood use, especially if those forests would recover C more slowly in an altered climate. If climate change increases productivity in a given area over a long period of time, increasing forest C stocks through intensive management and forest products, including biomass energy, may be especially effective. It is equally important to know which strategies might make some management practices unacceptable (e.g., reducing biodiversity). However, no standard evaluation framework exists to aid decision making on alternative management strategies for maximizing C storage while minimizing risks and tradeoffs. Here we discuss (1) where forest C is stored in the United States, (2) how to measure forest C through space and time, (3) effectiveness of various management strategies in reducing atmospheric greenhouse gases (GHG), and (4) effectiveness of incentives, regulations, and institutional arrangements for implementing C management

Centrality, rapidity and transverse momentum dependence of J/\u3c8 suppression in Pb-Pb collisions at 1asNN= 2.76TeV

The inclusive J/.nuclear modification factor (R-AA) in Pb-Pb collisions at root(NN)-N-S = 2.76TeVhas been measured by ALICE as a function of centrality in the e+ e-decay channel at mid-rapidity (| y| < 0.8) and as a function of centrality, transverse momentum and rapidity in the + -decay channel at forward-rapidity (2.5 < y < 4). The J/.yields measured in Pb-Pb are suppressed compared to those in ppcollisions scaled by the number of binary collisions. The RAAintegrated over a centrality range corresponding to 90% of the inelastic Pb-Pb cross section is 0.72 - 0.06(stat.) - 0.10(syst.) at mid-rapidity and 0.58 - 0.01(stat.) - 0.09(syst.) at forward-rapidity. At low transverse momentum, significantly larger values of RAAare measured at forward-rapidity compared to measurements at lower energy. These features suggest that a contribution to the J/.yield originates from charm quark (re) combination in the deconfined partonic medium

Enhanced infection prophylaxis reduces mortality in severely immunosuppressed HIV-infected adults and older children initiating antiretroviral therapy in Kenya, Malawi, Uganda and Zimbabwe: the REALITY trial

Meeting abstract FRAB0101LB from 21st International AIDS Conference 18–22 July 2016, Durban, South Africa. Introduction: Mortality from infections is high in the first 6 months of antiretroviral therapy (ART) among HIV‐infected adults and children with advanced disease in sub‐Saharan Africa. Whether an enhanced package of infection prophylaxis at ART initiation would reduce mortality is unknown. Methods: The REALITY 2×2×2 factorial open‐label trial (ISRCTN43622374) randomized ART‐naïve HIV‐infected adults and children >5 years with CD4 <100 cells/mm3. This randomization compared initiating ART with enhanced prophylaxis (continuous cotrimoxazole plus 12 weeks isoniazid/pyridoxine (anti‐tuberculosis) and fluconazole (anti‐cryptococcal/candida), 5 days azithromycin (anti‐bacterial/protozoal) and single‐dose albendazole (anti‐helminth)), versus standard‐of‐care cotrimoxazole. Isoniazid/pyridoxine/cotrimoxazole was formulated as a scored fixed‐dose combination. Two other randomizations investigated 12‐week adjunctive raltegravir or supplementary food. The primary endpoint was 24‐week mortality. Results: 1805 eligible adults (n = 1733; 96.0%) and children/adolescents (n = 72; 4.0%) (median 36 years; 53.2% male) were randomized to enhanced (n = 906) or standard prophylaxis (n = 899) and followed for 48 weeks (3.8% loss‐to‐follow‐up). Median baseline CD4 was 36 cells/mm3 (IQR: 16–62) but 47.3% were WHO Stage 1/2. 80 (8.9%) enhanced versus 108(12.2%) standard prophylaxis died before 24 weeks (adjusted hazard ratio (aHR) = 0.73 (95% CI: 0.54–0.97) p = 0.03; Figure 1) and 98(11.0%) versus 127(14.4%) respectively died before 48 weeks (aHR = 0.75 (0.58–0.98) p = 0.04), with no evidence of interaction with the two other randomizations (p > 0.8). Enhanced prophylaxis significantly reduced incidence of tuberculosis (p = 0.02), cryptococcal disease (p = 0.01), oral/oesophageal candidiasis (p = 0.02), deaths of unknown cause (p = 0.02) and (marginally) hospitalisations (p = 0.06) but not presumed severe bacterial infections (p = 0.38). Serious and grade 4 adverse events were marginally less common with enhanced prophylaxis (p = 0.06). CD4 increases and VL suppression were similar between groups (p > 0.2). Conclusions: Enhanced infection prophylaxis at ART initiation reduces early mortality by 25% among HIV‐infected adults and children with advanced disease. The pill burden did not adversely affect VL suppression. Policy makers should consider adopting and implementing this low‐cost broad infection prevention package which could save 3.3 lives for every 100 individuals treated

Incidence and risk factors for anastomotic failure in 1594 patients treated by transanal total mesorectal excision results from the international TATME registry

Objective: To determine the incidence of anastomotic-related morbidity following Transanal Total Mesorectal Excision (TaTME) and identify independent risk factors for failure. Background: Anastomotic leak and its sequelae are dreaded complications following gastrointestinal surgery. TaTME is a recent technique for rectal resection, which includes novel anastomotic techniques. Methods: Prospective study of consecutive reconstructed TaTME cases recorded over 30 months in 107 surgical centers across 29 countries. Primary endpoint was \u2018\u2018anastomotic failure,\u2019\u2019 defined as a composite endpoint of early or delayed leak, pelvic abscess, anastomotic fistula, chronic sinus, or anastomotic stricture. Multivariate regression analysis performed identifying independent risk factors of anastomotic failure and an observed risk score developed. Results: One thousand five hundred ninety-four cases with anastomotic reconstruction were analyzed; 96.6% performed for cancer. Median anastomotic height from anal verge was 3.0 2.0 cm with stapled techniques accounting for 66.0%. The overall anastomotic failure rate was 15.7%. This included early (7.8%) and delayed leak (2.0%), pelvic abscess (4.7%), anastomotic fistula (0.8%), chronic sinus (0.9%), and anastomotic stricture in 3.6% of cases. Independent risk factors of anastomotic failure were: male sex, obesity, smoking, diabetes mellitus, tumors >25 mm, excessive intraoperative blood loss, manual anastomosis, and prolonged perineal operative time. A scoring system for preoperative risk factors was associated with observed rates of anastomotic failure between 6.3% to 50% based on the cumulative score. Conclusions: Large tumors in obese, diabetic male patients who smoke have the highest risk of anastomotic failure. Acknowledging such risk factors can guide appropriate consent and clinical decision-making that may reduce anastomotic-related morbidity