The reactivity of lattice nitrogen within the Ni2Mo3N and NiCoMo3N phases

In this study, the reactivity of bulk lattice nitrogen within the filled β-Mn structured Ni2Mo3N phase has been investigated by application of powder neutron diffraction and heterolytic nitrogen isotopic exchange measurements. In contrast to Co3Mo3N, despite the similarity in the N immediate local environment comprising NMo6 octahedra, its reactivity is found to be limited and this lower reactivity was maintained upon the introduction of a significant proportion of cobalt to yield its filled β-Mn structured CoNiMo3N quaternary nitride counterpart

Estimating the NIH Efficient Frontier

Background: The National Institutes of Health (NIH) is among the world’s largest investors in biomedical research, with a mandate to: “…lengthen life, and reduce the burdens of illness and disability.” Its funding decisions have been criticized as insufficiently focused on disease burden. We hypothesize that modern portfolio theory can create a closer link between basic research and outcome, and offer insight into basic-science related improvements in public health. We propose portfolio theory as a systematic framework for making biomedical funding allocation decisions–one that is directly tied to the risk/reward trade-off of burden-of-disease outcomes. Methods and Findings: Using data from 1965 to 2007, we provide estimates of the NIH “efficient frontier”, the set of funding allocations across 7 groups of disease-oriented NIH institutes that yield the greatest expected return on investment for a given level of risk, where return on investment is measured by subsequent impact on U.S. years of life lost (YLL). The results suggest that NIH may be actively managing its research risk, given that the volatility of its current allocation is 17% less than that of an equal-allocation portfolio with similar expected returns. The estimated efficient frontier suggests that further improvements in expected return (89% to 119% vs. current) or reduction in risk (22% to 35% vs. current) are available holding risk or expected return, respectively, constant, and that 28% to 89% greater decrease in average years-of-life-lost per unit risk may be achievable. However, these results also reflect the imprecision of YLL as a measure of disease burden, the noisy statistical link between basic research and YLL, and other known limitations of portfolio theory itself. Conclusions: Our analysis is intended to serve as a proof-of-concept and starting point for applying quantitative methods to allocating biomedical research funding that are objective, systematic, transparent, repeatable, and expressly designed to reduce the burden of disease. By approaching funding decisions in a more analytical fashion, it may be possible to improve their ultimate outcomes while reducing unintended consequences

Life Events, Coping, and Posttraumatic Stress Symptoms among Chinese Adolescents Exposed to 2008 Wenchuan Earthquake, China

PURPOSE: To examine the relationship between negative life events, coping styles, and symptoms of post-traumatic stress disorder (PTSD) among adolescent survivors exposed to 2008 Wenchuan Earthquake, China. METHODS: A survey was conducted in a sample of 2250 adolescent students from two schools in Dujiangyan District, a seriously damaged area, 20 kilometers away from the epicenter, 6 months after the earthquake. Participants completed a self-administered questionnaire including demographics, negative life events, coping styles, and PTSD symptoms. RESULTS: Academic pressure was the strongest predictor of adolescents' PTSD symptoms among all negative life events. Main effects of negative life events, positive coping and negative coping on PTSD symptoms were significant in both younger adolescents and older adolescents, while the moderator effects of two coping styles were found significant only within older adolescents. CONCLUSIONS: Coping may play a role to moderate the relationship between post-earthquake negative life events and PTSD symptom, but the function seems to depend on the age of participants. Psychosocial coping skills training may be important in the prevention and intervention of mental health problems in adolescent survivors of traumatic earthquake

Collaboration for conservation: assessing countrywide carnivore occupancy dynamics from sparse data

Aim: Assessing the distribution and persistence of species across their range is a crucial component of wildlife conservation. It demands data at adequate spatial scales and over extended periods of time, which may only be obtained through collaborative efforts, and the development of methods that integrate heterogeneous datasets. We aimed to combine existing data on large carnivores to evaluate population dynamics and improve knowledge on their distribution nationwide. Location: Botswana. Methods: Between 2010 and 2016, we collated data on African wild dog, cheetah, leopard, brown and spotted hyaena and lion gathered with different survey methods by independent researchers across Botswana. We used a multi-species, multi-method dynamic occupancy model to analyse factors influencing occupancy, persistence and colonization, while accounting for imperfect detection. Lastly, we used the gained knowledge to predict the probability of occurrence of each species countrywide. Results: Wildlife areas and communal rangelands had similar occupancy probabilities for most species. Large carnivore occupancy was low in commercial farming areas and where livestock density was high, except for brown hyaena. Lion occupancy was negatively associated with human density; lion and spotted hyaena occupancy was high where rainfall was high, while the opposite applied to brown hyaena. Lion and leopard occupancy remained constant countrywide over the study period. African wild dog and cheetah occupancy declined over time in the south and north, respectively, whereas both hyaena species expanded their ranges. Countrywide predictions identified the highest occupancy for leopards and lowest for the two hyaena species. Main Conclusions: We highlight the necessity of data sharing and propose a generalizable analytical method that addresses the challenges of heterogeneous data common in ecology. Our approach, which enables a comprehensive multi-species assessment at large spatial and temporal scales, supports the development of data-driven conservation guidelines and the implementation of evidence-based management strategies nationally and internationally

Vascular mechanisms of post-COVID-19 conditions: rho-kinase is a novel target for therapy

BackgroundIn post-COVID-19 conditions (Long COVID), systemic vascular dysfunction is implicated but the mechanisms are uncertain, and treatment is imprecise.MethodsPatients convalescing after hospitalisation for COVID-19 and risk-factor matched controls underwent multisystem phenotyping using blood biomarkers, cardiorenal and pulmonary imaging, and gluteal subcutaneous biopsy (NCT04403607). Small resistance arteries were isolated and examined using wire myography, histopathology, immunohistochemistry, and spatial transcriptomics. Endothelium-independent (sodium nitroprusside) and -dependent (acetylcholine) vasorelaxation and vasoconstriction to the thromboxane A2 receptor agonist, U46619, and endothelin-1 (ET-1) in the presence or absence of a RhoA/Rho-kinase inhibitor (fasudil), were investigated.ResultsThirty-seven patients, including 27 (mean age 57 years, 48% women, 41% cardiovascular disease) three months post-COVID-19 and 10 controls (mean age 57 years, 20% women, 30% cardiovascular disease), were included. Compared with control responses, U46619-induced constriction was increased (p = 0.002) and endothelium-independent vasorelaxation was reduced in arteries from COVID-19 patients (p < 0.001). This difference was abolished by fasudil. Histopathology revealed greater collagen abundance in COVID-19 arteries (Masson's Trichrome (MT) 69.7% [95%CI: 67.8, 71.7]; picrosirius red 68.6% [95% CI: 64.4, 72.8]) versus controls (MT 64.9% [95%CI:59.4, 70.3] [p = 0.028]; picrosirius red 60.1% [95% CI: 55.4, 64.8], [p = 0.029]). Greater phosphorylated myosin light chain antibody-positive staining in vascular smooth muscle cells was observed in COVID-19 arteries (40.1%; 95% CI: 30.9, 49.3) vs. controls (10.0%; 95% CI: 4.4, 15.6) (p < 0.001). In proof-of-concept studies, gene pathways associated with extracellular matrix alteration, proteoglycan synthesis, and viral mRNA replication appeared to be upregulated.ConclusionPatients with post-COVID-19 conditions have enhanced vascular fibrosis and myosin light change phosphorylation. Rho-kinase activation represents a novel therapeutic target for clinical trials

Depletion of stromal cells expressing fibroblast activation protein-α from skeletal muscle and bone marrow results in cachexia and anemia.

Fibroblast activation protein-α (FAP) identifies stromal cells of mesenchymal origin in human cancers and chronic inflammatory lesions. In mouse models of cancer, they have been shown to be immune suppressive, but studies of their occurrence and function in normal tissues have been limited. With a transgenic mouse line permitting the bioluminescent imaging of FAP(+) cells, we find that they reside in most tissues of the adult mouse. FAP(+) cells from three sites, skeletal muscle, adipose tissue, and pancreas, have highly similar transcriptomes, suggesting a shared lineage. FAP(+) cells of skeletal muscle are the major local source of follistatin, and in bone marrow they express Cxcl12 and KitL. Experimental ablation of these cells causes loss of muscle mass and a reduction of B-lymphopoiesis and erythropoiesis, revealing their essential functions in maintaining normal muscle mass and hematopoiesis, respectively. Remarkably, these cells are altered at these sites in transplantable and spontaneous mouse models of cancer-induced cachexia and anemia. Thus, the FAP(+) stromal cell may have roles in two adverse consequences of cancer: their acquisition by tumors may cause failure of immunosurveillance, and their alteration in normal tissues contributes to the paraneoplastic syndromes of cachexia and anemia

Beyond outputs: pathways to symmetrical evaluations of university sustainable development partnerships

As the United Nations Decade of Education for Sustainable Development (2005–2014) draws to a close, it is timely to review ways in which the sustainable development initiatives of higher education institutions have been, and can be, evaluated. In their efforts to document and assess collaborative sustainable development program outcomes and impacts, universities in the North and South are challenged by similar conundrums that confront development agencies. This article explores pathways to symmetrical evaluations of transnationally partnered research, curricula, and public-outreach initiatives specifically devoted to sustainable development. Drawing on extensive literature and informed by international development experience, the authors present a novel framework for evaluating transnational higher education partnerships devoted to sustainable development that addresses design, management, capacity building, and institutional outreach. The framework is applied by assessing several full-term African higher education evaluation case studies with a view toward identifying key limitations and suggesting useful future symmetrical evaluation pathways. University participants in transnational sustainable development initiatives, and their supporting donors, would be well-served by utilizing an inclusive evaluation framework that is infused with principles of symmetry

The management of intra-abdominal infections from a global perspective : 2017 WSES guidelines for management of intra-abdominal infections

Intra-abdominal infections (IAIs) are common surgical emergencies and have been reported as major contributors to non-trauma deaths in the emergency departments worldwide. The cornerstones of effective treatment of IAIs are early recognition, adequate source control, and appropriate antimicrobial therapy. Prompt resuscitation of patients with ongoing sepsis is of utmost important. In hospitals worldwide, non-acceptance of, or lack of access to, accessible evidence-based practices and guidelines result in overall poorer outcome of patients suffering IAIs. The aim of this paper is to promote global standards of care in IAIs and update the 2013 WSES guidelines for management of intra-abdominal infections.Peer reviewe

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio