Using l‐Carnitine as a Pharmacologic Probe of the Interpatient and Metabolic Variability of Sepsis

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/162752/2/phar2448_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/162752/1/phar2448.pd

Trial Forge Guidance 4 : A guideline for reporting the results of randomised Studies Within A Trial (SWATs)

Acknowledgements We would like to thank those members of the PROMETHEUS programme who are not explicitly named as authors of this publication, but who provided valuable input to the delivery and conduct of the programme within which the guideline development sat. PROMETHEUS programme members include co-authors CA, LK, AP, DB, CC, DD, SG, KG, CH, CS, DT, and ST and P Bower (University of Manchester), L Culliford (University of Bristol), L Doherty (University of York), and R Emsley (Kings College London). We would like to thank public contributors who provided input and comment on earlier versions of this work. We would also like to thank the authors of the previous guidelines for reporting of embedded recruitment trials for their advice and input in the early stages of guideline development and to the independent reviewers and trialists who offered comments and piloting of the draft guideline. Funding Development of the SWAT reporting guideline was initiated as part of The PROMoting THE Use of SWATs (PROMETHEUS) programme, funded by the Medical Research Council (MRC) [grant number MR/R013748/1].Peer reviewe

Financial incentives for large-scale wetland restoration: beyond markets to common asset trusts

Wetlands provide $47.4 trillion/year worth of ecosystem services globally and support immense biodiversity, yet face widespread drainage and pollution, and large-scale wetlands restoration is urgently needed. Payment for ecosystem service (PES) schemes provide a viable avenue for funding large-scale wetland restoration. However, schemes around the globe differ substantially in their goals, structure, challenges, and effectiveness in supporting large-scale wetland restoration. Here, we suggest wetland-based PES schemes use common asset trusts (CATs) to build investment portfolios of wetlands across landscapes that sustain and enhance overall provision of multiple ecosystem services. CATs can meet the needs of multiple investors, permit bundled payments, and provide flexibility to invest in the restoration of numerous services/values, all using a coordinated, highly collaborative, prioritized, and transparent process. CATs would support financial viability, facilitate efficiency to reduce administrative burdens, and enable credibility and social licence building to restore wetland values and services globally

Dairy herd mastitis and reproduction: using simulation to aid interpretation of results from discrete time survival analysis

Probabilistic sensitivity analysis (PSA) is a simulation-based technique for evaluating the relative importance of different inputs to a complex process model. It is commonly employed in decision analysis and for evaluation of the potential impact of uncertainty in research findings on clinical practice, but has a wide variety of other possible applications. In this example, it was used to evaluate the association between herd-level udder health and reproductive performance in dairy herds. Although several recent studies have found relatively large associations between mastitis and fertility at the level of individual inseminations or lactations, the current study demonstrated that herd-level intramammary infection status is highly unlikely to have a clinically significant impact on the overall reproductive performance of a dairy herd under typical conditions. For example, a large increase in incidence rate of clinical mastitis (from 92 to 131 cases per 100 cows per year) would be expected to increase a herd's modified FERTEX score (a cost-based measure of overall reproductive performance) by just £4.501 per cow per year. The herd's background level of submission rate (proportion of eligible cows served every 21 days) and pregnancy risk (proportion of inseminations leading to a pregnancy) correlated strongly with overall reproductive performance and explained a large proportion of the between-herd variation in performance. PSA proved to be a highly useful technique to aid understanding of results from a complex statistical model, and has great potential for a wide variety of applications within the field of veterinary science

Extensive permethrin and DDT resistance in Anopheles arabiensis from eastern and central Sudan

<p>Abstract</p> <p>Background</p> <p>The distribution of insecticide treated nets (ITN) has been dramatically scaled up in eastern and central Sudan. Resistance to insecticides has already been reported in this region and there is an urgent need to develop appropriate resistance management strategies, which requires detailed information on the extent and causes of resistance. This study assessed resistance to permethrin and DDT in seven populations of <it>Anopheles arabiensis </it>from Sudan.</p> <p>Results</p> <p>Three out of the seven populations were defined as resistant to permethrin and five of six populations resistant to DDT according to WHO criteria. The 1014F kdr allele was present in all six populations tested and the presence of this allele was significantly correlated with resistance to permethrin (<it>P </it>= 0.0460). While homozygous 1014F individuals were statistically not more likely to survive (53.7%) permethrin than to be killed (38.6%) by the diagnostic dose, there was no difference in the likelihood of permethrin survival in heterozygotes (<it>P </it>= 0.7973). The susceptible genotypes were more likely to be killed by permethrin exposure than to survive (<it>P </it>= 0.0460). The 1014F allele failed to confer a survival advantage to the WHO diagnostic dose of DDT in either the homozygous or heterozygous state. The 1014S allele was not detected in any of the populations tested.</p> <p>Conclusion</p> <p>The kdr allele is certainly contributing to the extensive resistance to permethrin and DDT in Sudan but the high number of DDT (43%) and permethrin (16.7%) survivors that did not contain either kdr alleles suggests that other resistance mechanisms are also present in these populations. The high frequency of permethrin resistance throughout central and eastern Sudan is a cause of great concern for malaria control activities.</p

Genetic Drivers of Kidney Defects in the DiGeorge Syndrome

Background The DiGeorge syndrome, the most common of the microdeletion syndromes, affects multiple organs, including the heart, the nervous system, and the kidney. It is caused by deletions on chromosome 22q11.2; the genetic driver of the kidney defects is unknown. Methods We conducted a genomewide search for structural variants in two cohorts: 2080 patients with congenital kidney and urinary tract anomalies and 22,094 controls. We performed exome and targeted resequencing in samples obtained from 586 additional patients with congenital kidney anomalies. We also carried out functional studies using zebrafish and mice. Results We identified heterozygous deletions of 22q11.2 in 1.1% of the patients with congenital kidney anomalies and in 0.01% of population controls (odds ratio, 81.5; P=4.5×10(-14)). We localized the main drivers of renal disease in the DiGeorge syndrome to a 370-kb region containing nine genes. In zebrafish embryos, an induced loss of function in snap29, aifm3, and crkl resulted in renal defects; the loss of crkl alone was sufficient to induce defects. Five of 586 patients with congenital urinary anomalies had newly identified, heterozygous protein-altering variants, including a premature termination codon, in CRKL. The inactivation of Crkl in the mouse model induced developmental defects similar to those observed in patients with congenital urinary anomalies. Conclusions We identified a recurrent 370-kb deletion at the 22q11.2 locus as a driver of kidney defects in the DiGeorge syndrome and in sporadic congenital kidney and urinary tract anomalies. Of the nine genes at this locus, SNAP29, AIFM3, and CRKL appear to be critical to the phenotype, with haploinsufficiency of CRKL emerging as the main genetic driver. (Funded by the National Institutes of Health and others.)

Ross, Macdonald, and a Theory for the Dynamics and Control of Mosquito-Transmitted Pathogens

Ronald Ross and George Macdonald are credited with developing a mathematical model of mosquito-borne pathogen transmission. A systematic historical review suggests that several mathematicians and scientists contributed to development of the Ross-Macdonald model over a period of 70 years. Ross developed two different mathematical models, Macdonald a third, and various “Ross-Macdonald” mathematical models exist. Ross-Macdonald models are best defined by a consensus set of assumptions. The mathematical model is just one part of a theory for the dynamics and control of mosquito-transmitted pathogens that also includes epidemiological and entomological concepts and metrics for measuring transmission. All the basic elements of the theory had fallen into place by the end of the Global Malaria Eradication Programme (GMEP, 1955–1969) with the concept of vectorial capacity, methods for measuring key components of transmission by mosquitoes, and a quantitative theory of vector control. The Ross-Macdonald theory has since played a central role in development of research on mosquito-borne pathogen transmission and the development of strategies for mosquito-borne disease prevention

Evidence for perinatal and child health care guidelines in crisis settings: can Cochrane help?

<p>Abstract</p> <p>Background</p> <p>It is important that healthcare provided in crisis settings is based on the best available research evidence. We reviewed guidelines for child and perinatal health care in crisis situations to determine whether they were based on research evidence, whether Cochrane systematic reviews were available in the clinical areas addressed by these guidelines and whether summaries of these reviews were provided in Evidence Aid.</p> <p>Methods</p> <p>Broad internet searches were undertaken to identify relevant guidelines. Guidelines were appraised using AGREE and the clinical areas that were relevant to perinatal or child health were extracted. We searched The Cochrane Database of Systematic Reviews to identify potentially relevant reviews. For each review we determined how many trials were included, and how many were conducted in resource-limited settings.</p> <p>Results</p> <p>Six guidelines met selection criteria. None of the included guidelines were clearly based on research evidence. 198 Cochrane reviews were potentially relevant to the guidelines. These reviews predominantly addressed nutrient supplementation, breastfeeding, malaria, maternal hypertension, premature labour and prevention of HIV transmission. Most reviews included studies from developing settings. However for large portions of the guidelines, particularly health services delivery, there were no relevant reviews. Only 18 (9.1%) reviews have summaries in Evidence Aid.</p> <p>Conclusions</p> <p>We did not identify any evidence-based guidelines for perinatal and child health care in disaster settings. We found many Cochrane reviews that could contribute to the evidence-base supporting future guidelines. However there are important issues to be addressed in terms of the relevance of the available reviews and increasing the number of reviews addressing health care delivery.</p

The effects of vitamin D-2 or D-3 supplementation on glycaemic control and related metabolic parameters in people at risk of type 2 diabetes: protocol of a randomised double-blind placebo-controlled trial

This article is published under license to BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.London – Block grant from Tower Hamlets Primary Care NHS Trust and East London CLRN. Cambridge – From the operational budget of Medical Research Council Epidemiology Unit (MC_UP_A100_1003)