Lipidomic profiling in Crohn's disease: abnormalities in phosphatidylinositols, with preservation of ceramide, phosphatidylcholine and phosphatidylserine composition.

Crohn's disease is a chronic inflammatory condition largely affecting the terminal ileum and large bowel. A contributing cause is the failure of an adequate acute inflammatory response as a result of impaired secretion of pro-inflammatory cytokines by macrophages. This defective secretion arises from aberrant vesicle trafficking, misdirecting the cytokines to lysosomal degradation. Aberrant intestinal permeability is also well-established in Crohn's disease. Both the disordered vesicle trafficking and increased bowel permeability could result from abnormal lipid composition. We thus measured the sphingo- and phospholipid composition of macrophages, using mass spectrometry and stable isotope labelling approaches. Stimulation of macrophages with heat-killed Escherichia coli resulted in three main changes; a significant reduction in the amount of individual ceramide species, an altered composition of phosphatidylcholine, and an increased rate of phosphatidylcholine synthesis in macrophages. These changes were observed in macrophages from both healthy control individuals and patients with Crohn's disease. The only difference detected between control and Crohn's disease macrophages was a reduced proportion of newly-synthesised phosphatidylinositol 16:0/18:1 over a defined time period. Shotgun lipidomics analysis of macroscopically non-inflamed ileal biopsies showed a significant decrease in this same lipid species with overall preservation of sphingolipid, phospholipid and cholesterol composition

Modeling the effectiveness of One Health interventions against the zoonotic hookworm Ancylostoma ceylanicum

Hookworm disease is a major global public health concern, annually affecting 500-700 million of the world's poorest people. The World Health Organization is targeting the elimination of hookworm as a public health problem by 2030 using a strategy of mass drug administration (MDA) to at-risk human populations. However, in Southeast Asia and the Pacific the zoonotic hookworm species, Ancylostoma ceylanicum, is endemic in dogs and commonly infects people. This presents a potential impediment to the effectiveness of MDA that targets only humans. Here, we develop a novel multi-host (dog and human) transmission model of A. ceylanicum and compare the effectiveness of human-only and "One Health" (human plus dog) MDA strategies under a range of eco-epidemiological assumptions. We show that One Health interventions-targeting both dogs and humans-could suppress prevalence in humans to ≤ 1% by the end of 2030, even with only modest coverage (25-50%) of the animal reservoir. With increasing coverage, One Health interventions may even interrupt transmission. We discuss key unresolved questions on the eco-epidemiology of A. ceylanicum, the challenges of delivering MDA to animal reservoirs, and the growing importance of One Health interventions to human public health

TERC polymorphisms are associated both with susceptibility to colorectal cancer and with longer telomeres.

Shorter telomeres have been associated with increased risk of malignancy, including colorectal cancer (CRC). Telomere length is heritable and may be an intermediate phenotype linked to genetic susceptibility to CRC

Operational research in Malawi: making a difference with cotrimoxazole preventive therapy in patients with tuberculosis and HIV.

BACKGROUND: In Malawi, high case fatality rates in patients with tuberculosis, who were also co-infected with HIV, and high early death rates in people living with HIV during the initiation of antiretroviral treatment (ART) adversely impacted on treatment outcomes for the national tuberculosis and ART programmes respectively. This article i) discusses the operational research that was conducted in the country on cotrimoxazole preventive therapy, ii) outlines the steps that were taken to translate these findings into national policy and practice, iii) shows how the implementation of cotrimoxazole preventive therapy for both TB patients and HIV-infected patients starting ART was associated with reduced death rates, and iv) highlights lessons that can be learnt for other settings and interventions. DISCUSSION: District and facility-based operational research was undertaken between 1999 and 2005 to assess the effectiveness of cotrimoxazole preventive therapy in reducing death rates in TB patients and subsequently in patients starting ART under routine programme conditions. Studies demonstrated significant reductions in case fatality in HIV-infected TB patients receiving cotrimoxazole and in HIV-infected patients about to start ART. Following the completion of research, the findings were rapidly disseminated nationally at stakeholder meetings convened by the Ministry of Health and internationally through conferences and peer-reviewed scientific publications. The Ministry of Health made policy changes based on the available evidence, following which there was countrywide distribution of the updated policy and guidelines. Policy was rapidly moved to practice with the development of monitoring tools, drug procurement and training packages. National programme performance improved which showed a significant decrease in case fatality rates in TB patients as well as a reduction in early death in people with HIV starting ART. SUMMARY: Key lessons for moving this research endeavour through to policy and practice were the importance of placing operational research within the programme, defining relevant questions, obtaining "buy-in" from national programme staff at the beginning of projects and having key actors or "policy entrepreneurs" to push forward the policy-making process. Ultimately, any change in policy and practice has to benefit patients, and the ultimate judge of success is whether treatment outcomes improve or not

Validation of Exercise Capacity as a Surrogate Endpoint in Exercise-Based Rehabilitation for Heart Failure: A Meta-Analysis of Randomized Controlled Trials

This is the final version. Available on open access from Elsevier via the DOI in this recordObjectives: This study sought to validate exercise capacity (EC) as a surrogate for mortality, hospitalization, and health-related quality of life (HRQOL). Background: EC is often used as a primary outcome in exercise-based cardiac rehabilitation (CR) trials of heart failure (HF) via direct cardiorespiratory assessment of maximum oxygen uptake (VO2peak) or through submaximal tests, such as the 6-min walk test (6MWT). Methods: After a systematic review, 31 randomized trials of exercise-based CR compared with no exercise control (4,784 HF patients) were included. Outcomes were pooled using random effects meta-analyses, and inverse variance weighted linear regression equations were fitted to estimate the relationship between the CR on EC and all-cause mortality, hospitalization, and HRQOL. Spearman correlation coefficient (ρ), R2 at trial level, and surrogate threshold effect (STE) were calculated. STE represents the intercept of the prediction band of the regression line with null effect on the final outcome. Results: Exercise-based CR is associated with positive effects on EC measured through VO2peak (+3.10 ml/kg/min; 95% confidence interval [CI]: 2.01 to 4.20) or 6MWT (+41.15 m; 95% CI: 16.68 to 65.63) compared to control. The analyses showed a low level of association between improvements in EC (VO2peak or 6MWT) and mortality and hospitalization. Moderate levels of correlation between EC with HRQOL were seen (e.g., R2 <52%; |ρ| < 0.72). Estimated STE was an increase of 5 ml/kg/min for VO2peak and 80 m for 6MWT to predict a significant improvement in HRQOL. Conclusions: The study results indicate that EC is a poor surrogate endpoint for mortality and hospitalization but has moderate validity as a surrogate for HRQOL. Further research is needed to confirm these findings across other HF interventions.National Institute for Health Research (NIHR)University of Exete

Field testing a remote monitoring system for hand water pumps

Throughout Africa, many hand water pumps malfunction and remain inoperable for long periods of time. Previous studies from a number of Sub-Saharan countries have indicated that in some regions up to 65% of hand pumps may be broken. It is reported that robust monitoring of remote water pumps can help address some of these problems. However, traditional project monitoring strategies generally rely on physical site visits to remote locations. These visits can be time consuming and resource intensive, which in turn may delay the implementation of pump repairs. In contrast, recent years have seen the emergence of a range of new monitoring technologies that use mobile phone networks to rapidly report the operational status of water projects from remote sites. The authors describe the development of a new monitoring system, called MANTIS, which is intended for hand pumps in developing regions. The paper presents data from early field trials of MANTIS in Sierra Leone and The Gambia. The unit relays ‘near real time’ operational data from the water pump to an accessible on- line platform

Rapid reserve generation from a Francis Turbine for system frequency control

The increase in contributions from non base load renewables, such as wind and solar,can have adverse effects on the stability of an electrical grid. In this study, the possibility of rapidlyloading a Francis turbine from a tail water depression (TWD) mode for providing additional systemfrequency control is investigated. Based on the analysis of full-scale TWD test results and keyfindings from the transient testing of a micro-hydro scale turbine unit, a detailed description ofthe TWD transition process is given. The formulation of an improved turbine model for use inone-dimensional hydro-electric plant models is presented with simulation results compared tofull-scale data. The analytical model, which calculates output power according to the conservation ofangular momentum and identified sources of loss, is used in parallel with full-scale and model scaletest observations to elucidate the events and mechanisms occurring during this proposed transition.The output response, in terms of active power, was found to be highly dependent on guide vaneopening rate in both full-scale and model tests. For an approximate doubling in opening rate, theduration of the reverse power flow was reduced by 38% and 21%, for full-scale and model units,while the low pressure transient increased by 16% and 8%, respectively. The analytical model wasshown to capture the general response characteristic in all cases tested; however, output powerresponse was over predicted due to two identified model assumptions made, while, for the morerapid opening, the penstock pressure was under predicted by approximately 15%

Field trials of a new monitoring system for water pumps in Sierra Leone and The Gambia

Many hand water pumps across Sub-Saharan Africa break down prematurely and remain out of service for significant periods of time. This issue has been well documented, with reports suggesting that between 20% and 65% of hand pumps in a number of African countries are broken. It has also been reported that broken hand pumps in this region have represented between $1.2 and$1.5 billion of ineffective investment over the last twenty years. Regular post-construction monitoring of remote water pumps can help address these problems. However, in many instances traditional monitoring programmes require regular site visits to remote locations, which can delay the implementation of repairs and place heavy time and resource demands on supervisory bodies. In response there has been an emerging interest in the use of mobile phone based technologies to monitor water pumps. The authors describe a new monitoring system, called MANTIS (Monitoring & ANalytics To Improve Service), which is intended to be a context-appropriate monitoring tool for hand pumps in developing regions. The paper introduces field trials of this system that have been conducted in Sierra Leone and The Gambia. The unit relays ‘near real time’ operational data from the water pump via an SMS (Short Message Service) server to an accessible on-line platform