No investigations have been undertaken of risk factors for intensity of soil-transmitted helminth (STH) infection in Timor-Leste. This study provides the first analysis of risk factors for intensity ...of STH infection, as determined by quantitative PCR (qPCR), examining a broad range of water, sanitation and hygiene (WASH) and environmental factors, among communities in Manufahi District, Timor-Leste.
A baseline cross-sectional survey of 18 communities was undertaken as part of a cluster randomised controlled trial, with additional identically-collected data from six other communities. qPCR was used to assess STH infection from stool samples, and questionnaires administered to collect WASH, demographic, and socioeconomic data. Environmental information was obtained from open-access sources and linked to infection outcomes. Mixed-effects multinomial logistic regression was undertaken to assess risk factors for intensity of Necator americanus and Ascaris infection.
2152 participants provided stool and questionnaire information for this analysis. In adjusted models incorporating WASH, demographic and environmental variables, environmental variables were generally associated with infection intensity for both N. americanus and Ascaris spp. Precipitation (in centimetres) was associated with increased risk of moderate-intensity (adjusted relative risk ARR 6.1; 95% confidence interval CI 1.9-19.3) and heavy-intensity (ARR 6.6; 95% CI 3.1-14.1) N. americanus infection, as was sandy-loam soil around households (moderate-intensity ARR 2.1; 95% CI 1.0-4.3; heavy-intensity ARR 2.7; 95% CI 1.6-4.5; compared to no infection). For Ascaris, alkaline soil around the household was associated with reduced risk of moderate-intensity infection (ARR 0.21; 95% CI 0.09-0.51), and heavy-intensity infection (ARR 0.04; 95% CI 0.01-0.25). Few WASH risk factors were significant.
In this high-prevalence setting, strong risk associations with environmental factors indicate that anthelmintic treatment alone will be insufficient to interrupt STH transmission, as conditions are favourable for ongoing environmental transmission. Integrated STH control strategies should be explored as a priority.
Synthetically versatile alkyl sulfinates can be prepared from readily available amines, using Katritzky pyridinium salt intermediates. In a catalyst-free procedure, primary, secondary, and benzylic ...alkyl radicals are generated by photoinduced or thermally induced single-electron transfer (SET) from an electron donor–acceptor (EDA) complex, and trapped by SO2 to generate sulfonyl radicals. Hydrogen atom transfer (HAT) from Hantzsch ester gives alkyl sulfinate products, which are used to prepare a selection of medicinal chemistry relevant sulfonyl-containing motifs.
Abstract Combining simple amines with the bench‐stable sulfinylamine Tr‐NSO allows in situ preparation of reactive alkyl sulfinylamines, which when combined with alkyl radicals generated by ...photocatalytic decarboxylation, provides N‐alkyl sulfinamides. The reactions are broad in scope and tolerate a wide variety of functional groups on both the acid and amine components. The sulfinamide products are used to prepare a selection of challenging S(VI) products. The method provides a convenient way to use reactive and unstable alkyl sulfinylamines.
The determination of the strategy to ensure that the geometry for railway track is kept within acceptable limits, in a cost effective manner, is a complex process. It requires the simultaneous ...consideration of the activities which govern inspection, maintenance and renewal. In addition to this the geometry degradation process is dependent upon the maintenance history. The condition where the track geometry is shown to have deteriorated to a level where intervention is required can be improved using a tamping machine. Tamping is carried out by a special train which measures the geometry of the rails, predicts the correction needed, lifts the rails to the required position, inserts tines into the ballast either side of the sleepers and packs the ballast such that the correct rail position is attained. Whilst improving the geometry this process has the disadvantage that it also breaks the ballast which accelerates the track geometry degradation and reduces the time between interventions.
This paper describes a modelling process to predict the state of the track geometry given any specified asset management strategy. It is based on the Petri net method and in addition to predicting the track condition over time it can also compute the expected whole life costs. By varying the parameters which govern the inspection, maintenance and renewal of the ballast as the most cost effective means to achieve the required level of performance can be predicted.
The 14-3-3 family of adaptor proteins regulate diverse cellular functions including cell proliferation, metabolism, adhesion and apoptosis. Platelets express numerous 14-3-3 isoforms, including ...14-3-3ζ, which has previously been implicated in regulating GPIbα function. Here we show an important role for 14-3-3ζ in regulating arterial thrombosis. Interestingly, this thrombosis defect is not related to alterations in von Willebrand factor (VWF)-GPIb adhesive function or platelet activation, but instead associated with reduced platelet phosphatidylserine (PS) exposure and procoagulant function. Decreased PS exposure in 14-3-3ζ-deficient platelets is associated with more sustained levels of metabolic ATP and increased mitochondrial respiratory reserve, independent of alterations in cytosolic calcium flux. Reduced platelet PS exposure in 14-3-3ζ-deficient mice does not increase bleeding risk, but results in decreased thrombin generation and protection from pulmonary embolism, leading to prolonged survival. Our studies define an important role for 14-3-3ζ in regulating platelet bioenergetics, leading to decreased platelet PS exposure and procoagulant function.
A railway track asset management strategy must ensure that the condition of the track stays at an acceptable level, ensuring passenger comfort and safety. The determination of an efficient and ...effective strategy is a complex problem that requires consideration of the interrelated processes of deterioration, inspection, maintenance and renewal. Railway traffic causes the track’s geometry to deteriorate through time. When the track’s geometry has been assessed and seen to have deteriorated, maintenance is scheduled to restore the track’s geometry using a tamping machine. Tamping involves lifting the track to the required position before inserting vibrating tines into the ballast either side of the sleepers and using them to pack the ballast below. This process causes damage to the ballast, causing a relative acceleration in future track geometry deterioration and decreasing the time between subsequent maintenance interventions.
This paper describes a Markov model that can be used to investigate the asset management strategy applied to a railway track section. The model predicts the way that the track section’s condition changes with time for a given asset management strategy, which is defined through the specification of a number of model parameters. The model is applied to a track section with a specified maintenance strategy and is used to investigate the track’s performance for that strategy. Parameters corresponding to asset management decisions that relate to inspection, maintenance and renewal are then changed in order to illustrate the effects of the decisions on the track’s life cycle. The Markov model provides a simple yet powerful means of investigating the effects of an asset management strategy on a railway track section.
Abstract We present a comprehensive analysis of the evolution of the morphological and structural properties of a large sample of galaxies at z = 3–9 using early James Webb Space Telescope (JWST) ...CEERS NIRCam observations. Our sample consists of 850 galaxies at z > 3 detected in both Hubble Space Telescope (HST)/WFC3 and CEERS JWST/NIRCam images, enabling a comparison of HST and JWST morphologies. We conduct a set of visual classifications, with each galaxy in the sample classified three times. We also measure quantitative morphologies across all NIRCam filters. We find that galaxies at z > 3 have a wide diversity of morphologies. Galaxies with disks make up 60% of galaxies at z = 3, and this fraction drops to ∼30% at z = 6–9, while galaxies with spheroids make up ∼30%–40% across the redshift range, and pure spheroids with no evidence for disks or irregular features make up ∼20%. The fraction of galaxies with irregular features is roughly constant at all redshifts (∼40%–50%), while those that are purely irregular increases from ∼12% to ∼20% at z > 4.5. We note that these are apparent fractions, as many observational effects impact the visibility of morphological features at high redshift. On average, Spheroid-only galaxies have a higher Sérsic index, smaller size, and higher axis ratio than disk or irregular galaxies. Across all redshifts, smaller spheroid and disk galaxies tend to be rounder. Overall, these trends suggest that galaxies with established disks and spheroids exist across the full redshift range of this study, and further work with large samples at higher redshift is needed to quantify when these features first formed.
Sporadic vascular malformations (VMs) are complex congenital anomalies of blood vessels that lead to stroke, life-threatening bleeds, disfigurement, overgrowth, and/or pain. Therapeutic options are ...severely limited, and multidisciplinary management remains challenging, particularly for high-flow arteriovenous malformations (AVM).
To investigate the pathogenesis of sporadic intracranial and extracranial VMs in 160 children in which known genetic causes had been excluded, we sequenced DNA from affected tissue and optimized analysis for detection of low mutant allele frequency.
We discovered multiple mosaic-activating variants in 4 genes of the RAS/MAPK pathway, KRAS, NRAS, BRAF, and MAP2K1, a pathway commonly activated in cancer and responsible for the germline RAS-opathies. These variants were more frequent in high-flow than low-flow VMs. In vitro characterization and 2 transgenic zebrafish AVM models that recapitulated the human phenotype validated the pathogenesis of the mutant alleles. Importantly, treatment of AVM-BRAF mutant zebrafish with the BRAF inhibitor vemurafinib restored blood flow in AVM.
Our findings uncover a major cause of sporadic VMs of different clinical types and thereby offer the potential of personalized medical treatment by repurposing existing licensed cancer therapies.
This work was funded or supported by grants from the AVM Butterfly Charity, the Wellcome Trust (UK), the Medical Research Council (UK), the UK National Institute for Health Research, the L'Oreal-Melanoma Research Alliance, the European Research Council, and the National Human Genome Research Institute (US).
Multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) have emerged in high-HIV-prevalence settings, which generally lack laboratory infrastructure for diagnosing TB drug ...resistance. Even where available, inherent delays with current drug-susceptibility testing (DST) methods result in clinical deterioration and ongoing transmission of MDR and XDR-TB. Identifying clinical predictors of drug resistance may aid in risk stratification for earlier treatment and infection control.
We performed a retrospective case-control study of patients with MDR (cases), XDR (cases) and drug-susceptible (controls) TB in a high-HIV-prevalence setting in South Africa to identify clinical and demographic risk factors for drug-resistant TB. Controls were selected in a 1:1:1 ratio and were not matched. We calculated odds ratios (OR) and performed multivariate logistic regression to identify independent predictors.
We enrolled 116, 123 and 139 patients with drug-susceptible, MDR, and XDR-TB. More than 85% in all three patient groups were HIV-infected. In multivariate analysis, MDR and XDR-TB were each strongly associated with history of TB treatment failure (adjusted OR 51.7 CI 6.6-403.7 and 51.5 CI 6.4-414.0, respectively) and hospitalization more than 14 days (aOR 3.8 CI 1.1-13.3 and 6.1 CI 1.8-21.0, respectively). Prior default from TB treatment was not a risk factor for MDR or XDR-TB. HIV was a risk factor for XDR (aOR 8.2, CI 1.3-52.6), but not MDR-TB. Comparing XDR with MDR-TB patients, the only significant risk factor for XDR-TB was HIV infection (aOR 5.3, CI 1.0-27.6).
In this high-HIV-prevalence and drug-resistant TB setting, a history of prolonged hospitalization and previous TB treatment failure were strong risk factors for both MDR and XDR-TB. Given high mortality observed among patients with HIV and drug-resistant TB co-infection, previously treated and hospitalized patients should be considered for empiric second-line TB therapy while awaiting confirmatory DST results in settings with a high-burden of MDR/XDR-TB.
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