Estimating the causal effects of modifiable, non-genetic factors on Huntington disease progression using propensity score weighting

INTRODUCTION: Despite being genetically inherited, it is unclear how non-genetic factors (e.g., substance use, employment) might contribute to the progression and severity of Huntington's disease (HD). METHODS: We used propensity score (PS) weighting in a large (n = 2914) longitudinal dataset (Enroll-HD) to examine the impact of education, employment status, and use of tobacco, alcohol, and recreational and therapeutic drugs on HD progression. Each factor was investigated in isolation while controlling for 19 other factors to ensure that groups were balanced at baseline on potential confounders using PS weights. Outcomes were compared several years later using doubly robust models. RESULTS: Our results highlighted cases where modifiable (non-genetic) factors - namely light and moderate alcohol use and employment - would have been associated with HD progression in models that did not use PS weights to control for baseline imbalances. These associations did not hold once we applied PS weights to balance baseline groups. We also found potential evidence of a protective effect of substance use (primarily marijuana use), and that those who needed antidepressant treatment were likely to progress faster than non-users. CONCLUSIONS: Our study is the first to examine the effect of non-genetic factors on HD using a novel application of PS weighting. We show that previously-reported associated factors - including light and moderate alcohol use - are reduced and no longer significantly linked to HD progression after PS weighting. This indicates the potential value of PS weighting in examining non-genetic factors contributing to HD as well as in addressing the known biases that occur with observational data

The future of midlatitude cyclones

This is the final version. Available from the publisher via the DOI in this record.Purpose of Review This review brings together recent research on the structure, characteristics, dynamics, and impacts of extratropical cyclones in the future. It draws on research using idealized models and complex climate simulations, to evaluate what is known and unknown about these future changes. Recent Findings There are interacting processes that contribute to the uncertainties in future extratropical cyclone changes, e.g., changes in the horizontal and vertical structure of the atmosphere and increasing moisture content due to rising temperatures. Summary While precipitation intensity will most likely increase, along with associated increased latent heating, it is unclear to what extent and for which particular climate conditions this will feedback to increase the intensity of the cyclones. Future research could focus on bridging the gap between idealized models and complex climate models, as well as better understanding of the regional impacts of future changes in extratropical cyclones.Natural Environment Research Council (NERC

Induced Disjoint Paths in Circular-Arc Graphs in Linear Time

The Induced Disjoint Paths problem is to test whether a graph G with k distinct pairs of vertices (si,ti) contains paths P1,…,Pk such that Pi connects si and ti for i=1,…,k, and Pi and Pj have neither common vertices nor adjacent vertices (except perhaps their ends) for 1≤

Rapid, Automated Determination of Reaction Models and Kinetic Parameters

We herein report a novel kinetic modelling methodology whereby identification of the correct reaction model and kinetic parameters is conducted by an autonomous framework combined with transient flow measurements to enable comprehensive process understanding with minimal user input. An automated flow chemistry platform was employed to initially conduct linear flow-ramp experiments to rapidly map the reaction profile of three processes using transient flow data. Following experimental data acquisition, a computational approach was utilised to discriminate between all possible reaction models as well as identify the correct kinetic parameters for each process. Species that are known to participate in the process (starting materials, intermediates, products) are initially inputted by the user prior to flow ramp experiments, then all possible model candidates are compiled into a model library based on their potential to occur after mass balance assessment. Parallel computational optimisation then evaluates each model by algorithmically altering the kinetic parameters of the model to allow convergence of a simulated kinetic curve to the experimental data provided. Statistical analysis then determines the most likely reaction model based on model simplicity and agreement with experimental data. This automated approach to gaining full process understanding, whereby a small number of data-rich experiments are conducted, and the kinetics are evaluated autonomously, shows significant improvements on current industrial optimisation techniques in terms of labour, time and overall cost. The computational approach herein described can be employed using data from any set of experiments and the code is open-source

Design of Experiments for Screening

The aim of this paper is to review methods of designing screening experiments, ranging from designs originally developed for physical experiments to those especially tailored to experiments on numerical models. The strengths and weaknesses of the various designs for screening variables in numerical models are discussed. First, classes of factorial designs for experiments to estimate main effects and interactions through a linear statistical model are described, specifically regular and nonregular fractional factorial designs, supersaturated designs and systematic fractional replicate designs. Generic issues of aliasing, bias and cancellation of factorial effects are discussed. Second, group screening experiments are considered including factorial group screening and sequential bifurcation. Third, random sampling plans are discussed including Latin hypercube sampling and sampling plans to estimate elementary effects. Fourth, a variety of modelling methods commonly employed with screening designs are briefly described. Finally, a novel study demonstrates six screening methods on two frequently-used exemplars, and their performances are compared

Involving people with diabetes and the wider community in diabetes research: a realist review protocol.

BACKGROUND: Patient and public involvement in diabetes research is now actively encouraged in different countries because it is believed that involving people with experience of the condition will improve the quality and relevance of the research. However, reviews of patient involvement have noted that inadequate resources, patients' and communities' lack of research knowledge, and researchers' lack of skills to involve patients and communities in research may present significant contextual barriers. Little is known about the extent of patient/community involvement in designing or delivering interventions for people with diabetes. A realist review of involvement will contribute to assessing when, how and why involvement works, or does not work, to produce better diabetes interventions. METHODS/DESIGN: This protocol outlines the process for conducting a realist review to map how patients and the public have been involved in diabetes research to date. The review questions ask the following: How have people with diabetes and the wider community been involved in diabetes research? What are the characteristics of the process that appear to explain the relative success or failure of involvement? How has involvement (or lack of involvement) in diabetes research influenced the development and conduct of diabetes research? The degree of support in the surrounding context will be assessed alongside the ways in which people interact in different settings to identify patterns of interaction between context, mechanisms and outcomes in different research projects. The level and extent of the involvement will be described for each stage of the research project. The descriptions will be critically reviewed by the people with diabetes on our review team. In addition, researchers and patients in diabetes research will be asked to comment. Information from researcher-patient experiences and documents will be compared to theories of involvement across a range of disciplines to create a mid-range theory describing how involvement (or lack of involvement) in diabetes research influences the development and conduct of diabetes research

Focusing and Compression of Ultrashort Pulses through Scattering Media

Light scattering in inhomogeneous media induces wavefront distortions which pose an inherent limitation in many optical applications. Examples range from microscopy and nanosurgery to astronomy. In recent years, ongoing efforts have made the correction of spatial distortions possible by wavefront shaping techniques. However, when ultrashort pulses are employed scattering induces temporal distortions which hinder their use in nonlinear processes such as in multiphoton microscopy and quantum control experiments. Here we show that correction of both spatial and temporal distortions can be attained by manipulating only the spatial degrees of freedom of the incident wavefront. Moreover, by optimizing a nonlinear signal the refocused pulse can be shorter than the input pulse. We demonstrate focusing of 100fs pulses through a 1mm thick brain tissue, and 1000-fold enhancement of a localized two-photon fluorescence signal. Our results open up new possibilities for optical manipulation and nonlinear imaging in scattering media

Subtle changes in the flavour and texture of a drink enhance expectations of satiety

Background: The consumption of liquid calories has been implicated in the development of obesity and weight gain. Energy-containing drinks are often reported to have a weak satiety value: one explanation for this is that because of their fluid texture they are not expected to have much nutritional value. It is important to consider what features of these drinks can be manipulated to enhance their expected satiety value. Two studies investigated the perception of subtle changes in a drink’s viscosity, and the extent to which thick texture and creamy flavour contribute to the generation of satiety expectations. Participants in the first study rated the sensory characteristics of 16 fruit yogurt drinks of increasing viscosity. In study two, a new set of participants evaluated eight versions of the fruit yogurt drink, which varied in thick texture, creamy flavour and energy content, for sensory and hedonic characteristics and satiety expectations. Results: In study one, participants were able to perceive small changes in drink viscosity that were strongly related to the actual viscosity of the drinks. In study two, the thick versions of the drink were expected to be more filling and have a greater expected satiety value, independent of the drink’s actual energy content. A creamy flavour enhanced the extent to which the drink was expected to be filling, but did not affect its expected satiety. Conclusions: These results indicate that subtle manipulations of texture and creamy flavour can increase expectations that a fruit yogurt drink will be filling and suppress hunger, irrespective of the drink’s energy content. A thicker texture enhanced expectations of satiety to a greater extent than a creamier flavour, and may be one way to improve the anticipated satiating value of energy-containing beverages

Herd-level animal management factors associated with the occurrence of bovine neonatal pancytopenia in calves in a multicountry study

Since 2007, mortality associated with a previously unreported haemorrhagic disease has been observed in young calves in several European countries. The syndrome, which has been named ‘bovine neonatal pancytopenia’ (BNP), is characterised by thrombocytopenia, leukocytopenia and a panmyelophthisis. A herd-level case-control study was conducted in four BNP affected countries (Belgium, France, Germany and the Netherlands) to identify herd management risk factors for BNP occurrence. Data were collected using structured face-to-face and telephone interviews of farm managers and their local veterinarians. In total, 363 case farms and 887 control farms were included in a matched multivariable conditional logistic regression analysis. Case-control status was strongly associated with the odds of herd level use of the vaccine PregSure® BVD (PregSure, Pfizer Animal Health) (matched adjusted odds ratio (OR) 107.2; 95% CI: 41.0–280.1). This was also the case for the practices of feeding calves colostrum from the calf’s own dam (OR 2.0; 95% CI: 1.1–3.4) or feeding pooled colostrum (OR 4.1; 95% CI: 1.9–8.8). Given that the study had relatively high statistical power and represented a variety of cattle production and husbandry systems, it can be concluded with some confidence that no other herd level management factors are competent causes for a sufficient cause of BNP occurrence on herd level. It is suggested that genetic characteristics of the dams and BNP calves should be the focus of further investigations aimed at identifying the currently missing component causes that together with PregSure vaccination and colostrum feeding represent a sufficient cause for occurrence of BNP in calves

Multi-parallel qPCR provides increased sensitivity and diagnostic breadth for gastrointestinal parasites of humans: field-based inferences on the impact of mass deworming

BACKGROUND: Although chronic morbidity in humans from soil transmitted helminth (STH) infections can be reduced by anthelmintic treatment, inconsistent diagnostic tools make it difficult to reliably measure the impact of deworming programs and often miss light helminth infections. METHODS: Cryopreserved stool samples from 796 people (aged 2-81 years) in four villages in Bungoma County, western Kenya, were assessed using multi-parallel qPCR for 8 parasites and compared to point-of-contact assessments of the same stools by the 2-stool 2-slide Kato-Katz (KK) method. All subjects were treated with albendazole and all Ascaris lumbricoides expelled post-treatment were collected. Three months later, samples from 633 of these people were re-assessed by both qPCR and KK, re-treated with albendazole and the expelled worms collected. RESULTS: Baseline prevalence by qPCR (n = 796) was 17 % for A. lumbricoides, 18 % for Necator americanus, 41 % for Giardia lamblia and 15% for Entamoeba histolytica. The prevalence was <1% for Trichuris trichiura, Ancylostoma duodenale, Strongyloides stercoralis and Cryptosporidium parvum. The sensitivity of qPCR was 98% for A. lumbricoides and N. americanus, whereas KK sensitivity was 70% and 32%, respectively. Furthermore, qPCR detected infections with T. trichiura and S. stercoralis that were missed by KK, and infections with G. lamblia and E. histolytica that cannot be detected by KK. Infection intensities measured by qPCR and by KK were correlated for A. lumbricoides (r = 0.83, p < 0.0001) and N. americanus (r = 0.55, p < 0.0001). The number of A. lumbricoides worms expelled was correlated (p < 0.0001) with both the KK (r = 0.63) and qPCR intensity measurements (r = 0.60). CONCLUSIONS: KK may be an inadequate tool for stool-based surveillance in areas where hookworm or Strongyloides are common or where intensity of helminth infection is low after repeated rounds of chemotherapy. Because deworming programs need to distinguish between populations where parasitic infection is controlled and those where further treatment is required, multi-parallel qPCR (or similar high throughput molecular diagnostics) may provide new and important diagnostic information