Presymptomatic risk assessment for chronic non-communicable diseases

The prevalence of common chronic non-communicable diseases (CNCDs) far overshadows the prevalence of both monogenic and infectious diseases combined. All CNCDs, also called complex genetic diseases, have a heritable genetic component that can be used for pre-symptomatic risk assessment. Common single nucleotide polymorphisms (SNPs) that tag risk haplotypes across the genome currently account for a non-trivial portion of the germ-line genetic risk and we will likely continue to identify the remaining missing heritability in the form of rare variants, copy number variants and epigenetic modifications. Here, we describe a novel measure for calculating the lifetime risk of a disease, called the genetic composite index (GCI), and demonstrate its predictive value as a clinical classifier. The GCI only considers summary statistics of the effects of genetic variation and hence does not require the results of large-scale studies simultaneously assessing multiple risk factors. Combining GCI scores with environmental risk information provides an additional tool for clinical decision-making. The GCI can be populated with heritable risk information of any type, and thus represents a framework for CNCD pre-symptomatic risk assessment that can be populated as additional risk information is identified through next-generation technologies.Comment: Plos ONE paper. Previous version was withdrawn to be updated by the journal's pdf versio

The Anatomy of Asilisaurus kongwe, a Dinosauriform from the Lifua Member of the Manda Beds (~Middle Triassic) of Africa

The diagnosis of Dinosauria and interrelationships of the earliest dinosaurs relies on careful documentation of the anatomy of their closest relatives. These close relatives, or dinosaur “precursors,” are typically only documented by a handful of fossils from across Pangea and nearly all specimens are typically missing important regions (e.g., forelimbs, pelves, skulls) that appear to be important to help resolving the relationships of dinosaurs. Here, we fully describe the known skeletal elements of Asilisaurus kongwe, a dinosauriform from the Middle Triassic Manda Beds of the Ruhuhu Basin of Tanzania. The taxon is known from many disarticulated and partially articulated remains and, most importantly, from a spectacularly preserved associated skeleton of an individual containing much of the skull, pectoral and pelvic girdles, forelimb and hindlimb, and parts of the vertebral column including much of the tail. The unprecedented detail of the anatomy indicates that Asilisaurus kongwe had a unique skull that was short and had both a premaxillary and dentary edentulous margin, but retained a number of character states plesiomorphic for Archosauria, including a crocodylian-like ankle configuration and a rather short foot with well-developed metatarsals I and V. Additionally, character states present across the skeleton of Asilisaurus kongwe suggest it is more closely related to Silesaurus opolensis than to dinosaurs; thus suggesting high homoplasy and parallel trends within Silesauridae and within lineages of early dinosaurs. The anatomy of Asilisaurus kongwe and detailed description of early members of clades found outside Dinosauria are clearly needed to untangle the seemingly complex character evolution of the skeleton within avemetatarsalians.Fil: Nesbitt, Sterling J.. Virginia Polytechnic Institute; Estados UnidosFil: Langer, Max C.. Universidade de Sao Paulo; BrasilFil: Ezcurra, Martin Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Museo Argentino de Ciencias Naturales "Bernardino Rivadavia"; Argentin

PRISM (Program of Resources, Information and Support for Mothers) Protocol for a community-randomised trial [ISRCTN03464021]

BACKGROUND: In the year after birth one in six women has a depressive illness, and 30% are still depressed, or depressed again, when their child is 2 years old, 94% experience at least one major health problem (e.g. back pain, perineal pain, mastitis, urinary or faecal incontinence), 26% experience sexual problems and almost 20% have relationship problems with partners. Women with depression report less practical and emotional support from partners, less social support overall, more negative life events, and poorer physical health. Their perceptions of factors contributing to depression are lack of support, isolation, exhaustion and physical health problems. Fewer than one in three affected women seek help in primary care despite frequent contacts. METHODS/DESIGN: PRISM aims to reduce depression and physical health problems of recent mothers through primary care strategies to increase practitioners' response to these issues, and through community-based strategies to develop broader family and community supports for recent mothers. Eligible local governments will be recruited and randomised to intervention or comparison arms, after stratification (urban/rural, size, birth numbers, extent of community activity), avoiding contiguous boundaries. Maternal depression and physical health will be measured six months after birth, in a one year cohort of mothers, in intervention and comparison communities. The sample size to detect a 20% relative reduction in depression, adjusting for cluster sampling, and estimating a population response fraction of 67% is 5740 × 2. Analysis of the physical and mental health outcomes, by intention to treat, will adjust for the correlated structure of the data

Understanding valuation of travel time changes: are preferences different under different stated choice design settings?

Stated choice (SC) experiments are the most popular method to estimate the value of travel time changes (VTTC) of a population. In the simplest VTTC experiment, the SC design variables are time changes and cost changes. The levels of these variables create a particular setting from which preferences are inferred. This paper tries to answer the question “do preferences vary with SC settings?”. For this, we investigate the role of the variables used in the SC experiment on the estimation of the set of VTTC (i.e. mean and covariates). Ideally, one would like to observe the same individuals completing different SC experiments. Since that option is not available, an alternative approach is to use a large dataset of responses, and split it according to different levels of the variable of interest. We refer to this as partial data analysis. The estimation of the same model on each sub-sample provides insights into potential effects of the variable of interest. This approach is applied in relation to three design variables on the data for the last national VTTC study in the UK, using state-of-the-art model specifications. The results show several ways in which the estimated set of VTTC can be affected by the levels of SC design variables. We conclude that model estimates (including the VTTC and covariates) are different in different settings. Hence by focussing the survey on specific settings, sample level results will be affected accordingly. Our findings have implications for appraisal and can inform the construction of future SC experiments

Early Detection of Tuberculosis Outbreaks among the San Francisco Homeless: Trade-Offs Between Spatial Resolution and Temporal Scale

BACKGROUND: San Francisco has the highest rate of tuberculosis (TB) in the U.S. with recurrent outbreaks among the homeless and marginally housed. It has been shown for syndromic data that when exact geographic coordinates of individual patients are used as the spatial base for outbreak detection, higher detection rates and accuracy are achieved compared to when data are aggregated into administrative regions such as zip codes and census tracts. We examine the effect of varying the spatial resolution in the TB data within the San Francisco homeless population on detection sensitivity, timeliness, and the amount of historical data needed to achieve better performance measures. METHODS AND FINDINGS: We apply a variation of space-time permutation scan statistic to the TB data in which a patient's location is either represented by its exact coordinates or by the centroid of its census tract. We show that the detection sensitivity and timeliness of the method generally improve when exact locations are used to identify real TB outbreaks. When outbreaks are simulated, while the detection timeliness is consistently improved when exact coordinates are used, the detection sensitivity varies depending on the size of the spatial scanning window and the number of tracts in which cases are simulated. Finally, we show that when exact locations are used, smaller amount of historical data is required for training the model. CONCLUSION: Systematic characterization of the spatio-temporal distribution of TB cases can widely benefit real time surveillance and guide public health investigations of TB outbreaks as to what level of spatial resolution results in improved detection sensitivity and timeliness. Trading higher spatial resolution for better performance is ultimately a tradeoff between maintaining patient confidentiality and improving public health when sharing data. Understanding such tradeoffs is critical to managing the complex interplay between public policy and public health. This study is a step forward in this direction

F- and G-Actin Concentrations in Lamellipodia of Moving Cells

Cells protrude by polymerizing monomeric (G) into polymeric (F) actin at the tip of the lamellipodium. Actin filaments are depolymerized towards the rear of the lamellipodium in a treadmilling process, thereby supplementing a G-actin pool for a new round of polymerization. In this scenario the concentrations of F- and G-actin are principal parameters, but have hitherto not been directly determined. By comparing fluorescence intensities of bleached and unbleached regions of lamellipodia in B16-F1 mouse melanoma cells expressing EGFP-actin, before and after extraction with Triton X-100, we show that the ratio of F- to G-actin is 3.2+/−0.9. Using electron microscopy to determine the F-actin content, this ratio translates into F- and G-actin concentrations in lamellipodia of approximately 500 µM and 150 µM, respectively. The excess of G-actin, at several orders of magnitude above the critical concentrations at filament ends indicates that the polymerization rate is not limited by diffusion and is tightly controlled by polymerization/depolymerization modulators

A multi-phenotypic imaging screen to identify bacterial effectors by exogenous expression in a HeLa cell line

We present a high-content screen (HCS) for the simultaneous analysis of multiple phenotypes in HeLa cells expressing an autophagy reporter (mcherry-LC3) and one of 209 GFP-fused proteins from the Crohn’s Disease (CD)-associated bacterium, Adherent Invasive E. coli (AIEC) strain LF82. Using automated confocal microscopy and image analysis (CellProfiler), we localised GFP fusions within cells, and monitored their effects upon autophagy (an important innate cellular defence mechanism), cellular and nuclear morphology, and the actin cytoskeleton. This data will provide an atlas for the localisation of 209 AIEC proteins within human cells, as well as a dataset to analyse their effects upon many aspects of host cell morphology. We also describe an open-source, automated, image-analysis workflow to identify bacterial effectors and their roles via the perturbations induced in reporter cell lines when candidate effectors are exogenously expressed

Medical students’ preparedness for professional activities in early clerkships

Background Sufficient preparedness is important for transitions to workplace participation and learning in clinical settings. This study aims to analyse medical students’ preparedness for early clerkships using a three-dimensional, socio-cognitive, theory-based model of preparedness anchored in specific professional activities and their supervision level. Methods Medical students from a competency-based undergraduate curriculum were surveyed about preparedness for 21 professional activities and level of perceived supervision during their early clerkships via an online questionnaire. Preparedness was operationalized by the three dimensions of confidence to carry out clerkship activities, being prepared through university teaching and coping with failure by seeking support. Factors influencing preparedness and perceived stress as outcomes were analysed through step-wise regression. Results Professional activities carried out by the students (n = 147; 19.0%) and their supervision levels varied. While most students reported high confidence to perform the tasks, the activity-specific analysis revealed important gaps in preparation through university teaching. Students regularly searched for support in case of difficulty. One quarter of the variance of each preparedness dimension was explained by self-efficacy, supervision quality, amount of prior clerkship experience and nature of professional activities. Preparedness contributed to predicting perceived stress. Conclusions The applied three-dimensional concept of preparedness and the task-specific approach provided a detailed and meaningful view on medical students’ workplace participation and experiences in early clerkships