MR-Clust: clustering of genetic variants in Mendelian randomization with similar causal estimates.

MOTIVATION: Mendelian randomization is an epidemiological technique that uses genetic variants as instrumental variables to estimate the causal effect of a risk factor on an outcome. We consider a scenario in which causal estimates based on each variant in turn differ more strongly than expected by chance alone, but the variants can be divided into distinct clusters, such that all variants in the cluster have similar causal estimates. This scenario is likely to occur when there are several distinct causal mechanisms by which a risk factor influences an outcome with different magnitudes of causal effect. We have developed an algorithm MR-Clust that finds such clusters of variants, and so can identify variants that reflect distinct causal mechanisms. Two features of our clustering algorithm are that it accounts for differential uncertainty in the causal estimates, and it includes 'null' and 'junk' clusters, to provide protection against the detection of spurious clusters. RESULTS: Our algorithm correctly detected the number of clusters in a simulation analysis, outperforming methods that either do not account for uncertainty or do not include null and junk clusters. In an applied example considering the effect of blood pressure on coronary artery disease risk, the method detected four clusters of genetic variants. A post hoc hypothesis-generating search suggested that variants in the cluster with a negative effect of blood pressure on coronary artery disease risk were more strongly related to trunk fat percentage and other adiposity measures than variants not in this cluster. AVAILABILITY AND IMPLEMENTATION: MR-Clust can be downloaded from https://github.com/cnfoley/mrclust. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online

Publicly funded home care for older people in Ireland: Determinants of utilisation and policy implications

Background: The majority of older people are independent and self caring. When long-term care is required this is provided across a range of community and residential settings including the older person’s own home. Policy direction and the preference of older people are directed towards supporting older people to remain living in their homes for as long as possible. The majority of home care is provided informally by unpaid carers with a smaller proportion provided formally by paid carers. Formal care is predominantly publicly financed but may be delivered by public, private and not-for-profit organizations. The aim of this study was to identify the determinants of formal home care utilisation amongst community living older people in Ireland. Methodology: The study was cross-sectional in design using data from The Irish Longitudinal Study on Ageing (TILDA). Respondents were interviewed between 2009 and 2011; the response rate was 62%. The behavioural model of health service utilisation provided a framework for the analysis (Aday and Andersen, 1974). Results: Multivariable logistic regression revealed a wide range of factors which predict service utilisation. The strongest determinant of formal home care utilisation was self-reported difficulty with instrumental activities of daily living, followed by older age and living alone. Conclusions: The research provides a population based profile of the characteristics of older adults utilising formal home care services provided by the State. Policy implications include the need for a whole system perspective including standardized access and assessment procedures across the system and a shift in orientation away from domestic care towards greater provision of personal care at home. This study identifies a need to consider home care utilisation in older adults who self-report no limitations in either activities of daily living (ADL) or instrumental activities of daily living (IADL) when modeling the demand for home care in the future

Opposing Effects of Particle Pollution, Ozone, and Ambient Temperature on Arterial Blood Pressure

Background: Diabetes increases the risk of hypertension and orthostatic hypotension and raises the risk of cardiovascular death during heat waves and high pollution episodes

Clinical course, costs and predictive factors for response to treatment in carpal tunnel syndrome: The PALMS study protocol

Background Carpal tunnel syndrome (CTS) is the most common neuropathy of the upper limb and a significant contributor to hand functional impairment and disability. Effective treatment options include conservative and surgical interventions, however it is not possible at present to predict the outcome of treatment. The primary aim of this study is to identify which baseline clinical factors predict a good outcome from conservative treatment (by injection) or surgery in patients diagnosed with carpal tunnel syndrome. Secondary aims are to describe the clinical course and progression of CTS, and to describe and predict the UK cost of CTS to the individual, National Health Service (NHS) and society over a two year period. Methods/Design In this prospective observational cohort study patients presenting with clinical signs and symptoms typical of CTS and in whom the diagnosis is confirmed by nerve conduction studies are invited to participate. Data on putative predictive factors are collected at baseline and follow-up through patient questionnaires and include standardised measures of symptom severity, hand function, psychological and physical health, comorbidity and quality of life. Resource use and cost over the 2 year period such as prescribed medications, NHS and private healthcare contacts are also collected through patient self-report at 6, 12, 18 and 24 months. The primary outcome used to classify treatment success or failures will be a 5-point global assessment of change. Secondary outcomes include changes in clinical symptoms, functioning, psychological health, quality of life and resource use. A multivariable model of factors which predict outcome and cost will be developed. Discussion This prospective cohort study will provide important data on the clinical course and UK costs of CTS over a two-year period and begin to identify predictive factors for treatment success from conservative and surgical interventions

Climate change impacts on banana yields around the world

This is the author accepted manuscript. The final version is available from Nature Research via the DOI in this r4ecordData availability: All data used are publicly available and open access. All banana production data sources are listed in Supplementary Table 1. All climatic and topographic data sources are listed in the Methods.Nutritional diversity is a key element of food security1,2,3. However, research on the effects of climate change on food security has, thus far, focused on the main food grains4,5,6,7,8, while the responses of other crops, particularly those that play an important role in the developing world, are poorly understood. Bananas are a staple food and a major export commodity for many tropical nations9. Here, we show that for 27 countries—accounting for 86% of global dessert banana production—a changing climate since 1961 has increased annual yields by an average of 1.37 t ha−1. Past gains have been largely ubiquitous across the countries assessed and African producers will continue to see yield increases in the future. However, global yield gains could be dampened or disappear, reducing to 0.59 t ha−1 and 0.19 t ha−1 by 2050 under the climate scenarios for Representative Concentration Pathways 4.5 and 8.5, respectively, driven by declining yields in the largest producers and exporters. By quantifying climate-driven and technology-driven influences on yield, we also identify countries at risk from climate change and those capable of mitigating its effects or capitalizing on its benefits.Biotechnology and Biological Sciences Research Council (BBSRC)European Union Horizon 202

Unexpectedly rapid evolution of mandibular shape in hominins

Members of the hominins – namely the so-called ‘australopiths’ and the species of the genus Homo – are known to possess short and deep mandibles and relatively small incisors and canines. It is commonly assumed that this suite of traits evolved in early members of the clade in response to changing environmental conditions and increased consumption of though food items. With the emergence of Homo, the functional meaning of mandible shape variation is thought to have been weakened by technological advancements and (later) by the control over fire. In contrast to this expectation, we found that mandible shape evolution in hominins is exceptionally rapid as compared to any other primate clade, and that the direction and rate of shape change (from the ape ancestor) are no different between the australopiths and Homo. We deem several factors including the loss of honing complex, canine reduction, and the acquisition of different diets may have concurred in producing such surprisingly high evolutionary rates. This study reveals the evolution of mandibular shape in hominins has strong morpho-functional and ecological significance attached

Impact of Carnivory on Human Development and Evolution Revealed by a New Unifying Model of Weaning in Mammals

Our large brain, long life span and high fertility are key elements of human evolutionary success and are often thought to have evolved in interplay with tool use, carnivory and hunting. However, the specific impact of carnivory on human evolution, life history and development remains controversial. Here we show in quantitative terms that dietary profile is a key factor influencing time to weaning across a wide taxonomic range of mammals, including humans. In a model encompassing a total of 67 species and genera from 12 mammalian orders, adult brain mass and two dichotomous variables reflecting species differences regarding limb biomechanics and dietary profile, accounted for 75.5%, 10.3% and 3.4% of variance in time to weaning, respectively, together capturing 89.2% of total variance. Crucially, carnivory predicted the time point of early weaning in humans with remarkable precision, yielding a prediction error of less than 5% with a sample of forty-six human natural fertility societies as reference. Hence, carnivory appears to provide both a necessary and sufficient explanation as to why humans wean so much earlier than the great apes. While early weaning is regarded as essentially differentiating the genus Homo from the great apes, its timing seems to be determined by the same limited set of factors in humans as in mammals in general, despite some 90 million years of evolution. Our analysis emphasizes the high degree of similarity of relative time scales in mammalian development and life history across 67 genera from 12 mammalian orders and shows that the impact of carnivory on time to weaning in humans is quantifiable, and critical. Since early weaning yields shorter interbirth intervals and higher rates of reproduction, with profound effects on population dynamics, our findings highlight the emergence of carnivory as a process fundamentally determining human evolution

The Evolution of Compact Binary Star Systems

We review the formation and evolution of compact binary stars consisting of white dwarfs (WDs), neutron stars (NSs), and black holes (BHs). Binary NSs and BHs are thought to be the primary astrophysical sources of gravitational waves (GWs) within the frequency band of ground-based detectors, while compact binaries of WDs are important sources of GWs at lower frequencies to be covered by space interferometers (LISA). Major uncertainties in the current understanding of properties of NSs and BHs most relevant to the GW studies are discussed, including the treatment of the natal kicks which compact stellar remnants acquire during the core collapse of massive stars and the common envelope phase of binary evolution. We discuss the coalescence rates of binary NSs and BHs and prospects for their detections, the formation and evolution of binary WDs and their observational manifestations. Special attention is given to AM CVn-stars -- compact binaries in which the Roche lobe is filled by another WD or a low-mass partially degenerate helium-star, as these stars are thought to be the best LISA verification binary GW sources.Comment: 105 pages, 18 figure

Regulation of Cancer Aggressive Features in Melanoma Cells by MicroRNAs

MicroRNAs (miRNAs) are small non-coding RNAs with regulatory roles, which are involved in a broad spectrum of physiological and pathological processes, including cancer. A common strategy for identification of miRNAs involved in cell transformation is to compare malignant cells to normal cells. Here we focus on identification of miRNAs that regulate the aggressive phenotype of melanoma cells. To avoid differences due to genetic background, a comparative high-throughput miRNA profiling was performed on two isogenic human melanoma cell lines that display major differences in their net proliferation, invasion and tube formation activities. This screening revealed two major cohorts of differentially expressed miRNAs. We speculated that miRNAs up-regulated in the more-aggressive cell line contribute oncogenic features, while the down-regulated miRNAs are tumor suppressive. This assumption was further tested experimentally on five candidate tumor suppressive miRNAs (miR-31, -34a, -184, -185 and -204) and on one candidate oncogenic miRNA (miR-17-5p), all of which have never been reported before in cutaneous melanoma. Remarkably, all candidate Suppressive-miRNAs inhibited net proliferation, invasion or tube formation, while miR-17-5p enhanced cell proliferation. miR-34a and miR-185 were further shown to inhibit the growth of melanoma xenografts when implanted in SCID-NOD mice. Finally, all six candidate miRNAs were detected in 15 different metastatic melanoma specimens, attesting for the physiological relevance of our findings. Collectively, these findings may prove instrumental for understanding mechanisms of disease and for development of novel therapeutic and staging technologies for melanoma