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Abstract Chronic kidney diseases (CKD) have genetic associations with kidney function. Univariate genome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) associated with estimated glomerular filtration rate (eGFR) and blood urea nitrogen (BUN), two complementary kidney function markers. However, it is unknown whether additional SNPs for kidney function can be identified by multivariate statistical analysis. To address this, we applied canonical correlation analysis (CCA), a multivariate method, to two individual-level CKD genotype datasets, and metaCCA to two published GWAS summary statistics datasets. We identified SNPs previously associated with kidney function by published univariate GWASs with high replication rates, validating the metaCCA method. We then extended discovery and identified previously unreported lead SNPs for both kidney function markers, jointly. These showed expression quantitative trait loci (eQTL) colocalisation with genes having significant differential expression between CKD and healthy individuals. Several of these identified lead missense SNPs were predicted to have a functional impact, including in SLC14A2. We also identified previously unreported lead SNPs that showed significant correlation with both kidney function markers, jointly, in the European ancestry CKDGen, National Unified Renal Translational Research Enterprise (NURTuRE)-CKD and Salford Kidney Study (SKS) datasets. Of these, rs3094060 colocalised with FLOT1 gene expression and was significantly more common in CKD cases in both NURTURE-CKD and SKS, than in the general population. Overall, by using multivariate analysis by CCA, we identified additional SNPs and genes for both kidney function and CKD, that can be prioritised for further CKD analyses.

Summary: Desert animals have evolved systems that enable them to thrive under dry conditions. Focusing on the kidney, we have investigated the transcriptomic adaptations that enable a desert rodent, the Lesser Egyptian Jerboa (Jaculus jaculus), to withstand water deprivation and opportunistic rehydration. Analysis of the whole kidney transcriptome showed many differentially expressed genes in the Jerboa kidney, 6.4% of genes following dehydration and an even greater number (36.2%) following rehydration compared to control. Genes correlated with the rehydration condition included many ribosomal protein coding genes suggesting a concerted effort to accelerate protein synthesis when water is made available. We identify an increase in TGF-beta signaling antagonists in dehydration (e.g., GREM2). We also describe expression of multiple aquaporin and solute carrier transporters mapped to specific nephron segments. The desert adapted renal transcriptome presented here is a valuable resource to expand our understanding of osmoregulation beyond that derived from model organisms.

Abstract The extinction of a species in a plant–pollinator mutualistic community can cause cascading effects and lead to major biodiversity loss. The ecologically important task of predicting the severity of the cascading effects is made challenging by the complex network of interactions among the species. In this work, we analyze an ensemble of models of communities of plant and pollinator species. These models describe the mutualistic inter-species interactions by Boolean threshold functions. We show that identifying generalized positive feedback loops can help pinpoint the species whose extinction leads to catastrophic and substantial damage to the whole community. We compare these results with the damage percentage caused by the loss of species identified as important by previously studied structural measures and show that positive feedback loops and the information gained from them can identify certain crucial species that the other measures fail to find. We also suggest mitigation measures for two specific purposes: (1) prevent the damage to the community by protecting a subset of the species, and (2) restore the community after the damage by restoring a subset of species. Our analyses indicate that the generalized positive feedback loops predict the most efficient strategies to achieve these purposes. The correct identification of species in each category has important implications for conservation efforts and developing community management strategies.

The onset of the coronavirus disease 2019 (COVID-19) pandemic had far-reaching economic and social consequences, affecting economic well-being, health, mobility, relationships, and daily routines. What effect did the COVID-19 pandemic have on neighborhood social cohesion? Drawing on data from the National Survey of Children’s Health, the authors examine trends in neighborhood social cohesion as reported by caregivers of U.S. children from 2016 to 2021. Despite the substantial changes spurred by the COVID-19 pandemic, the authors find that the pandemic did not lead to a significant change in perceived neighborhood social cohesion. These findings reveal the durability of perceived neighborhood social cohesion, showing that it appears to be unaffected even by sizable changes in social and economic contexts. Moreover, the findings provide additional evidence of disparities in perceived neighborhood social cohesion across social groups and contribute to ongoing debates related to potential declines in neighborhood relationships.

DNA–protein crosslinks (DPCs) represent a unique and complex form of DNA damage formed by covalent attachment of proteins to DNA. DPCs are formed through a variety of mechanisms and can significantly impede essential cellular processes such as transcription and replication. For this reason, anti-cancer drugs that form DPCs have proven effective in cancer therapy. While cells rely on numerous different processes to remove DPCs, the molecular mechanisms responsible for orchestrating these processes remain obscure. Having this insight could potentially be harnessed therapeutically to improve clinical outcomes in the battle against cancer. In this review, we describe the ways cells enzymatically process DPCs. These processing events include direct reversal of the DPC via hydrolysis, nuclease digestion of the DNA backbone to delete the DPC and surrounding DNA, proteolytic processing of the crosslinked protein, as well as covalent modification of the DNA-crosslinked proteins with ubiquitin, SUMO, and Poly(ADP) Ribose (PAR).

The impact of invasion by a single non-native species on the function and structure of ecological communities can be significant, and the effects can become more drastic-and harder to predict-when multiple species invade as a group. Here we modify a dynamic Boolean model of plant-pollinator community assembly to consider the invasion of native communities by multiple invasive species that are selected either randomly or such that the invaders constitute a stable community. We show that, compared to random invasion, whole community invasion leads to final stable communities (where the initial process of species turnover has given way to a static or near-static set of species in the community) including both native and non-native species that are larger, more likely to retain native species, and which experience smaller changes to the topological measures of nestedness and connectance. We consider the relationship between the prevalence of mutualistic interactions among native and invasive species in the final stable communities and demonstrate that mutualistic interactions may act as a buffer against significant disruptions to the native community.

Summary: Background: In low-incidence countries, tuberculosis mainly affects migrants, mostly resulting from reactivation of latent tuberculosis infection (LTBI) acquired in high-incidence countries before migration. A nationwide primary care-based LTBI testing and treatment programme for migrants from high-incidence countries was therefore established in high tuberculosis incidence areas in England. We aimed to assess the effectiveness of this programme. Methods: We did a retrospective, population-based cohort study of migrants who registered in primary care between Jan 1, 2011, and Dec 31, 2018, in 55 high-burden areas with programmatic LTBI testing and treatment. Eligible individuals were aged 16–35 years, born in a high-incidence country, and had entered England in the past 5 years. Individuals who tested interferon-γ release assay (IGRA)-negative were advised about symptoms of tuberculosis, whereas those who tested IGRA-positive were clinically assessed to rule out active tuberculosis and offered preventive therapy. The primary outcome was incident tuberculosis notified to the national Enhanced Tuberculosis Surveillance system. Findings: Our cohort comprised 368 097 eligible individuals who had registered in primary care, of whom 37 268 (10·1%) were tested by the programme. 1446 incident cases of tuberculosis were identified: 166 cases in individuals who had IGRA testing (incidence 204 cases [95% CI 176–238] per 100 000 person-years) and 1280 in individuals without IGRA testing (82 cases [77–86] per 100 000 person-years). Overall, in our primary analysis including all diagnosed tuberculosis cases, a time-varying association was identified between LTBI testing and treatment and lower risk of incident tuberculosis (hazard ratio [HR] 0·76 [95% CI 0·63–0·91]) when compared with no testing. In stratified analysis by follow-up period, the intervention was associated with higher risk of tuberculosis diagnosis during the first 6 months of follow-up (9·93 [7·63–12·9) and a lower risk after 6 months (0·57 [0·41–0·79]). IGRA-positive individuals had higher risk of tuberculosis diagnosis than IGRA-negative individuals (31·9 [20·4–49·8]). Of 37 268 migrants who were tested, 6640 (17·8%) were IGRA-positive, of whom 1740 (26·2%) started preventive treatment. LTBI treatment lowered the risk of tuberculosis: of 135 incident cases in the IGRA-positive cohort, seven cases were diagnosed in the treated group (1·87 cases [95% CI 0·89–3·93] per 1000 person-years) and 128 cases were diagnosed in the untreated group (10·9 cases [9·16–12·9] per 1000 person-years; HR 0·14 [95% CI 0·06–0·32]). Interpretation: A low proportion of eligible migrants were tested by the programme and a small proportion of those testing positive started treatment. Despite this, programmatic LTBI testing and treatment of individuals migrating to a low-incidence region is effective at diagnosing active tuberculosis earlier and lowers the long-term risk of progression to tuberculosis. Increasing programme participation and treatment rates for those testing positive could substantially impact national tuberculosis incidence. Funding: National Institute for Health Research Health Protection Research Unit in Respiratory Infections.

Neighborhood social cohesion is strongly associated with health and well-being, especially among families with children. However, there is a widespread perception in the media, policy circles, and prominent research traditions that neighborhood social cohesion has decreased in recent decades for the United States as a whole and among certain subpopulations. Unfortunately, the empirical evidence for such trends is thin. In this study, we use data on families with children from two studies, the Survey of Income and Program Participation and the Fragile Families and Child Wellbeing Study, to explore trends in neighborhood social cohesion and how individual- and neighborhood-level characteristics pattern disparities in the experience of neighborhood social cohesion. Counter to popular perceptions, our results show increases in neighborhood social cohesion over recent decades, at least for families with children. However, our results reveal persistent disparities in the experience of neighborhood social cohesion by individual and neighborhood characteristics.

ABSTRACT The relation between water content and water potential is a key soil hydraulic property. The presence of rock fragments in soils can affect this property in bulk soil. In this study, we focused on the relation property determined with a WP4 dew point potentiometer. The objective was to evaluate the hypothesis that breaking large gravel-size particles into smaller fragments is a suitable strategy for accurate WP4 measurements in coarse materials without affecting the retention properties. Ten initial samples of basalt rock fragments with different weathering degrees were collected from the A horizon of an Entisol (Neossolo). Rock fragments initially sized between 38 to 4 mm were successively fractured into smaller fragments (size classes of 4-2, 1-0.25, and

Tuberculosis (TB) remains a public health threat in low TB incidence countries, through a combination of reactivated disease and onward transmission. Using surveillance data from the United Kingdom (UK) and the Netherlands (NL), we demonstrate a simple and predictable relationship between the probability of observing a cluster and its size (the number of cases with a single genotype). We demonstrate that the full range of observed cluster sizes can be described using a modified branching process model with the individual reproduction number following a Poisson lognormal distribution. We estimate that, on average, between 2010 and 2015, a TB case generated 0.41 (95% CrI 0.30,0.60) secondary cases in the UK, and 0.24 (0.14,0.48) secondary cases in the NL. A majority of cases did not generate any secondary cases. Recent transmission accounted for 39% (26%,60%) of UK cases and 23%(13%,37%) of NL cases. We predict that reducing UK transmission rates to those observed in the NL would result in 538(266,818) fewer cases annually in the UK. In conclusion, while TB in low incidence countries is strongly associated with reactivated infections, we demonstrate that recent transmission remains sufficient to warrant policies aimed at limiting local TB spread.

Background: Mycobacterial Interspersed Repetitive Unit-Variable Number Tandem Repeat (MIRU-VNTR) typing is widely used in high-income countries to determine Mycobacterium tuberculosis relatedness. Whole-genome sequencing (WGS) is known to deliver greater specificity, but no quantitative prospective comparison has yet been undertaken. Methods: We studied isolates from the English Midlands, sampled consecutively between 1 January 2012 and 31 December 2015. In addition to routinely performed MIRU-VNTR typing, DNA was extracted from liquid cultures and sequenced using Illumina technology. Demographic and epidemiological data for the relevant patients were extracted from the Enhanced Tuberculosis Surveillance system run by Public Health England. Closely related samples, defined using a threshold of five single nucleotide variants (SNVs), were compared to samples with identical MIRU-VNTR profiles, to samples from individuals with shared epidemiological risk factors, and to those with both characteristics. Findings: 1999 patients were identified for whom at least one M. tuberculosis isolate had been MIRU-VNTR typed and sequenced. Comparing epidemiological risk factors with close genetic relatedness, only co-residence had a positive predictive value of over 5%. Excluding co-resident individuals, 18.6% of patients with identical MIRU-VNTR profiles were within 5 SNVs. Where patients also shared social risk factors and ethnic group, this rose to 48%. Only 8% of MIRU-VNTR linked pairs in lineage 1 were within 5 SNV, compared to 31% in lineage 4. Interpretation: In the setting studied, this molecular epidemiological study shows MIRU-VNTR typing and epidemiological risk factors are poorly predictive of close genomic relatedness, assessed by SNV. MIRU-VNTR performance varies markedly by lineage. Funding: Public Health England, Health Innovation Challenge Fund, NIHR Health Protection Research Unit Oxford, NIHR Oxford Biomedical Research Centre. Keywords: Mycobacterium tuberculosis, Research in context

Abstract Background Small insertions and deletions (indels) have a significant influence in human disease and, in terms of frequency, they are second only to single nucleotide variants as pathogenic mutations. As the majority of mutations associated with complex traits are located outside the exome, it is crucial to investigate the potential pathogenic impact of indels in non-coding regions of the human genome. Results We present FATHMM-indel, an integrative approach to predict the functional effect, pathogenic or neutral, of indels in non-coding regions of the human genome. Our method exploits various genomic annotations in addition to sequence data. When validated on benchmark data, FATHMM-indel significantly outperforms CADD and GAVIN, state of the art models in assessing the pathogenic impact of non-coding variants. FATHMM-indel is available via a web server at indels.biocompute.org.uk. Conclusions FATHMM-indel can accurately predict the functional impact and prioritise small indels throughout the whole non-coding genome.

Introduction: Our purpose was to develop and test a brief, self-report, and scorable survey instrument for measuring population health profiles from the individual respondent's perspective. We defined population health as the state of physical, mental, and social well-being of a group of individuals, including determinants of their well-being.Materials and Methods: Respondents were adult patients in a community health center. Instrument items, an overall scale, and two subscales were developed and evaluated. Reliability was tested by Cronbach's alphas and test-retest correlations; construct validity was tested by correlations between scores and economic and clinical factors; criterion validity was tested by regression analyses for prediction of morbidity and health care utilization by baseline scores; and feasibility was tested by length of administration time.Results: This was a 2-years prospective study of 450 patients, mostly black non-Hispanics (54%) and Hispanics (29%), many with no health insurance (45%), and poor enough to meet the federal poverty level (73%). The Duke Population Health Profile (Duke-PH) was developed with a 14-item PH scale for overall population health profile and two 7-item subscales, one for social determinants and the other for health determinants. Validity of item selection was indicated by item convergent and item discriminant correlations. Scale and subscale reliability were supported for internal consistency by Cronbach's alphas of 0.63–0.73, and for temporal stability by test-retest correlations of 0.65–0.78. Support for construct validity was shown by the more favorable baseline subscale and scale mean scores for patients able to buy private insurance than for patients unable to afford it. Criterion validity was supported by regression analyses showing that baseline scale and subscale scores predicted both baseline morbidity and 6-months utilization. Feasibility was shown by the mean self-administration time of 3.9 min and mean interviewer-administration time of 5.8 min.Discussion: The strength of this study is support for Duke-PH reliability, validity, and feasibility in a community health center patient population. The new instrument is unique because it measures both social and health determinants of population health from the perspective of individuals in the population.

The "ship" of the Arabian and North African deserts, the one-humped dromedary camel (Camelus dromedarius) has a remarkable capacity to survive in conditions of extreme heat without needing to drink water. One of the ways that this is achieved is through the actions of the antidiuretic hormone arginine vasopressin (AVP), which is made in a specialised part of the brain called the hypothalamo-neurohypophyseal system (HNS), but exerts its effects at the level of the kidney to provoke water conservation. Interestingly, our electron microscopy studies have shown that the ultrastructure of the dromedary HNS changes according to season, suggesting that in the arid conditions of summer the HNS is in an activated state, in preparation for the likely prospect of water deprivation. Based on our dromedary genome sequence, we have carried out an RNAseq analysis of the dromedary HNS in summer and winter. Amongst the 171 transcripts found to be significantly differentially regulated (>2 fold change, p value

Background Development of children with cerebral palsy (CP) depends on the quality of parental care. The aim of the research was to compare parenting attitudes in mothers of children with CP to mothers of typically developing children, and to study the relationship between parenting attitudes and personality traits, stress, coping strategies and self-efficacy in mothers of children with CP. Participants and procedure Twenty-seven mothers of children with cerebral palsy (MCCP) (mean age 35.50 years, SD = 4.83) and twenty-eight mothers (mean age 35.60 years, SD = 4.27) of typically developing children (MTDC) participated in this study. Each parent had a child between the ages of two and seven years. A battery of tests was administered to both groups, which included the Parenting Attitudes Scale (SPR), the NEO Five-Factor Inventory (NEO-FFI), the Generalized Self-Efficacy Scale (GSES), and the COPE Inventory. Also, maternal stress and the amount of social support received were assessed. Results Although acceptance was the most common parental attitude among all participants, mothers of children with CP presented with a stronger tendency towards overprotective and demanding attitudes. MCCP obtained higher scores in neuroticism and lower in openness compared to MTDC. Furthermore, MCCP declared a higher level of distress than MTDC. There were no statistically significant differences between the two groups of mothers regarding self-efficacy, the level of social support or the most often used coping strategies. Neuroticism was found to be the best predictor of overprotective and demanding parental attitudes. Conclusions The study emphasises the importance of parenting programmes for mothers with children with CP to promote the development of autonomy among children with developmental difficulties.

BackgroundIt has become common practice to analyse large scale sequencing data with statistical approaches based around the aggregation of rare variants within the same gene. We applied a novel approach to rare variant analysis by collapsing variants together using protein domain and family coordinates, regarded to be a more discrete definition of a biologically functional unit.MethodsUsing Pfam definitions, we collapsed rare variants (Minor Allele Frequency ≤ 1%) together in three different ways 1) variants within single genomic regions which map to individual protein domains 2) variants within two individual protein domain regions which are predicted to be responsible for a protein-protein interaction 3) all variants within combined regions from multiple genes responsible for coding the same protein domain (i.e. protein families). A conventional collapsing analysis using gene coordinates was also undertaken for comparison. We used UK10K sequence data and investigated associations between regions of variants and lipid traits using the sequence kernel association test (SKAT).ResultsWe observed no strong evidence of association between regions of variants based on Pfam domain definitions and lipid traits. Quantile-Quantile plots illustrated that the overall distributions of p-values from the protein domain analyses were comparable to that of a conventional gene-based approach. Deviations from this distribution suggested that collapsing by either protein domain or gene definitions may be favourable depending on the trait analysed.ConclusionWe have collapsed rare variants together using protein domain and family coordinates to present an alternative approach over collapsing across conventionally used gene-based regions. Although no strong evidence of association was detected in these analyses, future studies may still find value in adopting these approaches to detect previously unidentified association signals.

BackgroundThe success of collapsing methods which investigate the combined effect of rare variants on complex traits has so far been limited. The manner in which variants within a gene are selected prior to analysis has a crucial impact on this success, which has resulted in analyses conventionally filtering variants according to their consequence. This study investigates whether an alternative approach to filtering, using annotations from recently developed bioinformatics tools, can aid these types of analyses in comparison to conventional approaches.Methods & resultsWe conducted a candidate gene analysis using the UK10K sequence and lipids data, filtering according to functional annotations using the resource CADD (Combined Annotation-Dependent Depletion) and contrasting results with 'nonsynonymous' and 'loss of function' consequence analyses. Using CADD allowed the inclusion of potentially deleterious intronic variants, which was not possible when filtering by consequence. Overall, different filtering approaches provided similar evidence of association, although filtering according to CADD identified evidence of association between ANGPTL4 and High Density Lipoproteins (P = 0.02, N = 3,210) which was not observed in the other analyses. We also undertook genome-wide analyses to determine how filtering in this manner compared to conventional approaches for gene regions. Results suggested that filtering by annotations according to CADD, as well as other tools known as FATHMM-MKL and DANN, identified association signals not detected when filtering by variant consequence and vice versa.ConclusionIncorporating variant annotations from non-coding bioinformatics tools should prove to be a valuable asset for rare variant analyses in the future. Filtering by variant consequence is only possible in coding regions of the genome, whereas utilising non-coding bioinformatics annotations provides an opportunity to discover unknown causal variants in non-coding regions as well. This should allow studies to uncover a greater number of causal variants for complex traits and help elucidate their functional role in disease.

Renewable energy will potentially make an important contribution towards the dual aims of meeting carbon emission reduction targets and future energy demand. However, some technologies have considerable potential to impact on the biodiversity of the environments in which they are placed. In this study, an assessment was undertaken of the realistic deployment potential of a range of renewable energy technologies in the UK, considering constraints imposed by biodiversity conservation priorities. We focused on those energy sources that have the potential to make important energy contributions but which might conflict with biodiversity conservation objectives. These included field-scale solar, bioenergy crops, wind energy (both onshore and offshore), wave and tidal stream energy. The spatially-explicit analysis considered the potential opportunity available for each technology, at various levels of ecological risk. The resultant maps highlight the energy resource available, physical and policy constraints to deployment, and ecological sensitivity (based on the distribution of protected areas and sensitive species). If the technologies are restricted to areas which currently appear not to have significant ecological constraints, the total potential energy output from these energy sources was estimated to be in the region of 5,547 TWh/yr. This would be sufficient to meet projected energy demand in the UK, and help to achieve carbon reduction targets. However, we highlight two important caveats. First, further ecological monitoring and surveillance is required to improve understanding of wildlife distributions and therefore potential impacts of utilising these energy sources. This is likely to reduce the total energy available, especially at sea. Second, some of the technologies under investigation are currently not deployed commercially. Consequently this potential energy will only be available if continued effort is put into developing these energy sources/technologies, to enable realisation of their full potential.

The United Kingdom implemented a containment strategy for pandemic (H1N1) 2009 through administering antiviral agents (AVs) to patients and their close contacts. This observational household cohort study describes the effect of AVs on household transmission. We followed 285 confirmed primary cases in 259 households with 761 contacts. At 2 weeks, the confirmed secondary attack rate (SAR) was 8.1% (62/761) and significantly higher in persons 50 years of age (18.9% vs. 1.2%, p

BackgroundPersonality disordered offenders (PDOs) are generally considered difficult to manage and to have a negative impact on staff working with them.AimsThis study aimed to provide an overview of studies examining the impact on staff of working with PDOs, identify impact areas associated with working with PDOs, identify gaps in existing research,and direct future research efforts.MethodsThe authors conducted a systematic review of the English-language literature from 1964-2014 across 20 databases in the medical and social sciences.Results27 papers were included in the review. Studies identified negative impacts upon staff including: negative attitudes, burnout, stress, negative counter-transferential experiences; two studies found positive impacts of job excitement and satisfaction, and the evidence related to perceived risk of violence from PDOs was equivocal. Studies demonstrated considerable heterogeneity and meta-analysis was not possible. The overall level of identified evidence was low: 23 studies (85%) were descriptive only, and only one adequately powered cohort study was found.ConclusionsThe review identified a significant amount of descriptive literature, but only one cohort study and no trials or previous systematic reviews of literatures. Clinicians and managers working with PDOs should be aware of the potential impacts identified, but there is an urgent need for further research focusing on the robust evaluation of interventions to minimise harm to staff working with offenders who suffer from personality disorder.

Xenobiotic-induced interstrand DNA–DNA cross-links (ICL) interfere with transcription and replication and can be converted to toxic DNA double strand breaks. In this work, we investigated cellular responses to 1,4-bis-(guan-7-yl)-2,3-butanediol (bis-N7G-BD) cross-links induced by 1,2,3,4-diepoxybutane (DEB). High pressure liquid chromatography electrospray ionization tandem mass spectrometry (HPLC-ESI+-MS/MS) assays were used to quantify the formation and repair of bis-N7G-BD cross-links in wild-type Chinese hamster lung fibroblasts (V79) and the corresponding isogenic clones V-H1 and V-H4, deficient in the XPD and FANCA genes, respectively. Both V-H1 and V-H4 cells exhibited enhanced sensitivity to DEB-induced cell death and elevated bis-N7G-BD cross-links. However, relatively modest increases of bis-N7G-BD adduct levels in V-H4 clones did not correlate with their hypersensitivity to DEB. Further, bis-N7G-BD levels were not elevated in DEB-treated human clones with defects in the XPA or FANCD2 genes. Comet assays and γ-H2AX focus analyses conducted with hamster cells revealed that ICL removal was associated with chromosomal double strand break formation, and that these breaks persisted in V-H4 cells as compared to control cells. Our findings suggest that ICL repair in cells with defects in the Fanconi anemia repair pathway is associated with aberrant re-joining of repair-induced double strand breaks, potentially resulting in lethal chromosome rearrangements.

Genome-wide association studies have identified a wealth of genetic variants involved in complex traits and multifactorial diseases. There is now considerable interest in testing variants for association with multiple phenotypes (pleiotropy) and for testing multiple variants for association with a single phenotype (gene-based association tests). Such approaches can increase statistical power by combining evidence for association over multiple phenotypes or genetic variants respectively. Canonical Correlation Analysis (CCA) measures the correlation between two sets of multidimensional variables, and thus offers the potential to combine these two approaches. To apply CCA, we must restrict the number of attributes relative to the number of samples. Hence we consider modules of genetic variation that can comprise a gene, a pathway or another biologically relevant grouping, and/or a set of phenotypes. In order to do this, we use an attribute selection strategy based on a binary genetic algorithm. Applied to a UK-based prospective cohort study of 4286 women (the British Women's Heart and Health Study), we find improved statistical power in the detection of previously reported genetic associations, and identify a number of novel pleiotropic associations between genetic variants and phenotypes. New discoveries include gene-based association of NSF with triglyceride levels and several genes (ACSM3, ERI2, IL18RAP, IL23RAP and NRG1) with left ventricular hypertrophy phenotypes. In multiple-phenotype analyses we find association of NRG1 with left ventricular hypertrophy phenotypes, fibrinogen and urea and pleiotropic relationships of F7 and F10 with Factor VII, Factor IX and cholesterol levels.

High early mortality in patients with HIV-1 starting antiretroviral therapy (ART) in sub-Saharan Africa, compared to Europe and North America, is well documented. Longer-term comparisons between settings have been limited by poor ascertainment of mortality in high burden African settings. This study aimed to compare mortality up to four years on ART between South Africa, Europe, and North America.Data from four South African cohorts in which patients lost to follow-up (LTF) could be linked to the national population register to determine vital status were combined with data from Europe and North America. Cumulative mortality, crude and adjusted (for characteristics at ART initiation) mortality rate ratios (relative to South Africa), and predicted mortality rates were described by region at 0-3, 3-6, 6-12, 12-24, and 24-48 months on ART for the period 2001-2010. Of the adults included (30,467 [South Africa], 29,727 [Europe], and 7,160 [North America]), 20,306 (67%), 9,961 (34%), and 824 (12%) were women. Patients began treatment with markedly more advanced disease in South Africa (median CD4 count 102, 213, and 172 cells/µl in South Africa, Europe, and North America, respectively). High early mortality after starting ART in South Africa occurred mainly in patients starting ART with CD4 count

BackgroundAround 67 million pets are owned by households in the United Kingdom, and an increasing number of these are exotic animals. Approximately a third of pets are purchased through retail outlets or direct from breeders. A wide range of infections can be associated with companion animals.ObjectivesThis study uses a systematic literature review to describe the transmission of zoonotic disease in humans associated with a pet shop or other location selling pets (incidents of rabies tracebacks and zoonoses from pet food were excluded).Data sourcesPubMed and EMBASE.ResultsFifty seven separate case reports or incidents were described in the 82 papers that were identified by the systematic review. Summary information on each incident is included in this manuscript. The infections include bacterial, viral and fungal diseases and range in severity from mild to life threatening. Infections associated with birds and rodents were the most commonly reported. Over half of the reports describe incidents in the Americas, and three of these were outbreaks involving more than 50 cases. Many of the incidents identified relate to infections in pet shop employees.LimitationsThis review may have been subject to publication bias, where unusual and unexpected zoonotic infections may be over-represented in peer-reviewed publications. It was also restricted to English-language articles so that pathogens that are more common in non-Western countries, or in more exotic animals not common in Europe and the Americas, may have been under-represented.Conclusions/implicationsA wide spectrum of zoonotic infections are acquired from pet shops. Salmonellosis and psittacosis were the most commonly documented diseases, however more unusual infections such as tularemia also appeared in the review. Given their potential to spread zoonotic infection, it is important that pet shops act to minimise the risk as far as possible.