Genetic characterization of the complete genome of a highly divergent simian T-lymphotropic virus (STLV) type 3 from a wild Cercopithecus mona monkey

<p>Abstract</p> <p>Background</p> <p>The recent discoveries of novel human T-lymphotropic virus type 3 (HTLV-3) and highly divergent simian T-lymphotropic virus type 3 (STLV-3) subtype D viruses from two different monkey species in southern Cameroon suggest that the diversity and cross-species transmission of these retroviruses are much greater than currently appreciated.</p> <p>Results</p> <p>We describe here the first full-length sequence of a highly divergent STLV-3d(Cmo8699AB) virus obtained by PCR-based genome walking using DNA from two dried blood spots (DBS) collected from a wild-caught <it>Cercopithecus mona </it>monkey. The genome of STLV-3d(Cmo8699AB) is 8913-bp long and shares only 77% identity to other PTLV-3s. Phylogenetic analyses using Bayesian and maximum likelihood inference clearly show that this highly divergent virus forms an independent lineage with high posterior probability and bootstrap support within the diversity of PTLV-3. Molecular dating of concatenated <it>gag-pol-env-tax </it>sequences inferred a divergence date of about 115,117 years ago for STLV-3d(Cmo8699AB) indicating an ancient origin for this newly identified lineage. Major structural, enzymatic, and regulatory gene regions of STLV-3d(Cmo8699AB) are intact and suggest viral replication and a predicted pathogenic potential comparable to other PTLV-3s.</p> <p>Conclusion</p> <p>When taken together, the inferred ancient origin of STLV-3d(Cmo8699AB), the presence of this highly divergent virus in two primate species from the same geographical region, and the ease with which STLVs can be transmitted across species boundaries all suggest that STLV-3d may be more prevalent and widespread. Given the high human exposure to nonhuman primates in this region and the unknown pathogenicity of this divergent PTLV-3, increased surveillance and expanded prevention activities are necessary. Our ability to obtain the complete viral genome from DBS also highlights further the utility of this method for molecular-based epidemiologic studies.</p

Large meta-analysis of multiple cancers reveals a common, compact and highly prognostic hypoxia metagene

BACKGROUND: There is a need to develop robust and clinically applicable gene expression signatures. Hypoxia is a key factor promoting solid tumour progression and resistance to therapy; a hypoxia signature has the potential to be not only prognostic but also to predict benefit from particular interventions. METHODS: An approach for deriving signatures that combine knowledge of gene function and analysis of in vivo co-expression patterns was used to define a common hypoxia signature from three head and neck and five breast cancer studies. Previously validated hypoxia-regulated genes (seeds) were used to generate hypoxia co-expression cancer networks. RESULTS: A common hypoxia signature, or metagene, was derived by selecting genes that were consistently co-expressed with the hypoxia seeds in multiple cancers. This was highly enriched for hypoxia-regulated pathways, and prognostic in multivariate analyses. Genes with the highest connectivity were also the most prognostic, and a reduced metagene consisting of a small number of top-ranked genes, including VEGFA, SLC2A1 and PGAM1, outperformed both a larger signature and reported signatures in independent data sets of head and neck, breast and lung cancers. CONCLUSION: Combined knowledge of multiple genes' function from in vitro experiments together with meta-analysis of multiple cancers can deliver compact and robust signatures suitable for clinical application

Exploring differential item functioning in the Western Ontario and McMaster Universities osteoarthritis index (WOMAC)

Background: The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) is a widely used patient reported outcome in osteoarthritis. An important, but frequently overlooked, aspect of validating health outcome measures is to establish if items exhibit differential item functioning (DIF). That is, if respondents have the same underlying level of an attribute, does the item give the same score in different subgroups or is it biased towards one subgroup or another. The aim of the study was to explore DIF in the Likert format WOMAC for the first time in a UK osteoarthritis population with respect to demographic, social, clinical and psychological factors. Methods: The sample comprised a community sample of 763 people with osteoarthritis who participated in the Somerset and Avon Survey of Health. The WOMAC was explored for DIF by gender, age, social deprivation, social class, employment status, distress, body mass index and clinical factors. Ordinal regression models were used to identify DIF items. Results: After adjusting for age, two items were identified for the physical functioning subscale as having DIF with age identified as the DIF factor for 2 items, gender for 1 item and body mass index for 1 item. For the WOMAC pain subscale, for people with hip osteoarthritis one item was identified with age-related DIF. The impact of the DIF items rarely had a significant effect on the conclusions of group comparisons. Conclusions: Overall, the WOMAC performed well with only a small number of DIF items identified. However, as DIF items were identified in for the WOMAC physical functioning subscale it would be advisable to analyse data taking into account the possible impact of the DIF items when weight, gender or especially age effects, are the focus of interest in UK-based osteoarthritis studies. Similarly for the WOMAC pain subscale in people with hip osteoarthritis it would be worthwhile to analyse data taking into account the possible impact of the DIF item when age comparisons are of primary interest

Vitality and the course of limitations in activities in osteoarthritis of the hip or knee

<p>Abstract</p> <p>Background</p> <p>The objective of the study was to determine whether psychological and social factors predict the course of limitations in activities in elderly patients with osteoarthritis of the hip or knee, in addition to established somatic and cognitive risk factors.</p> <p>Methods</p> <p>A longitudinal cohort study with a follow-up period of three years was conducted. Patients (N = 237) with hip or knee osteoarthritis were recruited from rehabilitation centers and hospitals. Body functions, comorbidity, cognitive functioning, limitations in activities and psychological and social factors (mental health, vitality, pain coping and perceived social support) were assessed. Statistical analyses included univariate and multivariate regression analyses. Psychological and social factors were added to a previously developed model with body functions, comorbidity and cognitive functioning.</p> <p>Results</p> <p>In knee OA, low vitality has a negative impact on the course of self-reported and performance-based limitations in activities, after controlling for somatic and cognitive factors. In hip OA, psychological and social factors had no additional contribution to the model.</p> <p>Conclusion</p> <p>Low vitality predicts deterioration of limitations in activities in elderly patients with osteoarthritis of the knee, in addition to established somatic and cognitive risk factors. However, the contribution of vitality is relatively small. Results of this study are relevant for the group of patients with knee or hip OA, attending hospitals and rehabilitation centers.</p

Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015

SummaryBackground The Global Burden of Diseases, Injuries, and Risk Factors Study 2015 provides an up-to-date synthesis of the evidence for risk factor exposure and the attributable burden of disease. By providing national and subnational assessments spanning the past 25 years, this study can inform debates on the importance of addressing risks in context. Methods We used the comparative risk assessment framework developed for previous iterations of the Global Burden of Disease Study to estimate attributable deaths, disability-adjusted life-years (DALYs), and trends in exposure by age group, sex, year, and geography for 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks from 1990 to 2015. This study included 388 risk-outcome pairs that met World Cancer Research Fund-defined criteria for convincing or probable evidence. We extracted relative risk and exposure estimates from randomised controlled trials, cohorts, pooled cohorts, household surveys, census data, satellite data, and other sources. We used statistical models to pool data, adjust for bias, and incorporate covariates. We developed a metric that allows comparisons of exposure across risk factors—the summary exposure value. Using the counterfactual scenario of theoretical minimum risk level, we estimated the portion of deaths and DALYs that could be attributed to a given risk. We decomposed trends in attributable burden into contributions from population growth, population age structure, risk exposure, and risk-deleted cause-specific DALY rates. We characterised risk exposure in relation to a Socio-demographic Index (SDI). Findings Between 1990 and 2015, global exposure to unsafe sanitation, household air pollution, childhood underweight, childhood stunting, and smoking each decreased by more than 25%. Global exposure for several occupational risks, high body-mass index (BMI), and drug use increased by more than 25% over the same period. All risks jointly evaluated in 2015 accounted for 57·8% (95% CI 56·6–58·8) of global deaths and 41·2% (39·8–42·8) of DALYs. In 2015, the ten largest contributors to global DALYs among Level 3 risks were high systolic blood pressure (211·8 million [192·7 million to 231·1 million] global DALYs), smoking (148·6 million [134·2 million to 163·1 million]), high fasting plasma glucose (143·1 million [125·1 million to 163·5 million]), high BMI (120·1 million [83·8 million to 158·4 million]), childhood undernutrition (113·3 million [103·9 million to 123·4 million]), ambient particulate matter (103·1 million [90·8 million to 115·1 million]), high total cholesterol (88·7 million [74·6 million to 105·7 million]), household air pollution (85·6 million [66·7 million to 106·1 million]), alcohol use (85·0 million [77·2 million to 93·0 million]), and diets high in sodium (83·0 million [49·3 million to 127·5 million]). From 1990 to 2015, attributable DALYs declined for micronutrient deficiencies, childhood undernutrition, unsafe sanitation and water, and household air pollution; reductions in risk-deleted DALY rates rather than reductions in exposure drove these declines. Rising exposure contributed to notable increases in attributable DALYs from high BMI, high fasting plasma glucose, occupational carcinogens, and drug use. Environmental risks and childhood undernutrition declined steadily with SDI; low physical activity, high BMI, and high fasting plasma glucose increased with SDI. In 119 countries, metabolic risks, such as high BMI and fasting plasma glucose, contributed the most attributable DALYs in 2015. Regionally, smoking still ranked among the leading five risk factors for attributable DALYs in 109 countries; childhood underweight and unsafe sex remained primary drivers of early death and disability in much of sub-Saharan Africa. Interpretation Declines in some key environmental risks have contributed to declines in critical infectious diseases. Some risks appear to be invariant to SDI. Increasing risks, including high BMI, high fasting plasma glucose, drug use, and some occupational exposures, contribute to rising burden from some conditions, but also provide opportunities for intervention. Some highly preventable risks, such as smoking, remain major causes of attributable DALYs, even as exposure is declining. Public policy makers need to pay attention to the risks that are increasingly major contributors to global burden. Funding Bill & Melinda Gates Foundation

Radiographic joint space narrowing in osteoarthritis of the knee: relationship to meniscal tears and duration of pain

[[abstract]]Objective The objective of this study was to assess, with knee radiography, joint space narrowing (JSN) and its relationship to meniscal tears, anterior cruciate ligament (ACL) ruptures, articular cartilage erosion, and duration of pain in patients with knee osteoarthritis. Materials and methods A total of 140 patients who had knee osteoarthritis and underwent primary total knee replacement (TKR) surgery, with unicompartmental medial tibiofemoral JSN (grade 1 or greater) and normal lateral compartments, were recruited. Polytomous logistic regression was used to assess the relationship between JSN and risk factors. Results All patients with JSN were categorized as grade 1 (n = 14, 10.0%), grade 2 (n = 64, 45.7%), or grade 3 (n = 62, 44.3%). Women presented with indications for a TKR at a younger age than men (mean age, 69 vs 73 years, P < 0.05). There were 123 (87.9%) meniscal tears and 58 (41.4%) partial (insufficient or attenuated ACL fibers) and 10 (7.1%) complete ACL ruptures; 115 of 134 (85.8%) patients had moderate to severe cartilage erosion. A higher grade of JSN was correlated with a higher frequency of meniscal tears [odds ratio (OR) 6.00, 95% CI 1.29–27.96 for grade 2 vs grade 1 JSN] and duration of knee pain (OR 1.25, 95% CI 1.01–1.53 for grade 3 vs grade 1 JSN). A higher grade of JSN was not correlated with a higher frequency of ACL rupture or articular cartilage erosion. Conclusion A higher grade of JSN is associated with a higher frequency of meniscal tears and long duration of knee pain in patients with knee osteoarthritis.[[incitationindex]]SCI[[booktype]]紙

Acute Sleep Deprivation and Circadian Misalignment Associated with Transition onto the First Night of Work Impairs Visual Selective Attention

Background: Overnight operations pose a challenge because our circadian biology promotes sleepiness and dissipates wakefulness at night. Since the circadian effect on cognitive functions magnifies with increasing sleep pressure, cognitive deficits associated with night work are likely to be most acute with extended wakefulness, such as during the transition from a day shift to night shift. Methodology/Principal Findings: To test this hypothesis we measured selective attention (with visual search), vigilance (with Psychomotor Vigilance Task [PVT]) and alertness (with a visual analog scale) in a shift work simulation protocol, which included four day shifts followed by three night shifts. There was a nocturnal decline in cognitive processes, some of which were most pronounced on the first night shift. The nighttime decrease in visual search sensitivity was most pronounced on the first night compared with subsequent nights (p = .04), and this was accompanied by a trend towards selective attention becoming ‘fast and sloppy’. The nighttime increase in attentional lapses on the PVT was significantly greater on the first night compared to subsequent nights (p<.05) indicating an impaired ability to sustain focus. The nighttime decrease in subjective alertness was also greatest on the first night compared with subsequent nights (p<.05). Conclusions/Significance: These nocturnal deficits in attention and alertness offer some insight into why occupational errors, accidents, and injuries are pronounced during night work compared to day work. Examination of the nighttime vulnerabilities underlying the deployment of attention can be informative for the design of optimal work schedules and the implementation of effective countermeasures for performance deficits during night work

Kidney organ donation: developing family practice initiatives to reverse inertia

<p>Abstract</p> <p>Background</p> <p>Kidney transplantation is associated with greater long term survival rates and improved quality of life compared with dialysis. Continuous growth in the number of patients with kidney failure has not been matched by an increase in the availability of kidneys for transplantation. This leads to long waiting lists, higher treatment costs and negative health outcomes.</p> <p>Discussion</p> <p>Misunderstandings, public uncertainty and issues of trust in the medical system, that limit willingness to be registered as a potential donor, could be addressed by community dissemination of information and new family practice initiatives that respond to individuals' personal beliefs and concerns regarding organ donation and transplantation.</p> <p>Summary</p> <p>Tackling both personal and public inertia on organ donation is important for any community oriented kidney donation campaign.</p

Shifting patterns of natural variation in the nuclear genome of caenorhabditis elegans

<p>Abstract</p> <p>Background</p> <p>Genome wide analysis of variation within a species can reveal the evolution of fundamental biological processes such as mutation, recombination, and natural selection. We compare genome wide sequence differences between two independent isolates of the nematode <it>Caenorhabditis elegans </it>(CB4856 and CB4858) and the reference genome (N2).</p> <p>Results</p> <p>The base substitution pattern when comparing N2 against CB4858 reveals a transition over transversion bias (1.32:1) that is not present in CB4856. In CB4856, there is a significant bias in the direction of base substitution. The frequency of A or T bases in N2 that are G or C bases in CB4856 outnumber the opposite frequencies for transitions as well as transversions. These differences were not observed in the N2/CB4858 comparison. Similarly, we observed a strong bias for deletions over insertions in CB4856 (1.44: 1) that is not present in CB4858. In both CB4856 and CB4858, there is a significant correlation between SNP rate and recombination rate on the autosomes but not on the X chromosome. Furthermore, we identified numerous significant hotspots of variation in the CB4856-N2 comparison.</p> <p>In both CB4856 and CB4858, based on a measure of the strength of selection (k_a/k_s), all the chromosomes are under negative selection and in CB4856, there is no difference in the strength of natural selection in either the autosomes versus X or between any of the chromosomes. By contrast, in CB4858, k_a/k_svalues are smaller in the autosomes than in the X chromosome. In addition, in CB4858, k_a/k_svalues differ between chromosomes.</p> <p>Conclusions</p> <p>The clear bias of deletions over insertions in CB4856 suggests that either the CB4856 genome is becoming smaller or the N2 genome is getting larger. We hypothesize the hotspots found represent alleles that are shared between CB4856 and CB4858 but not N2. Because the k_a/k_sratio in the X chromosome is higher than the autosomes on average in CB4858, purifying selection is reduced on the X chromosome.</p