Patient stratification and genomics: flares, fizzlers and foxes

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Testing for adaptive evolution of the female reproductive protein ZPC in mammals, birds and fishes reveals problems with the M7-M8 likelihood ratio test

BACKGROUND: Adaptive evolution appears to be a common feature of reproductive proteins across a very wide range of organisms. A promising way of addressing the evolutionary forces responsible for this general phenomenon is to test for adaptive evolution in the same gene but among groups of species, which differ in their reproductive biology. One can then test evolutionary hypotheses by asking whether the variation in adaptive evolution is consistent with the variation in reproductive biology. We have attempted to apply this approach to the study of a female reproductive protein, zona pellucida C (ZPC), which has been previously shown by the use of likelihood ratio tests (LRTs) to be under positive selection in mammals. RESULTS: We tested for evidence of adaptive evolution of ZPC in 15 mammalian species, in 11 avian species and in six fish species using three different LRTs (M1a-M2a, M7-M8, and M8a-M8). The only significant findings of adaptive evolution came from the M7-M8 test in mammals and fishes. Since LRTs of adaptive evolution may yield false positives in some situations, we examined the properties of the LRTs by several different simulation methods. When we simulated data to test the robustness of the LRTs, we found that the pattern of evolution in ZPC generates an excess of false positives for the M7-M8 LRT but not for the M1a-M2a or M8a-M8 LRTs. This bias is strong enough to have generated the significant M7-M8 results for mammals and fishes. CONCLUSION: We conclude that there is no strong evidence for adaptive evolution of ZPC in any of the vertebrate groups we studied, and that the M7-M8 LRT can be biased towards false inference of adaptive evolution by certain patterns of non-adaptive evolution

Social exclusion in adult informal carers: A systematic narrative review of the experiences of informal carers of people with dementia and mental illness.

Social exclusion has a negative impact on quality of life. People living with dementia or mental health disorders as well as informal carers have been separately described as socially excluded. The objective of this systematic narrative review was to examine the extent to which social exclusion experienced by adult informal carers of people living with dementia or severe mental health disorders has been identified and described in research literature. It synthesised qualitative and quantitative evidence and included the perspectives of carers themselves and of professionals. Eight electronic databases (1997–2017) were searched. Five relevant studies published between 2010 and 2016 were identified. All were qualitative and used interviews and focus groups. Study quality was variable and most were European. Two focused on carers of people living with dementia and three on carers of people with mental health disorders. Four investigated carers’ perspectives and experiences of social exclusion directly (total of 137 carer participants, predominantly parents, spouses and adult children), while the fifth focused on the perceptions of 65 participants working in health and social care. Stigma, financial difficulties and social isolation were highlighted in four studies and the challenges for carers in engaging in leisure activities were described in the fifth. Most conceptualised social exclusion as a form of stigma, or as resulting from stigma. One presented social exclusion as an element of carer burden. Two explicitly discussed the negative effects of social exclusion on carers. The dearth of research and the lack of specificity about social exclusion in carers was surprising. Future research should investigate aspects of social exclusion that may adversely affect carer well-being

Comparing badger (Meles meles) management strategies for reducing tuberculosis incidence in cattle

This is the final version of the article. Available from Public Library of Science via the DOI in this record.Bovine tuberculosis (bTB), caused by Mycobacterium bovis, continues to be a serious economic problem for the British cattle industry. The Eurasian badger (Meles meles) is partly responsible for maintenance of the disease and its transmission to cattle. Previous attempts to manage the disease by culling badgers have been hampered by social perturbation, which in some situations is associated with increases in the cattle herd incidence of bTB. Following the licensing of an injectable vaccine, we consider the relative merits of management strategies to reduce bTB in badgers, and thereby reduce cattle herd incidence. We used an established simulation model of the badger-cattle-TB system and investigated four proposed strategies: business as usual with no badger management, large-scale proactive badger culling, badger vaccination, and culling with a ring of vaccination around it. For ease of comparison with empirical data, model treatments were applied over 150 km(2) and were evaluated over the whole of a 300 km(2) area, comprising the core treatment area and a ring of approximately 2 km. The effects of treatment were evaluated over a 10-year period comprising treatment for five years and the subsequent five year period without treatment. Against a background of existing disease control measures, where 144 cattle herd incidents might be expected over 10 years, badger culling prevented 26 cattle herd incidents while vaccination prevented 16. Culling in the core 150 km(2) plus vaccination in a ring around it prevented about 40 cattle herd breakdowns by partly mitigating the negative effects of culling, although this approach clearly required greater effort. While model outcomes were robust to uncertainty in parameter estimates, the outcomes of culling were sensitive to low rates of land access for culling, low culling efficacy, and the early cessation of a culling strategy, all of which were likely to lead to an overall increase in cattle disease.Funding: The UK Department for Environment, Food and Rural Affairs (Defra, http://ww2.defra.gov.uk/) funded this work. Defra designed the three strategies to investigate, but had no role in data collection and analysis, decision to publish, or preparation of the manuscript

Usefulness of computed tomography based three-dimensional reconstructions to assess the critical shoulder angle.

BACKGROUND: The critical shoulder angle (CSA) is a radiographic measurement that provides an assessment of both glenoid inclination and acromial length. Higher values may correlate with the presence of rotator cuff tears. However, it is difficult to obtain a high-quality true anteroposterior (AP) radiograph of the shoulder, with any excess scapular version or flexion/extension resulting in deviation from the true CSA value. Three-dimensional (3D) bony reconstructions of computed tomography (CT) shoulder scans may be able to be rotated to obtain a similar view to that of true AP radiographs. AIM: To compare CSA measurements performed on 3D bony CT reconstructions, with those on corresponding true AP radiographs. METHODS: CT shoulder scans were matched with true AP radiographs that were classified as either Suter-Henninger type A or C quality. 3D bony reconstructions were segmented from the CT scans, and rotated to replicate an ideal true AP view. Two observers performed CSA measurements using both CT and radiographic images. Measurements were repeated after a one week interval. Reliability was assessed using intraclass correlation coefficients (ICCs) and Bland-Altman plots [bias, limits of agreement (LOA)]. RESULTS: Twenty CT shoulder scans were matched. The mean CSA values were 32.55° (± 4.26°) with radiographs and 29.82° (± 3.49°) with the CT-based method [mean difference 2.73° (± 2.86°); P < 0.001; bias +2.73°; LOA -2.17° to +7.63°]. There was a strong correlation between the two methods (r = 0.748; P < 0.001). Intra-observer reliability was similar, but the best intra-observer values were achieved by the most experienced observer using the CT-based method [ICC: 0.983 (0.958-0.993); bias +0.03°, LOA -1.28° to +1.34°]. Inter-observer reliability was better with the CT-based method [ICC: 0.897 (0.758-0.958), bias +0.24°, LOA -2.93° to +3.41°]. CONCLUSION: The described CT-based method may be a suitable alternative for critical shoulder angle measurement, as it overcomes the difficulty in obtaining a true AP radiographic view

Measurement of Thermal Stress in Railroad Rails Using Ultrasonic SH Waves

The use of welded joints in railroad tracks has led to problems of rail buckling brought about by the development of large compressive stresses during hot days. On cold days, tensile stresses can actually fracture the rail. In order to prevent this source of derailments, it is desirable to develop an easily used instrument to measure the level of stress in an arbitrary section of track in the field. Ultrasonic birefringence, acoustic emission and certain magnetic phenomena have all been used to attack this problem but they all suffer from the necessity for calibrating the sensor under stress-free conditions in order to correct for metallurgical structure variations. A new ultrasonic technique based on using surface skimming shear horizontal ultrasonic waves generated and detected by EMATs was investigated here because it rigorously eliminates the effects of metallurgical texture as well as unreliable coupling of the transducer to the part. Tests on sections of rail mounted in a 200,000 pound testing machine at the University of New Mexico demonstrated that the theory for the basic phenomenon is correct and that the stress level can be measured in spite of the presence of considerable texture in the rail microstructure

Access to health care in South Africa - the influence of race and class

Objectives. The first democratic government elected in South Africa in 1994 inherited huge inequities in  health status and health provision across all sections of the population. This study set out to assess the  impact of the new government's commitment to address these inequities and implement policies to  improve population health in general and address inequalities in health care in particular. Design. A 1998  household survey assessed many aspects of health delivery, including their own perceived and actual access to health care among different segments of South African society. Results. Race was the main predictor of perceived changes in access to health care, with black, coloured and Indian respondents significantly more likely to feel that access had improved since 1994, compared with white respondents. Socio-economic status (SES) was the main predictor of actual access to health care, with low and middle  SES classes significantly less likely to access care when ill.Conclusions. One-third of  respondents perceived health care access to have improved between 1994 and 1998, and this response was partially determined along racial lines. About one-quarter reported an inability to access health care when they required it, and this response was partially determined along socio-economic lines. This set of contrasting responses suggests that at a political level perceptions are largely influenced by race, but at the operational level actual access is influenced by SES.

Emerging concepts in the pathogenesis of antineutrophil cytoplasmic antibody-associated vasculitis.

PURPOSE OF REVIEW: Antineutrophil cytoplasmic antibodies (ANCAs) remain central to our current understanding of the pathogenesis of ANCA-associated vasculitis (AAV), and this review considers recent developments in the context of four key questions: are there targets for ANCA beyond myeloperoxidase (MPO) and proteinase 3 (PR3); are all ANCA pathogenic; how are ANCAs generated; and how do ANCA cause disease? RECENT FINDINGS: B-cell epitope mapping raises the possibility that only a subset of ANCA may be pathogenic. Anti-lysosomal-associated membrane protein 2 autoantibodies have recently emerged as a novel form of ANCA and can be found in anti-MPO and anti-PR3 negative disease. These also provide recent evidence for molecular mimicry in the pathogenesis of AAV, but a definitive proof in human AAV remains elusive. Neutrophil extracellular traps may represent an important mechanism by which MPO and PR3 are taken up by dendritic cells for presentation to the adaptive immune system, and the role of the alternative pathway of complement in AAV has recently been emphasized, with therapeutic implications. SUMMARY: Our current understanding of the pathogenesis of AAV not only reinforces the central role of neutrophils but also provides a sound rationale for B-cell and complement-directed therapies.This work was supported by the Wellcome Trust through a Translational Medicine and Therapeutics PhD Studentship, the National Institute of Health Research Cambridge Biomedical Research Centre and an MRC Programme grant. The Cambridge Institute for Medical Research is in receipt of Wellcome Trust Strategic Award 079895.This is the accepted manuscript. The final version is available from Wolters Kluwer at http://journals.lww.com/co-rheumatology/pages/articleviewer.aspx?year=2015&issue=03000&article=00016&type=abstract

Cytokine mRNA expression responses to resistance, aerobic, and concurrent exercise in sedentary middle-aged men

Concurrent resistance and aerobic exercise (CE) is recommended to ageing populations, though is postulated to induce diminished acute molecular responses. Given that contraction-induced cytokine mRNA expression reportedly mediates remunerative postexercise molecular responses, it is necessary to determine whether cytokine mRNA expression may be diminished after CE. Eight middle-aged men (age, 53.3 ±1.8 years; body mass index, 29.4 ± 1.4 kg·m-2) randomly completed (balanced for completion order) 8 × 8 leg extensions at 70% maximal strength (RE), 40 min of cycling at 55% of peak aerobic workload (AE), or (workload-matched) 50% RE and 50% AE (CE). Muscle (vastus lateralis) was obtained pre-exercise, and at 1 h and 4 h postexercise, and analyzed for changes of glycogen concentration, tumor necrosis factor (TNF)α, TNF receptor-1 and -2 (TNF-R1 and TNF-R2, respectively), interleukin (IL)-6, IL-6R, IL-1β, and IL-1 receptor-antagonist (IL-1ra). All exercise modes upregulated cytokine mRNA expression at 1hpostexercise comparably (TNFα, TNF-R1, TNF-R2, IL-1β, IL-6) (p 0.05). Moreover, AE and RE upregulated IL-1β and IL-1ra expression, whereas CE upregulated IL-1β expression only (p 0.05). In conclusion, in middle-aged men, all modes induced commensurate cytokine mRNA expression at 1 h postexercise; however, only CE resulted in ameliorated expression at 4 h postexercise. Whether the RE or AE components of CE are independently or cumulatively sufficient to upregulate cytokine responses, or whether they collectively inhibit cytokine mRNA expression, remains to be determined

The Contribution of Transcriptomics to Biomarker Development in Systemic Vasculitis and SLE.

A small but increasing number of gene expression based biomarkers are becoming available for routine clinical use, principally in oncology and transplantation. These underscore the potential of gene expression arrays and RNA sequencing for biomarker development, but this potential has not yet been fully realized and most candidates do not progress beyond the initial report. The first part of this review examines the process of gene expression- based biomarker development, highlighting how systematic biases and confounding can significantly skew study outcomes. Adequate validation in an independent cohort remains the single best means of protecting against these concerns. The second part considers gene-expression based biomarkers in Systemic Lupus Erythematosus (SLE) and systemic vasculitis. The type 1 interferon inducible gene signature remains by far the most studied in autoimmune rheumatic disease. While initially presented as an objective, blood-based biomarker of active SLE, subsequent research has shown that it is not specific to SLE and that its association with disease activity is considerably more nuanced than first thought. Nonetheless, it is currently under evaluation in ongoing trials of anti-interferon therapy. Other candidate markers of note include a prognostic CD8+ T-cell gene signature validated in SLE and ANCA-associated vasculitis, and a disease activity biomarker for SLE derived from modules of tightly correlated genes.This is the author accepted manuscript. The final version is available from Bentham Science via http://dx.doi.org/10.2174/138161282166615031313025