98 research outputs found

    Dealing with missing standard deviation and mean values in meta-analysis of continuous outcomes: a systematic review

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    Background: Rigorous, informative meta-analyses rely on availability of appropriate summary statistics or individual participant data. For continuous outcomes, especially those with naturally skewed distributions, summary information on the mean or variability often goes unreported. While full reporting of original trial data is the ideal, we sought to identify methods for handling unreported mean or variability summary statistics in meta-analysis. Methods: We undertook two systematic literature reviews to identify methodological approaches used to deal with missing mean or variability summary statistics. Five electronic databases were searched, in addition to the Cochrane Colloquium abstract books and the Cochrane Statistics Methods Group mailing list archive. We also conducted cited reference searching and emailed topic experts to identify recent methodological developments. Details recorded included the description of the method, the information required to implement the method, any underlying assumptions and whether the method could be readily applied in standard statistical software. We provided a summary description of the methods identified, illustrating selected methods in example meta-analysis scenarios. Results: For missing standard deviations (SDs), following screening of 503 articles, fifteen methods were identified in addition to those reported in a previous review. These included Bayesian hierarchical modelling at the meta-analysis level; summary statistic level imputation based on observed SD values from other trials in the meta-analysis; a practical approximation based on the range; and algebraic estimation of the SD based on other summary statistics. Following screening of 1124 articles for methods estimating the mean, one approximate Bayesian computation approach and three papers based on alternative summary statistics were identified. Illustrative meta-analyses showed that when replacing a missing SD the approximation using the range minimised loss of precision and generally performed better than omitting trials. When estimating missing means, a formula using the median, lower quartile and upper quartile performed best in preserving the precision of the meta-analysis findings, although in some scenarios, omitting trials gave superior results. Conclusions: Methods based on summary statistics (minimum, maximum, lower quartile, upper quartile, median) reported in the literature facilitate more comprehensive inclusion of randomised controlled trials with missing mean or variability summary statistics within meta-analyses

    More than just talk: the framing of transactional sex and its implications for vulnerability to HIV in Lesotho, Madagascar and South Africa

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    Background 'Transactional sex' was regarded by the mid-1990s as an important determinant of HIV transmission, particularly in sub-Saharan Africa. Little attention has been paid to what the terms used to denote transactional sex suggest about how it is understood. This study provides a nuanced set of descriptions of the meaning of transactional sex in three settings. Furthermore, we discuss how discourses around transactional sex suggest linkages to processes of globalization and hold implications for vulnerability to HIV. Methods The analysis in this article is based on three case studies conducted as part of a multi-country research project that investigated linkages between economic globalization and HIV. In this analysis, we contextualize and contrast the 'talk' about transactional sex through the following research methods in three study sites: descriptions revealed through semi-structured interviews with garment workers in Lesotho; focus groups with young women and men in Antananarivo, Madagascar; and focus groups and in-depth interviews with young women and men in Mbekweni, South Africa. Results Participants' talk about transactional sex reveals two themes: (1) 'The politics of differentiation' reflects how participants used language to demarcate identities, and distance themselves from contextually-based marginalized identities; and (2) 'Gender, agency and power' describes how participants frame gendered-power within the context of transactional sex practices, and reflects on the limitations to women's power as sexual agents in these exchanges. Talk about transactional sex in our study settings supports the assertion that emerging transactional sexual practices are linked with processes of globalization tied to consumerism. Conclusions By focusing on 'talk' about transactional sex, we locate definitions of transactional sex, and how terms used to describe transactional sex are morally framed for people within their local context. We take advantage of an opportunity to comparatively explore such talk across three different study sites, and contribute to a better understanding of both emerging sexual practices and their implications for HIV vulnerability. Our work underlines that transactional sex needs to be reflected as it is perceived: something very different from, but of at least equal concern to, formal sex work in the efforts to curb HIV transmission

    Examining International Clinical Internships for Canadian Physical Therapy Students from 1997 to 2007

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    Purpose: To describe international clinical internships (ICIs) for Canadian physical therapy (PT) students, explore the experiences of individuals involved in ICIs, and develop recommendations for future ICIs based on these findings

    Novel mutations expand the clinical spectrum of DYNC1H1-associated spinal muscular atrophy

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    OBJECTIVE To expand the clinical phenotype of autosomal dominant congenital spinal muscular atrophy with lower extremity predominance (SMA-LED) due to mutations in the dynein, cytoplasmic 1, heavy chain 1 (DYNC1H1) gene. METHODS Patients with a phenotype suggestive of a motor, non-length-dependent neuronopathy predominantly affecting the lower limbs were identified at participating neuromuscular centers and referred for targeted sequencing of DYNC1H1. RESULTS We report a cohort of 30 cases of SMA-LED from 16 families, carrying mutations in the tail and motor domains of DYNC1H1, including 10 novel mutations. These patients are characterized by congenital or childhood-onset lower limb wasting and weakness frequently associated with cognitive impairment. The clinical severity is variable, ranging from generalized arthrogryposis and inability to ambulate to exclusive and mild lower limb weakness. In many individuals with cognitive impairment (9/30 had cognitive impairment) who underwent brain MRI, there was an underlying structural malformation resulting in polymicrogyric appearance. The lower limb muscle MRI shows a distinctive pattern suggestive of denervation characterized by sparing and relative hypertrophy of the adductor longus and semitendinosus muscles at the thigh level, and diffuse involvement with relative sparing of the anterior-medial muscles at the calf level. Proximal muscle histopathology did not always show classic neurogenic features. CONCLUSION Our report expands the clinical spectrum of DYNC1H1-related SMA-LED to include generalized arthrogryposis. In addition, we report that the neurogenic peripheral pathology and the CNS neuronal migration defects are often associated, reinforcing the importance of DYNC1H1 in both central and peripheral neuronal functions

    Autophagy suppresses the formation of hepatocyte-derived cancer-initiating ductular progenitor cells in the liver

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    Hepatocellular carcinoma (HCC) is driven by repeated rounds of inflammation, leading to fibrosis, cirrhosis, and, ultimately, cancer. A critical step in HCC formation is the transition from fibrosis to cirrhosis, which is associated with a change in the liver parenchyma called ductular reaction. Here, we report a genetically engineered mouse model of HCC driven by loss of macroautophagy and hemizygosity of phosphatase and tensin homolog, which develops HCC involving ductular reaction. We show through lineage tracing that, following loss of autophagy, mature hepatocytes dedifferentiate into biliary-like liver progenitor cells (ductular reaction), giving rise to HCC. Furthermore, this change is associated with deregulation of yes-associated protein and transcriptional coactivator with PDZ-binding motif transcription factors, and the combined, but not individual, deletion of these factors completely reverses the dedifferentiation capacity and tumorigenesis. These findings therefore increase our understanding of the cell of origin of HCC development and highlight new potential points for therapeutic intervention

    Absent expansion of AXIN2+ hepatocytes and altered physiology in Axin2CreERT2 mice challenges the role of pericentral hepatocytes in homeostatic liver regeneration

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    Background & Aims: Mouse models of lineage tracing have helped to describe the important subpopulations of hepatocytes responsible for liver regeneration. However, conflicting results have been obtained from different models. Herein, we aimed to reconcile these conflicting reports by repeating a key lineage-tracing study from pericentral hepatocytes and characterising this Axin2CreERT2 model in detail. Methods: We performed detailed characterisation of the labelled population in the Axin2CreERT2 model. We lineage traced this cell population, quantifying the labelled population over 1 year and performed in-depth phenotypic comparisons, including transcriptomics, metabolomics and analysis of proteins through immunohistochemistry, of Axin2CreERT2 mice to WT counterparts. Results: We found that after careful definition of a baseline population, there are marked differences in labelling between male and female mice. Upon induced lineage tracing there was no expansion of the labelled hepatocyte population in Axin2CreERT2 mice. We found substantial evidence of disrupted homeostasis in Axin2CreERT2 mice. Offspring are born with sub-Mendelian ratios and adult mice have perturbations of hepatic Wnt/β-catenin signalling and related metabolomic disturbance. Conclusions: We find no evidence of predominant expansion of the pericentral hepatocyte population during liver homeostatic regeneration. Our data highlight the importance of detailed preclinical model characterisation and the pitfalls which may occur when comparing across sexes and backgrounds of mice and the effects of genetic insertion into native loci. Impact and implications: Understanding the source of cells which regenerate the liver is crucial to harness their potential to regrow injured livers. Herein, we show that cells which were previously thought to repopulate the liver play only a limited role in physiological regeneration. Our data helps to reconcile differing conclusions drawn from results from a number of prior studies and highlights methodological challenges which are relevant to preclinical models more generally

    Effects of Elevated Temperature and Carbon Dioxide on the Growth and Survival of Larvae and Juveniles of Three Species of Northwest Atlantic Bivalves

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    Rising CO2 concentrations and water temperatures this century are likely to have transformative effects on many coastal marine organisms. Here, we compared the responses of two life history stages (larval, juvenile) of three species of calcifying bivalves (Mercenaria mercenaria, Crassostrea virginica, and Argopecten irradians) to temperatures (24 and 28°C) and CO2 concentrations (∼250, 390, and 750 ppm) representative of past, present, and future summer conditions in temperate estuaries. Results demonstrated that increases in temperature and CO2 each significantly depressed survival, development, growth, and lipid synthesis of M. mercenaria and A. irradians larvae and that the effects were additive. Juvenile M. mercenaria and A. irradians were negatively impacted by higher temperatures while C. virginica juveniles were not. C. virginica and A. irradians juveniles were negatively affected by higher CO2 concentrations, while M. mercenaria was not. Larvae were substantially more vulnerable to elevated CO2 than juvenile stages. These findings suggest that current and future increases in temperature and CO2 are likely to have negative consequences for coastal bivalve populations

    Activation and Deactivation of a Robust Immobilized Cp*Ir-Transfer Hydrogenation Catalyst: A Multielement in Situ X-ray Absorption Spectroscopy Study

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    A highly robust immobilized [Cp*IrCl2]2 precatalyst on Wang resin for transfer hydrogenation, which can be recycled up to 30 times, was studied using a novel combination of X-ray absorption spectroscopy (XAS) at Ir L3-edge, Cl K-edge, and K K-edge. These culminate in in situ XAS experiments that link structural changes of the Ir complex with its catalytic activity and its deactivation. Mercury poisoning and “hot filtration” experiments ruled out leached Ir as the active catalyst. Spectroscopic evidence indicates the exchange of one chloride ligand with an alkoxide to generate the active precatalyst. The exchange of the second chloride ligand, however, leads to a potassium alkoxide–iridate species as the deactivated form of this immobilized catalyst. These findings could be widely applicable to the many homogeneous transfer hydrogenation catalysts with Cp*IrCl substructure

    Exploring synergies between human rights and public health ethics: A whole greater than the sum of its parts

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    <p>Abstract</p> <p>Background</p> <p>The fields of human rights and public health ethics are each concerned with promoting health and elucidating norms for action. To date, however, little has been written about the contribution that these two justificatory frameworks can make together. This article explores how a combined approach may make a more comprehensive contribution to resolving normative health issues and to advancing a normative framework for global health action than either approach made alone. We explore this synergy by first providing overviews of public health ethics and of international human rights law relevant to health and, second, by articulating complementarities between human rights and public health ethics.</p> <p>Discussion</p> <p>We argue that public health ethics can contribute to human rights by: (a) reinforcing the normative claims of international human rights law, (b) strengthening advocacy for human rights, and (c) bridging the divide between public health practitioners and human rights advocates in certain contemporary health domains. We then discuss how human rights can contribute to public health ethics by contributing to discourses on the determinants of health through: (a) definitions of the right to health and the notion of the indivisibility of rights, (b) emphasis on the duties of states to progressively realize the health of citizens, and (c) recognition of the protection of human rights as itself a determinant of health. We also discuss the role that human rights can play for the emergent field of public health ethics by refocusing attention on the health and illness on marginalized individuals and populations.</p> <p>Summary</p> <p>Actors within the fields of public health, ethics and human rights can gain analytic tools by embracing the untapped potential for collaboration inherent in such a combined approach.</p

    Hepatic glutamine synthetase controls N5-methylglutamine in homeostasis and cancer

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    Glutamine synthetase (GS) activity is conserved from prokaryotes to humans, where the ATP-dependent production of glutamine from glutamate and ammonia is essential for neurotransmission and ammonia detoxification. Here, we show that mammalian GS uses glutamate and methylamine to produce a methylated glutamine analog, N5-methylglutamine. Untargeted metabolomics revealed that liver-specific GS deletion and its pharmacological inhibition in mice suppress hepatic and circulating levels of N5-methylglutamine. This alternative activity of GS was confirmed in human recombinant enzyme and cells, where a pathogenic mutation in the active site (R324C) promoted the synthesis of N5-methylglutamine over glutamine. N5-Methylglutamine is detected in the circulation, and its levels are sustained by the microbiome, as demonstrated by using germ-free mice. Finally, we show that urine levels of N5-methylglutamine correlate with tumor burden and GS expression in a β-catenin-driven model of liver cancer, highlighting the translational potential of this uncharacterized metabolite
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