A Journey of Hope: giving research participants a voice to share their experiences and improve community engagement around advanced HIV disease in Uganda [version 2; peer review: 2 approved]

Over the last decade excellent progress has been made globally in HIV management thanks to antiretroviral therapy (ART) rollout and international guidelines now recommending immediate initiation of ART in people living with HIV. Despite this, advanced HIV disease (CD4 less than 200 cells/mL) and opportunistic infections remain a persistent challenge and contribute significantly to HIV-associated mortality, which equates to 23,000 deaths in Uganda in 2018 alone. Our Meningitis Research Team based in Uganda is committed to conducting clinical trials to answer important questions regarding diagnostics and management of HIV-associated opportunistic infections, including tuberculosis and cryptococcal meningitis. However, clinical research is impossible without research participants and results are meaningless unless they are translated into benefits for those affected by the disease. Therefore, we held a series of community engagement events with the aims of 1) giving research participants a voice to share their experiences of clinical research and messages of hope around advanced HIV disease with the community, 2) dispelling myths and stigma around HIV, and 3) raising awareness about the complications of advanced HIV disease and local clinical research and recent scientific advances. The purpose of this Open Letter is to describe our community engagement experience in Uganda, where we aimed to give clinical research participants a greater voice to share their experiences. These activities build upon decades of work in HIV community engagement and lays a platform for future research and engagement activities

Physician Compensation from Salary and Quality of Diabetes Care

OBJECTIVE: To examine the association between physician-reported percent of total compensation from salary and quality of diabetes care. DESIGN: Cross-sectional analysis. PARTICIPANTS: Physicians (n = 1248) and their patients with diabetes mellitus (n = 4200) enrolled in 10 managed care plans. MEASUREMENTS: We examined the associations between physician-reported percent compensation from salary and processes of care including receipt of dilated eye exams and foot exams, advice to take aspirin, influenza immunizations, and assessments of glycemic control, proteinuria, and lipid profile, intermediate outcomes such as adequate control of hemoglobin A1c, lipid levels, and systolic blood pressure levels, and satisfaction with provider communication and perceived difficulty getting needed care. We used hierarchical logistic regression models to adjust for clustering at the health plan and physician levels, as well as for physician and patient covariates. We adjusted for plan as a fixed effect, meaning we estimated variation between physicians using the variance within a particular health plan only, to minimize confounding by other unmeasured health plan variables. RESULTS: In unadjusted analyses, patients of physicians who reported higher percent compensation from salary (>90%) were more likely to receive 5 of 7 diabetes process measures and more intensive lipid management and to have an HbA1c<8.0% than patients of physicians who reported lower percent compensation from salary (<10%). However, these associations did not persist after adjustment. CONCLUSIONS: Our findings suggest that salary, as opposed to fee-for-service compensation, is not independently associated with diabetes processes and intermediate outcomes

Beyond the therapeutic: a Habermasian view of self-help groups’ place in the public sphere

Self-help groups in the United Kingdom continue to grow in number and address virtually every conceivable health condition, but they remain the subject of very little theoretical analysis. The literature to date has predominantly focused on their therapeutic effects on individual members. And yet they are widely presumed to fulfil a broader civic role and to encourage democratic citizenship. The article uses Habermas’ model of the public sphere as an analytical tool with which to reconsider the literature on self-help groups in order to increase our knowledge of their civic functions. In doing this it also aims to illustrate the continuing relevance of Habermas’ work to our understanding of issues in health and social care. We consider, within the context of current health policies and practices, the extent to which self-help groups with a range of different forms and functions operate according to the principles of communicative rationality that Habermas deemed key to democratic legitimacy. We conclude that self-help groups’ civic role is more complex than is usually presumed and that various factors including groups’ leadership, organisational structure and links with public agencies can affect their efficacy within the public sphere

Association of lung function, chest radiographs and clinical features in infants with cystic fibrosis

The optimal strategy for monitoring cystic fibrosis (CF) lung disease in infancy remains unclear

Actigraph Accelerometer-Defined Boundaries for Sedentary Behaviour and Physical Activity Intensities in 7 Year Old Children

Background: Accurate objective assessment of sedentary and physical activity behaviours during childhood is integral to the understanding of their relation to later health outcomes, as well as to documenting the frequency and distribution of physical activity within a population.Purpose: To calibrate the Actigraph GT1M accelerometer, using energy expenditure (EE) as the criterion measure, to define thresholds for sedentary behaviour and physical activity categories suitable for use in a large scale epidemiological study in young children.Methods: Accelerometer-based assessments of physical activity (counts per minute) were calibrated against EE measures (kcal.kg(-1).hr(-1)) obtained over a range of exercise intensities using a COSMED K4b(2) portable metabolic unit in 53 seven-year-old children. Children performed seven activities: lying down viewing television, sitting upright playing a computer game, slow walking, brisk walking, jogging, hopscotch and basketball. Threshold count values were established to identify sedentary behaviour and light, moderate and vigorous physical activity using linear discriminant analysis (LDA) and evaluated using receiver operating characteristic (ROC) curve analysis.Results: EE was significantly associated with counts for all non-sedentary activities with the exception of jogging. Threshold values for accelerometer counts (counts. minute(-1)) were = 3841 for light, moderate and vigorous physical activity respectively. The area under the ROC curves for discrimination of sedentary behaviour and vigorous activity were 0.98. Boundaries for light and moderate physical activity were less well defined (0.61 and 0.60 respectively). Sensitivity and specificity were higher for sedentary (99% and 97%) and vigorous (95% and 91%) than for light (60% and 83%) and moderate (61% and 76%) thresholds.Conclusion: The accelerometer cut points established in this study can be used to classify sedentary behaviour and to distinguish between light, moderate and vigorous physical activity in children of this age

A Journey of Hope: giving research participants a voice to share their experiences and improve community engagement around advanced HIV disease in Uganda

Over the last decade excellent progress has been made globally in HIV management thanks to antiretroviral therapy (ART) rollout and international guidelines now recommending immediate initiation of ART in people living with HIV. Despite this, advanced HIV disease (CD4 less than 200 cells/mL) and opportunistic infections remain a persistent challenge and contribute significantly to HIV-associated mortality, which equates to 23,000 deaths in Uganda in 2018 alone. Our Meningitis Research Team based in Uganda is committed to conducting clinical trials to answer important questions regarding diagnostics and management of HIV-associated opportunistic infections, including tuberculosis and cryptococcal meningitis. However, clinical research is impossible without research participants and results are meaningless unless they are translated into benefits for those affected by the disease. Therefore, we held a series of community engagement events with the aims of 1) giving research participants a voice to share their experiences of clinical research and messages of hope around advanced HIV disease with the community, 2) dispelling myths and stigma around HIV, and 3) raising awareness about the complications of advanced HIV disease and local clinical research and recent scientific advances. The purpose of this Open Letter is to describe our community engagement experience in Uganda, where we aimed to give clinical research participants a greater voice to share their experiences. These activities build upon decades of work in HIV community engagement and lays a platform for future research and engagement activities.</ns4:p

Whole-genome sequencing of acral melanoma reveals genomic complexity and diversity

To increase understanding of the genomic landscape of acral melanoma, a rare form of melanoma occurring on palms, soles or nail beds, whole genome sequencing of 87 tumors with matching transcriptome sequencing for 63 tumors was performed. Here we report that mutational signature analysis reveals a subset of tumors, mostly subungual, with an ultraviolet radiation signature. Significantly mutated genes are BRAF, NRAS, NF1, NOTCH2, PTEN and TYRP1. Mutations and amplification of KIT are also common. Structural rearrangement and copy number signatures show that whole genome duplication, aneuploidy and complex rearrangements are common. Complex rearrangements occur recurrently and are associated with amplification of TERT, CDK4, MDM2, CCND1, PAK1 and GAB2, indicating potential therapeutic options.This work was supported by a National Health and Medical Research Council of Australia (NHMRC) Program Grant (1093017, G.J.M., R.A.S., N.H., G.V.L., J.F.T.), an NHMRC project grant (APP1123217) and NHMRC Fellowship grants (R.A.S., N.K.H. - APP1139071, G.VL.). G.V.L is supported by an NHMRC Practitioner Fellowship and the University of Sydney Medical Foundation. R.A.S is supported by an NHMRC Practitioner Fellowship. J.S.W. is supported by a NHMRC early career fellowship (1111678). N.W. is supported by an NHMRC Senior Research Fellowship (1139071). N.K.H. is supported by an NHMRC Senior Principal Research Fellowship (1117663). P.M.F. was supported by the Deborah and John McMurtrie MIA Pathology Fellowship. T.J.D. was supported by the Jani Haenke Melanoma Pathology Fellowship. Support from Melanoma Institute Australia, the Royal Prince Alfred Hospital and New South Wales Health Pathology is also gratefully acknowledged

Mapping genomic loci implicates genes and synaptic biology in schizophrenia

Schizophrenia has a heritability of 60-80%1, much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead