Bioinformatics sequence databases such as Genbank or UniProt contain hundreds of millions of records of genomic data. These records are derived from direct submissions from individual laboratories, as well as from bulk submissions from large-scale sequencing centres; their diversity and scale means that they suffer from a range of data quality issues including errors, discrepancies, redundancies, ambiguities, incompleteness and inconsistencies with the published literature. In this work, we seek to investigate and analyze the data quality of sequence databases from the perspective of a curator, who must detect anomalous and suspicious records. Specifically, we emphasize the detection of inconsistent records with respect to the literature. Focusing on GenBank, we propose a set of 24 quality indicators, which are based on treating a record as a query into the published literature, and then use query quality predictors. We then carry out an analysis that shows that the proposed quality indicators and the quality of the records have a mutual relationship, in which one depends on the other. We propose to represent record-literature consistency as a vector of these quality indicators. By reducing the dimensionality of this representation for visualization purposes using principal component analysis, we show that records which have been reported as inconsistent with the literature fall roughly in the same area, and therefore share similar characteristics. By manually analyzing records not previously known to be erroneous that fall in the same area than records know to be inconsistent, we show that one record out of four is inconsistent with respect to the literature. This high density of inconsistent record opens the way towards the development of automatic methods for the detection of faulty records. We conclude that literature inconsistency is a meaningful strategy for identifying suspicious records. Database URL: https://github.com/rbouadjenek/DQBioinformatics.

Interaction analysis of GWAS can detect signal that would be ignored by single variant analysis, yet few robust interactions in humans have been detected. Recent work has highlighted interactions in the MHC region between known HLA risk haplotypes for various autoimmune diseases. To better understand the genetic interactions underlying celiac disease (CD), we have conducted exhaustive genome-wide scans for pairwise interactions in five independent CD case-control studies, using a rapid model-free approach to examine over 500 billion SNP pairs in total. We found 14 independent interaction signals within the MHC region that achieved stringent replication criteria across multiple studies and were independent of known CD risk HLA haplotypes. The strongest independent CD interaction signal corresponded to genes in the HLA class III region, in particular PRRC2A and GPANK1/C6orf47, which are known to contain variants for non-Hodgkin's lymphoma and early menopause, co-morbidities of celiac disease. Replicable evidence for statistical interaction outside the MHC was not observed. Both within and between European populations, we observed striking consistency of two-locus models and model distribution. Within the UK population, models of CD based on both interactions and additive single-SNP effects increased explained CD variance by approximately 1% over those of single SNPs. The interactions signal detected across the five cohorts indicates the presence of novel associations in the MHC region that cannot be detected using additive models. Our findings have implications for the determination of genetic architecture and, by extension, the use of human genetics for validation of therapeutic targets.

GenBank, the EMBL European Nucleotide Archive and the DNA DataBank of Japan, known collectively as the International Nucleotide Sequence Database Collaboration or INSDC, are the three most significant nucleotide sequence databases. Their records are derived from laboratory work undertaken by different individuals, by different teams, with a range of technologies and assumptions and over a period of decades. As a consequence, they contain a great many duplicates, redundancies and inconsistencies, but neither the prevalence nor the characteristics of various types of duplicates have been rigorously assessed. Existing duplicate detection methods in bioinformatics only address specific duplicate types, with inconsistent assumptions; and the impact of duplicates in bioinformatics databases has not been carefully assessed, making it difficult to judge the value of such methods. Our goal is to assess the scale, kinds and impact of duplicates in bioinformatics databases, through a retrospective analysis of merged groups in INSDC databases. Our outcomes are threefold: (1) We analyse a benchmark dataset consisting of duplicates manually identified in INSDC-a dataset of 67 888 merged groups with 111 823 duplicate pairs across 21 organisms from INSDC databases - in terms of the prevalence, types and impacts of duplicates. (2) We categorize duplicates at both sequence and annotation level, with supporting quantitative statistics, showing that different organisms have different prevalence of distinct kinds of duplicate. (3) We show that the presence of duplicates has practical impact via a simple case study on duplicates, in terms of GC content and melting temperature. We demonstrate that duplicates not only introduce redundancy, but can lead to inconsistent results for certain tasks. Our findings lead to a better understanding of the problem of duplication in biological databases.Database URL: the merged records are available at https://cloudstor.aarnet.edu.au/plus/index.php/s/Xef2fvsebBEAv9w.

PURPOSE: To explore the potential relationship between optic disc haemorrhage, venous pulsation pressure (VPP), ocular perfusion pressures and visual field change in glaucomatous and glaucoma suspect eyes. MATERIALS AND METHODS: This prospective observational study examined 155 open angle glaucoma or glaucoma suspect eyes from 78 patients over 5 years. Patients were followed with 3 monthly non-mydriatic disc photographs, 6 monthly standard automated perimetry and annual ophthalmodynamometry. The number of disc haemorrhages in each hemidisc was counted across the study period. Visual field rate of change was calculated using linear regression on the sensitivity of each location over time, then averaged for the matching hemifield. VPP and central retinal artery diastolic pressure (CRADP) were calculated from the measured ophthalmodynanometric forces (ODF). The difference between brachial artery diastolic pressure (DiastBP) and CRADP was calculated as an index of possible flow pathology along the carotid and ophthalmic arteries. RESULTS: Mean age of the cohort was 71.9 ± 7.3 Years. 76 out of 155 eyes (49%) followed for a mean period of 64.2 months had at least 1 disc haemorrhage. 62 (81.6%) of these 76 eyes had recurrent haemorrhages, with a mean of 5.94 recurrences over 64.2 months. Using univariate analysis, rate of visual field change (P<0.0001), VPP (P = 0.0069), alternative ocular perfusion pressure (CRADP-VPP, P = 0.0036), carotid resistance index (DiastBP-CRADP, P = 0.0108) and mean brachial blood pressure (P = 0.0203) were significantly associated with the number of disc haemorrhages. Using multivariate analysis, increased baseline visual field sensitivity (P = 0.0243, coefficient = 0.0275) was significantly associated with disc haemorrhage, in conjunction with higher VPP (P = 0.0029, coefficient = 0.0631), higher mean blood pressure (P = 0.0113, coefficient = 0.0190), higher carotid resistance index (P = 0.0172, coefficient = 0.0566), and rate of visual field loss (P<0.0001, coefficient = -2.0695). CONCLUSIONS: Higher VPP was associated with disc haemorrhage and implicates the involvement of venous pathology, but the effect size is small. Additionally, a greater carotid resistance index suggests that flow pathology in the ophthalmic or carotid arteries may be associated with disc haemorrhage.

BACKGROUND: Stroke telemedicine can reduce healthcare inequities by increasing access to specialists. Successful telemedicine networks require specialists adapting clinical practice to provide remote consultations. Variation in experiences of specialists between different countries is unknown. To support future implementation, we compared perceptions of Australian and United Kingdom specialists providing remote acute stroke consultations. METHODS: Specialist participants were identified using purposive sampling from two new services: Australia's Victorian Stroke Telemedicine Program (n = 6; 2010-13) and the United Kingdom's Cumbria and Lancashire telestroke network (n = 5; 2010-2012). Semi-structured interviews were conducted pre- and post-implementation, recorded and transcribed verbatim. Deductive thematic and content analysis (NVivo) was undertaken by two independent coders using Normalisation Process Theory to explore integration of telemedicine into practice. Agreement between coders was M = 91%, SD = 9 and weighted average κ = 0.70. RESULTS: Cross-cultural similarities and differences were found. In both countries, specialists described old and new consulting practices, the purpose and value of telemedicine systems, and concerns regarding confidence in the assessment and diagnostic skills of unknown colleagues requesting telemedicine support. Australian specialists discussed how remote consultations impacted on usual roles and suggested future improvements, while United Kingdom specialists discussed system governance, policy and procedures. CONCLUSION: Australian and United Kingdom specialists reported telemedicine required changes in work practice and development of new skills. Both groups described potential for improvements in stroke telemedicine systems with Australian specialists more focused on role change and the United Kingdom on system governance issues. Future research should examine if cross-cultural variation reflects different models of care and extends to other networks.

BACKGROUND: A key component of achieving universal health coverage is ensuring that all populations have access to quality health care. Examining where gains have occurred or progress has faltered across and within countries is crucial to guiding decisions and strategies for future improvement. We used the Global Burden of Diseases, Injuries, and Risk Factors Study 2016 (GBD 2016) to assess personal health-care access and quality with the Healthcare Access and Quality (HAQ) Index for 195 countries and territories, as well as subnational locations in seven countries, from 1990 to 2016. METHODS: Drawing from established methods and updated estimates from GBD 2016, we used 32 causes from which death should not occur in the presence of effective care to approximate personal health-care access and quality by location and over time. To better isolate potential effects of personal health-care access and quality from underlying risk factor patterns, we risk-standardised cause-specific deaths due to non-cancers by location-year, replacing the local joint exposure of environmental and behavioural risks with the global level of exposure. Supported by the expansion of cancer registry data in GBD 2016, we used mortality-to-incidence ratios for cancers instead of risk-standardised death rates to provide a stronger signal of the effects of personal health care and access on cancer survival. We transformed each cause to a scale of 0-100, with 0 as the first percentile (worst) observed between 1990 and 2016, and 100 as the 99th percentile (best); we set these thresholds at the country level, and then applied them to subnational locations. We applied a principal components analysis to construct the HAQ Index using all scaled cause values, providing an overall score of 0-100 of personal health-care access and quality by location over time. We then compared HAQ Index levels and trends by quintiles on the Socio-demographic Index (SDI), a summary measure of overall development. As derived from the broader GBD study and other data sources, we examined relationships between national HAQ Index scores and potential correlates of performance, such as total health spending per capita. FINDINGS: In 2016, HAQ Index performance spanned from a high of 97·1 (95% UI 95·8-98·1) in Iceland, followed by 96·6 (94·9-97·9) in Norway and 96·1 (94·5-97·3) in the Netherlands, to values as low as 18·6 (13·1-24·4) in the Central African Republic, 19·0 (14·3-23·7) in Somalia, and 23·4 (20·2-26·8) in Guinea-Bissau. The pace of progress achieved between 1990 and 2016 varied, with markedly faster improvements occurring between 2000 and 2016 for many countries in sub-Saharan Africa and southeast Asia, whereas several countries in Latin America and elsewhere saw progress stagnate after experiencing considerable advances in the HAQ Index between 1990 and 2000. Striking subnational disparities emerged in personal health-care access and quality, with China and India having particularly large gaps between locations with the highest and lowest scores in 2016. In China, performance ranged from 91·5 (89·1-93·6) in Beijing to 48·0 (43·4-53·2) in Tibet (a 43·5-point difference), while India saw a 30·8-point disparity, from 64·8 (59·6-68·8) in Goa to 34·0 (30·3-38·1) in Assam. Japan recorded the smallest range in subnational HAQ performance in 2016 (a 4·8-point difference), whereas differences between subnational locations with the highest and lowest HAQ Index values were more than two times as high for the USA and three times as high for England. State-level gaps in the HAQ Index in Mexico somewhat narrowed from 1990 to 2016 (from a 20·9-point to 17·0-point difference), whereas in Brazil, disparities slightly increased across states during this time (a 17·2-point to 20·4-point difference). Performance on the HAQ Index showed strong linkages to overall development, with high and high-middle SDI countries generally having higher scores and faster gains for non-communicable diseases. Nonetheless, countries across the development spectrum saw substantial gains in some key health service areas from 2000 to 2016, most notably vaccine-preventable diseases. Overall, national performance on the HAQ Index was positively associated with higher levels of total health spending per capita, as well as health systems inputs, but these relationships were quite heterogeneous, particularly among low-to-middle SDI countries. INTERPRETATION: GBD 2016 provides a more detailed understanding of past success and current challenges in improving personal health-care access and quality worldwide. Despite substantial gains since 2000, many low-SDI and middle-SDI countries face considerable challenges unless heightened policy action and investments focus on advancing access to and quality of health care across key health services, especially non-communicable diseases. Stagnating or minimal improvements experienced by several low-middle to high-middle SDI countries could reflect the complexities of re-orienting both primary and secondary health-care services beyond the more limited foci of the Millennium Development Goals. Alongside initiatives to strengthen public health programmes, the pursuit of universal health coverage hinges upon improving both access and quality worldwide, and thus requires adopting a more comprehensive view-and subsequent provision-of quality health care for all populations. FUNDING: Bill & Melinda Gates Foundation.

In April 2020 a Group of Eight Taskforce was convened, consisting of over 100 researchers, to provide independent, research-based recommendations to the Commonwealth Government on a "Roadmap to Recovery" from COVID-19. The report covered issues ranging from pandemic control and relaxation of social distancing measures, to well-being and special considerations for vulnerable populations. Our work focused on the critical needs of Aboriginal and Torres Strait Islander communities; this paper presents an overview of our recommendations to the Roadmap report. In addressing the global challenges posed by pandemics for citizens around the world, Indigenous people are recognised as highly vulnerable. At the time of writing Australia's First Nations Peoples have been largely spared from COVID-19 in comparison to other Indigenous populations globally. Our recommendations emphasise self-determination and equitable needs-based funding to support Indigenous communities to recover from COVID-19, addressing persistent overcrowded housing, and a focus on workforce, especially for regional and remote communities. These latter two issues have been highlighted as major issues of risk for Indigenous communities in Australia It remains to be seen how governments across Australia take up these recommendations to support Indigenous peoples' health and healing journey through yet another, potentially catastrophic, health crisis.

Human leukocyte antigen (HLA)-independent, T cell-mediated targeting of cancer cells would allow immune destruction of malignancies in all individuals. Here, we use genome-wide CRISPR-Cas9 screening to establish that a T cell receptor (TCR) recognized and killed most human cancer types via the monomorphic MHC class I-related protein, MR1, while remaining inert to noncancerous cells. Unlike mucosal-associated invariant T cells, recognition of target cells by the TCR was independent of bacterial loading. Furthermore, concentration-dependent addition of vitamin B-related metabolite ligands of MR1 reduced TCR recognition of cancer cells, suggesting that recognition occurred via sensing of the cancer metabolome. An MR1-restricted T cell clone mediated in vivo regression of leukemia and conferred enhanced survival of NSG mice. TCR transfer to T cells of patients enabled killing of autologous and nonautologous melanoma. These findings offer opportunities for HLA-independent, pan-cancer, pan-population immunotherapies.

To examine the effect of acute and chronic exercise on adipose tissue GLUT4 expression, a total of 20 healthy, male subjects performed one of two studies. Ten subjects performed cycle ergometer exercise for 60 min at 73 ± 2% VO2 peak and abdominal adipose tissue samples were obtained immediately before and after exercise and after 3 h of recovery. Another 10 subjects completed 10 days of exercise training, comprising a combination of six sessions of 60 min at 75% VO2 peak and four sessions of 6 × 5 min at 90% VO2 peak, separated by 3 min at 40% VO2 peak. Abdominal adipose tissue and vastus lateralis muscle samples were obtained before training and 24 h after the last training session. A single bout of exercise did not change adipose tissue GLUT4 mRNA; however, there was a small, but significant, reduction in adipose tissue GLUT4 protein expression 3 h after exercise. There were no changes in adipose tissue GLUT4 or COX-IV expression following exercise training. In contrast, skeletal muscle GLUT4 and COX-IV were increased by 47% and 44%, respectively following exercise training. The exercise training-induced increase in GLUT4 expression was similar in both type I and type IIa single muscle fibers. Our results indicate that neither a single exercise bout, nor 10 days of exercise training, increased adipose tissue GLUT4, in contrast with the increases observed in skeletal muscle GLUT4 expression.

Purpose: Correctly classifying progression in moderate to advanced glaucoma is difficult. Pointwise visual field test-retest variability is high for sensitivities below approximately 20 dB; hence, reliably detecting progression requires many test repeats. We developed a testing approach that does not attempt to threshold accurately in areas with high variability, but instead expends presentations increasing spatial fidelity. Methods: Our visual field procedure Australian Reduced Range Extended Spatial Test (ARREST; a variant of the Bayesian procedure Zippy Estimation by Sequential Testing [ZEST]) applies the following approach: once a location has an estimated sensitivity of <17 dB (a "defect"), it is checked that it is not an absolute defect (<0 dB, "blind"). Saved presentations are used to test extra locations that are located near the defect. Visual field deterioration events are either: (1) decreasing in the range of 40 to 17 dB, (2) decreasing from >17 dB to "defect", or (3) "defect" to blind. To test this approach we used an empirical database of progressing moderate-advanced 24-2 visual fields (121 eyes) that we "reverse engineered" to create visual field series that progressed from normal to the end observed field. ARREST and ZEST were run on these fields with test accuracy, presentation time, and ability to detect progression compared. Results: With specificity for detecting progression matched at 95%, ZEST and ARREST showed similar sensitivity for detecting progression. However, ARREST used approximately 25% to 40% fewer test presentations to achieve this result in advanced visual field damage. ARREST spatially defined the visual field deficit with greater precision than ZEST due to the addition of non-24-2 locations. Conclusions: Spending time trying to accurately measure visual field locations that have high variability is not productive. Our simulations indicate that giving up attempting to quantify size III white-on-white sensitivities below 17 dB and using the presentations saved to test extra locations should better describe progression in moderate-to-advanced glaucoma in shorter time. Translational Relevance: ARREST is a new visual field test algorithm that provides better spatial definition of visual field defects in faster test time than current procedures. This outcome is achieved by substituting inaccurate quantification of sensitivities <17 dB with new spatial locations.

Biological databases represent an extraordinary collective volume of work. Diligently built up over decades and comprising many millions of contributions from the biomedical research community, biological databases provide worldwide access to a massive number of records (also known as entries) [1]. Starting from individual laboratories, genomes are sequenced, assembled, annotated, and ultimately submitted to primary nucleotide databases such as GenBank [2], European Nucleotide Archive (ENA) [3], and DNA Data Bank of Japan (DDBJ) [4] (collectively known as the International Nucleotide Sequence Database Collaboration, INSDC). Protein records, which are the translations of these nucleotide records, are deposited into central protein databases such as the UniProt KnowledgeBase (UniProtKB) [5] and the Protein Data Bank (PDB) [6]. Sequence records are further accumulated into different databases for more specialized purposes: RFam [7] and PFam [8] for RNA and protein families, respectively; DictyBase [9] and PomBase [10] for model organisms; as well as ArrayExpress [11] and Gene Expression Omnibus (GEO) [12] for gene expression profiles. These databases are selected as examples; the list is not intended to be exhaustive. However, they are representative of biological databases that have been named in the “golden set” of the 24th Nucleic Acids Research database issue (in 2016). The introduction of that issue highlights the databases that “consistently served as authoritative, comprehensive, and convenient data resources widely used by the entire community and offer some lessons on what makes a successful database” [13]. In addition, the associated information about sequences is also propagated into non-sequence databases, such as PubMed (https://www.ncbi.nlm.nih.gov/pubmed/) for scientific literature or Gene Ontology (GO) [14] for function annotations. These databases in turn benefit individual studies, many of which use these publicly available records as the basis for their own research.

The antigen-presenting molecule MR1 presents microbial metabolites related to vitamin B2 biosynthesis to mucosal-associated invariant T cells (MAIT cells). Although bacteria and fungi drive the MR1 biosynthesis pathway, viruses have not previously been implicated in MR1 expression or its antigen presentation. We demonstrate that several herpesviruses inhibit MR1 cell surface upregulation, including a potent inhibition by herpes simplex virus type 1 (HSV-1). This virus profoundly suppresses MR1 cell surface expression and targets the molecule for proteasomal degradation, whereas ligand-induced cell surface expression of MR1 prior to infection enables MR1 to escape HSV-1-dependent targeting. HSV-1 downregulation of MR1 is dependent on de novo viral gene expression, and we identify the Us3 viral gene product as functioning to target MR1. Furthermore, HSV-1 downregulation of MR1 disrupts MAIT T cell receptor (TCR) activation. Accordingly, virus-mediated targeting of MR1 defines an immunomodulatory strategy that functionally disrupts the MR1-MAIT TCR axis.