Rare SLC13A1 variants associate with intervertebral disc disorder highlighting role of sulfate in disc pathology.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked DownloadBack pain is a common and debilitating disorder with largely unknown underlying biology. Here we report a genome-wide association study of back pain using diagnoses assigned in clinical practice; dorsalgia (119,100 cases, 909,847 controls) and intervertebral disc disorder (IDD) (58,854 cases, 922,958 controls). We identify 41 variants at 33 loci. The most significant association (ORIDD = 0.92, P = 1.6 × 10-39; ORdorsalgia = 0.92, P = 7.2 × 10-15) is with a 3'UTR variant (rs1871452-T) in CHST3, encoding a sulfotransferase enzyme expressed in intervertebral discs. The largest effects on IDD are conferred by rare (MAF = 0.07 - 0.32%) loss-of-function (LoF) variants in SLC13A1, encoding a sodium-sulfate co-transporter (LoF burden OR = 1.44, P = 3.1 × 10-11); variants that also associate with reduced serum sulfate. Genes implicated by this study are involved in cartilage and bone biology, as well as neurological and inflammatory processes.European Commission European Commission Joint Research Centre Novo Nordisk Foundation Novocure Limite

Global burden of 369 diseases and injuries in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019

Background: In an era of shifting global agendas and expanded emphasis on non-communicable diseases and injuries along with communicable diseases, sound evidence on trends by cause at the national level is essential. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) provides a systematic scientific assessment of published, publicly available, and contributed data on incidence, prevalence, and mortality for a mutually exclusive and collectively exhaustive list of diseases and injuries. Methods: GBD estimates incidence, prevalence, mortality, years of life lost (YLLs), years lived with disability (YLDs), and disability-adjusted life-years (DALYs) due to 369 diseases and injuries, for two sexes, and for 204 countries and territories. Input data were extracted from censuses, household surveys, civil registration and vital statistics, disease registries, health service use, air pollution monitors, satellite imaging, disease notifications, and other sources. Cause-specific death rates and cause fractions were calculated using the Cause of Death Ensemble model and spatiotemporal Gaussian process regression. Cause-specific deaths were adjusted to match the total all-cause deaths calculated as part of the GBD population, fertility, and mortality estimates. Deaths were multiplied by standard life expectancy at each age to calculate YLLs. A Bayesian meta-regression modelling tool, DisMod-MR 2.1, was used to ensure consistency between incidence, prevalence, remission, excess mortality, and cause-specific mortality for most causes. Prevalence estimates were multiplied by disability weights for mutually exclusive sequelae of diseases and injuries to calculate YLDs. We considered results in the context of the Socio-demographic Index (SDI), a composite indicator of income per capita, years of schooling, and fertility rate in females younger than 25 years. Uncertainty intervals (UIs) were generated for every metric using the 25th and 975th ordered 1000 draw values of the posterior distribution. Findings: Global health has steadily improved over the past 30 years as measured by age-standardised DALY rates. After taking into account population growth and ageing, the absolute number of DALYs has remained stable. Since 2010, the pace of decline in global age-standardised DALY rates has accelerated in age groups younger than 50 years compared with the 1990–2010 time period, with the greatest annualised rate of decline occurring in the 0–9-year age group. Six infectious diseases were among the top ten causes of DALYs in children younger than 10 years in 2019: lower respiratory infections (ranked second), diarrhoeal diseases (third), malaria (fifth), meningitis (sixth), whooping cough (ninth), and sexually transmitted infections (which, in this age group, is fully accounted for by congenital syphilis; ranked tenth). In adolescents aged 10–24 years, three injury causes were among the top causes of DALYs: road injuries (ranked first), self-harm (third), and interpersonal violence (fifth). Five of the causes that were in the top ten for ages 10–24 years were also in the top ten in the 25–49-year age group: road injuries (ranked first), HIV/AIDS (second), low back pain (fourth), headache disorders (fifth), and depressive disorders (sixth). In 2019, ischaemic heart disease and stroke were the top-ranked causes of DALYs in both the 50–74-year and 75-years-and-older age groups. Since 1990, there has been a marked shift towards a greater proportion of burden due to YLDs from non-communicable diseases and injuries. In 2019, there were 11 countries where non-communicable disease and injury YLDs constituted more than half of all disease burden. Decreases in age-standardised DALY rates have accelerated over the past decade in countries at the lower end of the SDI range, while improvements have started to stagnate or even reverse in countries with higher SDI. Interpretation: As disability becomes an increasingly large component of disease burden and a larger component of health expenditure, greater research and developm nt investment is needed to identify new, more effective intervention strategies. With a rapidly ageing global population, the demands on health services to deal with disabling outcomes, which increase with age, will require policy makers to anticipate these changes. The mix of universal and more geographically specific influences on health reinforces the need for regular reporting on population health in detail and by underlying cause to help decision makers to identify success stories of disease control to emulate, as well as opportunities to improve. Funding: Bill & Melinda Gates Foundation. © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 licens

Analyses of non-coding somatic drivers in 2,658 cancer whole genomes.

The discovery of drivers of cancer has traditionally focused on protein-coding genes1-4. Here we present analyses of driver point mutations and structural variants in non-coding regions across 2,658 genomes from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium5 of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). For point mutations, we developed a statistically rigorous strategy for combining significance levels from multiple methods of driver discovery that overcomes the limitations of individual methods. For structural variants, we present two methods of driver discovery, and identify regions that are significantly affected by recurrent breakpoints and recurrent somatic juxtapositions. Our analyses confirm previously reported drivers6,7, raise doubts about others and identify novel candidates, including point mutations in the 5' region of TP53, in the 3' untranslated regions of NFKBIZ and TOB1, focal deletions in BRD4 and rearrangements in the loci of AKR1C genes. We show that although point mutations and structural variants that drive cancer are less frequent in non-coding genes and regulatory sequences than in protein-coding genes, additional examples of these drivers will be found as more cancer genomes become available

GLA:D-(R) Back group-based patient education integrated with exercises to support self-management of back pain- development, theories and scientific evidence-

BackgroundClinical guidelines recommend that people with back pain be given information and education about their back pain, advice to remain active and at work, and exercises to improve mobility and physical activity. Guidelines, however, rarely describe how this is best delivered. The aim of this paper is to present the development, theories, and underlying evidence for GLA:D Back - a group education and exercise program that translates guideline recommendations into a clinician-delivered program for the promotion of self-management in people with persistent/recurrent back pain.MethodsGLA:D Back, which included a rationale and objectives for the program, theory and evidence for the interventions, and program materials, was developed using an iterative process. The content of patient education and exercise programs tested in randomised trials was extracted and a multidisciplinary team of expert researchers and clinicians prioritised common elements hypothesised to improve back pain beliefs and management skills. The program was tested on eight people with persistent back pain in a university clinic and 152 patients from nine primary care physiotherapy and chiropractic clinics. Following feedback from the clinicians and patients involved, the working version of the program was created.ResultsEducational components included pain mechanisms, pain modulation, active coping strategies, imaging, physical activity, and exercise that emphasised a balance between the sum of demands and the individuals capacity. These were operationalised in PowerPoint presentations with supporting text to aid clinicians in delivering two one-hour patient education lectures.The exercise program included 16 supervised one-hour sessions over 8weeks, each comprising a warm-up section and eight types of exercises for general flexibility and strengthening of six different muscle groups at four levels of difficulty. The aims of the exercises were to improve overall back fitness and, at the same time, encourage patients to explore variations in movement by incorporating education content into the exercise sessions.ConclusionFrom current best evidence about prognostic factors in back pain and effective treatments for back pain, research and clinical experts developed a ready-to-use structured program - GLA:D (R) Back - to support self-management for people with persistent/recurrent back pain.Funding Agencies|SELFBACK project (European Union Horizon 2020 research and innovation programme) [689043]</p

Implementation of clinical guidelines for osteoarthritis together (IMPACT): protocol for a participatory health research approach to implementing high value care

Background: The evidence-based interventions of exercise and education have been strongly recommended as  part of prominent clinical guidelines for hip and knee osteoarthritis (OA) for more than ten years. Despite the wealth  of strong evidence that exists, implementation in practice is sub-optimal. This paper describes the key methodologies used in the co-design, tailoring, and evaluation of the IMPACT project implementation strategies, to confront this  problem across multiple levels (micro, meso, macro) in public and private healthcare settings in Ireland. Methods: Using a type III hybrid implementation-efectiveness design, a participatory, dynamic and iterative process  will be used to tailor and evaluate multi-level implementation strategies using the following stages: 1) Co-design the  implementation strategies with key stakeholders using best evidence, a theory-driven implementation framework  (Consolidated Framework for Implementation Research), local context and expert consensus; 2) Pilot and evaluate the implementation strategies by training physiotherapists to deliver the evidence-based Good Life with osteoArthritis Denmark (GLA:D®) education and exercise programme using the implementation strategies, and conduct a mixed-methods process evaluation; 3) Adapt the implementation strategies based on implementation process evaluation indicators from stage two. The adapted strategies will be used for scale-up and sustainability in subsequent GLA:D® Ireland training programmes that will be rolled out nationally. Evaluation of efectiveness on patient and cost outcomes will continue up to 12months post-programme delivery, using an online patient registry and pre-post design. Discussion: This implementation science project aims to use participatory health research to address a gap in management of OA across public and private healthcare settings. This research has the potential to change practice and  promote a policy of exercise and physical activity referral for chronic musculoskeletal disease that utilises community engagement efectively and enacts change ‘together’, with involvement of researchers, decision-makers, clinicians and patients. </p

Influence of biomechanical characteristics on pain and function outcomes from exercise in medial knee osteoarthritis and varus malalignment: Exploratory analyses from a randomized controlled trial

ObjectiveTo investigate whether selected biomechanical characteristics influence changes in pain and physical function with exercise in people with medial knee osteoarthritis (OA) and varus malalignment

Singapore KneE osTeoarthritis CoHort (SKETCH): protocol for a multi-centre prospective cohort study

Background: Knee osteoarthritis (OA) is a leading cause of global disability. The understanding of the role of psychosocial factors in knee OA outcomes is still evolving particularly in an Asian context. The primary aim of this study is to explore psychosocial factors that prognosticate short and long-term clinical outcomes, productivity, and healthcare utilization in patients with knee OA. Secondary aims are to explore the mediation and directional relationships and the role it plays in predicting the discordance between self-reported measures (SRM), physical-performance measures (PPMs) and objective clinical parameters. Methods: A multi-centre prospective cohort study of community ambulant knee OA patients seeking treatment in the tertiary healthcare institutions in Singapore will be conducted. Patients with secondary arthritis, significant cognitive impairment, severe medical comorbidities or previous knee arthroplasty will be excluded. Primary clinical outcome measure is the Knee injury and OA Outcome Score-12 (KOOS-12). Baseline characteristics include sociodemographic status, arthritis status including symptom duration and radiographic severity, comorbidities and functional status through Charlson Comorbidities Index (CCI), Barthel Index (BI) and Parker Mobility Score (PMS). Psychosocial variables include social support, kinesiophobia, negative affect, self-efficacy, injustice, chronic illness shame and the built environment. Clinical outcomes include quality of life, physical performance, global assessment, satisfaction and physical activity levels. Productivity and healthcare utilization will be assessed by a modified OA Cost and Consequences Questionnaire (OCC-Q) and the Work Productivity and Activity Impairment Questionnaire (WPAI). Variables will be collected at baseline, 4, 12 months and yearly thereafter. Regression, mediation and structural equation modelling will be used for analysis. Discussion: Results will allow contextualization, identification, and phenotyping of the critical (and potentially modifiable) psychosocial parameters that predict positive clinical outcomes in the OA population to guide optimization and refinement of healthcare and community. This will facilitate: 1. identification of high-risk knee OA subpopulations that will likely experience poor outcomes and 2. formulation of targeted multidisciplinary comprehensive approaches to address these psychosocial factors to optimize non-surgical treatment care, maximize functional outcomes and create more value-based care model for knee OA.Published versionFunding: NHG Population Health Grant (PHG20/S/T/1/4)

Rare SLC13A1 variants associate with intervertebral disc disorder highlighting role of sulfate in disc pathology

Back pain is a common and debilitating disorder with largely unknown underlying biology. Here we report a genome-wide association study of back pain using diagnoses assigned in clinical practice; dorsalgia (119,100 cases, 909,847 controls) and intervertebral disc disorder (IDD) (58,854 cases, 922,958 controls). We identify 41 variants at 33 loci. The most significant association (ORIDD = 0.92, P = 1.6 × 10−39; ORdorsalgia = 0.92, P = 7.2 × 10−15) is with a 3’UTR variant (rs1871452-T) in CHST3, encoding a sulfotransferase enzyme expressed in intervertebral discs. The largest effects on IDD are conferred by rare (MAF = 0.07 − 0.32%) loss-of-function (LoF) variants in SLC13A1, encoding a sodium-sulfate co-transporter (LoF burden OR = 1.44, P = 3.1 × 10−11); variants that also associate with reduced serum sulfate. Genes implicated by this study are involved in cartilage and bone biology, as well as neurological and inflammatory processes