Week 48 outcomes from the BRAAVE 2020 study: a randomised switch to bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) in African American adults with HIV

Background: Black Americans are disproportionately impacted by HIV. The BRAAVE 2020 study, evaluated the safety and efficacy of switching to the guidelines- recommended single- tablet regimen bictegravir, emtricitabine, tenofovir alafenamide (B/F/TAF) in Black adults through week (W) 48. Method: Adults with HIV self- identifying as Black or African American and virologically suppressed on 2 NRTIs plus a 3rd agent were randomised (2:1) to switch to open- label B/F/TAF once daily or stay on their baseline regimen (SBR). Prior virologic failure was allowed except failure on an INSTI. Prior resistance to NNRTIs, PIs and/or NRTIs was permitted except K65R/E/N, ≥3 thymidine analog mutations or T69- insertions. Primary INSTI- resistance was excluded. SBR participants switched to B/F/TAF at W24. Efficacy was assessed at W24 (Primary endpoint, noninferiority margin 6%) and at W48 as the proportion with HIV- 1 RNA ≥50 c/mL by FDA Snapshot and by changes in CD4 count. Safety was assessed by adverse events (AE) and lab results. Results: 495 were randomised and treated (B/F/TAF n = 330, SBR n = 165): 32% cis women, 2% transgender women, median age 49 years (range 18– 79) and 10% had pre- existing M184V/I mutation. At W24, 1% (2/328) on B/F/TAF vs 2% (3/165) on SBR had HIV- 1 RNA ≥50 c/mL (difference - 1.2%; 95% CI - 4.8% to 0.9%) demonstrating non-inferiority of B/F/TAF; 2 with pre- existing primary INSTI resistance were excluded from analysis. 163 assigned to SBR completed W24 and switched to B/F/TAF (SBR to B/F/TAF). At W48 1% (3/328) originally randomised to B/F/TAF and 0 SBR to B/F/TAF had HIV- 1 RNA ≥50 c/mL. Baseline NRTI resistance did not affect the efficacy of B/F/TAF. No treatment emergent resistance was detected. Median (IQR) weight increased 0.9 kg (- 1.5, 4.1) and 0.6 kg (- 1.0, 3.1) for B/F/TAF and SBR to B/F/TAF groups, respectively. Study drug- related AEs occurred in 10% of participants while on B/F/TAF; most were grade 1. Conclusion: Switching to B/F/TAF was highly effective for Black adults regardless of baseline regimen or pre- existing NRTI resistance and was associated with few treatment re-lated AEs or discontinuations

Forty-eight-week efficacy and safety and early CNS tolerability of doravirine (MK-1439), a novel NNRTI, with TDF/FTC in ART-naive HIV-positive patients

INTRODUCTION: Doravirine (DOR) is an investigational NNRTI (aka MK-1439) that retains activity against common NNRTI-resistant mutants. We have previously reported the Part 1 results from a two-part, randomized, double-blind, Phase IIb study in ART-naïve HIV-1-positive patients (1). At doses of 25, 50, 100 and 200 mg qd, DOR plus open-label tenofovir/emtricitabine (TDF/FTC) demonstrated potent antiretroviral activity comparable to EFV 600 mg qhs plus TDF/FTC and was generally well tolerated at week 24. DOR 100 mg was selected for use in patients continuing in Part 1 and those newly enrolled in Part 2. METHODS: Patients receiving DOR 25, 50 or 200 mg in Part 1 were switched to 100 mg after dose selection. In Part 2, 132 additional patients were randomized 1:1 to DOR 100 mg qd or EFV 600 mg qhs (each with TDF/FTC). We present week 48 efficacy and safety results for all patients in Part 1, and early (week 8) CNS tolerability only for patients randomized to DOR 100 mg or to EFV in Parts 1 and 2 combined. The primary safety endpoint is the % of patients with pre-specified CNS events (all causality) by week 8 for DOR 100 mg qd vs EFV (Parts 1 + 2 combined). RESULTS: Part 1 week 48 efficacy and safety results are shown below. CONCLUSIONS: In ART-naïve, HIV-1-positive patients also receiving TDF/FTC, DOR 100 mg qd demonstrated potent antiretroviral activity and immunological effect at week 48 and was generally safe and well tolerated. Patients who received DOR 100 mg qd had significantly fewer treatment-emergent CNS AEs by week 8 than those who received EFV

Rhodopsin kinase and arrestin binding control the decay of photoactivated rhodopsin and dark adaptation of mouse rods

Photoactivation of vertebrate rhodopsin converts it to the physiologically active Meta II (R*) state, which triggers the rod light response. Meta II is rapidly inactivated by the phosphorylation of C-terminal serine and threonine residues by G-protein receptor kinase (Grk1) and subsequent binding of arrestin 1 (Arr1). Meta II exists in equilibrium with the more stable inactive form of rhodopsin, Meta III. Dark adaptation of rods requires the complete thermal decay of Meta II/Meta III into opsin and all-trans retinal and the subsequent regeneration of rhodopsin with 11-cis retinal chromophore. In this study, we examine the regulation of Meta III decay by Grk1 and Arr1 in intact mouse rods and their effect on rod dark adaptation. We measure the rates of Meta III decay in isolated retinas of wild-type (WT), Grk1-deficient (Grk1(−/−)), Arr1-deficient (Arr1(−/−)), and Arr1-overexpressing (Arr1(ox)) mice. We find that in WT mouse rods, Meta III peaks ∼6 min after rhodopsin activation and decays with a time constant (τ) of 17 min. Meta III decay slows in Arr1(−/−) rods (τ of ∼27 min), whereas it accelerates in Arr1(ox) rods (τ of ∼8 min) and Grk1(−/−) rods (τ of ∼13 min). In all cases, regeneration of rhodopsin with exogenous 11-cis retinal is rate limited by the decay of Meta III. Notably, the kinetics of rod dark adaptation in vivo is also modulated by the levels of Arr1 and Grk1. We conclude that, in addition to their well-established roles in Meta II inactivation, Grk1 and Arr1 can modulate the kinetics of Meta III decay and rod dark adaptation in vivo

Global, regional, and national burden of other musculoskeletal disorders, 1990–2020, and projections to 2050: a systematic analysis of the Global Burden of Disease Study 2021

Background Musculoskeletal disorders include more than 150 different conditions affecting joints, muscles, bones, ligaments, tendons, and the spine. To capture all health loss from death and disability due to musculoskeletal disorders, the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) includes a residual musculoskeletal category for conditions other than osteoarthritis, rheumatoid arthritis, gout, low back pain, and neck pain. This category is called other musculoskeletal disorders and includes, for example, systemic lupus erythematosus and spondylopathies. We provide updated estimates of the prevalence, mortality, and disability attributable to other musculoskeletal disorders and forecasted prevalence to 2050. Methods Prevalence of other musculoskeletal disorders was estimated in 204 countries and territories from 1990 to 2020 using data from 68 sources across 23 countries from which subtraction of cases of rheumatoid arthritis, osteoarthritis, low back pain, neck pain, and gout from the total number of cases of musculoskeletal disorders was possible. Data were analysed with Bayesian meta-regression models to estimate prevalence by year, age, sex, and location. Years lived with disability (YLDs) were estimated from prevalence and disability weights. Mortality attributed to other musculoskeletal disorders was estimated using vital registration data. Prevalence was forecast to 2050 by regressing prevalence estimates from 1990 to 2020 with Socio-demographic Index as a predictor, then multiplying by population forecasts. Findings Globally, 494 million (95% uncertainty interval 431–564) people had other musculoskeletal disorders in 2020, an increase of 123·4% (116·9–129·3) in total cases from 221 million (192–253) in 1990. Cases of other musculoskeletal disorders are projected to increase by 115% (107–124) from 2020 to 2050, to an estimated 1060 million (95% UI 964–1170) prevalent cases in 2050; most regions were projected to have at least a 50% increase in cases between 2020 and 2050. The global age-standardised prevalence of other musculoskeletal disorders was 47·4% (44·9–49·4) higher in females than in males and increased with age to a peak at 65–69 years in male and female sexes. In 2020, other musculoskeletal disorders was the sixth ranked cause of YLDs globally (42·7 million [29·4–60·0]) and was associated with 83 100 deaths (73 600–91 600). Interpretation Other musculoskeletal disorders were responsible for a large number of global YLDs in 2020. Until individual conditions and risk factors are more explicitly quantified, policy responses to this burden remain a challenge. Temporal trends and geographical differences in estimates of non-fatal disease burden should not be overinterpreted as they are based on sparse, low-quality data.publishedVersio

Age-sex differences in the global burden of lower respiratory infections and risk factors, 1990-2019 : results from the Global Burden of Disease Study 2019

BACKGROUND: The global burden of lower respiratory infections (LRIs) and corresponding risk factors in children older than 5 years and adults has not been studied as comprehensively as it has been in children younger than 5 years. We assessed the burden and trends of LRIs and risk factors across all age groups by sex, for 204 countries and territories. METHODS: In this analysis of data for the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019, we used clinician-diagnosed pneumonia or bronchiolitis as our case definition for LRIs. We included International Classification of Diseases 9th edition codes 079.6, 466-469, 470.0, 480-482.8, 483.0-483.9, 484.1-484.2, 484.6-484.7, and 487-489 and International Classification of Diseases 10th edition codes A48.1, A70, B97.4-B97.6, J09-J15.8, J16-J16.9, J20-J21.9, J91.0, P23.0-P23.4, and U04-U04.9. We used the Cause of Death Ensemble modelling strategy to analyse 23 109 site-years of vital registration data, 825 site-years of sample vital registration data, 1766 site-years of verbal autopsy data, and 681 site-years of mortality surveillance data. We used DisMod-MR 2.1, a Bayesian meta-regression tool, to analyse age-sex-specific incidence and prevalence data identified via systematic reviews of the literature, population-based survey data, and claims and inpatient data. Additionally, we estimated age-sex-specific LRI mortality that is attributable to the independent effects of 14 risk factors. FINDINGS: Globally, in 2019, we estimated that there were 257 million (95% uncertainty interval [UI] 240-275) LRI incident episodes in males and 232 million (217-248) in females. In the same year, LRIs accounted for 1·30 million (95% UI 1·18-1·42) male deaths and 1·20 million (1·07-1·33) female deaths. Age-standardised incidence and mortality rates were 1·17 times (95% UI 1·16-1·18) and 1·31 times (95% UI 1·23-1·41) greater in males than in females in 2019. Between 1990 and 2019, LRI incidence and mortality rates declined at different rates across age groups and an increase in LRI episodes and deaths was estimated among all adult age groups, with males aged 70 years and older having the highest increase in LRI episodes (126·0% [95% UI 121·4-131·1]) and deaths (100·0% [83·4-115·9]). During the same period, LRI episodes and deaths in children younger than 15 years were estimated to have decreased, and the greatest decline was observed for LRI deaths in males younger than 5 years (-70·7% [-77·2 to -61·8]). The leading risk factors for LRI mortality varied across age groups and sex. More than half of global LRI deaths in children younger than 5 years were attributable to child wasting (population attributable fraction [PAF] 53·0% [95% UI 37·7-61·8] in males and 56·4% [40·7-65·1] in females), and more than a quarter of LRI deaths among those aged 5-14 years were attributable to household air pollution (PAF 26·0% [95% UI 16·6-35·5] for males and PAF 25·8% [16·3-35·4] for females). PAFs of male LRI deaths attributed to smoking were 20·4% (95% UI 15·4-25·2) in those aged 15-49 years, 30·5% (24·1-36·9) in those aged 50-69 years, and 21·9% (16·8-27·3) in those aged 70 years and older. PAFs of female LRI deaths attributed to household air pollution were 21·1% (95% UI 14·5-27·9) in those aged 15-49 years and 18·2% (12·5-24·5) in those aged 50-69 years. For females aged 70 years and older, the leading risk factor, ambient particulate matter, was responsible for 11·7% (95% UI 8·2-15·8) of LRI deaths. INTERPRETATION: The patterns and progress in reducing the burden of LRIs and key risk factors for mortality varied across age groups and sexes. The progress seen in children younger than 5 years was clearly a result of targeted interventions, such as vaccination and reduction of exposure to risk factors. Similar interventions for other age groups could contribute to the achievement of multiple Sustainable Development Goals targets, including promoting wellbeing at all ages and reducing health inequalities. Interventions, including addressing risk factors such as child wasting, smoking, ambient particulate matter pollution, and household air pollution, would prevent deaths and reduce health disparities. FUNDING: Bill & Melinda Gates Foundation

Mindfulness may both moderate and mediate the effect of physical fitness on cardiovascular responses to stress: a speculative hypothesis

This Document is Protected by copyright and was first published by Frontiers. All rights reserved. it is reproduced with permission.The psychological construct of mindfulness refers to an awareness that emerges by intentionally paying attention to the present experience in a non-judgmental or evaluative way. This particular quality of awareness has been associated to several indicators of physical and psychological health, and can be developed using mindfulness-based interventions (MBIs), and therefore MBIs have been successfully applied as preventive and complementary interventions and therapies in medicine and psychology. Together with quiet sitting and lying meditation practices, mindful physical exercises such as "mindful walking" and "mindful movement" are key elements in MBIs and couple muscular activity with an internally directed focus, improving interoceptive attention to bodily sensations. In addition, MBIs seem to share similar mechanisms with physical fitness (PF) by which they may influence cardiovascular responses to stress. Based on these facts, it is feasible to raise the question of whether physical training itself may induce the development of that particular quality of awareness associated with mindfulness, or if one's dispositional mindfulness (DM) (the tendency to be more mindful in daily life) could moderate the effects of exercise on cardiovascular response to stress. The role of mindfulness as a mediator or moderator of the effect of exercise training on cardiovascular responses to stress has barely been studied. In this study, we have hypothesized pathways (moderation and mediation) by which mindfulness could significantly influence the effects of PF on cardiovascular responses to stress and discussed potential practical ways to test these hypotheses.Marcelo M. P. Demarzo is grateful to the CNPq - Brazilian National Council for Research and Technology Development for a postdoctoral fellowship under supervision of Professor Javier Garcia-Campayo ("Science without Borders Program"). The authors would like to thank the reviewers for the constructive environment for debating hypotheses and concepts presented herein, which effectively allowed the manuscript's development and improvement.Demarzo, MMP.; Montero-Marin, J.; Stein, PK.; Cebolla, A.; Guixeres Provinciale, J.; Garcia-Campayo, J. (2014). Mindfulness may both moderate and mediate the effect of physical fitness on cardiovascular responses to stress: a speculative hypothesis. Frontiers in Physiology. 5(105):1-8. doi:10.3389/fphys.2014.00105S185105Baron, R. M., & Kenny, D. A. (1986). The moderator–mediator variable distinction in social psychological research: Conceptual, strategic, and statistical considerations. Journal of Personality and Social Psychology, 51(6), 1173-1182. doi:10.1037/0022-3514.51.6.1173Baum, C., Kuyken, W., Bohus, M., Heidenreich, T., Michalak, J., & Steil, R. (2009). The Psychometric Properties of the Kentucky Inventory of Mindfulness Skills in Clinical Populations. Assessment, 17(2), 220-229. doi:10.1177/1073191109356525Bohlmeijer, E., ten Klooster, P. M., Fledderus, M., Veehof, M., & Baer, R. (2011). Psychometric Properties of the Five Facet Mindfulness Questionnaire in Depressed Adults and Development of a Short Form. Assessment, 18(3), 308-320. doi:10.1177/1073191111408231Bonadonna, R. (2003). Meditationʼs Impact on Chronic Illness. Holistic Nursing Practice, 17(6), 309-319. doi:10.1097/00004650-200311000-00006Brand, S., Holsboer-Trachsler, E., Naranjo, J. R., & Schmidt, S. (2012). Influence of Mindfulness Practice on Cortisol and Sleep in Long-Term and Short-Term Meditators. Neuropsychobiology, 65(3), 109-118. doi:10.1159/000330362Bränström, R., Duncan, L. G., & Moskowitz, J. T. (2011). The association between dispositional mindfulness, psychological well-being, and perceived health in a Swedish population-based sample. British Journal of Health Psychology, 16(2), 300-316. doi:10.1348/135910710x501683BREUS, M. J., & O’CONNOR, P. J. (1998). Exercise-induced anxiolysis: a test of the «time out» hypothesis in high anxious females. Medicine & Science in Sports & Exercise, 30(7), 1107-1112. doi:10.1097/00005768-199807000-00013Britton, W. B., Haynes, P. L., Fridel, K. W., & Bootzin, R. R. (2012). Mindfulness-Based Cognitive Therapy Improves Polysomnographic and Subjective Sleep Profiles in Antidepressant Users with Sleep Complaints. Psychotherapy and Psychosomatics, 81(5), 296-304. doi:10.1159/000332755BROWN, D. R., WANG, Y., WARD, A., EBBELING, C. B., FORTLAGE, L., PULEO, E., … RIPPE, J. M. (1995). Chronic psychological effects of exercise and exercise plus cognitive strategies. Medicine & Science in Sports & Exercise, 27(5), 765???775. doi:10.1249/00005768-199505000-00021Brown, K. W., Goodman, R. J., & Inzlicht, M. (2012). Dispositional mindfulness and the attenuation of neural responses to emotional stimuli. Social Cognitive and Affective Neuroscience, 8(1), 93-99. doi:10.1093/scan/nss004Brown, K. W., & Ryan, R. M. (2003). The benefits of being present: Mindfulness and its role in psychological well-being. Journal of Personality and Social Psychology, 84(4), 822-848. doi:10.1037/0022-3514.84.4.822CARSON, J. W., CARSON, K. M., GIL, K. M., & BAUCOM, D. H. (2006). MINDFULNESS-BASED RELATIONSHIP ENHANCEMENT (MBRE) IN COUPLES. Mindfulness-Based Treatment Approaches, 309-331. doi:10.1016/b978-012088519-0/50015-0Ciesla, J. A., Reilly, L. C., Dickson, K. S., Emanuel, A. S., & Updegraff, J. A. (2012). Dispositional Mindfulness Moderates the Effects of Stress Among Adolescents: Rumination as a Mediator. Journal of Clinical Child & Adolescent Psychology, 41(6), 760-770. doi:10.1080/15374416.2012.698724Creswell, J. D., Irwin, M. R., Burklund, L. J., Lieberman, M. D., Arevalo, J. M. G., Ma, J., … Cole, S. W. (2012). Mindfulness-Based Stress Reduction training reduces loneliness and pro-inflammatory gene expression in older adults: A small randomized controlled trial. Brain, Behavior, and Immunity, 26(7), 1095-1101. doi:10.1016/j.bbi.2012.07.006Cullen, M. (2011). Mindfulness-Based Interventions: An Emerging Phenomenon. Mindfulness, 2(3), 186-193. doi:10.1007/s12671-011-0058-1Demarzo, M. M. P., & Stein, P. K. (2012). Mental Stress and Exercise Training Response: Stress-sleep Connection may be Involved. Frontiers in Physiology, 3. doi:10.3389/fphys.2012.00178Dimidjian, S., & Kleiber, B. (2013). Being Mindful About the Use of Mindfulness in Clinical Contexts. Cognitive and Behavioral Practice, 20(1), 57-59. doi:10.1016/j.cbpra.2012.02.006Duncan, L. G., & Bardacke, N. (2009). Mindfulness-Based Childbirth and Parenting Education: Promoting Family Mindfulness During the Perinatal Period. Journal of Child and Family Studies, 19(2), 190-202. doi:10.1007/s10826-009-9313-7Edelman, D., Oddone, E. Z., Liebowitz, R. S., Yancy, W. S., Olsen, M. K., Jeffreys, A. S., … Gaudet, T. W. (2006). A multidimensional integrative medicine intervention to improve cardiovascular risk. Journal of General Internal Medicine, 21(7), 728-734. doi:10.1111/j.1525-1497.2006.00495.xFarb, N. A. S., Segal, Z. V., & Anderson, A. K. (2012). Mindfulness meditation training alters cortical representations of interoceptive attention. Social Cognitive and Affective Neuroscience, 8(1), 15-26. doi:10.1093/scan/nss066Fortney, L., & Taylor, M. (2010). Meditation in Medical Practice: A Review of the Evidence and Practice. Primary Care: Clinics in Office Practice, 37(1), 81-90. doi:10.1016/j.pop.2009.09.004Garcia, M. C., Pompéia, S., Hachul, H., Kozasa, E. H., de Souza, A. A. L., Tufik, S., & Mello, L. E. A. M. (2014). Is mindfulness associated with insomnia after menopause? Menopause, 21(3), 301-305. doi:10.1097/gme.0b013e31829996fcGarcia-Campayo, J., Navarro-Gil, M., Andrés, E., Montero-Marin, J., López-Artal, L., & Demarzo, M. M. (2014). Validation of the Spanish versions of the long (26 items) and short (12 items) forms of the Self-Compassion Scale (SCS). Health and Quality of Life Outcomes, 12(1), 4. doi:10.1186/1477-7525-12-4Gardner, F. L., & Moore, Z. E. (2012). Mindfulness and acceptance models in sport psychology: A decade of basic and applied scientific advancements. Canadian Psychology/Psychologie canadienne, 53(4), 309-318. doi:10.1037/a0030220Garland, E. L., Gaylord, S. A., Boettiger, C. A., & Howard, M. O. (2010). Mindfulness Training Modifies Cognitive, Affective, and Physiological Mechanisms Implicated in Alcohol Dependence: Results of a Randomized Controlled Pilot Trial. Journal of Psychoactive Drugs, 42(2), 177-192. doi:10.1080/02791072.2010.10400690Garland, S. N., Campbell, T., Samuels, C., & Carlson, L. E. (2013). Dispositional mindfulness, insomnia, sleep quality and dysfunctional sleep beliefs in post-treatment cancer patients. Personality and Individual Differences, 55(3), 306-311. doi:10.1016/j.paid.2013.03.003Goldin, P., Ziv, M., Jazaieri, H., & Gross, J. J. (2012). Randomized Controlled Trial of Mindfulness-Based Stress Reduction Versus Aerobic Exercise: Effects on the Self-Referential Brain Network in Social Anxiety Disorder. Frontiers in Human Neuroscience, 6. doi:10.3389/fnhum.2012.00295Grossman, P. (2011). Defining mindfulness by how poorly I think I pay attention during everyday awareness and other intractable problems for psychology’s (re)invention of mindfulness: Comment on Brown et al. (2011). Psychological Assessment, 23(4), 1034-1040. doi:10.1037/a0022713Gryffin, P. A., & Chen, W. C. (2013). Implications ofT’ai Chifor Smoking Cessation. The Journal of Alternative and Complementary Medicine, 19(2), 141-145. doi:10.1089/acm.2011.0094Hagins, M., States, R., Selfe, T., & Innes, K. (2013). Effectiveness of Yoga for Hypertension: Systematic Review and Meta-Analysis. Evidence-Based Complementary and Alternative Medicine, 2013, 1-13. doi:10.1155/2013/649836Hayes-Skelton, S., & Graham, J. (2012). Decentering as a Common Link among Mindfulness, Cognitive Reappraisal, and Social Anxiety. Behavioural and Cognitive Psychotherapy, 41(3), 317-328. doi:10.1017/s1352465812000902Hölzel, B. K., Lazar, S. W., Gard, T., Schuman-Olivier, Z., Vago, D. R., & Ott, U. (2011). How Does Mindfulness Meditation Work? Proposing Mechanisms of Action From a Conceptual and Neural Perspective. Perspectives on Psychological Science, 6(6), 537-559. doi:10.1177/1745691611419671Huang, C.-J., Webb, H. E., Zourdos, M. C., & Acevedo, E. O. (2013). Cardiovascular reactivity, stress, and physical activity. 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Global, regional, and national burden of rheumatoid arthritis, 1990–2020, and projections to 2050: a systematic analysis of the Global Burden of Disease Study 2021

Background Rheumatoid arthritis is a chronic autoimmune inflammatory disease associated with disability and premature death. Up-to-date estimates of the burden of rheumatoid arthritis are required for health-care planning, resource allocation, and prevention. As part of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021, we provide updated estimates of the prevalence of rheumatoid arthritis and its associated deaths and disability-adjusted life-years (DALYs) by age, sex, year, and location, with forecasted prevalence to 2050. Methods Rheumatoid arthritis prevalence was estimated in 204 countries and territories from 1990 to 2020 using Bayesian meta-regression models and data from population-based studies and medical claims data (98 prevalence and 25 incidence studies). Mortality was estimated from vital registration data with the Cause of Death Ensemble model (CODEm). Years of life lost (YLL) were calculated with use of standard GBD lifetables, and years lived with disability (YLDs) were estimated from prevalence, a meta-analysed distribution of rheumatoid arthritis severity, and disability weights. DALYs were calculated by summing YLLs and YLDs. Smoking was the only risk factor analysed. Rheumatoid arthritis prevalence was forecast to 2050 by logistic regression with Socio-Demographic Index as a predictor, then multiplying by projected population estimates. Findings In 2020, an estimated 17·6 million (95% uncertainty interval 15·8–20·3) people had rheumatoid arthritis worldwide. The age-standardised global prevalence rate was 208·8 cases (186·8–241·1) per 100 000 population, representing a 14·1% (12·7–15·4) increase since 1990. Prevalence was higher in females (age-standardised female-to-male prevalence ratio 2·45 [2·40–2·47]). The age-standardised death rate was 0·47 (0·41–0·54) per 100 000 population (38 300 global deaths [33 500–44 000]), a 23·8% (17·5–29·3) decrease from 1990 to 2020. The 2020 DALY count was 3 060 000 (2 320 000–3 860 000), with an age-standardised DALY rate of 36·4 (27·6–45·9) per 100 000 population. YLDs accounted for 76·4% (68·3–81·0) of DALYs. Smoking risk attribution for rheumatoid arthritis DALYs was 7·1% (3·6–10·3). We forecast that 31·7 million (25·8–39·0) individuals will be living with rheumatoid arthritis worldwide by 2050. Interpretation Rheumatoid arthritis mortality has decreased globally over the past three decades. Global age-standardised prevalence rate and YLDs have increased over the same period, and the number of cases is projected to continue to increase to the year 2050. Improved access to early diagnosis and treatment of rheumatoid arthritis globally is required to reduce the future burden of the disease.publishedVersio

Global, regional, and national prevalence and mortality burden of sickle cell disease, 2000–2021: a systematic analysis from the Global Burden of Disease Study 2021

Background Previous global analyses, with known underdiagnosis and single cause per death attribution systems, provide only a small insight into the suspected high population health effect of sickle cell disease. Completed as part of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021, this study delivers a comprehensive global assessment of prevalence of sickle cell disease and mortality burden by age and sex for 204 countries and territories from 2000 to 2021. Methods We estimated cause-specific sickle cell disease mortality using standardised GBD approaches, in which each death is assigned to a single underlying cause, to estimate mortality rates from the International Classification of Diseases (ICD)-coded vital registration, surveillance, and verbal autopsy data. In parallel, our goal was to estimate a more accurate account of sickle cell disease health burden using four types of epidemiological data on sickle cell disease: birth incidence, age-specific prevalence, with-condition mortality (total deaths), and excess mortality (excess deaths). Systematic reviews, supplemented with ICD-coded hospital discharge and insurance claims data, informed this modelling approach. We employed DisMod-MR 2.1 to triangulate between these measures—borrowing strength from predictive covariates and across age, time, and geography—and generated internally consistent estimates of incidence, prevalence, and mortality for three distinct genotypes of sickle cell disease: homozygous sickle cell disease and severe sickle cell β-thalassaemia, sickle-haemoglobin C disease, and mild sickle cell β-thalassaemia. Summing the three models yielded final estimates of incidence at birth, prevalence by age and sex, and total sickle cell disease mortality, the latter of which was compared directly against cause-specific mortality estimates to evaluate differences in mortality burden assessment and implications for the Sustainable Development Goals (SDGs). Findings Between 2000 and 2021, national incidence rates of sickle cell disease were relatively stable, but total births of babies with sickle cell disease increased globally by 13·7% (95% uncertainty interval 11·1–16·5), to 515 000 (425 000–614 000), primarily due to population growth in the Caribbean and western and central sub-Saharan Africa. The number of people living with sickle cell disease globally increased by 41·4% (38·3–44·9), from 5·46 million (4·62–6·45) in 2000 to 7·74 million (6·51–9·2) in 2021. We estimated 34 400 (25 000–45 200) cause-specific all-age deaths globally in 2021, but total sickle cell disease mortality burden was nearly 11-times higher at 376 000 (303 000–467 000). In children younger than 5 years, there were 81 100 (58 800–108 000) deaths, ranking total sickle cell disease mortality as 12th (compared to 40th for cause-specific sickle cell disease mortality) across all causes estimated by the GBD in 2021. Interpretation Our findings show a strikingly high contribution of sickle cell disease to all-cause mortality that is not apparent when each death is assigned to only a single cause. Sickle cell disease mortality burden is highest in children, especially in countries with the greatest under-5 mortality rates. Without comprehensive strategies to address morbidity and mortality associated with sickle cell disease, attainment of SDG 3.1, 3.2, and 3.4 is uncertain. Widespread data gaps and correspondingly high uncertainty in the estimates highlight the urgent need for routine and sustained surveillance efforts, further research to assess the contribution of conditions associated with sickle cell disease, and widespread deployment of evidence-based prevention and treatment for those with sickle cell disease.publishedVersio