Gates Foundation Research Articles

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.

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. 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. 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. 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. Bill & Melinda Gates Foundation, Institute of Bone and Joint Research, and Global Alliance for Musculoskeletal Health.

Burden and risk factors of chronic obstructive pulmonary disease in Sub-Saharan African countries, 1990–2019: a systematic analysis for the Global Burden of disease study 2019

Sub-Saharan Africa (SSA) has experienced a surge of non-communicable diseases (NCDs) including chronic obstructive pulmonary disease (COPD) over the past two decades. Using data from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD), in this study we have estimated the burden and attributable risk factors of COPD across SSA countries between 1990 and2019. COPD burden and its attributable risk factors were estimated using data from the 2019 GBD. Percentage change was estimated to show the trend of COPD estimates from 1990 to 2019. COPD estimates attributable by risk factors were also reported to ascertain the risk factor that brings the greatest burden by sex and locations (at country and regions level). In 2019, all-age prevalent cases of COPD in SSA were estimated to be 10.3 million (95% Uncertainty Intervals (UI) 9.7 million to 10.9 million) showing an increase of 117% compared with the number of all-age COPD cases in 1990. From 1990 to 2019, SSA underwent an increased percentage change in all-age YLDs due toCOPD ranging from 41% in Lesotho to 203% in Equatorial Guinea. The largest premature mortality due to COPD was reported from Central SSA accounting for 729 subjects (95% UI, 509-1078). The highest rate of DALYs attributable to COPD was observed in Lesotho. Household air pollution from solid fuel was the primary contributor of the age standardized YLDs, death rate, and DALYs rate per 100,000 population. The prevalence of COPD in SSA has had a steady increase over the past three decades and has progressively become a major public health burden across the region. Household air pollution from solid fuel is the primary contributor to COPD related burden, and its percentage contribution showed a similar trend to the reduction of COPD attributed age-standardized DALY rate. The methodological limitations of surveys and datapoints included in the GBD need to be considered when interpreting these associations. There are no specific fundings received for this study. The Global Burden of Disease study was supported by funding from the Bill & Melinda Gates Foundation.

Feasibility and impact of school-based nutrition education interventions on the diets of adolescent girls in Ethiopia: a non-masked, cluster-randomised, controlled trial.

Adolescence is a critical period of physical and psychological development, especially for girls, because poor nutrition can affect their wellbeing as well as that of their children. We aimed to assess the feasibility and impact of a package of nutrition education interventions delivered through public primary schools on the diets of adolescent girls in Ethiopia. In this non-masked, cluster-randomised, controlled trial, primary schools (clusters) in the Southern Nations, Nationalities, and People's Region and Somali region of Ethiopia were randomly allocated to the intervention group (nutrition information provided during flag ceremonies, classroom lessons, school club meetings, peer group mentoring, BMI measurement and counselling, and parent-teacher meetings) or the control group (standard academic curriculum on health and nutrition) by use of computer-generated pseudo-random numbers. Duration of the school-based interventions was 4 months, and the key messages were related to dietary diversity (eating a variety of foods), energy adequacy (eating breakfast and healthy snacks), and healthy food choices (avoiding junk foods). Adolescent girls were eligible for participation if aged 10-14 years and enrolled in grades 4-8 in a study school. Data were collected with two independent cross-sectional surveys: baseline before the start of implementation and endline 1·5 years later. The primary outcome of impact was dietary diversity score, defined as the number of food groups (out of ten) consumed over the previous 24 h using a list-based method, and minimum dietary diversity, defined as the proportion of girls who consumed foods from at least five of the ten food groups, in the intention-to-treat population. We also assessed intervention exposure as a measure of feasibility. We estimated intervention effects using linear regression models for mean differences at endline, with SEs clustered at the school level, and controlled for adolescent age, region, household food security, and wealth. The trial is registered with ClinicalTrials.Gov, NCT04121559, and is complete. 27 primary schools were randomly allocated to the intervention group and 27 to the control group. Between March 22 and April 29, 2021, 536 adolescent girls participated in the endline survey (270 in the intervention group and 266 in the control group), with median age of 13·3 years (IQR 12·1-14·0). At endline, the dietary diversity score was 5·37 (SD 1·66) food groups in the intervention group and 3·98 (1·43) food groups in the control group (adjusted mean difference 1·33, 95% CI 0·90-1·75, p<0·0001). Increased minimum dietary diversity was also associated with the intervention (182 [67%] of 270 in the intervention group vs 76 [29%] of 266 in the control group; adjusted odds ratio 5·37 [95% CI 3·04-9·50], p<0·0001). 256 (95%) of 270 adolescent girls in the intervention group were exposed to at least one of the five in-school intervention components. Integrating nutrition interventions into primary schools in Ethiopia was feasible and increased dietary diversity incrementally among adolescent girls, but could be limited in changing other food choice behaviours, such as junk food consumption, based on nutrition education alone. Bill & Melinda Gates Foundation.

Review of the India Adolescent Health Strategy in the context of disease burden among adolescents

A nuanced understanding of the health needs of adolescents in the context of the India Adolescent Health Strategy (IAHS) is needed to inform policy interventions for improving the health and well-being of adolescents in India. Using data from the Global Burden of Diseases, Injuries, and Risk Factors Study 2019, we identified the top ten causes of years of life lost (YLLs), years lived with disability (YLDs), and disability-adjusted life years (DALYs) disaggregated by sex and age group (10-14 and 15-19 years) for India and its states in 2019. To inform the IAHS of refinement or expansion in focus needed to improve adolescent health in India, we reviewed the extent to which the top 10 causes of disease burden are addressed in the IAHS, and the availability of and age- and sex-disaggregation in the service utilisation data for adolescents captured in the Adolescent Friendly Health Clinic monitoring information system (AFHC MIS) and Health Management Information System (HMIS). We also reviewed the availability of and age-and sex-disaggregation in the data capture at the population level for the IAHS outcome indicators in the data sources identified in the IAHS operational framework. Females in the 10-14 and 15-19 years age groups suffered 6.75 million and 9.25 million DALYs, respectively, 39.1% and 44.2% of which were YLLs; the corresponding DALYs for males were 6.71 million and 9.65 million (42.3% and 41.1% YLLs), respectively. Within the 6 thematic areas of the IAHS, most strategies and indicators identified are for sexual and reproductive health followed by nutrition, and broadly these conditions accounted for YLDs and not YLLs in adolescents. Significant gaps in the IAHS in comparison to the disease burden for fatal diseases and conditions were seen across injuries, communicable diseases, and non-communicable diseases. Injuries accounted for 65.9% and 45.3% of YLLs in males and females aged 15-19 years, and 40.8% in males aged 10-14 years. Specifically, road injuries (15.3%, 95% UI 11.0-18.0) and self-harm (11.3%, 95% UI 8.7-14.2) accounted for most of the injury deaths in 15-19 years whereas drowning (7.7% 95% UI 5.8-9.6) and road injuries (6.9%, 95% UI 4.7-8.6) accounted for the most injury deaths in 10-14 years males. However, only self-harm and gender-based violence are specifically addressed in the IAHS with non-specific interventions for other injuries. Diarrhoea, lower respiratory infections, malaria, encephalitis, tuberculosis, typhoid, cirrhosis, and hepatitis are the other disease conditions accounting for YLLs and DALYs in adolescents but these are neither addressed in the IAHS nor in service provision under the AFHC MIS. There is no age- or sex-disaggregation in the cause of death data captured in the HMIS to allow an understanding of mortality in adolescents. For the IAHS outcome indicators at the population level, data capture for the 10-14 years irrespective of sex was largely missing from the population surveys and none of the surveys captured data for either females or males aged 15-19 years for physical inactivity and mental health indicators. The considerable differences seen in the IAHS thematic focus as compared with the leading causes of fatal and non-fatal disease burden in adolescents in India, and in the availability of population-level data to monitor the outcome indicators of the IAHS can pose substantial limitations for improving adolescent health in India. The findings in this paper can be utilized by decision makers to refine action aimed at improving adolescent health and well-being. Bill & Melinda Gates Foundation.

Increasing Prevalence of Artemisinin-Resistant HRP2-Negative Malaria in Eritrea

BackgroundAlthough the clinical efficacy of antimalarial artemisinin-based combination therapies in Africa remains high, the recent emergence of partial resistance to artemisinin in Plasmodium falciparum on the continent is troubling, given the lack of alternative treatments.MethodsIn this study, we used data from drug-efficacy studies conducted between 2016 and 2019 that evaluated 3-day courses of artemisinin-based combination therapy (artesunate–amodiaquine or artemether–lumefantrine) for uncomplicated malaria in Eritrea to estimate the percentage of patients with day-3 positivity (i.e., persistent P. falciparum parasitemia 3 days after the initiation of therapy). We also assayed parasites for mutations in Pfkelch13 as predictive markers of partial resistance to artemisinin and screened for deletions in hrp2 and hrp3 that result in variable performance of histidine rich protein 2 (HRP2)–based rapid diagnostic tests for malaria.ResultsWe noted an increase in the percentage of patients with day-3 positivity from 0.4% (1 of 273) in 2016 to 1.9% (4 of 209) in 2017 and 4.2% (15 of 359) in 2019. An increase was also noted in the prevalence of the Pfkelch13 R622I mutation, which was detected in 109 of 818 isolates before treatment, from 8.6% (24 of 278) in 2016 to 21.0% (69 of 329) in 2019. The odds of day-3 positivity increased by a factor of 6.2 (95% confidence interval, 2.5 to 15.5) among the patients with Pfkelch13 622I variant parasites. Partial resistance to artemisinin, as defined by the World Health Organization, was observed in Eritrea. More than 5% of the patients younger than 15 years of age with day-3 positivity also had parasites that carried Pfkelch13 R622I. In vitro, the R622I mutation conferred a low level of resistance to artemisinin when edited into NF54 and Dd2 parasite lines. Deletions in both hrp2 and hrp3 were identified in 16.9% of the parasites that carried the Pfkelch13 R622I mutation, which made them potentially undetectable by HRP2-based rapid diagnostic tests.ConclusionsThe emergence and spread of P. falciparum lineages with both Pfkelch13-mediated partial resistance to artemisinin and deletions in hrp2 and hrp3 in Eritrea threaten to compromise regional malaria control and elimination campaigns. (Funded by the Bill and Melinda Gates Foundation and others; Australian New Zealand Clinical Trials Registry numbers, ACTRN12618001223224, ACTRN12618000353291, and ACTRN12619000859189.)

Potential population-level effectiveness of one-dose HPV vaccination in low-income and middle-income countries: a mathematical modelling analysis

Given the accumulating evidence that one-dose vaccination could provide high and sustained protection against human papillomavirus (HPV) infection and related diseases, we examined the population-level effectiveness and efficiency of one-dose HPV vaccination of girls compared with two-dose vaccination, using mathematical modelling. In this mathematical modelling study, we used HPV-ADVISE LMIC, an individual-based transmission-dynamic model independently calibrated to four epidemiologically diverse low-income and middle-income countries (LMICs; India, Nigeria, Uganda, and Viet Nam). We parameterised and calibrated the model using sexual behaviour and epidemiological data identified from international population-based datasets and the literature. All base-case vaccination scenarios start in 2023 with the nonavalent vaccine and assumed 80% vaccination coverage with one or two doses. We assumed that two doses of vaccine provide 100% efficacy against vaccine-type infections and a lifelong duration of protection. We examined a non-inferior vaccination scenario for one dose compared with two doses, pessimistic scenarios of lower one-dose vaccine efficacy (85%) or a shorter duration of protection (ie, 20 or 30 years), and the effectiveness of a mitigation scenario in which schedules would switch from one dose to two doses. We also did sensitivity analyses by varying vaccination coverage. We used three outcomes: the relative reduction in cervical cancer incidence, the number of cervical cancers averted, and the number of vaccine doses needed to prevent one cervical cancer. Assuming non-inferior vaccine characteristics for one dose compared with two doses, the model projections show that two-dose or one-dose routine vaccination of girls aged 9 years (with a multi-age cohort vaccination of girls aged 10-14 years) would avert 12·0 million (80% UI 9·5-14·5) cervical cancers in India, 4·7 million (3·4-5·8) in Nigeria, 2·3 million (1·9-2·6) in Uganda, and 0·4 million (0·2-0·5) in Viet Nam over 100 years. Under pessimistic assumptions of lower one-dose efficacy (85%) or a shorter duration of protection (ie, 30 years), one-dose routine vaccination would avert 69% (61-80) to 94% (92-96) of the cervical cancers averted with two-dose routine vaccination. However, when assuming a duration of protection of 20 years, one-dose routine vaccination would avert substantially fewer cervical cancers (ie, 35% [26-44] to 69% [65-71] of the cervical cancers averted with two-dose routine vaccination). A switch from one-dose to two-dose routine vaccination of girls aged 9 years, with a one-dose catch-up of girls aged 10-14 years, 5 years after the start of the vaccination programme, could mitigate potential losses in cervical cancer prevention from a short one-dose duration of protection (averting 92% [83-98] to 99% [97-100]) of the cervical cancers averted with two-dose routine vaccination). One-dose routine vaccination would result in fewer doses needed to prevent one cervical cancer than two-dose routine vaccination, even if the duration of protection is as low as 20 years. Finally, for countries with two-dose routine vaccination, adding one-dose multi-age cohort vaccination in the first year would provide similar benefits as a two-dose multi-age cohort vaccination, and would be more efficient even under the pessimistic assumptions of lower one-dose vaccine efficacy or duration of protection. One-dose routine vaccination could avert most of the cervical cancers averted with two-dose vaccination while being more efficient, provided the duration of one-dose protection is greater than 20-30 years (depending on the LMIC). The doses saved by introducing one-dose routine vaccination could offer the opportunity to vaccinate girls before they age out of the vaccination window of 9-14 years and, potentially, to vaccinate boys or older age groups. Fonds de recherche du Québec-Santé, Digital Research Alliance of Canada, Bill & Melinda Gates Foundation.

Effectiveness of long-lasting insecticidal nets with pyriproxyfen–pyrethroid, chlorfenapyr–pyrethroid, or piperonyl butoxide–pyrethroid versus pyrethroid only against malaria in Tanzania: final-year results of a four-arm, single-blind, cluster-randomised trial

New classes of long-lasting insecticidal nets (LLINs) containing two active ingredients have been recently recommended by WHO in areas where malaria vectors are resistant to pyrethroids. This policy was based on evidence generated by the first 2 years of our recently published trial in Tanzania. In this Article, we report the final third-year trial findings, which are necessary for assessing the long-term effectiveness of new classes of LLIN in the community and the replacement intervals required. A third year of follow-up of a four-arm, single-blind, cluster-randomised controlled trial of dual active ingredient LLINs was conducted between July 14, 2021, and Feb 10, 2022, in Misungwi, Tanzania. Restricted randomisation was used to assign 84 clusters to the four LLIN groups (1:1:1:1) to receive either standard pyrethroid (PY) LLINs (reference), chlorfenapyr-PY LLINs, pyriproxyfen-PY LLINs, or piperonyl butoxide (PBO)-PY LLINs. All households received one LLIN for every two people. Data collection was done in consenting households in the cluster core area with at least one child between 6 months and 15 years of age who permanently resided in the selected household. Exclusion criteria were householders absent during the visit, living in the cluster buffer area, no adult caregiver capable of giving informed consent, or eligible children who were severely ill. Field staff and study participants were masked to allocation, and those analysing data were not. The primary 24-month endpoint was reported previously; here, we present the secondary outcome, malaria infection prevalence in children at 36 months post LLIN distribution, reported in the intention-to-treat analysis. The trial was registered with ClinicalTrials.gov (NCT03554616) and is now complete. Overall usage of study nets was 1023 (22·3%) of 4587 people at 36 months post distribution. In the standard PY LLIN group, malaria infection was prevalent in 407 (37·4%) of 1088 participants, compared with 261 (22·8%) of 1145 in the chlorfenapyr-PY LLIN group (odds ratio 0·57, 95% CI 0·38-0·86; p=0·0069), 338 (32·2%) of 1048 in the PBO-PY LLIN group (0·95, 0·64-1·42; p=0·80), and 302 (28·8%) of 1050 in the pyriproxyfen-PY LLIN group (0·82, 0·55-1·23; p=0·34). None of the participants or caregivers reported side-effects. Despite low coverage, the protective efficacy against malaria offered by chlorfenapyr-PY LLINs was superior to that provided by standard PY LLINs over a 3-year LLIN lifespan. Appropriate LLIN replacement strategies to maintain adequate usage of nets will be necessary to maximise the full potential of these nets. Department for International Development, UK Medical Research Council, Wellcome Trust, Department of Health and Social Care, and Bill & Melinda Gates Foundation via the Innovative Vector Control Consortium.

Ranking age-specific modifiable risk factors for cardiovascular disease and mortality: evidence from a population-based longitudinal study

Cardiovascular disease (CVD) remains a paramount contemporary health challenge. This study examined age-specific effects of 14 risk factors on CVD and mortality in different age groups. We analyzed data from 226,759 CVD-free participants aged 40 years and older in the UK Biobank during the period from baseline time (2006-2010) to September 30, 2021. The primary CVD outcome was a composite of incident coronary artery disease, heart failure, and stroke. We calculated age-specific hazard ratios (HRs) and population-attributable fractions (PAF) for CVD and mortality associated with 14 potentially modifiable risk factors. During 12.17-year follow-up, 23,838 incident CVD cases and 11,949 deaths occurred. Age-specific disparities were observed in the risk factors contributing to CVD, and the overall PAF declined with age (PAF of 56.53% in middle-age; 49.78% in quinquagenarian; 42.45% in the elderly). Metabolic factors had the highest PAF in each age group, with hypertension (14.04% of the PAF) and abdominal obesity (9.58% of the PAF) being prominent. Behavioral factors had the highest PAF in the middle-aged group (10.68% of the PAF), and smoking was the leading behavioral factor in all age groups. In socioeconomic and psychosocial risk clusters, low income contributed most among middle-aged (3.74% of the PAF) and elderly groups (3.66% of the PAF), while less education accounted more PAF for quinquagenarian group (4.46% of the PAF). Similar age-specific patterns were observed for cardiovascular subtypes and mortality. A large fraction of CVD cases and deaths were associated with modifiable risk factors in all age groups. Targeted efforts should focus on the most impactful risk factors, as well as age-specific modifiable risk factors. These findings may inform the development of more precise medical strategies to prevent and manage CVD and related mortality. The work was supported by the Bill & Melinda Gates Foundation (grant number: INV-016826 to Hualiang Lin) and the National Natural Science Foundation of China (grant number: 82373534 to Hualiang Lin).

Understanding yellow fever-associated myocardial injury: an autopsy study

Yellow fever (YF) is a viral hemorrhagic fever, endemic in parts of South America and Africa. There is scarce evidence about the pathogenesis of the myocardial injury. The objective of this study is to evaluate the cardiac pathology in fatal cases of YF. This retrospective autopsy study included cases from the São Paulo (Brazil) epidemic of 2017-2019. We reviewed medical records and performed cardiac tissue histopathological evaluation, electron microscopy, immunohistochemical assays, RT-qPCR for YF virus (YFV)-RNA, and proteomics analysis on inflammatory and endothelial biomarkers. Seventy-three confirmed YF cases with a median age of 48 (34-60) years were included. We observed myocardial fibrosis in 68 (93.2%) patients; cardiomyocyte hypertrophy in 68 (93.2%); endothelial alterations in 67 (91.8%); fiber necrosis in 50 (68.5%); viral myocarditis in 9 (12.3%); and secondary myocarditis in 5 (6.8%). Four out of five patients with 17DD vaccine-associated viscerotropic disease presented with myocarditis. The cardiac conduction system showed edema, hemorrhages and endothelial fibrinoid necrosis. Immunohistochemistry detected CD68-positive inflammatory interstitial cells and YFV antigens in endothelial and inflammatory cells. YFV-RNA was detected positive in 95.7% of the cardiac samples. The proteomics analysis demonstrated that YF patients had higher levels of multiple inflammatory and endothelial biomarkers in comparison to cardiovascular controls, and higher levels of interferon gamma-induced protein 10 (IP-10) in comparison to sepsis (p=0.01) and cardiovascular controls (p<0.001) in Dunn test. Myocardial injury is frequent in severe YF, due to multifactorial mechanisms, including direct YFV-mediated damage, endothelial cell injury, and inflammatory response, with a possible prominent role for IP-10. This study was funded by Fundação de Amparo à Pesquisa do Estado de São Paulo, Bill and Melinda Gates Foundation, Conselho Nacional de Desenvolvimento Científico e Tecnológico, Coordenação de Aperfeiçoamento de Pessoal de Nível Superior.

Effect of primaquine dose on the risk of recurrence in patients with uncomplicated Plasmodium vivax: a systematic review and individual patient data meta-analysis

Primaquine is used to eliminate Plasmodium vivax hypnozoites, but its optimal dosing regimen remains unclear. We undertook a systematic review and individual patient data meta-analysis to investigate the efficacy and tolerability of different primaquine dosing regimens to prevent P vivax recurrence. For this systematic review and individual patient data meta-analysis, we searched MEDLINE, Web of Science, Embase, and Cochrane Central for prospective clinical studies of uncomplicated P vivax from endemic countries published between Jan 1, 2000, and June 8, 2023. We included studies if they had active follow-up of at least 28 days, and if they included a treatment group with daily primaquine given over multiple days, where primaquine was commenced within 7 days of schizontocidal treatment and was given alone or coadministered with chloroquine or one of four artemisinin-based combination therapies (ie, artemether-lumefantrine, artesunate-mefloquine, artesunate-amodiaquine, or dihydroartemisinin-piperaquine). We excluded studies if they were on prevention, prophylaxis, or patients with severe malaria, or if data were extracted retrospectively from medical records outside of a planned trial. For the meta-analysis, we contacted the investigators of eligible trials to request individual patient data and we then pooled data that were made available by Aug 23, 2021. We assessed the effects of total dose and duration of primaquine regimens on the rate of first P vivax recurrence between day 7 and day 180 by Cox's proportional hazards regression (efficacy analysis). The effect of primaquine daily dose on gastrointestinal symptoms on days 5-7 was assessed by modified Poisson regression (tolerability analysis). The study was registered with PROSPERO, CRD42019154470. Of 226 identified studies, 23 studies with patient-level data from 6879 patients from 16 countries were included in the efficacy analysis. At day 180, the risk of recurrence was 51·0% (95% CI 48·2-53·9) in 1470 patients treated without primaquine, 19·3% (16·9-21·9) in 2569 patients treated with a low total dose of primaquine (approximately 3·5 mg/kg), and 8·1% (7·0-9·4) in 2811 patients treated with a high total dose of primaquine (approximately 7 mg/kg), regardless of primaquine treatment duration. Compared with treatment without primaquine, the rate of P vivax recurrence was lower after treatment with low-dose primaquine (adjusted hazard ratio 0·21, 95% CI 0·17-0·27; p<0·0001) and high-dose primaquine (0·10, 0·08-0·12; p<0·0001). High-dose primaquine had greater efficacy than low-dose primaquine in regions with high and low relapse periodicity (ie, the time from initial infection to vivax relapse). 16 studies with patient-level data from 5609 patients from ten countries were included in the tolerability analysis. Gastrointestinal symptoms on days 5-7 were reported by 4·0% (95% CI 0·0-8·7) of 893 patients treated without primaquine, 6·2% (0·5-12·0) of 737 patients treated with a low daily dose of primaquine (approximately 0·25 mg/kg per day), 5·9% (1·8-10·1) of 1123 patients treated with an intermediate daily dose (approximately 0·5 mg/kg per day) and 10·9% (5·7-16·1) of 1178 patients treated with a high daily dose (approximately 1 mg/kg per day). 20 of 23 studies included in the efficacy analysis and 15 of 16 in the tolerability analysis had a low or unclear risk of bias. Increasing the total dose of primaquine from 3·5 mg/kg to 7 mg/kg can reduce P vivax recurrences by more than 50% in most endemic regions, with a small associated increase in gastrointestinal symptoms. Australian National Health and Medical Research Council, Bill & Melinda Gates Foundation, and Medicines for Malaria Venture.

Primaquine dose and the risk of haemolysis in patients with uncomplicated Plasmodium vivax malaria: a systematic review and individual patient data meta-analysis

Primaquine radical cure is used to treat dormant liver-stage parasites and prevent relapsing Plasmodium vivax malaria but is limited by concerns of haemolysis. We undertook a systematic review and individual patient data meta-analysis to investigate the haematological safety of different primaquine regimens for P vivax radical cure. For this systematic review and individual patient data meta-analysis, we searched MEDLINE, Web of Science, Embase, and Cochrane Central for prospective clinical studies of uncomplicated P vivax from endemic countries published between Jan 1, 2000, and June 8, 2023. We included studies if they had active follow-up of at least 28 days, if they included a treatment group with daily primaquine given over multiple days where primaquine was commenced within 3 days of schizontocidal treatment and was given alone or coadministered with chloroquine or one of four artemisinin-based combination therapies (ie, artemether-lumefantrine, artesunate-mefloquine, artesunate-amodiaquine, or dihydroartemisinin-piperaquine), and if they recorded haemoglobin or haematocrit concentrations on day 0. We excluded studies if they were on prevention, prophylaxis, or patients with severe malaria, or if data were extracted retrospectively from medical records outside of a planned trial. For the meta-analysis, we contacted the investigators of eligible trials to request individual patient data and we then pooled data that were made available by Aug 23, 2021. The main outcome was haemoglobin reduction of more than 25% to a concentration of less than 7 g/dL by day 14. Haemoglobin concentration changes between day 0 and days 2-3 and between day 0 and days 5-7 were assessed by mixed-effects linear regression for patients with glucose-6-phosphate dehydrogenase (G6PD) activity of (1) 30% or higher and (2) between 30% and less than 70%. The study was registered with PROSPERO, CRD42019154470 and CRD42022303680. Of 226 identified studies, 18 studies with patient-level data from 5462 patients from 15 countries were included in the analysis. A haemoglobin reduction of more than 25% to a concentration of less than 7 g/dL occurred in one (0·1%) of 1208 patients treated without primaquine, none of 893 patients treated with a low daily dose of primaquine (<0·375 mg/kg per day), five (0·3%) of 1464 patients treated with an intermediate daily dose (0·375 mg/kg per day to <0·75 mg/kg per day), and six (0·5%) of 1269 patients treated with a high daily dose (≥0·75 mg/kg per day). The covariate-adjusted mean estimated haemoglobin changes at days 2-3 were -0·6 g/dL (95% CI -0·7 to -0·5), -0·7 g/dL (-0·8 to -0·5), -0·6 g/dL (-0·7 to -0·4), and -0·5 g/dL (-0·7 to -0·4), respectively. In 51 patients with G6PD activity between 30% and less than 70%, the adjusted mean haemoglobin concentration on days 2-3 decreased as G6PD activity decreased; two patients in this group who were treated with a high daily dose of primaquine had a reduction of more than 25% to a concentration of less than 7 g/dL. 17 of 18 included studies had a low or unclear risk of bias. Treatment of patients with G6PD activity of 30% or higher with 0·25-0·5 mg/kg per day primaquine regimens and patients with G6PD activity of 70% or higher with 0·25-1 mg/kg per day regimens were associated with similar risks of haemolysis to those in patients treated without primaquine, supporting the safe use of primaquine radical cure at these doses. Australian National Health and Medical Research Council, Bill & Melinda Gates Foundation, and Medicines for Malaria Venture.

Rebalancing of mitochondrial homeostasis through an NAD+-SIRT1 pathway preserves intestinal barrier function in severe malnutrition

The intestine of children with severe malnutrition (SM) shows structural and functional changes that are linked to increased infection and mortality. SM dysregulates the tryptophan-kynurenine pathway, which may impact processes such as SIRT1- and mTORC1-mediated autophagy and mitochondrial homeostasis. Using a mouse and organoid model of SM, we studied the repercussions of these dysregulations on malnutrition enteropathy and the protective capacity of maintaining autophagy activity and mitochondrial health. SM was induced through feeding male weanling C57BL/6 mice a low protein diet (LPD) for 14-days. Mice were either treated with the NAD+-precursor, nicotinamide; an mTORC1-inhibitor, rapamycin; a SIRT1-activator, resveratrol; or SIRT1-inhibitor, EX-527. Malnutrition enteropathy was induced in enteric organoids through amino-acid deprivation. Features of and pathways to malnutrition enteropathy were examined, including paracellular permeability, nutrient absorption, and autophagic, mitochondrial, and reactive-oxygen-species (ROS) abnormalities. LPD-feeding and ensuing low-tryptophan availability led to villus atrophy, nutrient malabsorption, and intestinal barrier dysfunction. In LPD-fed mice, nicotinamide-supplementation was linked to SIRT1-mediated activation of mitophagy, which reduced damaged mitochondria, and improved intestinal barrier function. Inhibition of mTORC1 reduced intestinal barrier dysfunction and nutrient malabsorption. Findings were validated and extended using an organoid model, demonstrating that resolution of mitochondrial ROS resolved barrier dysfunction. Malnutrition enteropathy arises from a dysregulation of the SIRT1 and mTORC1 pathways, leading to disrupted autophagy, mitochondrial homeostasis, and ROS. Whether nicotinamide-supplementation in children with SM could ameliorate malnutrition enteropathy should be explored in clinical trials. This work was supported by the Bill and Melinda Gates Foundation, the Sickkids Research Institute, the Canadian Institutes of Health Research, and the University Medical Center Groningen.

Global burden of peripheral artery disease and its risk factors, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019

Peripheral artery disease is a growing public health problem. We aimed to estimate the global disease burden of peripheral artery disease, its risk factors, and temporospatial trends to inform policy and public measures. Data on peripheral artery disease were modelled using the Global Burden of Disease, Injuries, and Risk Factors Study (GBD) 2019 database. Prevalence, disability-adjusted life years (DALYs), and mortality estimates of peripheral artery disease were extracted from GBD 2019. Total DALYs and age-standardised DALY rate of peripheral artery disease attributed to modifiable risk factors were also assessed. In 2019, the number of people aged 40 years and older with peripheral artery disease was 113 million (95% uncertainty interval [UI] 99·2-128·4), with a global prevalence of 1·52% (95% UI 1·33-1·72), of which 42·6% was in countries with low to middle Socio-demographic Index (SDI). The global prevalence of peripheral artery disease was higher in older people, (14·91% [12·41-17·87] in those aged 80-84 years), and was generally higher in females than in males. Globally, the total number of DALYs attributable to modifiable risk factors in 2019 accounted for 69·4% (64·2-74·3) of total peripheral artery disease DALYs. The prevalence of peripheral artery disease was highest in countries with high SDI and lowest in countries with low SDI, whereas DALY and mortality rates showed U-shaped curves, with the highest burden in the high and low SDI quintiles. The total number of people with peripheral artery disease has increased globally from 1990 to 2019. Despite the lower prevalence of peripheral artery disease in males and low-income countries, these groups showed similar DALY rates to females and higher-income countries, highlighting disproportionate burden in these groups. Modifiable risk factors were responsible for around 70% of the global peripheral artery disease burden. Public measures could mitigate the burden of peripheral artery disease by modifying risk factors. Bill & Melinda Gates Foundation.

Potential cost-effectiveness of community availability of tenofovir, lamivudine, and dolutegravir for HIV prevention and treatment in east, central, southern, and west Africa: a modelling analysis

Post-exposure prophylaxis (PEP) offers protection from HIV after condomless sex, but is not widely available in a timely manner in east, central, southern, and west Africa. To inform the potential pilot implementation of such an approach, we modelled the effect and cost-effectiveness of making PEP consisting of tenofovir, lamivudine, and dolutegravir (TLD) freely and locally available in communities without prescription, with the aim of enabling PEP use within 24 h of condomless sex. Free community availability of TLD (referred to as community TLD) might also result in some use of TLD as pre-exposure prophylaxis (PrEP) and as antiretroviral therapy for people living with HIV. Using an existing individual-based model (HIV Synthesis), we explicitly modelled the potential positive and negative effects of community TLD. Through the sampling of parameter values we created 1000 setting-scenarios, reflecting the uncertainty in assumptions and a range of settings similar to those seen in east, central, southern, and west Africa (with a median HIV prevalence of 14·8% in women and 8·1% in men). For each setting scenario, we considered the effects of community TLD. TLD PEP was assumed to have at least 90% efficacy in preventing HIV infection after condomless sex with a person living with HIV. The modelled effects of community TLD availability based on an assumed high uptake of TLD resulted in a mean reduction in incidence of 31% (90% range over setting scenarios, 6% increase to 57% decrease) over 20 years, with an HIV incidence reduction over 50 years in 91% of the 1000 setting scenarios, deaths averted in 55% of scenarios, reduction in costs in 92% of scenarios, and disability-adjusted life-years averted in 64% of scenarios with community TLD. Community TLD was cost-effective in 90% of setting scenarios and cost-saving (with disability-adjusted life-years averted) in 58% of scenarios. When only examining setting scenarios in which there was lower uptake of community TLD, community TLD is cost-effective in 92% of setting scenarios. The introduction of community TLD, enabling greater PEP access, is a promising approach to consider further in pilot implementation projects. Bill & Melinda Gates Foundation to the HIV Modelling Consortium.

Catastrophic health expenditure during the COVID-19 pandemic in five countries: a time-series analysis

The COVID-19 pandemic disrupted health systems in 2020, but it is unclear how financial hardship due to out-of-pocket (OOP) health-care costs was affected. We analysed catastrophic health expenditure (CHE) in 2020 in five countries with available household expenditure data: Belarus, Mexico, Peru, Russia, and Viet Nam. In Mexico and Peru, we also conducted an analysis of drivers of change in CHE in 2020 using publicly available data. In this time-series analysis, we defined CHE as when OOP health-care spending exceeds 10% of consumption expenditure. Data for 2004-20 were obtained from individual and household level survey microdata (available for Mexico and Peru only), and tabulated data from the National Statistical Committee of Belarus and the World Bank Health Equity and Financial Protection Indicator database (for Viet Nam and Russia). We compared 2020 CHE with the CHE predicted from historical trends using an ensemble model. This method was also used to assess drivers of CHE: insurance coverage, OOP expenditure, and consumption expenditure. Interrupted time-series analysis was used to investigate the role of stay-at-home orders in March, 2020 in changes in health-care use and sector (ie, private vs public). In Mexico, CHE increased to 5·6% (95% uncertainty interval [UI] 5·1-6·2) in 2020, higher than predicted (3·2%, 2·5-4·0). In Belarus, CHE was 13·5% (11·8-15·2) in 2020, also higher than predicted (9·7%, 7·7-11·3). CHE was not different than predicted by past trends in Russia, Peru, and Viet Nam. Between March and April, 2020, health-care visits dropped by 4·6 (2·6-6·5) percentage points in Mexico and by 48·3 (40·6-56·0) percentage points in Peru, and the private share of health-care visits increased by 7·3 (4·3-10·3) percentage points in Mexico and by 20·7 (17·3-24·0) percentage points in Peru. In three of the five countries studied, health systems either did not protect people from the financial risks of health care or did not maintain health-care access in 2020, an indication of health systems failing to maintain basic functions. If the 2020 response to the COVID-19 pandemic accelerated shifts to private health-care use, policies to cover costs in that sector or motivate patients to return to the public sector are needed to maintain financial risk protection. The Bill & Melinda Gates Foundation.

Spatial heterogeneity in intimate partner violence across the 640 districts of India: a secondary analysis of a cross-sectional, population-based survey by use of model-based small-area estimation

Although intimate partner violence (IPV) against women is a substantial challenge in India, response is limited by little evidence on substate prevalence. District-level IPV estimates are essential in targeted response and prevention efforts, but cannot be directly calculated from the National Family Health Surveys (NFHS), which is the main source of nationally representative IPV estimates in India. We aimed to use small-area estimation techniques to derive reliable estimates of physical, emotional, and sexual IPV for the 640 districts of India. For this secondary analysis of a cross-sectional, population-based survey, we used model-based small-area estimation techniques linking data from the 2015-16 NFHS-4 and the 2011 Indian Population and Housing Census (2011 Indian Census) to derive district-level estimates of physical, emotional, and sexual IPV for the 640 districts of India in the previous 12 months. Only women who had ever been married aged 15-49 years, who were interviewed in NFHS-4, and who were included in the domestic violence module were eligible for inclusion in this analysis. Data collection occurred between Jan 20, 2015, and Dec 4, 2016. The 2011 Indian Census was conducted in all 640 districts from Feb 9 to Feb 28, 2011. It collected information on a range of data including sociodemographic data and housing characteristics. The primary outcomes of this analysis were the district-level mean proportions of women who experienced physical IPV, emotional IPV, and sexual IPV in the previous 12 months. This outcome was estimated for all women aged 15-49 years who had ever been married in the 640 districts of India that were included in the 2011 Indian Census. 699 686 women aged 15-49 years were interviewed in NFHS-4. One woman per household in a randomly selected 15% of households was chosen for participation in the domestic violence module, resulting in 83 397 (11·9%) of 699 686 women included. Of these 83 397 women, 14 377 (17·2%) were excluded as they had never been married and 3007 (3·6%) were excluded due to privacy limitations. The mean prevalence of physical IPV in the previous 12 months was 22·5% (95% CI 21·9-23·2), of emotional IPV in the previous 12 months was 11·4% (11·0-11·9), and of sexual IPV in the previous 12 months was 5·2% (4·9-5·5). Model-based estimates revealed intrastate and interstate IPV variations. In Bihar, which had the highest state-level physical IPV prevalence (35·1%, 33·3-37·0), district-level estimates varied from 23·5% (23·0-23·9) in Siwan to 42·7% (42·3-43·1) in Purbi Champaran. In Tamil Nadu, which had the highest state-level emotional IPV prevalence (19·0%, 17·4-20·8), district estimates ranged between 13·7% (13·2-14·1) in Kanniyakumari and 30·2% (29·5-30·8) in Sivaganga. Bihar also had the highest state-level sexual IPV prevalence (11·1%, 9·9-12·4), with estimates ranging between 6·3% (6·1-6·6) in Siwan and 18·1% (17·6-18·6) in Saharsa. Across districts, there was substantial spatial clustering of IPV prevalence. This reliable district-level estimation of IPV prevalence in the 640 districts of India has important policy implications. The ability to track substate levels of IPV over time enables the identification of progress in reducing IPV; recognises the heterogeneity of culture and context in India; and informs the targeting of resources, interventions, and prevention programmes to districts with the greatest need. Bill & Melinda Gates Foundation.

Sex differences in mortality among children, adolescents, and young people aged 0–24 years: a systematic assessment of national, regional, and global trends from 1990 to 2021

Differences in mortality exist between sexes because of biological, genetic, and social factors. Sex differentials are well documented in children younger than 5 years but have not been systematically examined for ages 5-24 years. We aimed to estimate the sex ratio of mortality from birth to age 24 years and reconstruct trends in sex-specific mortality between 1990 and 2021 for 200 countries, major regions, and the world. We compiled comprehensive databases on the mortality sex ratio (ratio of male to female mortality rates) for individuals aged 0-4 years, 5-14 years, and 15-24 years. The databases contain mortality rates from death registration systems, full birth and sibling histories from surveys, and reports on household deaths in censuses. We modelled the sex ratio of age-specific mortality as a function of the mortality in both sexes using Bayesian hierarchical time-series models. We report the levels and trends of sex ratios and estimate the expected female mortality and excess female mortality rates (the difference between the estimated female mortality and the expected female mortality) to identify countries with outlying sex ratios. Globally, the mortality sex ratio was 1·13 (ie, boys were more likely to die than girls of the same age) for ages 0-4 years (90% uncertainty interval 1·11 to 1·15) in 2021. This ratio increased with age to 1·16 (1·12 to 1·20) for 5-14 years, reaching 1·65 for 15-24 years (1·52 to 1·75). In all age groups, the global sex ratio of mortality increased between 1990 and 2021, driven by faster declines in female mortality. In 2021, the probability of a newborn male reaching age 25 years was 94·1% (93·7 to 94·4), compared with 95·1% for a newborn female (94·7 to 95·3). We found a disadvantage of females versus males (compared with countries with similar total mortality) in 2021 in five countries for ages 0-4 years (Algeria, Bangladesh, Egypt, India, and Iran), one country (Suriname) for ages 5-14 years, and 13 countries for ages 15-24 years (including Bangladesh and India). We found the reverse pattern (disadvantage of males vs females compared with countries of similar total mortality) in one country in ages 0-4 years (Vietnam) and eight countries in ages 15-24 years (including Brazil and Mexico). Globally, the number of excess female deaths from birth to age 24 years was 86 563 (-6059 to 164 000) in 2021, down from 544 636 (453 982 to 633 265) in 1990. The global sex ratio of mortality for all age groups in the first 25 years of life increased between 1990 and 2021. Targeted interventions should focus on countries with outlying sex ratios of mortality to reduce disparities due to discrimination in health care, nutrition, and violence. The Bill & Melinda Gates Foundation, US Agency for International Development, and King Abdullah University of Science and Technology.

Immune persistence of an inactivated poliovirus vaccine derived from the Sabin strain: a 10-year follow-up of a phase 3 study

In a previous phase 3 clinical trial, we showed that an inactivated poliovirus vaccine derived from the Sabin strain (sIPV) can induce neutralising antibodies against currently circulating and reference wild poliovirus strains. However, the immune persistence of sIPV remains to be evaluated. In this study, 400 participants who were eligible for an early phase 3 clinical trial (Jan 1, 2012-Aug 31, 2014) in Pingle County, GuanXi Province, China, were initially involved in one site. Of the participants in the previous phase 3 clinical trial, sera of 287, 262, 237, and 207 participants were sampled at the ages of 4, 6, 8, and 10 years, respectively, after the prime-boost regimen. Neutralising antibodies against attenuated Sabin strains were detected using these serum samples to determine immune persistence. The serum neutralising antibodies titre of 1:8 against poliovirus types 1, 2, and 3 is considered to be a seroprotection level for polio. The trial is registered at ClinicalTrials.gov, NCT01510366. The protective rates against poliovirus types 1, 2, and 3 in the sIPV group were all 100% at 10 years after the booster immunisation, compared with 98.1%, 100%, and 97.1%, respectively, in the wIPV control group after 10 years. After the booster at 18 months, the geometric mean titres (GMTs) of neutralising antibodies against poliovirus types 1, 2, and 3 in the sIPV group were 13,265.6, 7856.7, and 6432.2, respectively, and the GMTs in the control group (inoculated with inactivated poliovirus vaccine derived from wild strain (wIPV)) were 3915.6, 2842.6, and 4982.7, respectively. With increasing time after booster immunisation, the GMTs of neutralising antibodies against poliovirus types 1, 2, and 3 gradually decreased in both the sIPV and wIPV groups. At the age of ten years, the GMTs of neutralising antibodies against poliovirus types 1, 2, and 3 in the sIPV group were 452.3, 392.8, and 347.5, respectively, and the GMTs in the wIPV group 108.5, 154.8, and 229.3, respectively, which were still at a higher-than-protective level (1:8). Both sIPV and wIPV maintained sufficiently high immune persistence against poliovirus types 1, 2, and 3 for at least 10 years after booster immunisation. Yunnan Provincial Science and Technology Department, the Bill and Melinda Gates Foundation, the National High-tech Research and Development Program, the National International Science and Technology Cooperation Project, the Yunnan Application Basic Research Project, the Innovation Team Project of Xie He, the Yunnan International Scientific and Technological Cooperation Project, and the Medical and Technology Innovation Project of Xie He.

Bacillus Calmette-Guérin vaccination for protection against recurrent herpes labialis: a nested randomised controlled trial

Recurrences of herpes simplex virus (HSV) in the orofacial region (herpes labialis or cold sores) impact quality-of-life. We aimed to study whether the bacille Calmette-Guérin (BCG) vaccine can attenuate cold sore recurrences through off-target immunomodulatory effects. In this nested randomised controlled trial within the multicentre, phase 3 BRACE trial, 6828 healthcare workers were randomised in 36 sites in Australia, the Netherlands, Spain, the United Kingdom and Brazil, to receive BCG-Denmark or no BCG (1:1 ratio using a web-based procedure) and followed for 12 months with 3-monthly questionnaires. Exclusion criteria included contraindication to BCG vaccine or previous vaccination with BCG within the past year, any other live-attenuated vaccine within the last month, or any COVID-specific vaccine. The intervention group received one intradermal dose of 0.1mL of BCG-Denmark corresponding to 2-8 x 105 colony forming units of Mycobacterium bovis, Danish strain 1331. The primary outcome was the difference in restricted mean survival time (i.e., time to first cold-sore recurrence), in participants with frequent recurrent herpes labialis (≥4 recurrences/year), analysed by intention-to-treat. Secondary outcomes addressed additional questions, including analyses in other sub-populations. Adverse events were monitored closely during the first 3 months and were reported in all participants who received one dose of study drug according to intervention received. The BRACE trial is registered with ClinicalTrials.gov, NCT04327206. Between March 30, 2020 and February 18, 2021, 84 individuals with frequent recurrent cold sores were randomly assigned to BCG (n=38) or control (n=46). The average time to first cold-sore recurrence was 1.55 months longer in the BCG group (95% CI 0.27-2.82, p=0.02) than the control group (hazard ratio 0.54, 95% CI 0.32-0.91; intention-to-treat). The beneficial effect of BCG was greater in the as-treated population (difference 1.91 months, 95% CI 0.69-3.12, p=0.003; hazard ratio 0.45, 95% CI 0.26-0.76). In prespecified subgroup analyses, only sex modified the treatment effect (interaction p=0.007), with benefit restricted to males. Over 12 months, a greater proportion of participants in the BCG group compared with the control group reported a decrease in duration (61% vs 21%), severity (74% vs 21%), frequency (55% vs 21%), and impact on quality of life (42% vs 15%) of cold sore recurrences. In participants who had ever had a cold sore, there was also a decrease in self-reported burden of recurrences in the BCG group. In participants who had never had a cold sore, there was an increased risk of a first episode in the BCG group (risk difference 1.4%; 95% CI 0.3-2.6%, p=0.02). There were no safety concerns. BCG-Denmark vaccination had a beneficial effect on herpes labialis, particularly in males with frequent recurrences, but may increase the risk of a first cold sore. Bill & Melinda Gates Foundation, the Minderoo Foundation, Sarah and Lachlan Murdoch, the Royal Children's Hospital Foundation, Health Services Union NSW, the Peter Sowerby Foundation, SA Health, the Insurance Advisernet Foundation, the NAB Foundation, the Calvert-Jones Foundation, the Modara Pines Charitable Foundation, the UHG Foundation Pty Ltd, Epworth Healthcare, and individual donors.

Global, regional, and national incidence of six major immune-mediated inflammatory diseases: findings from the global burden of disease study 2019

The causes for immune-mediated inflammatory diseases (IMIDs) are diverse and the incidence trends of IMIDs from specific causes are rarely studied. The study aims to investigate the pattern and trend of IMIDs from 1990 to2019. We collected detailed information on six major causes of IMIDs, including asthma, inflammatory bowel disease, multiple sclerosis, rheumatoid arthritis, psoriasis, and atopic dermatitis, between 1990 and 2019, derived from the Global Burden of Disease study in 2019. The average annual percent change (AAPC) in number of incidents and age standardized incidence rate (ASR) on IMIDs, by sex, age, region, and causes, were calculated to quantify the temporal trends. In 2019, rheumatoid arthritis, atopic dermatitis, asthma, multiple sclerosis, psoriasis, inflammatory bowel disease accounted 1.59%, 36.17%, 54.71%, 0.09%, 6.84%, 0.60% of overall new IMIDs cases, respectively. The ASR of IMIDs showed substantial regional and global variation with the highest in High SDI region, High-income North America, and United States of America. Throughout human lifespan, the age distribution of incident cases from six IMIDs was quite different. Globally, incident cases of IMIDs increased with an AAPC of 0.68 and the ASR decreased with an AAPC of-0.34 from 1990 to 2019. The incident cases increased across six IMIDs, the ASR of rheumatoid arthritis increased (0.21, 95% CI 0.18, 0.25), while the ASR of asthma (AAPC=-0.41), inflammatory bowel disease (AAPC=-0.72), multiple sclerosis (AAPC=-0.26), psoriasis (AAPC=-0.77), and atopic dermatitis (AAPC=-0.15) decreased. The ASR of overall and six individual IMID increased with SDI at regional and global level. Countries with higher ASR in 1990 experienced a more rapid decrease in ASR. The incidence patterns of IMIDs varied considerably across the world. Innovative prevention and integrative management strategy are urgently needed to mitigate the increasing ASR of rheumatoid arthritis and upsurging new cases of other five IMIDs, respectively. The Global Burden of Disease Study is funded by the Bill and Melinda Gates Foundation. The project funded by Scientific Research Fund of Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital (2022QN38).