METHODS: Oxy-PICU was a pragmatic, multicentre, open-label, randomised controlled trial in 15 UK paediatric intensive care units (PICUs). Children admitted as an emergency, who were older than 38 weeks corrected gestational age and younger than 16 years receiving invasive ventilation and supplemental oxygen were randomly allocated in a 1:1 ratio via a concealed, central, web-based randomisation system to conservative peripheral oxygen saturations ([SpO2] 88-92%) or liberal (SpO2 >94%) targets. The primary outcome was the duration of organ support at 30 days following random allocation, a rank-based endpoint with death either on or before day 30 as the worst outcome (a score equating to 31 days of organ support), with survivors assigned a score between 1 and 30 depending on the number of calendar days of organ support received. The primary effect estimate was the probabilistic index, a value greater than 0·5 indicating more than 50% probability that conservative oxygenation is superior to liberal oxygenation for a randomly selected patient. All participants in whom consent was available were included in the intention-to-treat analysis. The completed study was registered with the ISRCTN registry (ISRCTN92103439).

FINDINGS: Between Sept 1, 2020, and May 15, 2022, 2040 children were randomly allocated to conservative or liberal oxygenation groups. Consent was available for 1872 (92%) of 2040 children. The conservative oxygenation group comprised 939 children (528 [57%] of 927 were female and 399 [43%] of 927 were male) and the liberal oxygenation group included 933 children (511 [56%] of 920 were female and 409 [45%] of 920 were male). Duration of organ support or death in the first 30 days was significantly lower in the conservative oxygenation group (probabilistic index 0·53, 95% CI 0·50-0·55; p=0·04 Wilcoxon rank-sum test, adjusted odds ratio 0·84 [95% CI 0·72-0·99]). Prespecified adverse events were reported in 24 (3%) of 939 patients in the conservative oxygenation group and 36 (4%) of 933 patients in the liberal oxygenation group.

INTERPRETATION: Among invasively ventilated children who were admitted as an emergency to a PICU receiving supplemental oxygen, a conservative oxygenation target resulted in a small, but significant, greater probability of a better outcome in terms of duration of organ support at 30 days or death when compared with a liberal oxygenation target. Widespread adoption of a conservative oxygenation saturation target (SpO2 88-92%) could help improve outcomes and reduce costs for the sickest children admitted to PICUs.

METHODS: Solidarity enrolled consenting adults (aged ≥18 years) recently hospitalised with, in the view of their doctor, definite COVID-19 and no contraindication to any of the study drugs, regardless of any other patient characteristics. Participants were randomly allocated, in equal proportions between the locally available options, to receive whichever of the four study drugs (lopinavir, hydroxychloroquine, IFN-β1a, or remdesivir) were locally available at that time or no study drug (controls). All patients also received the local standard of care. No placebos were given. The protocol-specified primary endpoint was in-hospital mortality, subdivided by disease severity. Secondary endpoints were progression to ventilation if not already ventilated, and time-to-discharge from hospital. Final log-rank and Kaplan-Meier analyses are presented for remdesivir, and are appended for all four study drugs. Meta-analyses give weighted averages of the mortality findings in this and all other randomised trials of these drugs among hospital inpatients. Solidarity is registered with ISRCTN, ISRCTN83971151, and ClinicalTrials.gov, NCT04315948.

FINDINGS: Between March 22, 2020, and Jan 29, 2021, 14 304 potentially eligible patients were recruited from 454 hospitals in 35 countries in all six WHO regions. After the exclusion of 83 (0·6%) patients with a refuted COVID-19 diagnosis or encrypted consent not entered into the database, Solidarity enrolled 14 221 patients, including 8275 randomly allocated (1:1) either to remdesivir (ten daily infusions, unless discharged earlier) or to its control (allocated no study drug although remdesivir was locally available). Compliance was high in both groups. Overall, 602 (14·5%) of 4146 patients assigned to remdesivir died versus 643 (15·6%) of 4129 assigned to control (mortality rate ratio [RR] 0·91 [95% CI 0·82-1·02], p=0·12). Of those already ventilated, 151 (42·1%) of 359 assigned to remdesivir died versus 134 (38·6%) of 347 assigned to control (RR 1·13 [0·89-1·42], p=0·32). Of those not ventilated but on oxygen, 14·6% assigned to remdesivir died versus 16·3% assigned to control (RR 0·87 [0·76-0·99], p=0·03). Of 1730 not on oxygen initially, 2·9% assigned to remdesivir died versus 3·8% assigned to control (RR 0·76 [0·46-1·28], p=0·30). Combining all those not ventilated initially, 11·9% assigned to remdesivir died versus 13·5% assigned to control (RR 0·86 [0·76-0·98], p=0·02) and 14·1% versus 15·7% progressed to ventilation (RR 0·88 [0·77-1·00], p=0·04). The non-prespecified composite outcome of death or progression to ventilation occurred in 19·6% assigned to remdesivir versus 22·5% assigned to control (RR 0·84 [0·75-0·93], p=0·001). Allocation to daily remdesivir infusions (vs open-label control) delayed discharge by about 1 day during the 10-day treatment period. A meta-analysis of mortality in all randomised trials of remdesivir versus no remdesivir yielded similar findings.

INTERPRETATION: Remdesivir has no significant effect on patients with COVID-19 who are already being ventilated. Among other hospitalised patients, it has a small effect against death or progression to ventilation (or both).

METHODS: The prevalence and attributable burden of each target indicator were estimated by age group, sex, and year in 204 countries and territories from 2012 to 2021 in the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021, the most comprehensive assessment of causes of death, disability, and risk factors to date. Country-specific relative performance to date was evaluated with a Bayesian meta-regression model that compares prevalence to expected values based on Socio-demographic Index (SDI), a composite indicator of societal development status. Target progress was forecasted from 2021 up to 2050 by modelling past trends with meta-regression using a combination of key quantities and then extrapolating future projections of those quantities.

FINDINGS: In 2021, a few countries had already met some of the GNTs: five for exclusive breastfeeding, four for stunting, 96 for child wasting, and three for child overweight, and none met the target for low birthweight or anaemia in females of reproductive age. Since 2012, the annualised rates of change (ARC) in the prevalence of child overweight increased in 201 countries and territories and ARC in the prevalence of anaemia in females of reproductive age decreased considerably in 26 countries. Between 2012 and 2021, SDI was strongly associated with indicator prevalence, apart from exclusive breastfeeding (|r-|=0·46-0·86). Many countries in sub-Saharan Africa had a decrease in the prevalence of multiple indicators that was more rapid than expected on the basis of SDI (the differences between observed and expected ARCs for child stunting and wasting were -0·5% and -1·3%, respectively). The ARC in the attributable burden of low birthweight, child stunting, and child wasting decreased faster than the ARC of the prevalence for each in most low-income and middle-income countries. In 2030, we project that 94 countries will meet one of the six targets, 21 countries will meet two targets, and 89 countries will not meet any targets. We project that seven countries will meet the target for exclusive breastfeeding, 28 for child stunting, and 101 for child wasting, and no countries will meet the targets for low birthweight, child overweight, and anaemia. In 2050, we project that seven additional countries will meet the target for exclusive breastfeeding, five for low birthweight, 96 for child stunting, nine for child wasting, and one for child overweight, and no countries are projected to meet the anaemia target.

INTERPRETATION: Based on current levels and past trends, few GNTs will be met by 2030. Major reductions in attributable burden for exclusive breastfeeding and anthropometric indicators should be recognised as huge scientific and policy successes, but the comparative lack of progress in reducing the prevalence of each, along with stagnant anaemia in women of reproductive age and widespread increases in child overweight, suggests a tenuous status quo. Continued investment in preventive and treatment efforts for acute childhood illness is crucial to prevent backsliding. Parallel development of effective treatments, along with commitment to multisectoral, long-term policies to address the determinants and causes of suboptimal nutrition, are sorely needed to gain ground.

METHODS: This multicentre, randomised, placebo-controlled, phase 2b trial was done at 60 hospitals and clinics in 20 countries. Eligible study participants were aged between 12 and 75 years with a documented history of GPP as per the European Rare and Severe Psoriasis Expert Network criteria, with a history of at least two past GPP flares, and a GPP Physician Global Assessment (GPPGA) score of 0 or 1 at screening and random assignment. Patients were randomly assigned (1:1:1:1) to receive subcutaneous placebo, subcutaneous low-dose spesolimab (300 mg loading dose followed by 150 mg every 12 weeks), subcutaneous medium-dose spesolimab (600 mg loading dose followed by 300 mg every 12 weeks), or subcutaneous high-dose spesolimab (600 mg loading dose followed by 300 mg every 4 weeks) over 48 weeks. The primary objective was to demonstrate a non-flat dose-response curve on the primary endpoint, time to first GPP flare.

FINDINGS: From June 8, 2020, to Nov 23, 2022, 157 patients were screened, of whom 123 were randomly assigned. 92 were assigned to receive spesolimab (30 high dose, 31 medium dose, and 31 low dose) and 31 to placebo. All patients were either Asian (79 [64%] of 123) or White (44 [36%]). Patient groups were similar in sex distribution (76 [62%] female and 47 [38%] male), age (mean 40·4 years, SD 15·8), and GPP Physician Global Assessment score. A non-flat dose-response relationship was established on the primary endpoint. By week 48, 35 patients had GPP flares; seven (23%) of 31 patients in the low-dose spesolimab group, nine (29%) of 31 patients in the medium-dose spesolimab group, three (10%) of 30 patients in the high-dose spesolimab group, and 16 (52%) of 31 patients in the placebo group. High-dose spesolimab was significantly superior versus placebo on the primary outcome of time to GPP flare (hazard ratio [HR]=0·16, 95% CI 0·05-0·54; p=0·0005) endpoint. HRs were 0·35 (95% CI 0·14-0·86, nominal p=0·0057) in the low-dose spesolimab group and 0·47 (0·21-1·06, p=0·027) in the medium-dose spesolimab group. We established a non-flat dose-response relationship for spesolimab compared with placebo, with statistically significant p values for each predefined model (linear p=0·0022, emax1 p=0·0024, emax2 p=0·0023, and exponential p=0·0034). Infection rates were similar across treatment arms; there were no deaths and no hypersensitivity reactions leading to discontinuation.

INTERPRETATION: High-dose spesolimab was superior to placebo in GPP flare prevention, significantly reducing the risk of a GPP flare and flare occurrence over 48 weeks. Given the chronic nature of GPP, a treatment for flare prevention is a significant shift in the clinical approach, and could ultimately lead to improvements in patient morbidity and quality of life.

METHODS: We estimated all-age and age-specific deaths and disability-adjusted life-years (DALYs) attributable to and associated with bacterial AMR for 22 pathogens, 84 pathogen-drug combinations, and 11 infectious syndromes in 204 countries and territories from 1990 to 2021. We collected and used multiple cause of death data, hospital discharge data, microbiology data, literature studies, single drug resistance profiles, pharmaceutical sales, antibiotic use surveys, mortality surveillance, linkage data, outpatient and inpatient insurance claims data, and previously published data, covering 520 million individual records or isolates and 19 513 study-location-years. We used statistical modelling to produce estimates of AMR burden for all locations, including those with no data. Our approach leverages the estimation of five broad component quantities: the number of deaths involving sepsis; the proportion of infectious deaths attributable to a given infectious syndrome; the proportion of infectious syndrome deaths attributable to a given pathogen; the percentage of a given pathogen resistant to an antibiotic of interest; and the excess risk of death or duration of an infection associated with this resistance. Using these components, we estimated disease burden attributable to and associated with AMR, which we define based on two counterfactuals; respectively, an alternative scenario in which all drug-resistant infections are replaced by drug-susceptible infections, and an alternative scenario in which all drug-resistant infections were replaced by no infection. Additionally, we produced global and regional forecasts of AMR burden until 2050 for three scenarios: a reference scenario that is a probabilistic forecast of the most likely future; a Gram-negative drug scenario that assumes future drug development that targets Gram-negative pathogens; and a better care scenario that assumes future improvements in health-care quality and access to appropriate antimicrobials. We present final estimates aggregated to the global, super-regional, and regional level.

FINDINGS: In 2021, we estimated 4·71 million (95% UI 4·23-5·19) deaths were associated with bacterial AMR, including 1·14 million (1·00-1·28) deaths attributable to bacterial AMR. Trends in AMR mortality over the past 31 years varied substantially by age and location. From 1990 to 2021, deaths from AMR decreased by more than 50% among children younger than 5 years yet increased by over 80% for adults 70 years and older. AMR mortality decreased for children younger than 5 years in all super-regions, whereas AMR mortality in people 5 years and older increased in all super-regions. For both deaths associated with and deaths attributable to AMR, meticillin-resistant Staphylococcus aureus increased the most globally (from 261 000 associated deaths [95% UI 150 000-372 000] and 57 200 attributable deaths [34 100-80 300] in 1990, to 550 000 associated deaths [500 000-600 000] and 130 000 attributable deaths [113 000-146 000] in 2021). Among Gram-negative bacteria, resistance to carbapenems increased more than any other antibiotic class, rising from 619 000 associated deaths (405 000-834 000) in 1990, to 1·03 million associated deaths (909 000-1·16 million) in 2021, and from 127 000 attributable deaths (82 100-171 000) in 1990, to 216 000 (168 000-264 000) attributable deaths in 2021. There was a notable decrease in non-COVID-related infectious disease in 2020 and 2021. Our forecasts show that an estimated 1·91 million (1·56-2·26) deaths attributable to AMR and 8·22 million (6·85-9·65) deaths associated with AMR could occur globally in 2050. Super-regions with the highest all-age AMR mortality rate in 2050 are forecasted to be south Asia and Latin America and the Caribbean. Increases in deaths attributable to AMR will be largest among those 70 years and older (65·9% [61·2-69·8] of all-age deaths attributable to AMR in 2050). In stark contrast to the strong increase in number of deaths due to AMR of 69·6% (51·5-89·2) from 2022 to 2050, the number of DALYs showed a much smaller increase of 9·4% (-6·9 to 29·0) to 46·5 million (37·7 to 57·3) in 2050. Under the better care scenario, across all age groups, 92·0 million deaths (82·8-102·0) could be cumulatively averted between 2025 and 2050, through better care of severe infections and improved access to antibiotics, and under the Gram-negative drug scenario, 11·1 million AMR deaths (9·08-13·2) could be averted through the development of a Gram-negative drug pipeline to prevent AMR deaths.

INTERPRETATION: This study presents the first comprehensive assessment of the global burden of AMR from 1990 to 2021, with results forecasted until 2050. Evaluating changing trends in AMR mortality across time and location is necessary to understand how this important global health threat is developing and prepares us to make informed decisions regarding interventions. Our findings show the importance of infection prevention, as shown by the reduction of AMR deaths in those younger than 5 years. Simultaneously, our results underscore the concerning trend of AMR burden among those older than 70 years, alongside a rapidly ageing global community. The opposing trends in the burden of AMR deaths between younger and older individuals explains the moderate future increase in global number of DALYs versus number of deaths. Given the high variability of AMR burden by location and age, it is important that interventions combine infection prevention, vaccination, minimisation of inappropriate antibiotic use in farming and humans, and research into new antibiotics to mitigate the number of AMR deaths that are forecasted for 2050.

METHODS: We estimated deaths associated with 33 bacterial genera or species across 11 infectious syndromes in 2019 using methods from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019, in addition to a subset of the input data described in the Global Burden of Antimicrobial Resistance 2019 study. This study included 343 million individual records or isolates covering 11 361 study-location-years. We used three modelling steps to estimate the number of deaths associated with each pathogen: deaths in which infection had a role, the fraction of deaths due to infection that are attributable to a given infectious syndrome, and the fraction of deaths due to an infectious syndrome that are attributable to a given pathogen. Estimates were produced for all ages and for males and females across 204 countries and territories in 2019. 95% uncertainty intervals (UIs) were calculated for final estimates of deaths and infections associated with the 33 bacterial pathogens following standard GBD methods by taking the 2·5th and 97·5th percentiles across 1000 posterior draws for each quantity of interest.

FINDINGS: From an estimated 13·7 million (95% UI 10·9-17·1) infection-related deaths in 2019, there were 7·7 million deaths (5·7-10·2) associated with the 33 bacterial pathogens (both resistant and susceptible to antimicrobials) across the 11 infectious syndromes estimated in this study. We estimated deaths associated with the 33 bacterial pathogens to comprise 13·6% (10·2-18·1) of all global deaths and 56·2% (52·1-60·1) of all sepsis-related deaths in 2019. Five leading pathogens-Staphylococcus aureus, Escherichia coli, Streptococcus pneumoniae, Klebsiella pneumoniae, and Pseudomonas aeruginosa-were responsible for 54·9% (52·9-56·9) of deaths among the investigated bacteria. The deadliest infectious syndromes and pathogens varied by location and age. The age-standardised mortality rate associated with these bacterial pathogens was highest in the sub-Saharan Africa super-region, with 230 deaths (185-285) per 100 000 population, and lowest in the high-income super-region, with 52·2 deaths (37·4-71·5) per 100 000 population. S aureus was the leading bacterial cause of death in 135 countries and was also associated with the most deaths in individuals older than 15 years, globally. Among children younger than 5 years, S pneumoniae was the pathogen associated with the most deaths. In 2019, more than 6 million deaths occurred as a result of three bacterial infectious syndromes, with lower respiratory infections and bloodstream infections each causing more than 2 million deaths and peritoneal and intra-abdominal infections causing more than 1 million deaths.

INTERPRETATION: The 33 bacterial pathogens that we investigated in this study are a substantial source of health loss globally, with considerable variation in their distribution across infectious syndromes and locations. Compared with GBD Level 3 underlying causes of death, deaths associated with these bacteria would rank as the second leading cause of death globally in 2019; hence, they should be considered an urgent priority for intervention within the global health community. Strategies to address the burden of bacterial infections include infection prevention, optimised use of antibiotics, improved capacity for microbiological analysis, vaccine development, and improved and more pervasive use of available vaccines. These estimates can be used to help set priorities for vaccine need, demand, and development.

METHODS: In this pragmatic, multicentre, parallel-group, unmasked, randomised, non-inferiority trial, children aged 5-16 years with suspected non-perforated appendicitis (based on clinical diagnosis with or without radiological diagnosis) were recruited from 11 children's hospitals in Canada, the USA, Finland, Sweden, and Singapore. Patients were randomly assigned (1:1) to the antibiotic or the appendicectomy group with an online stratified randomisation tool, with stratification by sex, institution, and duration of symptoms (≥48 h vs <48 h). The primary outcome was treatment failure within 1 year of random assignment. In the antibiotic group, failure was defined as removal of the appendix, and in the appendicectomy group, failure was defined as a normal appendix based on pathology. In both groups, failure was also defined as additional procedures related to appendicitis requiring general anaesthesia. Interim analysis was done to determine whether inferiority was to be declared at the halfway point. We used a non-inferiority design with a margin of 20%. All outcomes were assessed in participants with 12-month follow-up data. The trial was registered at ClinicalTrials.gov (NCT02687464).

FINDINGS: Between Jan 20, 2016, and Dec 3, 2021, 936 patients were enrolled and randomly assigned to appendicectomy (n=459) or antibiotics (n=477). At 12-month follow-up, primary outcome data were available for 846 (90%) patients. Treatment failure occurred in 153 (34%) of 452 patients in the antibiotic group, compared with 28 (7%) of 394 in the appendicectomy group (difference 26·7%, 90% CI 22·4-30·9). All but one patient meeting the definition for treatment failure with appendicectomy were those with negative appendicectomies. Of those who underwent appendicectomy in the antibiotic group, 13 (8%) had normal pathology. There were no deaths or serious adverse events in either group. The relative risk of having a mild-to-moderate adverse event in the antibiotic group compared with the appendicectomy group was 4·3 (95% CI 2·1-8·7; p<0·0001).

INTERPRETATION: Based on cumulative failure rates and a 20% non-inferiority margin, antibiotic management of non-perforated appendicitis was inferior to appendicectomy.

METHODS: We used data from 1108 population-representative studies with 141 million participants aged 18 years and older with measurements of fasting glucose and glycated haemoglobin (HbA1c), and information on diabetes treatment. We defined diabetes as having a fasting plasma glucose (FPG) of 7·0 mmol/L or higher, having an HbA1c of 6·5% or higher, or taking medication for diabetes. We defined diabetes treatment as the proportion of people with diabetes who were taking medication for diabetes. We analysed the data in a Bayesian hierarchical meta-regression model to estimate diabetes prevalence and treatment.

FINDINGS: In 2022, an estimated 828 million (95% credible interval [CrI] 757-908) adults (those aged 18 years and older) had diabetes, an increase of 630 million (554-713) from 1990. From 1990 to 2022, the age-standardised prevalence of diabetes increased in 131 countries for women and in 155 countries for men with a posterior probability of more than 0·80. The largest increases were in low-income and middle-income countries in southeast Asia (eg, Malaysia), south Asia (eg, Pakistan), the Middle East and north Africa (eg, Egypt), and Latin America and the Caribbean (eg, Jamaica, Trinidad and Tobago, and Costa Rica). Age-standardised prevalence neither increased nor decreased with a posterior probability of more than 0·80 in some countries in western and central Europe, sub-Saharan Africa, east Asia and the Pacific, Canada, and some Pacific island nations where prevalence was already high in 1990; it decreased with a posterior probability of more than 0·80 in women in Japan, Spain, and France, and in men in Nauru. The lowest prevalence in the world in 2022 was in western Europe and east Africa for both sexes, and in Japan and Canada for women, and the highest prevalence in the world in 2022 was in countries in Polynesia and Micronesia, some countries in the Caribbean and the Middle East and north Africa, as well as Pakistan and Malaysia. In 2022, 445 million (95% CrI 401-496) adults aged 30 years or older with diabetes did not receive treatment (59% of adults aged 30 years or older with diabetes), 3·5 times the number in 1990. From 1990 to 2022, diabetes treatment coverage increased in 118 countries for women and 98 countries for men with a posterior probability of more than 0·80. The largest improvement in treatment coverage was in some countries from central and western Europe and Latin America (Mexico, Colombia, Chile, and Costa Rica), Canada, South Korea, Russia, Seychelles, and Jordan. There was no increase in treatment coverage in most countries in sub-Saharan Africa; the Caribbean; Pacific island nations; and south, southeast, and central Asia. In 2022, age-standardised treatment coverage was lowest in countries in sub-Saharan Africa and south Asia, and treatment coverage was less than 10% in some African countries. Treatment coverage was 55% or higher in South Korea, many high-income western countries, and some countries in central and eastern Europe (eg, Poland, Czechia, and Russia), Latin America (eg, Costa Rica, Chile, and Mexico), and the Middle East and north Africa (eg, Jordan, Qatar, and Kuwait).

INTERPRETATION: In most countries, especially in low-income and middle-income countries, diabetes treatment has not increased at all or has not increased sufficiently in comparison with the rise in prevalence. The burden of diabetes and untreated diabetes is increasingly borne by low-income and middle-income countries. The expansion of health insurance and primary health care should be accompanied with diabetes programmes that realign and resource health services to enhance the early detection and effective treatment of diabetes.

THE IMPACTS OF CLIMATE CHANGE ON HUMAN HEALTH: The world has observed a 1°C temperature rise above pre-industrial levels, with feedback cycles and polar amplification resulting in a rise as high as 3°C in north western Canada., Eight of the ten hottest years on record have occurred in the past decade. Such rapid change is primarily driven by the combustion of fossil fuels, consumed at a rate of 171 000 kg of coal, 116 000 000 L of gas, and 186 000 L of oil per s.– Progress in mitigating this threat is intermittent at best, with carbon dioxide emissions continuing to rise in 2018. Importantly, many of the indicators contained in this report suggest the world is following this “business as usual” pathway. The carbon intensity of the energy system has remained unchanged since 1990 (indicator 3.1.1), and from 2016 to 2018, total primary energy supply from coal increased by 1·7%, reversing a previously recorded downward trend (indicator 3.1.2). Correspondingly, the health-care sector is responsible for about 4·6% of global emissions, a value which is steadily rising across most major economies (indicator 3.6). Global fossil fuel consumption subsidies increased by 50% over the past 3 years, reaching a peak of almost US$430 billion in 2018 (indicator 4.4.1). A child born today will experience a world that is more than four degrees warmer than the pre-industrial average, with climate change impacting human health from infancy and adolescence to adulthood and old age. Across the world, children are among the worst affected by climate change. Downward trends in global yield potential for all major crops tracked since 1960 threaten food production and food security, with infants often the worst affected by the potentially permanent effects of undernutrition (indicator 1.5.1). Children are among the most susceptible to diarrhoeal disease and experience the most severe effects of dengue fever. Trends in climate suitability for disease transmission are particularly concerning, with nine of the ten most suitable years for the transmission of dengue fever on record occurring since 2000 (indicator 1.4.1). Similarly, since an early 1980s baseline, the number of days suitable for Vibrio (a pathogen responsible for part of the burden of diarrhoeal disease) has doubled, and global suitability for coastal Vibrio cholerae has increased by 9·9% indicator 1.4.1). Through adolescence and beyond, air pollution—principally driven by fossil fuels, and exacerbated by climate change—damages the heart, lungs, and every other vital organ. These effects accumulate over time, and into adulthood, with global deaths attributable to ambient fine particulate matter (PM2·5) remaining at 2·9 million in 2016 (indicator 3.3.2) and total global air pollution deaths reaching 7 million. Later in life, families and livelihoods are put at risk from increases in the frequency and severity of extreme weather conditions, with women among the most vulnerable across a range of social and cultural contexts. Globally, 77% of countries experienced an increase in daily population exposure to wildfires from 2001–14 to 2015–18 (indicator 1.2.1). India and China sustained the largest increases, with an increase of over 21 million exposures in India and 17 million exposures in China over this time period. In low-income countries, almost all economic losses from extreme weather events are uninsured, placing a particularly high burden on individuals and households (indicator 4.1). Temperature rise and heatwaves are increasingly limiting the labour capacity of various populations. In 2018, 133·6 billion potential work hours were lost globally, 45 billion more than the 2000 baseline, and southern areas of the USA lost 15–20% of potential daylight work hours during the hottest month of 2018 (indicator 1.1.4). Populations aged 65 years and older are particularly vulnerable to the health effects of climate change, and especially to extremes of heat. From 1990 to 2018, populations in every region have become more vulnerable to heat and heatwaves, with Europe and the Eastern Mediterranean remaining the most vulnerable (indicator 1.1.1). In 2018, these vulnerable populations experienced 220 million heatwave exposures globally, breaking the previous record of 209 million set in 2015 (indicator 1.1.3). Already faced with the challenge of an ageing population, Japan had 32 million heatwave exposures affecting people aged 65 years and older in 2018, the equivalent of almost every person in this age group experiencing a heatwave. Finally, although difficult to quantify, the downstream risks of climate change, such as migration, poverty exacerbation, violent conflict, and mental illness, affect people of all ages and all nationalities. A business as usual trajectory will result in a fundamentally altered world, with the indicators described providing a glimpse of the implications of this pathway. The life of every child born today will be profoundly affected by climate change. Without accelerated intervention, this new era will come to define the health of people at every stage of their lives.

METHODS: In this pooled analysis, we studied 133,118 individuals (63,559 with hypertension and 69,559 without hypertension), median age of 55 years (IQR 45-63), from 49 countries in four large prospective studies and estimated 24-h urinary sodium excretion (as group-level measure of intake). We related this to the composite outcome of death and major cardiovascular disease events over a median of 4.2 years (IQR 3.0-5.0) and blood pressure.

FINDINGS: Increased sodium intake was associated with greater increases in systolic blood pressure in individuals with hypertension (2.08 mm Hg change per g sodium increase) compared with individuals without hypertension (1.22 mm Hg change per g; pinteraction<0.0001). In those individuals with hypertension (6835 events), sodium excretion of 7 g/day or more (7060 [11%] of population with hypertension: hazard ratio [HR] 1.23 [95% CI 1.11-1.37]; p<0.0001) and less than 3 g/day (7006 [11%] of population with hypertension: 1.34 [1.23-1.47]; p<0.0001) were both associated with increased risk compared with sodium excretion of 4-5 g/day (reference 25% of the population with hypertension). In those individuals without hypertension (3021 events), compared with 4-5 g/day (18,508 [27%] of the population without hypertension), higher sodium excretion was not associated with risk of the primary composite outcome (≥ 7 g/day in 6271 [9%] of the population without hypertension; HR 0.90 [95% CI 0.76-1.08]; p=0.2547), whereas an excretion of less than 3 g/day was associated with a significantly increased risk (7547 [11%] of the population without hypertension; HR 1.26 [95% CI 1.10-1.45]; p=0.0009).

INTERPRETATION: Compared with moderate sodium intake, high sodium intake is associated with an increased risk of cardiovascular events and death in hypertensive populations (no association in normotensive population), while the association of low sodium intake with increased risk of cardiovascular events and death is observed in those with or without hypertension. These data suggest that lowering sodium intake is best targeted at populations with hypertension who consume high sodium diets.

THE RECORD-BREAKING HUMAN COSTS OF CLIMATE CHANGE: Data in this year’s report show that people all around the world are facing record-breaking threats to their wellbeing, health, and survival from the rapidly changing climate. Of the 15 indicators monitoring climate change-related health hazards, exposures, and impacts, ten reached concerning new records in their most recent year of data. Heat-related mortality of people older than 65 years increased by a record-breaking 167%, compared with the 1990s, 102 percentage points higher than the 65% that would have been expected without temperature rise (indicator 1.1.5). Heat exposure is also increasingly affecting physical activity and sleep quality, in turn affecting physical and mental health. In 2023, heat exposure put people engaging in outdoor physical activity at risk of heat stress (moderate or higher) for a record high of 27·7% more hours than on average in the 1990s (indicator 1.1.2) and led to a record 6% more hours of sleep lost in 2023 than the average during 1986–2005 (indicator 1.1.4). People worldwide are also increasingly at risk from life-threatening extreme weather events. Between 1961–90 and 2014–23, 61% of the global land area saw an increase in the number of days of extreme precipitation (indicator 1.2.3), which in turn increases the risk of flooding, infectious disease spread, and water contamination. In parallel, 48% of the global land area was affected by at least 1 month of extreme drought in 2023, the second largest affected area since 1951 (indicator 1.2.2). The increase in drought and heatwave events since 1981–2010 was, in turn, associated with 151 million more people experiencing moderate or severe food insecurity across 124 countries assessed in 2022, the highest recorded value (indicator 1.4.2). The hotter and drier weather conditions are increasingly favouring the occurrence of sand and dust storms. This weather-environmental phenomenon contributed to a 31% increase in the number of people exposed to dangerously high particulate matter concentrations between 2003–07 and 2018–22 (indicator 1.2.4). Meanwhile, changing precipitation patterns and rising temperatures are favouring the transmission of deadly infectious diseases such as dengue, malaria, West Nile virus-related illness, and vibriosis, putting people at risk of transmission in previously unaffected locations (indicators 1.3.1–1.3.4). Compounding these impacts, climate change is affecting the social and economic conditions on which health and wellbeing depend. The average annual economic losses from weather-related extreme events increased by 23% from 2010–14 to 2019–23, to US$227 billion (a value exceeding the gross domestic product [GDP] of about 60% of the world’s economies; indicator 4.1.1). Although 60·5% of losses in very high Human Development Index (HDI) countries were covered by insurance, the vast majority of those in countries with lower HDI levels were uninsured, with local communities bearing the brunt of the physical and economic losses (indicator 4.1.1). Extreme weather and climate change-related health impacts are also affecting labour productivity, with heat exposure leading to a record high loss of 512 billion potential labour hours in 2023, worth $835 billion in potential income losses (indicators 1.1.3 and 4.1.3). Low and medium HDI countries were most affected by these losses, which amounted to 7·6% and 4·4% of their GDP, respectively (indicator 4.1.3). With the most underserved communities most affected, these economic impacts further reduce their capacity to cope with and recover from the growing impacts of climate change, thereby amplifying global inequities. Concerningly, multiple hazards revealed by individual indicators are likely to have simultaneous compounding and cascading impacts on the complex and inter-connected human systems that sustain good health, disproportionately threatening people’s health and survival with every fraction of a degree of increase in global mean temperature. Despite years of monitoring exposing the imminent health threats of climate inaction, the health risks people face have been exacerbated by years of delays in adaptation, which have left people ill-protected from the growing threats of climate change. Only 68% of countries reported high-to-very-high implementation of legally mandated health emergency management capacities in 2023, of which just 11% were low HDI countries (indicator 2.2.5). Moreover, only 35% of countries reported having health early warning systems for heat-related illness, whereas 10% did so for mental and psychosocial conditions (indicator 2.2.1). Scarcity of financial resources was identified as a key barrier to adaptation, including by 50% of the cities that reported they were not planning to undertake climate change and health risk assessments (indicator 2.1.3). Indeed, adaptation projects with potential health benefits represented just 27% of all the Green Climate Fund’s adaptation funding in 2023, despite a 137% increase since 2021 (indicator 2.2.4). With universal health coverage still unattained in most countries, financial support is needed to strengthen health systems and ensure that they can protect people from growing climate change-related health hazards. The unequal distribution of financial resources and technical capacity is leaving the most vulnerable populations further unprotected from the growing health risks.

FUELLING THE FIRE: As well as exposing the inadequacy of adaptation efforts to date, this year’s report reveals a world veering away from the goal of limiting temperature rise to 1·5°C, with concerning new records broken across indicators monitoring greenhouse gas emissions and the conditions that enable them. Far from declining, global energy-related CO2 emissions reached an all-time high in 2023 (indicator 3.1.1). Oil and gas companies are reinforcing the global dependence on fossil fuels and—partly fuelled by the high energy prices and windfall profits of the global energy crisis—most are further expanding their fossil fuel production plans. As of March, 2024, the 114 largest oil and gas companies were on track to exceed emissions consistent with 1·5°C of heating by 189% in 2040, up from 173% 1 year before (indicator 4.2.2). As a result, their strategies are pushing the world further off track from meeting the goals of the Paris Agreement, further threatening people’s health and survival. Although renewable energy could provide power to remote locations, its adoption is lagging, particularly in the most vulnerable countries. The consequences of this delay reflect the human impacts of an unjust transition. Globally, 745 million people still lack access to electricity and are facing the harms of energy poverty on health and wellbeing. The burning of polluting biomass (eg, wood or dung) still accounts for 92% of the energy used in the home by people in low HDI countries (indicator 3.1.2), and only 2·3% of electricity in these countries comes from clean renewables, compared with 11·6% in very high HDI countries (indicators 3.1.1). This persistent burning of fossil fuel and biomass led to at least 3·33 million deaths from outdoor fine particulate matter (PM2·5) air pollution globally in 2021 alone (indicator 3.2.1), and the domestic use of dirty solid fuels caused 2·3 million deaths from indoor air pollution in 2020 across 65 countries analysed (indicator 3.2.2). Compounding the growth in energy-related greenhouse gas emissions, almost 182 million hectares of forests were lost between 2016 and 2022 (indicator 3.4), reducing the world’s natural capacity to capture atmospheric CO2. In parallel, the consumption of red meat and dairy products, which contributed to 11·2 million deaths attributable to unhealthy diets in 2021 (indicator 3.3.2), has led to a 2·9% increase in agricultural greenhouse gas emissions since 2016 (indicator 3.3.1). Health systems themselves, although essential to protect people’s health, are also increasingly contributing to the problem. Greenhouse gas emissions from health care have increased by 36% since 2016, making health systems increasingly unprepared to operate in a net zero emissions future and pushing health care further from its guiding principle of doing no harm (indicator 3.5). The growing accumulation of greenhouse gases in the atmosphere is pushing the world to a future of increasingly dangerous health hazards and reducing the chances of survival of vulnerable people all around the globe.

HEALTH-THREATENING FINANCIAL FLOWS: With the availability of financial resources a key barrier to tackling climate change, a rapid growth in predictable and equitable investment is urgently needed to avoid the most dangerous impacts of climate change. A growing body of literature shows that the economic benefits of a transition to net zero greenhouse gas emissions will far exceed the costs of inaction. Healthier, more resilient populations will further support more prosperous and sustainable economies (indicators 4.1.2–4.1.4). However, although funding to enable potentially life-saving climate change adaptation and mitigation activities remains scarce, substantial financial resources are being allocated to activities that harm health and perpetuate a fossil fuel-based economy. The resulting reliance on fossil fuel energy has meant many countries faced sharp increases in energy prices following Russia’s invasion of Ukraine and the resulting disruption of fossil fuel supplies. To keep energy affordable to local populations, many governments resorted to increasing their explicit fossil fuel subsidies. Consequently, 84% of countries studied still operated net negative carbon prices (explicit net fossil fuel subsidies) in 2022, for a record high net total of $1·4 trillion (indicator 4.3.3), with the sums involved often comparable to countries’ total health budgets. In addition, although clean energy investment grew by 10% globally in 2023—exceeding fossil fuel investment by 73%—considerable regional disparities exist. Clean energy investment is 38% lower than fossil fuel spending in emerging market and developing economies outside China. Clean energy spending in these countries only accounted for 17·4% of the global total. Moreover, investment in energy efficiency and end use, essential for a just transition, decreased by 1·3% in 2023 (indicator 4.3.1). The resulting expansion of fossil fuel assets is increasingly jeopardising the economies on which people’s livelihoods depend. On the current trajectory, the world already faces potential global income losses ranging from 11% to 29% by 2050. The number of fossil fuel industry employees reached 11·8 million in 2022, increasing the size of a workforce whose employment cannot be sustained in a world that avoids the most catastrophic human impacts of climate change (indicator 4.2.1). Meanwhile, ongoing investments in coal power have pushed the value of coal-fired power generation assets that risk becoming stranded within 10 years (between 2025 and 2034) in a 1·5°C trajectory to a cumulative total of $164·5 billion—a value that will increase if coal investments persist (indicator 4.2.3). The prioritisation of fossil fuel-based systems means most countries remain ill-prepared for the vital transition to zero greenhouse gas emission economies. As a result of an unjust transition, the risk is unequally distributed: preparedness scores for the transition to a net zero greenhouse gas economy were below the global average in all countries with a low HDI, 96% of those with a medium HDI, and 84% of those with a high HDI, compared with just 7% of very high HDI countries (indicator 4.2.4).

DEFINING THE HEALTH PROFILE OF PEOPLE WORLDWIDE: Following decades of delays in climate change action, avoiding the most severe health impacts of climate change now requires aligned, structural, and sustained changes across most human systems, including energy, transportation, agriculture, food, and health care. Importantly, a global transformation of financial systems is required, shifting resources away from the fossil fuel-based economy towards a zero emissions future. Putting people’s health at the centre of climate change policy making is key to ensuring this transition protects wellbeing, reduces health inequities, and maximises health gains. Some indicators reveal incipient progress and important opportunities for delivering this health-centred transformation. As of December, 2023, 50 countries reported having formally assessed their health vulnerabilities and adaptation needs, up from 11 the previous year, and the number of countries that reported having a Health National Adaptation Plan increased from four in 2022 to 43 in 2023 (indicators 2.1.1 and 2.1.2). Additionally, 70% of 279 public health education institutions worldwide reported providing education in climate and health in 2023, essential to build capacities for health professionals to help shape this transition (indicator 2.2.6). Regarding the energy sector, the global share of electricity from clean modern renewables reached a record high of 10·5% in 2021 (indicator 3.1.1); clean energy investment exceeded fossil fuel investment by 73% in 2023 (indicator 4.3.1); and renewable energy-related employment has grown 35·6% since 2016, providing healthier and more sustainable employment opportunities than those in the fossil fuel industry (indicator 4.2.1). Importantly, mostly as a result of coal phase-down in high and very high HDI countries, deaths attributable to outdoor PM2·5 from fossil fuel combustion decreased by 6·9% between 2016 and 2021 (indicator 3.2.1), showing the life-saving potential of coal phase-out. Important progress was made within international negotiations, which opened new opportunities to protect health in the face of climate change. After years of leadership from WHO on climate change and health, its Fourteenth General Programme of Work, adopted in May, 2024, made responding to climate change its first strategic priority. Within climate negotiations themselves, the 28th Conference of the Parties (COP28) of the United Nations Framework Convention on Climate Change (UNFCCC) featured the first health thematic day in 2023: 151 countries endorsed the COP28 United Arab Emirates Declaration on Climate and Health, and the Global Goal on Adaptation set a specific health target. The outcome of the first Global Stocktake of the Paris Agreement also recognised the right to health and a healthy environment, urging parties to take further health adaptation efforts, and opened a new opportunity for human survival, health, and wellbeing to be prioritised in the updated Nationally Determined Contributions (NDCs) due in 2025. The pending decision of how the Loss and Damage fund will be governed and the definition of the New Collective Quantified Goal on Climate Finance during COP29 provide further opportunities to secure the financial support crucial for a healthy net zero transition. Although still insufficient to protect people’s health from climate change, these emerging signs of progress help open new opportunities to deliver a healthy, prosperous future. However, much remains to be done.