METHODS: To assess the effects of non-calcium-based phosphate binders on intermediate cardiovascular markers, we conducted a multicenter, double-blind trial, randomizing 278 participants with stage 3b or 4 CKD and serum phosphate >1.00 mmol/L (3.10 mg/dl) to 500 mg lanthanum carbonate or matched placebo thrice daily for 96 weeks. We analyzed the primary outcome, carotid-femoral pulse wave velocity, using a linear mixed effects model for repeated measures. Secondary outcomes included abdominal aortic calcification and serum and urine markers of mineral metabolism.

RESULTS: A total of 138 participants received lanthanum and 140 received placebo (mean age 63.1 years; 69% male, 64% White). Mean eGFR was 26.6 ml/min per 1.73 m2; 45% of participants had diabetes and 32% had cardiovascular disease. Mean serum phosphate was 1.25 mmol/L (3.87 mg/dl), mean pulse wave velocity was 10.8 m/s, and 81.3% had abdominal aortic calcification at baseline. At 96 weeks, pulse wave velocity did not differ significantly between groups, nor did abdominal aortic calcification, serum phosphate, parathyroid hormone, FGF23, and 24-hour urinary phosphate. Serious adverse events occurred in 63 (46%) participants prescribed lanthanum and 66 (47%) prescribed placebo. Although recruitment to target was not achieved, additional analysis suggested this was unlikely to have significantly affected the principle findings.

CONCLUSIONS: In patients with stage 3b/4 CKD, treatment with lanthanum over 96 weeks did not affect arterial stiffness or aortic calcification compared with placebo. These findings do not support the role of intestinal phosphate binders to reduce cardiovascular risk in patients with CKD who have normophosphatemia.

METHODS: We conducted an observational substudy of patients who had POAF, were at elevated cardiovascular risk, and were enrolled in the PeriOperative Ischemic Evaluation (POISE)-1, 2 and 3 trials between 2002 and 2021. POAF was defined as new, clinically important atrial fibrillation occurring within 30 days after surgery. We assessed the use of rhythm-control and anticoagulation treatment in response to POAF, at hospital discharge and at 30 days after surgery. We assessed for temporal trends using multivariable logistic regression.

RESULTS: Of the 27,896 patients included, 545 (1.9%) developed clinically important POAF. Patients received rhythm-control treatment in 48.6% of cases. The level of use of rhythm-control treatment increased over the course of the trials (POISE-1 vs POISE-2 vs POISE-3; 40.9% vs 49.5% vs 59.1%). A later randomization date was associated independently with use of rhythm-control treatment (odds ratio, 1.05 per year; 95% confidence interval, 1.01-1.09). Anticoagulation treatment was prescribed in 21% of POAF cases. The level of anticoagulation treatement use was higher in POISE-3, compared to that in the 2 previous trials (POISE-1 vs POISE-2 vs POISE-3-16.4% vs 16.5% vs 33.6%). A later randomization date was associated independently with use of anticoagulation treatment (odds ratio, 1.06 per year; 95% confidence interval, 1.02-1.11).

METHODS: The Strategic Timing of AntiRetroviral Treatment (START) trial, as previously reported, randomly assigned 4684 ART-naive HIV-positive adults with CD4+ counts .500 cells/mm3 to immediate treatment initiation after random assignment (n = 2325) or deferred treatment (n= 2359). In 2015, a 57% lower risk of the primary end point (AIDS, SNA, or death) for the immediate group was reported, and the deferred group was offered ART. This article reports the follow-up that continued to December 31, 2021. Cox proportional-hazards models were used to compare hazard ratios for the primary end point from randomization through December 31, 2015, versus January 1, 2016, through December 31, 2021.

RESULTS: Through December 31, 2015, approximately 7 months after the cutoff date from the previous report, the median CD4+ count was 648 and 460 cells/mm3 in the immediate and deferred groups, respectively, at treatment initiation. The percentage of follow-up time spent taking ART was 95% and 36% for the immediate and deferred groups, respectively, and the time-averaged CD4+ difference was 199 cells/mm3. After January 1, 2016, the percentage of follow-up time on treatment was 97.2% and 94.1% for the immediate and deferred groups, respectively, and the CD4+ count difference was 155 cells/mm3. After January 1, 2016, a total of 89 immediate and 113 deferred group participants experienced a primary end point (hazard ratio of 0.79 [95% confidence interval, 0.60 to 1.04] versus hazard ratio of 0.47 [95% confidence interval, 0.34 to 0.65; P<0.001]) before 2016 (P=0.02 for hazard ratio difference).

OBJECTIVE: We performed an analysis of genetic variants associated with leukocyte telomere length to assess the relationship between telomere length and RCC risk using Mendelian randomization, an approach unaffected by biases from temporal variability and reverse causation that might have affected earlier investigations.

DESIGN, SETTING, AND PARTICIPANTS: Genotypes from nine telomere length-associated variants for 10 784 cases and 20 406 cancer-free controls from six genome-wide association studies (GWAS) of RCC were aggregated into a weighted genetic risk score (GRS) predictive of leukocyte telomere length.

OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Odds ratios (ORs) relating the GRS and RCC risk were computed in individual GWAS datasets and combined by meta-analysis.

RESULTS AND LIMITATIONS: Longer genetically inferred telomere length was associated with an increased risk of RCC (OR=2.07 per predicted kilobase increase, 95% confidence interval [CI]:=1.70-2.53, p<0.0001). As a sensitivity analysis, we excluded two telomere length variants in linkage disequilibrium (R2>0.5) with GWAS-identified RCC risk variants (rs10936599 and rs9420907) from the telomere length GRS; despite this exclusion, a statistically significant association between the GRS and RCC risk persisted (OR=1.73, 95% CI=1.36-2.21, p<0.0001). Exploratory analyses for individual histologic subtypes suggested comparable associations with the telomere length GRS for clear cell (N=5573, OR=1.93, 95% CI=1.50-2.49, p<0.0001), papillary (N=573, OR=1.96, 95% CI=1.01-3.81, p=0.046), and chromophobe RCC (N=203, OR=2.37, 95% CI=0.78-7.17, p=0.13).

CONCLUSIONS: Our investigation adds to the growing body of evidence indicating some aspect of longer telomere length is important for RCC risk.

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.

OBJECTIVE: To determine levels and trends in the fatal and nonfatal burden of diseases and injuries among younger children (aged <5 years), older children (aged 5-9 years), and adolescents (aged 10-19 years) between 1990 and 2013 in 188 countries from the Global Burden of Disease (GBD) 2013 study.

EVIDENCE REVIEW: Data from vital registration, verbal autopsy studies, maternal and child death surveillance, and other sources covering 14,244 site-years (ie, years of cause of death data by geography) from 1980 through 2013 were used to estimate cause-specific mortality. Data from 35,620 epidemiological sources were used to estimate the prevalence of the diseases and sequelae in the GBD 2013 study. Cause-specific mortality for most causes was estimated using the Cause of Death Ensemble Model strategy. For some infectious diseases (eg, HIV infection/AIDS, measles, hepatitis B) where the disease process is complex or the cause of death data were insufficient or unavailable, we used natural history models. For most nonfatal health outcomes, DisMod-MR 2.0, a Bayesian metaregression tool, was used to meta-analyze the epidemiological data to generate prevalence estimates.

FINDINGS: Of the 7.7 (95% uncertainty interval [UI], 7.4-8.1) million deaths among children and adolescents globally in 2013, 6.28 million occurred among younger children, 0.48 million among older children, and 0.97 million among adolescents. In 2013, the leading causes of death were lower respiratory tract infections among younger children (905.059 deaths; 95% UI, 810,304-998,125), diarrheal diseases among older children (38,325 deaths; 95% UI, 30,365-47,678), and road injuries among adolescents (115,186 deaths; 95% UI, 105,185-124,870). Iron deficiency anemia was the leading cause of years lived with disability among children and adolescents, affecting 619 (95% UI, 618-621) million in 2013. Large between-country variations exist in mortality from leading causes among children and adolescents. Countries with rapid declines in all-cause mortality between 1990 and 2013 also experienced large declines in most leading causes of death, whereas countries with the slowest declines had stagnant or increasing trends in the leading causes of death. In 2013, Nigeria had a 12% global share of deaths from lower respiratory tract infections and a 38% global share of deaths from malaria. India had 33% of the world's deaths from neonatal encephalopathy. Half of the world's diarrheal deaths among children and adolescents occurred in just 5 countries: India, Democratic Republic of the Congo, Pakistan, Nigeria, and Ethiopia.

METHODS: Using LDScore regression, we explored the genetic correlation between endometrial cancer and ovarian cancer. To identify loci associated with the risk of both cancers, we implemented a pipeline of statistical genetic analyses (i.e., inverse-variance meta-analysis, colocalization, and M-values) and performed analyses stratified by subtype. Candidate target genes were then prioritized using functional genomic data.

RESULTS: Genetic correlation analysis revealed significant genetic correlation between the two cancers (rG = 0.43, P = 2.66 × 10-5). We found seven loci associated with risk for both cancers (P Bonferroni < 2.4 × 10-9). In addition, four novel subgenome-wide regions at 7p22.2, 7q22.1, 9p12, and 11q13.3 were identified (P < 5 × 10-7). Promoter-associated HiChIP chromatin loops from immortalized endometrium and ovarian cell lines and expression quantitative trait loci data highlighted candidate target genes for further investigation.

CONCLUSIONS: Using cross-cancer GWAS meta-analysis, we have identified several joint endometrial and ovarian cancer risk loci and candidate target genes for future functional analysis.

METHODS: We generated updated estimates of child mortality in early neonatal (age 0-6 days), late neonatal (7-28 days), postneonatal (29-364 days), childhood (1-4 years), and under-5 (0-4 years) age groups for 188 countries from 1970 to 2013, with more than 29,000 survey, census, vital registration, and sample registration datapoints. We used Gaussian process regression with adjustments for bias and non-sampling error to synthesise the data for under-5 mortality for each country, and a separate model to estimate mortality for more detailed age groups. We used explanatory mixed effects regression models to assess the association between under-5 mortality and income per person, maternal education, HIV child death rates, secular shifts, and other factors. To quantify the contribution of these different factors and birth numbers to the change in numbers of deaths in under-5 age groups from 1990 to 2013, we used Shapley decomposition. We used estimated rates of change between 2000 and 2013 to construct under-5 mortality rate scenarios out to 2030.

FINDINGS: We estimated that 6·3 million (95% UI 6·0-6·6) children under-5 died in 2013, a 64% reduction from 17·6 million (17·1-18·1) in 1970. In 2013, child mortality rates ranged from 152·5 per 1000 livebirths (130·6-177·4) in Guinea-Bissau to 2·3 (1·8-2·9) per 1000 in Singapore. The annualised rates of change from 1990 to 2013 ranged from -6·8% to 0·1%. 99 of 188 countries, including 43 of 48 countries in sub-Saharan Africa, had faster decreases in child mortality during 2000-13 than during 1990-2000. In 2013, neonatal deaths accounted for 41·6% of under-5 deaths compared with 37·4% in 1990. Compared with 1990, in 2013, rising numbers of births, especially in sub-Saharan Africa, led to 1·4 million more child deaths, and rising income per person and maternal education led to 0·9 million and 2·2 million fewer deaths, respectively. Changes in secular trends led to 4·2 million fewer deaths. Unexplained factors accounted for only -1% of the change in child deaths. In 30 developing countries, decreases since 2000 have been faster than predicted attributable to income, education, and secular shift alone.

INTERPRETATION: Only 27 developing countries are expected to achieve MDG 4. Decreases since 2000 in under-5 mortality rates are accelerating in many developing countries, especially in sub-Saharan Africa. The Millennium Declaration and increased development assistance for health might have been a factor in faster decreases in some developing countries. Without further accelerated progress, many countries in west and central Africa will still have high levels of under-5 mortality in 2030.