METHODS: We conducted a large agnostic pathway-based meta-analysis of GWAS data using the summary-based adaptive rank truncated product method to identify gene sets and pathways associated with pancreatic ductal adenocarcinoma (PDAC) in 9040 cases and 12 496 controls. We performed expression quantitative trait loci (eQTL) analysis and functional annotation of the top SNPs in genes contributing to the top associated pathways and gene sets. All statistical tests were two-sided.

RESULTS: We identified 14 pathways and gene sets associated with PDAC at a false discovery rate of less than 0.05. After Bonferroni correction (P ≤ 1.3 × 10-5), the strongest associations were detected in five pathways and gene sets, including maturity-onset diabetes of the young, regulation of beta-cell development, role of epidermal growth factor (EGF) receptor transactivation by G protein-coupled receptors in cardiac hypertrophy pathways, and the Nikolsky breast cancer chr17q11-q21 amplicon and Pujana ATM Pearson correlation coefficient (PCC) network gene sets. We identified and validated rs876493 and three correlating SNPs (PGAP3) and rs3124737 (CASP7) from the Pujana ATM PCC gene set as eQTLs in two normal derived pancreas tissue datasets.

OBJECTIVE: To report the first year's screening results for all men at enrollment in the study.

DESIGN, SETTING AND PARTICIPANTS: We recruited men aged 40-69 yr with germline BRCA1/2 mutations and a control group of men who have tested negative for a pathogenic BRCA1 or BRCA2 mutation known to be present in their families. All men underwent prostate-specific antigen (PSA) testing at enrollment, and those men with PSA >3 ng/ml were offered prostate biopsy.

OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: PSA levels, PCa incidence, and tumour characteristics were evaluated. The Fisher exact test was used to compare the number of PCa cases among groups and the differences among disease types.

RESULTS AND LIMITATIONS: We recruited 2481 men (791 BRCA1 carriers, 531 BRCA1 controls; 731 BRCA2 carriers, 428 BRCA2 controls). A total of 199 men (8%) presented with PSA >3.0 ng/ml, 162 biopsies were performed, and 59 PCas were diagnosed (18 BRCA1 carriers, 10 BRCA1 controls; 24 BRCA2 carriers, 7 BRCA2 controls); 66% of the tumours were classified as intermediate- or high-risk disease. The positive predictive value (PPV) for biopsy using a PSA threshold of 3.0 ng/ml in BRCA2 mutation carriers was 48%-double the PPV reported in population screening studies. A significant difference in detecting intermediate- or high-risk disease was observed in BRCA2 carriers. Ninety-five percent of the men were white, thus the results cannot be generalised to all ethnic groups.

CONCLUSIONS: The IMPACT screening network will be useful for targeted PCa screening studies in men with germline genetic risk variants as they are discovered. These preliminary results support the use of targeted PSA screening based on BRCA genotype and show that this screening yields a high proportion of aggressive disease.

METHOD: The prognostic effect of PR status was based on the analysis of data from 45,088 European patients with breast cancer from 49 studies in the Breast Cancer Association Consortium. Cox proportional hazard models were used to estimate the hazard ratio for PR status. Data from a New Zealand study of 11,365 patients with early invasive breast cancer were used for external validation. Model calibration and discrimination were used to test the model performance.

RESULTS: Having a PR-positive tumour was associated with a 23% and 28% lower risk of dying from breast cancer for women with oestrogen receptor (ER)-negative and ER-positive breast cancer, respectively. The area under the ROC curve increased with the addition of PR status from 0.807 to 0.809 for patients with ER-negative tumours (p = 0.023) and from 0.898 to 0.902 for patients with ER-positive tumours (p = 2.3 × 10-6) in the New Zealand cohort. Model calibration was modest with 940 observed deaths compared to 1151 predicted.

MATERIALS AND METHODS: Clinicians managing male infertility were invited to complete an online survey on practices related to SDF diagnostic and treatment approaches. Their responses related to the technical aspects of SDF testing, current professional society guidelines, and the literature were used to generate expert recommendations via the Delphi method. Finally, challenges related to SDF that the clinicians encounter in their daily practice were captured.

RESULTS: The survey was completed by 436 reproductive clinicians. Overall, terminal deoxynucleotidyl transferase deoxyuridine triphosphate Nick-End Labeling (TUNEL) is the most commonly used assay chosen by 28.6%, followed by the sperm chromatin structure assay (24.1%), and the sperm chromatin dispersion (19.1%). The choice of the assay was largely influenced by availability (70% of respondents). A threshold of 30% was the most selected cut-off value for elevated SDF by 33.7% of clinicians. Of respondents, 53.6% recommend SDF testing after 3 to 5 days of abstinence. Although 75.3% believe SDF testing can provide an explanation for many unknown causes of infertility, the main limiting factors selected by respondents are a lack of professional society guideline recommendations (62.7%) and an absence of globally accepted references for SDF interpretation (50.3%).

METHODS: We analyzed data from 3004 individuals with biopsy-proven metabolic dysfunction-associated steatotic liver disease (MASLD) across 29 Chinese and 9 international cohorts to validate the acMASH index and develop the acFibroMASH index. Additionally, we utilized the independent external data from a multi-national cohort of 9034 patients with MASLD to examine associations between the acFibroMASH index and the risk of LREs.

RESULTS: In the pooled global cohort, the acMASH index identified MASH with an area under the receiver operating characteristic curve (AUROC) of 0.802 (95% confidence interval [CI], 0.786-0.818). The acFibroMASH index (including the acMASH index plus liver stiffness measurement) accurately identified fibrotic MASH with an AUROC of 0.808 in the derivation cohort and 0.800 in the validation cohort. Notably, the AUROC for the acFibroMASH index was 0.835 (95% CI, 0.786-0.882), superior to that of the FAST score at 0.750 (95% CI, 0.693-0.800; P < .01) in predicting the 5-year risk of LREs. Patients with acFibroMASH >0.39 had a higher risk of LREs than those with acFibroMASH <0.15 (adjusted hazard ratio, 11.23; 95% CI, 3.98-31.66).

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.

METHODS: We used a panel of 34 putative susceptibility genes to perform sequencing on samples from 60,466 women with breast cancer and 53,461 controls. In separate analyses for protein-truncating variants and rare missense variants in these genes, we estimated odds ratios for breast cancer overall and tumor subtypes. We evaluated missense-variant associations according to domain and classification of pathogenicity.

RESULTS: Protein-truncating variants in 5 genes (ATM, BRCA1, BRCA2, CHEK2, and PALB2) were associated with a risk of breast cancer overall with a P value of less than 0.0001. Protein-truncating variants in 4 other genes (BARD1, RAD51C, RAD51D, and TP53) were associated with a risk of breast cancer overall with a P value of less than 0.05 and a Bayesian false-discovery probability of less than 0.05. For protein-truncating variants in 19 of the remaining 25 genes, the upper limit of the 95% confidence interval of the odds ratio for breast cancer overall was less than 2.0. For protein-truncating variants in ATM and CHEK2, odds ratios were higher for estrogen receptor (ER)-positive disease than for ER-negative disease; for protein-truncating variants in BARD1, BRCA1, BRCA2, PALB2, RAD51C, and RAD51D, odds ratios were higher for ER-negative disease than for ER-positive disease. Rare missense variants (in aggregate) in ATM, CHEK2, and TP53 were associated with a risk of breast cancer overall with a P value of less than 0.001. For BRCA1, BRCA2, and TP53, missense variants (in aggregate) that would be classified as pathogenic according to standard criteria were associated with a risk of breast cancer overall, with the risk being similar to that of protein-truncating variants.