OBJECTIVE: To characterize tumors associated with BC susceptibility genes in large-scale population- or hospital-based studies.

DESIGN, SETTING, AND PARTICIPANTS: The multicenter, international case-control analysis of the BRIDGES study included 42 680 patients and 46 387 control participants, comprising women aged 18 to 79 years who were sampled independently of family history from 38 studies. Studies were conducted between 1991 and 2016. Sequencing and analysis took place between 2016 and 2021.

EXPOSURES: Protein-truncating variants and likely pathogenic missense variants in ATM, BARD1, BRCA1, BRCA2, CHEK2, PALB2, RAD51C, RAD51D, and TP53.

MAIN OUTCOMES AND MEASURES: The intrinsic-like BC subtypes as defined by estrogen receptor, progesterone receptor, and ERBB2 (formerly known as HER2) status, and tumor grade; morphology; size; stage; lymph node involvement; subtype-specific odds ratios (ORs) for carrying protein-truncating variants and pathogenic missense variants in the 9 BC susceptibility genes.

RESULTS: The mean (SD) ages at interview (control participants) and diagnosis (cases) were 55.1 (11.9) and 55.8 (10.6) years, respectively; all participants were of European or East Asian ethnicity. There was substantial heterogeneity in the distribution of intrinsic subtypes by gene. RAD51C, RAD51D, and BARD1 variants were associated mainly with triple-negative disease (OR, 6.19 [95% CI, 3.17-12.12]; OR, 6.19 [95% CI, 2.99-12.79]; and OR, 10.05 [95% CI, 5.27-19.19], respectively). CHEK2 variants were associated with all subtypes (with ORs ranging from 2.21-3.17) except for triple-negative disease. For ATM variants, the association was strongest for the hormone receptor (HR)+ERBB2- high-grade subtype (OR, 4.99; 95% CI, 3.68-6.76). BRCA1 was associated with increased risk of all subtypes, but the ORs varied widely, being highest for triple-negative disease (OR, 55.32; 95% CI, 40.51-75.55). BRCA2 and PALB2 variants were also associated with triple-negative disease. TP53 variants were most strongly associated with HR+ERBB2+ and HR-ERBB2+ subtypes. Tumors occurring in pathogenic variant carriers were of higher grade. For most genes and subtypes, a decline in ORs was observed with increasing age. Together, the 9 genes were associated with 27.3% of all triple-negative tumors in women 40 years or younger.

METHODS: We used data from 3,184 BRCA1 and 2,157 BRCA2 families in the Consortium of Investigators of Modifiers of BRCA1/2 to estimate age-specific relative (RR) and absolute risks for 22 first primary cancer types adjusting for family ascertainment.

RESULTS: BRCA1 PVs were associated with risks of male breast (RR = 4.30; 95% CI, 1.09 to 16.96), pancreatic (RR = 2.36; 95% CI, 1.51 to 3.68), and stomach (RR = 2.17; 95% CI, 1.25 to 3.77) cancers. Associations with colorectal and gallbladder cancers were also suggested. BRCA2 PVs were associated with risks of male breast (RR = 44.0; 95% CI, 21.3 to 90.9), stomach (RR = 3.69; 95% CI, 2.40 to 5.67), pancreatic (RR = 3.34; 95% CI, 2.21 to 5.06), and prostate (RR = 2.22; 95% CI, 1.63 to 3.03) cancers. The stomach cancer RR was higher for females than males (6.89 v 2.76; P = .04). The absolute risks to age 80 years ranged from 0.4% for male breast cancer to approximately 2.5% for pancreatic cancer for BRCA1 carriers and from approximately 2.5% for pancreatic cancer to 27% for prostate cancer for BRCA2 carriers.

METHODS: The GA2 LEN ADCARE network and partners as well as all stakeholders, abbreviated as the AD-ICPs working group, were involved in the discussion and preparation of the AD ICPs during a series of subgroup workshops and meetings in years 2020 and 2021, after which the document was circulated within all GAL2 EN ADCARE centres.

RESULTS: The AD-ICPs outline the diagnostic procedures, possible co-morbidities, different available treatment options including differential approaches for the pediatric population, and the role of the pharmacists and other stakeholders, as well as remaining unmet needs in the management of AD.

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.

OBJECTIVE: The objectives are to (1) establish an international cohort of affected and unaffected individuals with PD-linked variants; (2) provide harmonized and quality-controlled clinical characterization data for each included individual; and (3) further promote collaboration of researchers in the field of monogenic PD.

METHODS: We conducted a worldwide, systematic online survey to collect individual-level data on individuals with PD-linked variants in SNCA, LRRK2, VPS35, PRKN, PINK1, DJ-1, as well as selected pathogenic and risk variants in GBA and corresponding demographic, clinical, and genetic data. All registered cases underwent thorough quality checks, and pathogenicity scoring of the variants and genotype-phenotype relationships were analyzed.

RESULTS: We collected 3888 variant carriers for our analyses, reported by 92 centers (42 countries) worldwide. Of the included individuals, 3185 had a diagnosis of PD (ie, 1306 LRRK2, 115 SNCA, 23 VPS35, 429 PRKN, 75 PINK1, 13 DJ-1, and 1224 GBA) and 703 were unaffected (ie, 328 LRRK2, 32 SNCA, 3 VPS35, 1 PRKN, 1 PINK1, and 338 GBA). In total, we identified 269 different pathogenic variants; 1322 individuals in our cohort (34%) were indicated as not previously published.

METHODS: We identified suicide data from official public-sector sources for countries/areas-within-countries, searching websites and academic literature and contacting data custodians and authors as necessary. We sent our first data request on 22nd June 2021 and stopped collecting data on 31st October 2021. We used interrupted time series (ITS) analyses to model the association between the pandemic's emergence and total suicides and suicides by sex-, age- and sex-by-age in each country/area-within-country. We compared the observed and expected numbers of suicides in the pandemic's first nine and first 10-15 months and used meta-regression to explore sources of variation.

FINDINGS: We sourced data from 33 countries (24 high-income, six upper-middle-income, three lower-middle-income; 25 with whole-country data, 12 with data for area(s)-within-the-country, four with both). There was no evidence of greater-than-expected numbers of suicides in the majority of countries/areas-within-countries in any analysis; more commonly, there was evidence of lower-than-expected numbers. Certain sex, age and sex-by-age groups stood out as potentially concerning, but these were not consistent across countries/areas-within-countries. In the meta-regression, different patterns were not explained by countries' COVID-19 mortality rate, stringency of public health response, economic support level, or presence of a national suicide prevention strategy. Nor were they explained by countries' income level, although the meta-regression only included data from high-income and upper-middle-income countries, and there were suggestions from the ITS analyses that lower-middle-income countries fared less well.

INTERPRETATION: Although there are some countries/areas-within-countries where overall suicide numbers and numbers for certain sex- and age-based groups are greater-than-expected, these countries/areas-within-countries are in the minority. Any upward movement in suicide numbers in any place or group is concerning, and we need to remain alert to and respond to changes as the pandemic and its mental health and economic consequences continue.

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.