Non-optimal temperature-attributable mortality and morbidity burden by cause, age and sex under climate and population change scenarios: a nationwide modelling study in Japan.

Background: Future temperature effects on mortality and morbidity may differ. However, studies comparing projected future temperature-attributable mortality and morbidity in the same setting are limited. Moreover, these studies did not consider future population change, human adaptation, and the variations in subpopulation susceptibility. Thus, we simultaneously projected the temperature-related mortality and morbidity by cause, age, and sex under population change, and human adaptation scenarios in Japan, a super-ageing society. Methods: We used daily mean temperatures, mortality, and emergency ambulance dispatch (a sensitive indicator for morbidity) in 47 prefectures of Japan from 2015 to 2019 as the reference for future projections. Future mortality and morbidity were generated at prefecture level using four shared socioeconomic pathway (SSP) scenarios considering population changes. We calculated future temperature-related mortality and morbidity by combining baseline values with future temperatures and existing temperature risk functions by cause (all-cause, circulatory, respiratory), age (<65 years, ≥65 years), and sex under various climate change and SSP scenarios (SSP1-2.6, SSP2-4.5, SSP3-7.0, and SSP5-8.5). Full human adaptation was simulated based on empirical evidence using a fixed percentile of minimum mortality or morbidity temperature (MMT), while no adaptation was simulated with a fixed absolute MMT. Findings: A future temporal decline in mortality burden attributable to non-optimal temperatures was observed, driven by greater cold-related deaths than heat-related deaths. In contrast, temperature-related morbidity increased over time, which was primarily driven by heat. In the 2050s and 2090s, under a moderate scenario, there are 83.69 (95% empirical confidence interval [eCI] 38.32-124.97) and 77.31 (95% eCI 36.84-114.47) all-cause deaths per 100,000 population, while there are 345.07 (95% eCI 258.31-438.66) and 379.62 (95% eCI 271.45-509.05) all-cause morbidity associated with non-optimal temperatures. These trends were largely consistent across causes, age, and sex groups. Future heat-attributable health burden is projected to increase substantially, with spatiotemporal variations and is particularly pronounced among individuals ≥65 y and males. Full human adaptation could yield a decreasing temperature-attributable mortality and morbidity in line with a decreasing population. Interpretation: Our findings could support the development of targeted mitigation and adaptation strategies to address future heat-related impacts effectively. This includes improved healthcare allocations for ambulance dispatch and hospital preventive measures during heat periods, particularly custom-tailored to address specific health outcomes and vulnerable subpopulations. Funding: Japan Science and Technology Agency and Environmental Restoration and Conservation Agency and Ministry of the Environment of Japan.

Integrating observational and modelled data to advance the understanding of heat stress effects on pregnant subsistence farmers in the gambia.

Studies on the effect of heat stress on pregnant women are scarce, particularly in highly vulnerable populations. To support the risk assessment of pregnant subsistence farmers in the West Kiang district, The Gambia we conducted a study on the pathophysiological effects of extreme heat stress and assessed the applicability of heat stress indices. From ERA5 climate reanalysis we added location-specific modelled solar radiation to datasets of a previous observational cohort study involving on-site measurements of 92 women working in the heat. Associations between physiological and environmental variables were assessed through Pearson correlation coefficient analysis, mixed effect linear models with random intercepts per participant and confirmatory composite analysis. We found Pearson correlations between r-values of 0 and 0.54, as well as independent effects of environmental variables on skin- and tympanic temperature, but not on heart rate, within a confidence interval of 98%. Pregnant women experienced stronger pathophysiological effects from heat stress in their third rather than in their second trimester. Environmental heat stress significantly altered maternal heat strain, particularly under humid conditions above a 50% relative humidity threshold, demonstrating interactive effects. Based on our results, we recommend including heat stress indices (e.g. UTCI or WBGT) in local heat-health warning systems.

A test method for assessing chronic oral toxicity of a pesticide to solitary nesting orchard bees, Osmia spp. (Hymenoptera: Megachilidae).

Orchard bees of the genus Osmia Panzer are important pollinators of fruit trees in various regions of the world, with some species commercially available in the United States and Europe. In addition to their pollination services, Osmia lignaria, Osmia cornifrons, Osmia bicornis, and Osmia cornuta have been identified as potential model species for solitary bees in pesticide risk assessment and have been used for the development of new methods to test acute lethal effects via contact and oral routes of exposure. Our goal was to expand the available methodology to characterize the toxicity of pesticides for these solitary bees through a chronic oral test for adult bees. Chronic oral toxicity of pesticides to orchard bees has been reported, but methods differ among research groups. In our study, O. lignaria, O. cornifrons, O. bicornis, and O. cornuta female bees had access to sucrose solution ad libitum in separate, species-specific 10-day tests. Mean body mass, mean daily consumption, and survival differed among the studied bee species. The dose-response test design was validated with dimethoate, a reference toxic compound, and chronic toxicity endpoints were estimated for the 4 Osmia species. The median lethal daily doses normalized by weight for O. lignaria, O. bicornis, O. cornuta, and O. cornifrons were within the same order of magnitude at 0.23, 0.26, 0.49, and 0.61 µg dimethoate/g bee/day, respectively. The methodology described here was aligned as much as possible with the available honey bee and bumble bee standard methods to facilitate the comparison of chronic toxicity profiles among bee species.

Transcriptional Analysis of Cancer Cachexia: Conserved and Unique Features Across Pre-Clinical Models and Biological Sex.

Studies suggest heterogeneity in cancer cachexia (CC) among models and biological sexes, yet examinations comparing models and sexes are scarce. We compared the transcriptional landscape of skeletal muscle across murine CC models and biological sexes during early and late CC. Global gene expression analyses were performed on gastrocnemius (LLC-Lewis Lung Carcinoma), quadriceps (KPC-pancreatic), and tibialis anterior (C26-colorectal and ApcMin/+) muscles across biological sexes. Differentially expressed genes (DEGs) were identified using an adj-p-value of <0.05, followed by pathway and computational cistrome analyses. Integrating all controls, early, and late-stage of all models and sexes revealed up to 68% of DEGs and pathways were enriched at early and late CC, indicating a conserved transcriptional profile during CC development. Comparing DEGs and pathways within sexes and across models, in early-CC, the transcriptional response was highly heterogeneous. At late-stage, 11.5% of upregulated and 10% of downregulated genes were shared between models in males, while 18.9% of upregulated and 7% of downregulated DEGs were shared in females. Shared DEGs were enriched in proteasome and mitophagy/autophagy pathways (upregulated), and downregulation of energy metabolism pathways in males only. Between sexes, though proportion of shared DEGs was low (<16%), similar pathway enrichment was observed, including proteasome and mitophagy at late-stage CC. In early-CC, Osmr upregulation was the only commonality across all models and sexes, while CLOCK and ARNTL/BMAL1 were predicted transcriptional factors associated with dysregulations in all three male models. This study highlights sex and model differences in CC progression and suggests conserved transcriptional changes as potential therapeutic targets.

Rainfall events and daily mortality across 645 global locations: two stage time series analysis.

OBJECTIVE: To examine the associations between characteristics of daily rainfall (intensity, duration, and frequency) and all cause, cardiovascular, and respiratory mortality. DESIGN: Two stage time series analysis. SETTING: 645 locations across 34 countries or regions. POPULATION: Daily mortality data, comprising a total of 109 954 744 all cause, 31 164 161 cardiovascular, and 11 817 278 respiratory deaths from 1980 to 2020. MAIN OUTCOME MEASURE: Association between daily mortality and rainfall events with return periods (the expected average time between occurrences of an extreme event of a certain magnitude) of one year, two years, and five years, with a 14 day lag period. A continuous relative intensity index was used to generate intensity-response curves to estimate mortality risks at a global scale. RESULTS: During the study period, a total of 50 913 rainfall events with a one year return period, 8362 events with a two year return period, and 3301 events with a five year return period were identified. A day of extreme rainfall with a five year return period was significantly associated with increased daily all cause, cardiovascular, and respiratory mortality, with cumulative relative risks across 0-14 lag days of 1.08 (95% confidence interval 1.05 to 1.11), 1.05 (1.02 to 1.08), and 1.29 (1.19 to 1.39), respectively. Rainfall events with a two year return period were associated with respiratory mortality only, whereas no significant associations were found for events with a one year return period. Non-linear analysis revealed protective effects (relative risk <1) with moderate-heavy rainfall events, shifting to adverse effects (relative risk >1) with extreme intensities. Additionally, mortality risks from extreme rainfall events appeared to be modified by climate type, baseline variability in rainfall, and vegetation coverage, whereas the moderating effects of population density and income level were not significant. Locations with lower variability of baseline rainfall or scarce vegetation coverage showed higher risks. CONCLUSION: Daily rainfall intensity is associated with varying health effects, with extreme events linked to an increasing relative risk for all cause, cardiovascular, and respiratory mortality. The observed associations varied with local climate and urban infrastructure.

Characterization of Laboratory-Confirmed Creutzfeldt-Jakob Disease From 3 Ontario Tertiary Care Centers Between 2012 and 2022: A Retrospective Cohort Study.

Background: Globally, Creutzfeldt-Jakob disease (CJD) affects one in one million people annually, but there is a paucity of recent Canadian data. This study summarizes epidemiology trends and diagnostic timelines of laboratory-confirmed CJD cases in three tertiary Ontario hospitals. Method: Using laboratory information systems, we identified 30 patients with a laboratory-confirmed CJD diagnosis between 2012 and 2022 at three major tertiary hospitals in Ontario. Retrospective chart reviews were then completed. Results: Patients had a mean of 2.2 hospital visits (SD, 1.2) prior to being admitted for testing. The most common symptom presentations included loss of coordination (63.3%), behavioral changes (60%), progressive mobility loss (53.4%), memory loss (50.0%), and involuntary movements (50.0%). Magnetic resonance imaging findings showed potential CJD in 76.7% of cases, and 56.7% exhibited periodic sharp wave complexes characteristic of CJD on electroencephalogram. The mean duration from symptom onset to microbiologic testing was 91 days (SD, 90.7). End-point quaking-induced conversion (EP-QuIC) testing of cerebrospinal fluid was positive in 90.0% of patients, while 83.3% tested positive for 14-3-3 on enzyme-linked immunosorbent assay. Elevated cerebrospinal fluid 14-3-3 levels significantly correlated with shorter duration from symptom onset to death (R 2 = 0.71, F = 19.55, P = .0022). Post-diagnosis, 46.7% of patients were discharged home, 16.6% were transferred to external palliative care or hospice facilities, and 36.7% died during admission. The mean time from symptom onset to death was 121 days (SD, 120.7), and from diagnosis to death 35 days (SD, 83.9). Conclusions: This study highlights the importance of early CJD consideration and laboratory testing when appropriate neurologic symptoms are present.

Effect of heat stress in the first 1000 days of life on fetal and infant growth: a secondary analysis of the ENID randomised controlled trial.

BACKGROUND: The intersecting crises of climate change, food insecurity, and undernutrition disproportionately affect children. Understanding the effect of heat on growth from conception to 2 years of age is important because of mortality and morbidity implications in the near term and over the life course. METHODS: In this secondary analysis, we used longitudinal pregnancy cohort data from the Early Nutrition and Immunity Development (ENID) randomised controlled trial in West Kiang, The Gambia, which occurred between Jan 20, 2010, and Feb 10, 2015. The ENID trial assessed micronutrient supplementation in the first 1000 days of life starting from 20 weeks' gestation, during which anthropometric measurements were collected prospectively. We used multivariable linear regression to assess the effect of heat stress (defined by Universal Thermal Climate Index [UTCI]) on intrauterine growth restriction based on length-for-gestational age Z score (LGAZ), weight-for-gestational age Z score (WGAZ), and head circumference-for-gestational age Z score (HCGAZ) at birth, and assessed for effect modification of supplement intervention on the relationship between heat stress and infant anthropometry. We used multivariable, multilevel linear regression to evaluate the effect of heat stress on infant growth postnatally based on weight-for-height Z score (WHZ), weight-for-age Z score (WAZ), and height-for-age Z score (HAZ) from 0 to 2 years of age. FINDINGS: Complete data were available for 668 livebirth outcomes (329 [49%] female infants and 339 [51%] male infants). With each 1°C increase in mean daily maximum UTCI exposure, in the first trimester, we observed a reduction in WGAZ (-0·04 [95% CI -0·09 to 0·00]), whereas in the third trimester, we observed an increase in HCGAZ (0·06 [95% CI 0·00 to 0·12]), although 95% CIs included 0. Maternal protein-energy supplementation in the third trimester was associated with reduced WGAZ (-0·16 [-0·30 to -0·02]) with each 1°C increase in mean daily maximum UTCI exposure, while no effect of heat stress on WGAZ was found with either standard care (iron and folate) or multiple micronutrient supplementation. For the postnatal analysis, complete anthropometric data at 2 years were available for 645 infants (316 [49%] female infants and 329 [51%] male infants). Postnatally, heat stress effect varied by infant age, with infants aged 6-18 months being the most affected. In infants aged 12 months exposed to a mean daily UTCI of 30°C (preceding 90-day period) versus 25°C UTCI, we observed reductions in mean WHZ (-0·43 [95% CI -0·57 to -0·29]) and mean WAZ (-0·35 [95% CI -0·45 to -0·26]). We observed a marginal increase in HAZ with increasing heat stress exposure at age 6 months, but no effect at older ages. INTERPRETATION: Our results suggest that heat stress impacts prenatal and postnatal growth up to 2 years of age but sensitivity might vary by age. In the context of a rapidly warming planet, these findings could have short-term and long-term health effects for the individual, and immediate and future implications for public child health. FUNDING: Wellcome Trust.

Impacts of land-use and land-cover changes on temperature-related mortality.

Background: Land-use and land-cover change (LULCC) can substantially affect climate through biogeochemical and biogeophysical effects. Here, we examine the future temperature-mortality impact for two contrasting LULCC scenarios in a background climate of low greenhouse gas concentrations. The first LULCC scenario implies a globally sustainable land use and socioeconomic development (sustainability). In the second LULCC scenario, sustainability is implemented only in the Organisation for Economic Cooperation and Development countries (inequality). Methods: Using the Multi-Country Multi-City (MCC) dataset on mortality from 823 locations in 52 countries and territories, we estimated the temperature-mortality exposure-response functions (ERFs). The LULCC and noLULCC scenarios were implemented in three fully coupled Earth system models (ESMs): Community Earth System Model, Max Planck Institute Earth System Model, and European Consortium Earth System Model. Next, using temperature from the ESMs' simulations and the estimated location-specific ERFs, we assessed the temperature-related impact on mortality for the LULCC and noLULCC scenarios around the mid and end century. Results: Under sustainability, the multimodel mean changes in excess mortality range from -1.1 to +0.6 percentage points by 2050-2059 across all locations and from -1.4 to +0.5 percentage points by 2090-2099. Under inequality, these vary from -0.7 to +0.9 percentage points by 2050-2059 and from -1.3 to +2 percentage points by 2090-2099. Conclusions: While an unequal socioeconomic development and unsustainable land use could increase the burden of heat-related mortality in most regions, globally sustainable land use has the potential to reduce it in some locations. However, the total (cold and heat) impact on mortality is very location specific and strongly depends on the underlying climate change scenario due to nonlinearity in the temperature-mortality relationship.

Mitochondrial antioxidant SkQ1 attenuates C26 cancer-induced muscle wasting in males and improves muscle contractility in female tumor-bearing mice.

Mitochondrial dysfunction is a hallmark of cancer cachexia (CC). Mitochondrial reactive oxygen species (ROS) are elevated in muscle shortly after tumor onset. Targeting mitochondrial ROS may be a viable option to prevent CC. The aim of this study was to evaluate the efficacy of a mitochondria-targeted antioxidant, SkQ1, to mitigate CC in both biological sexes. Male and female Balb/c mice were injected bilaterally with colon 26 adenocarcinoma (C26) cells (total 1 × 106 cells) or PBS (equal volume control). SkQ1 was dissolved in drinking water (∼250 nmol/kg body wt/day) and administered to mice beginning 7 days following tumor induction, whereas control groups consumed normal drinking water. In vivo muscle contractility of dorsiflexors, deuterium oxide-based protein synthesis, mitochondrial respiration and mRNA content of mitochondrial, protein turnover, and calcium channel-related markers were assessed at endpoint (25 days following tumor induction). Two-way ANOVAs, followed by Tukey's post hoc test when interactions were significant (P ≤ 0.05), were performed. SkQ1 attenuated cancer-induced atrophy, promoted protein synthesis, and abated Redd1 and Atrogin induction in gastrocnemius of C26 male mice. In female mice, SkQ1 decreased muscle mass and increased catabolic signaling in the plantaris of tumor-bearing mice, as well as reduced mitochondrial oxygen consumption, regardless of tumor. However, in females, SkQ1 enhanced muscle contractility of the dorsiflexors with concurrent induction of Ryr1, Serca1, and Serca2a in TA. In conclusion, the mitochondria-targeted antioxidant SkQ1 may attenuate CC-induced muscle loss in males, while improving muscle contractile function in tumor-bearing female mice, suggesting sexual dimorphism in the effects of this mitochondrial therapy in CC.NEW & NOTEWORTHY Herein, we assess the efficacy of the mitochondria-targeted antioxidant SkQ1 to mitigate cancer cachexia (CC) in both biological sexes. We demonstrate that SkQ1 administration attenuates muscle wasting induced by C26 tumors in male, but not female, mice. Conversely, we identify that in females, SkQ1 improves muscle contractility. These phenotypic adaptations to SkQ1 are aligned with respective responses in muscle protein synthesis, mitochondrial respiration, and mRNA content of protein turnover, as well as mitochondrial and calcium handling-related markers.

Structural Heterogeneity of the Rabies Virus Virion.

Rabies virus (RABV) is among the first recognized viruses of public health concern and has historically contributed to the development of viral vaccines. Despite these significances, the three-dimensional structure of the RABV virion remains unknown due to the challenges in isolating structurally homogenous virion samples in sufficient quantities needed for structural investigation. Here, by combining the capabilities of cryogenic electron tomography (cryoET) and microscopy (cryoEM), we determined the three-dimensional structure of the wild-type RABV virion. Tomograms of RABV virions reveal a high level of structural heterogeneity among the bullet-shaped virion particles encompassing the glycoprotein (G) trimer-decorated envelope and the nucleocapsid composed of RNA, nucleoprotein (N), and matrix protein (M). The structure of the trunk region of the virion was determined by cryoEM helical reconstruction, revealing a one-start N-RNA helix bound by a single layer of M proteins at an N:M ratio of 1. The N-M interaction differs from that in fellow rhabdovirus vesicular stomatitis virus (VSV), which features two layers of M stabilizing the N-RNA helix at an M:N ratio of 2. These differences in both M-N stoichiometry and binding allow RABV to flex its N-RNA helix more freely and point to different mechanisms of viral assembly between these two bullet-shaped rhabdoviruses.

The impact of climate variation on the spread of Shiga toxin-producing E. coli.

BACKGROUND: Shiga toxin-producing Escherichia coli (STEC) is influenced by seasonality, but there is limited understanding of how specific climatic variables contribute to disease spread. This information aids in understanding disease transmission dynamics and could potentially inform public health modeling. METHODS: This retrospective cohort study analyzed public health data from Ontario, Canada, between 2012 and 2021, along with historical climate data from Environment Canada. We employed Seasonal Autoregressive Integrated Moving Average (S-ARIMA) models to assess how temperature and precipitation impact the incidence of STEC infections, measured per 10,000,000 population. RESULTS: The study included 1658 confirmed STEC cases. A significant correlation was found between STEC incidence and climatic variables. Each degree Celsius increase in maximum temperature was associated with a rise of 3 STEC cases per 10,000,000 population (Centers for Disease Control and Prevention (2024)). Additionally, each millimeter of increased precipitation correlated with an increase of 1.1 cases per 10,000,000 population. CONCLUSIONS: The findings demonstrate a significant impact of temperature and precipitation on STEC transmission, highlighting the importance of integrating meteorological data into public health surveillance. This integration may help inform public health responses and support healthcare systems in planning for future outbreaks. Further studies are needed to refine predictive models and develop effective early warning systems for clinical settings.

Temporal variations in the short-term effects of ambient air pollution on cardiovascular and respiratory mortality: a pooled analysis of 380 urban areas over a 22-year period.

BACKGROUND: Ambient air pollution, including particulate matter (such as PM10 and PM2·5) and nitrogen dioxide (NO2), has been linked to increases in mortality. Whether populations' vulnerability to these pollutants has changed over time is unclear, and studies on this topic do not include multicountry analysis. We evaluated whether changes in exposure to air pollutants were associated with changes in mortality effect estimates over time. METHODS: We extracted cause-specific mortality and air pollution data collected between 1995 and 2016 from the Multi-Country Multi-City (MCC) Collaborative Research Network database. We applied a two-stage approach to analyse the short-term effects of NO2, PM10, and PM2·5 on cause-specific mortality using city-specific time series regression analyses and multilevel random-effects meta-analysis. We assessed changes over time using a longitudinal meta-regression with time as a linear fixed term and explored potential sources of heterogeneity and two-pollutant models. FINDINGS: Over 21·6 million cardiovascular and 7·7 million respiratory deaths in 380 cities across 24 countries over the study period were included in the analysis. All three air pollutants showed decreasing concentrations over time. The pooled results suggested no significant temporal change in the effect estimates per unit exposure of PM10, PM2·5, or NO2 and mortality. However, the risk of cardiovascular mortality increased from 0·37% (95% CI -0·05 to 0·80) in 1998 to 0·85% (0·55 to 1·16) in 2012 with a 10 µg/m3 increase in PM2·5. Two-pollutant models generally showed similar results to single-pollutant models for PM fractions and indicated temporal differences for NO2. INTERPRETATION: Although air pollution levels decreased during the study period, the effect sizes per unit increase in air pollution concentration have not changed. This observation might be due to the composition, toxicity, and sources of air pollution, as well as other factors, such as socioeconomic determinants or changes in population distribution and susceptibility. FUNDING: None.

The Multi-Country Multi-City Collaborative Research Network: An international research consortium investigating environment, climate, and health.

Research on the health risks of environmental factors and climate change requires epidemiological evidence on associated health risks at a global scale. Multi-center studies offer an excellent framework for this purpose, but they present various methodological and logistical problems. This contribution illustrates the experience of the Multi-Country Multi-City Collaborative Research Network, an international collaboration working on a global research program on the associations between environmental stressors, climate, and health in a multi-center setting. The article illustrates the collaborative scheme based on mutual contribution and data and method sharing, describes the collection of a huge multi-location database, summarizes published research findings and future plans, and discusses advantages and limitations. The Multi-Country Multi-City represents an example of a collaborative research framework that has greatly contributed to advance knowledge on the health impacts of climate change and other environmental factors and can be replicated to address other research questions across various research fields.

Temperature-mortality associations by age and cause: a multi-country multi-city study.

Background: Heterogeneity in temperature-mortality relationships across locations may partly result from differences in the demographic structure of populations and their cause-specific vulnerabilities. Here we conduct the largest epidemiological study to date on the association between ambient temperature and mortality by age and cause using data from 532 cities in 33 countries. Methods: We collected daily temperature and mortality data from each country. Mortality data was provided as daily death counts within age groups from all, cardiovascular, respiratory, or noncardiorespiratory causes. We first fit quasi-Poisson regression models to estimate location-specific associations for each age-by-cause group. For each cause, we then pooled location-specific results in a dose-response multivariate meta-regression model that enabled us to estimate overall temperature-mortality curves at any age. The age analysis was limited to adults. Results: We observed high temperature effects on mortality from both cardiovascular and respiratory causes compared to noncardiorespiratory causes, with the highest cold-related risks from cardiovascular causes and the highest heat-related risks from respiratory causes. Risks generally increased with age, a pattern most consistent for cold and for nonrespiratory causes. For every cause group, risks at both temperature extremes were strongest at the oldest age (age 85 years). Excess mortality fractions were highest for cold at the oldest ages. Conclusions: There is a differential pattern of risk associated with heat and cold by cause and age; cardiorespiratory causes show stronger effects than noncardiorespiratory causes, and older adults have higher risks than younger adults.

Geographical Patterns in Mortality Impacts Due To Heatwaves of Different Characteristics in Spanish Cities.

The impact of heatwaves (HWs) on human health is a topic of growing interest due to the global magnification of these phenomena and their substantial socio-economic impacts. As for other countries of Southern Europe, Spain is a region highly affected by heat and its increase under climate change. This is observed in the mean values and the increasing incidence of extreme weather events and associated mortality. Despite the vast knowledge on this topic, it remains unclear whether specific types and characteristics of HW are particularly harmful to the population and whether this shows a regional interdependency. The present study provides a comprehensive analysis of the relationship between HW characteristics and mortality in 12 Spanish cities. We used separated time series analysis in each city applying a quasi-Poisson regression model and distributed lag linear and non-linear models. Results show an increase in the mortality risk under HW conditions in the cities with a lower HW frequency. However, this increase exhibits remarkable differences across the cities under study not showing any general pattern in the HW characteristics-mortality association. This relationship is shown to be complex and strongly dependent on the local properties of each city pointing out the crucial need to examine and understand on a local scale the HW characteristics and the HW-mortality relationship for an efficient design and implementation of prevention measures.

Regional variation in the role of humidity on city-level heat-related mortality.

The rising humid heat is regarded as a severe threat to human survivability, but the proper integration of humid heat into heat-health alerts is still being explored. Using state-of-the-art epidemiological and climatological datasets, we examined the association between multiple heat stress indicators (HSIs) and daily human mortality in 739 cities worldwide. Notable differences were observed in the long-term trends and timing of heat events detected by HSIs. Air temperature (Tair) predicts heat-related mortality well in cities with a robust negative Tair-relative humidity correlation (CT-RH). However, in cities with near-zero or weak positive CT-RH, HSIs considering humidity provide enhanced predictive power compared to Tair. Furthermore, the magnitude and timing of heat-related mortality measured by HSIs could differ largely from those associated with Tair in many cities. Our findings provide important insights into specific regions where humans are vulnerable to humid heat and can facilitate the further enhancement of heat-health alert systems.

Heat, humidity and health impacts: how causal diagrams can help tell the complex story.

The global health burden associated with exposure to heat is a grave concern and is projected to further increase under climate change. While physiological studies have demonstrated the role of humidity alongside temperature in exacerbating heat stress for humans, epidemiological findings remain conflicted. Understanding the intricate relationships between heat, humidity, and health outcomes is crucial to inform adaptation and drive increased global climate change mitigation efforts. This article introduces 'directed acyclic graphs' (DAGs) as causal models to elucidate the analytical complexity in observational epidemiological studies that focus on humid-heat-related health impacts. DAGs are employed to delineate implicit assumptions often overlooked in such studies, depicting humidity as a confounder, mediator, or an effect modifier. We also discuss complexities arising from using composite indices, such as wet-bulb temperature. DAGs representing the health impacts associated with wet-bulb temperature help to understand the limitations in separating the individual effect of humidity from the perceived effect of wet-bulb temperature on health. General examples for regression models corresponding to each of the causal assumptions are also discussed. Our goal is not to prioritize one causal model but to discuss the causal models suitable for representing humid-heat health impacts and highlight the implications of selecting one model over another. We anticipate that the article will pave the way for future quantitative studies on the topic and motivate researchers to explicitly characterize the assumptions underlying their models with DAGs, facilitating accurate interpretations of the findings. This methodology is applicable to similarly complex compound events.

All-cause, cardiovascular, and respiratory mortality and wildfire-related ozone: a multicountry two-stage time series analysis.

BACKGROUND: Wildfire activity is an important source of tropospheric ozone (O3) pollution. However, no study to date has systematically examined the associations of wildfire-related O3 exposure with mortality globally. METHODS: We did a multicountry two-stage time series analysis. From the Multi-City Multi-Country (MCC) Collaborative Research Network, data on daily all-cause, cardiovascular, and respiratory deaths were obtained from 749 locations in 43 countries or areas, representing overlapping periods from Jan 1, 2000, to Dec 31, 2016. We estimated the daily concentration of wildfire-related O3 in study locations using a chemical transport model, and then calibrated and downscaled O3 estimates to a resolution of 0·25°â€ˆ× 0·25° (approximately 28 km2 at the equator). Using a random-effects meta-analysis, we examined the associations of short-term wildfire-related O3 exposure (lag period of 0-2 days) with daily mortality, first at the location level and then pooled at the country, regional, and global levels. Annual excess mortality fraction in each location attributable to wildfire-related O3 was calculated with pooled effect estimates and used to obtain excess mortality fractions at country, regional, and global levels. FINDINGS: Between 2000 and 2016, the highest maximum daily wildfire-related O3 concentrations (≥30 µg/m3) were observed in locations in South America, central America, and southeastern Asia, and the country of South Africa. Across all locations, an increase of 1 µg/m3 in the mean daily concentration of wildfire-related O3 during lag 0-2 days was associated with increases of 0·55% (95% CI 0·29 to 0·80) in daily all-cause mortality, 0·44% (-0·10 to 0·99) in daily cardiovascular mortality, and 0·82% (0·18 to 1·47) in daily respiratory mortality. The associations of daily mortality rates with wildfire-related O3 exposure showed substantial geographical heterogeneity at the country and regional levels. Across all locations, estimated annual excess mortality fractions of 0·58% (95% CI 0·31 to 0·85; 31 606 deaths [95% CI 17 038 to 46 027]) for all-cause mortality, 0·41% (-0·10 to 0·91; 5249 [-1244 to 11 620]) for cardiovascular mortality, and 0·86% (0·18 to 1·51; 4657 [999 to 8206]) for respiratory mortality were attributable to short-term exposure to wildfire-related O3. INTERPRETATION: In this study, we observed an increase in all-cause and respiratory mortality associated with short-term wildfire-related O3 exposure. Effective risk and smoke management strategies should be implemented to protect the public from the impacts of wildfires. FUNDING: Australian Research Council and the Australian National Health and Medical Research Council.

Exploring heterogeneity: a dive into preclinical models of cancer cachexia.

Cancer cachexia (CC) is a multifactorial and complex syndrome experienced by up to 80% of patients with cancer and implicated in ∼40% of cancer-related deaths. Given its significant impact on patients' quality of life and prognosis, there has been a growing emphasis on elucidating the underlying mechanisms of CC using preclinical models. However, the mechanisms of cachexia appear to differ across several variables including tumor type and model and biologic variables such as sex. These differences may be exacerbated by variance in experimental approaches and data reporting. This review examines literature spanning from 2011 to March 2024, focusing on common preclinical models of CC, including Lewis Lung Carcinoma, pancreatic KPC, and colorectal colon-26 and Apcmin/+ models. Our analysis reveals considerable heterogeneity in phenotypic outcomes, and investigated mechanisms within each model, with particular attention to sex differences that may be exacerbated through methodological differences. Although searching for unified mechanisms is critical, we posit that effective treatment approaches are likely to leverage the heterogeneity presented by the tumor and pertinent biological variables to direct specific interventions. In exploring this heterogeneity, it becomes critical to consider methodological and data reporting approaches to best inform further research.