Heat-related illness is an increasing global health threat, with heatstroke representing its most severe form and frequently causing cerebellar injury characterised by selective Purkinje neuron loss. The molecular basis of this regional vulnerability remains unclear. Here, we integrated transcriptomic data from human heat exposure experiments, patients with heatstroke, primary human neurons, and cortical organoids to define conserved responses to heat stress and investigate determinants of cerebellar susceptibility. Across datasets, heat stress induced a highly conserved transcriptional programme dominated by suppression of ribosome biogenesis, RNA processing, translation, and metabolic pathways, consistent with reduced biosynthetic and energy-demanding activity. Mapping these signatures to human brain atlases revealed that the cerebellum showed the lowest enrichment of downregulated genes, while heatstroke exhibited a distinct regional transcriptional pattern compared with experimental heat exposure. At the cellular level, granule and Purkinje neurons showed the strongest association with heat-responsive gene suppression. Purkinje-enriched genes were linked to synaptic organisation, neurotransmission, membrane excitability, and ion transport. Connectivity Map analysis identified compounds predicted to reverse the heatstroke transcriptional signature, including the mTOR inhibitor KU-0063794. These findings identify a conserved molecular response to heat stress and suggest that selective Purkinje vulnerability reflects intrinsic metabolic and electrophysiological properties rather than preferential activation of canonical heat-shock pathways.

Heat-related mortality remains health challenges exacerbated by climate change, with sex-based differences in outcomes, yet underlying mechanisms remain poorly understood. This study examined transcriptomic responses to heat exposure in peripheral blood mononuclear cells from 19 patients with heat stroke (HS; 8 males, mean age 64.8 ± 6.6 yr; 11 females, mean age 49.7 ± 11 yr) and 19 controls (11 males, mean age 48.9 ± 9.6 yr; 8 females, mean age 44.9 ± 11.8 yr). At admission, gene expression revealed upregulation of heat shock protein genes, and pathway analysis demonstrated activation of heat shock and unfolded protein responses across both sexes consistent with proteotoxic stress. However, distinct metabolic, oxidative stress, cell cycle control, and immune responses were observed within each sex. Females displayed inhibition of protein synthesis, oxidative phosphorylation, and metabolic pathways, including glucose metabolism, indicative of a hypometabolic state. Males maintained metabolic activity precooling and enhanced adenosine triphosphate production postcooling. Females activated nuclear factor erythroid 2-related factor 2 (NRF2)-mediated oxidative stress responses and inhibited DNA replication and mitosis, potentially mitigating genomic instability, whereas these pathways showed limited regulation in males. Females promoted innate immunity via interleukin (IL)-6, inflammasome, and triggering receptor expressed on myeloid cells 1 (TREM1) signaling, whereas males showed suppression of both innate and adaptive immunity, including IL-12, Th1, and T-cell receptor pathways. Upstream analysis identified over 100 transcription factors in both sexes. Males primarily relied on transcriptional mechanisms, whereas females also exhibited translational regulation via La ribonucleoprotein 1 (LARP1), fragile X messenger ribonucleoprotein 1 (FMR1), insulin-like growth factor 2 mRNA binding protein 1 (IGF2BP1), and eukaryotic translation initiation factor 6 (EIF6). These findings suggest distinct, sex-specific molecular adaptations to heat stroke, underscoring the need for targeted therapeutic strategies to mitigate heat-induced morbidity and mortality.NEW & NOTEWORTHY Heat-related mortality continues to rise with climate change. Our transcriptomic analysis reveals distinct sex-specific metabolic strategies to heat stroke: females enter a hypometabolic state, an evolutionary adaptation that conserves energy, whereas males sustain metabolic activity. Transcription factors and a subset of translation regulators in females modulate proteostasis and bioenergetics, driving these sex-specific pathways. These novel findings highlight the critical need to consider sex-specific differences in heat-related illnesses and inform carefully targeted interventions to improve patient outcomes.

This study investigates the molecular responses to heatstroke in young and old patients by comparing whole-genome transcriptomes between age groups. We analyzed transcriptomic profiles from patients categorized into two age-defined cohorts: young (mean age = 44.9 ± 6 yr) and old (mean age = 66.1 ± 4 yr). Control subjects, exposed to similar environmental heat conditions but without developing heatstroke, were also included in the analysis to provide a baseline for comparison. Despite uniform heatstroke severity at admission, as indicated by core body temperature, consciousness level, and organ damage markers, notable gene expression differences emerged. Old patients showed 37% fewer differentially expressed genes compared with young patients at admission, with a shift toward gene upregulation, deviating from the usual downregulation seen in heat stress responses. Both age groups exhibited increased heat shock protein gene expression, activated the heat stress, and unfolded protein responses indicating comparable proteotoxic stress. Nonetheless, age-specific differences were evident in critical regulatory pathways like Sirtuin, mTOR, and p53 signaling, along with key pathways related to proteostasis, energy metabolism, oxidative stress, and immune responses. Following cooling, older adults exhibited a decline in the heat stress response and a cessation of the unfolded protein response, in contrast to the sustained responses seen in younger individuals. This pattern suggests an age-related adaptability or a diminished protective response capacity with aging. These findings provide insights into the biological mechanisms that may contribute to age-specific vulnerabilities to heat.NEW & NOTEWORTHY Our study reveals distinct molecular responses to heatstroke across age groups, with older adults showing fewer differentially expressed genes and an atypical pattern of gene upregulation, contrasting with the downregulation in usual heat stress responses. It also uncovers a reduced heat stress response and an abbreviated unfolded protein response in older adults, likely impairing their cellular repair mechanisms. This contributes to increased vulnerability during severe heat waves, underscoring the urgent need for age-specific interventions.

The increasing use of time-series analyses in exploring the relationship between daily ambient temperature and mortality has expanded our understanding of the potential health impacts of climate change. However, it raises significant concerns about the risk of overinterpretation and misattribution of statistical findings. This review examines the methodological assumptions and interpretation pitfalls prevalent in current research on ambient temperature-mortality associations. Extremely elevated ambient temperatures are well-known to elicit physiological stress and increase mortality risk; however, there is no physiological evidence for lethality risk within normal ambient temperature ranges. Despite this, many studies attribute mortality risks across the entire ambient temperature-mortality curve, including normal range ambient temperatures, thus oversimplifying complex underlying physiological processes. Overinterpretation may lead to inaccurate assessments and misguided public health policies. We caution against the tendency to extrapolate results from extreme heat conditions to milder, more typical summer ambient temperature ranges. We advocate for an interdisciplinary approach that combines physiological, clinical, and epidemiological perspectives, with a strong emphasis on the role of behavioral thermoregulation and socio-economic factors to link normal range ambient temperatures with mortality. We recommend analyses centered on excess mortality during defined heatwave periods, and to incorporate heat stress biomarkers to substantiate causal claims for temperatures below heatwaves threshold. A careful approach to interpreting ambient temperature-mortality associations is crucial for formulating evidence-based public health policies.

Background Global temperatures are on the rise, leading to more frequent and severe heatwaves with associated health risks. Heat-related illnesses (HRIs) are an increasing threat for travellers to hot climate destinations. This study was designed to elucidate the interplay between increasing ambient temperatures, incidence of HRIs and the effectiveness of mitigation strategies during the annual Hajj mass gathering over a 40-year period. Methods An observational study was conducted utilizing historical records spanning four decades of meteorological data, and the rates of heat stroke (HS) and heat exhaustion (HE) during the Hajj pilgrimage in Mecca, Saudi Arabia. With an annual population exceeding 2 million participants from over 180 countries, the study analysed temporal variations in weather conditions over two distinct Hajj hot cycles and correlated it with the occurrence of HS and HE. The effectiveness of deployed mitigation measures in alleviating health vulnerabilities between the two cycles was also assessed. Results Throughout the study period, average dry and wet bulb temperatures in Mecca escalated by 0.4 degrees C (Mann-Kendall P < 0.0001) and 0.2 degrees C (Mann-Kendall P = 0.25) per decade, respectively. Both temperatures were strongly correlated with the incidence of HS and HE (P < 0.001). Despite the intensifying heat, the mitigation strategies including individual, structural and community measures were associated with a substantial 74.6% reduction in HS cases and a 47.6% decrease in case fatality rate. Conclusion The study underscores the escalating climate-related health risks in Mecca over the study period. The mitigation measures' efficacy in such a globally representative setting emphasizes the findings' generalizability and the importance of refining public health interventions in the face of rising temperatures.

Heat exhaustion (HE) is a common, yet obscure, heat-related illness that affects millions of people yearly and its burden is projected to rise due to climate change. A comprehensive literature synthesis is lacking despite previous studies on various HE aspects. This systematic review aims to fill this gap by identifying and synthesizing available evidence on the risk factors, symptoms, biomarkers, treatment options, and outcomes for HE. The review focused on HE during the Muslim (Hajj) pilgrimage where the condition is endemic. We conducted a structured search of MEDLINE/PubMed, Embase, Web of Science Core Collection, SCOPUS, and CINAHL databases. We summarized the data from eligible studies and synthesized them in narrative form using pooled descriptive statistics. Ten studies were included between 1980 and 2019, reporting over 1,194 HE cases. HE cases presented with elevated core temperature (up to 40°C) and mainly affected older males from the Middle East and North Africa region, with overweight individuals at a higher risk. Clinical symptoms included hyperventilation, fatigue, dizziness, headaches, nausea, and vomiting, but not central nervous system disturbances. HE was associated with cardiac stress, and with water, electrolyte, and acid-base alterations. Cooling and hydration therapy were the primary management strategies, leading to a low mortality rate (pooled case fatality rate=0.11 % [95 % CI: 0.01, 0.3]). Most cases recovered within a few hours without complications. HE is associated with cardiac stress and changes in homeostasis, leading to distinct clinical symptoms. Early diagnosis and treatment of HE are crucial in reducing the risk of complications and mortality. The review provides insights into the pathophysiology and outcomes of HE, adding to the scarce literature on the subject. Prospero registration number: CRD42022325759.

BACKGROUND: Although the association between ambient temperature and mortality in local populations is evident, this relationship remains unclear in transient populations (e.g., due to immigration, mass gatherings, or displacement). The holy city of Mecca annually shelters two populations comprising its residents and the transitory Hajj pilgrims (>2 million people from >180 countries). Both live side by side in a hot desert climate, rendering the development of evidence-based heat-protective measures challenging. OBJECTIVES: We aimed to characterize the ambient temperature-mortality relationship and burden for the Mecca resident and Hajj transient populations, which have distinct levels of adaptation to ambient temperature. METHODS: We analyzed daily air temperature and mortality data for Mecca residents and pilgrims over nine Hajj seasons between 2006 and 2014, using a fitted standard time-series Poisson model. We characterized the temperature-mortality relationship with a distributed lag nonlinear model with 10 d of lag. We determined the minimum mortality temperature (MMT) and attributable deaths for heat and cold for the two populations. RESULTS: The median average daily temperature during the Hajj seasons was 30 degrees C (19 degrees C-37 degrees C). There were 8,543 and 10,457 nonaccidental deaths reported during the study period among Mecca residents and pilgrims, respectively. The MMT was 2.5 degrees C lower for pilgrims in comparison with the MMT for Mecca residents (23.5 degrees C vs. 26.0 degrees C). The temperature-mortality relationship shape varied from inverted J to U shape for the Mecca and pilgrim populations, respectively. Neither hot nor cold temperatures had a statistically significant association with mortality in Mecca residents. In contrast, for pilgrims, elevated temperatures were associated with significantly high attributable mortality of 70.8% [95% confidence interval (CI): 62.8, 76.0]. The effect of heat on pilgrims was immediate and sustained. DISCUSSION: Our findings indicate that pilgrims and Mecca residents exposed to the same hot environmental conditions exhibited distinct health outcomes. This conclusion suggests that a precision public health approach may be warranted to protect against high environmental temperature during mass gatherings of diverse populations. https://doi.org/10.1289/EHP9838

AbstractHeat stroke is a perilous condition marked by severe hyperthermia and extensive multiorgan dysfunction, posing a considerable risk of mortality if not promptly identified and treated. Furthermore, the complex biological mechanisms underlying heat stroke‐induced tissue and cell damage across organ systems remain incompletely understood. This knowledge gap has hindered the advancement of effective preventive and therapeutic strategies against this condition. In this narrative review, we synthesize key insights gained over a decade using a translational baboon model of heat stroke. By replicating heat stroke pathology in a non‐human primate species that closely resembles humans, we have unveiled novel insights into the pathways of organ injury and cell death elicited by this condition. Here, we contextualize and integrate the lessons learned concerning heat stroke pathophysiology and recovery, areas that are inherently challenging to investigate directly in human subjects. We suggest novel research directions to advance the understanding of the complex mechanisms underlying cell death and organ injury. This may lead to precise therapeutic strategies that benefit individuals suffering from this debilitating condition.

BackgroundAlthough classic heat stroke (HS) is one of the most ancient conditions known to humans, the description of its early clinical manifestations, natural course, and complications remains uncertain. ObjectivesA systematic review of the demographics, clinical characteristics, biomarkers, therapy, and outcomes of HS during the Muslim (Hajj) pilgrimage in the desert climate of Mecca, Saudi Arabia. MethodsWe searched the MEDLINE, Embase, Web of Science Core Collection, SCOPUS, and CINAHL databases from inception to April 2022. We summarized the data from eligible studies and synthesized them in narrative form using pooled descriptive statistics. ResultsForty-four studies, including 2632 patients with HS, met the inclusion criteria. Overweight or obesity, diabetes, and cardiovascular disease were prevalent among cases of HS. Evidence suggests that extreme hyperthermia (pooled mean = 42.0 degrees C [95% confidence interval (CI): 41.9, 42.1], range 40-44.8 degrees C) with hot and dry skin (>99% of cases) and severe loss of consciousness (mean Glasgow Coma Scale <8 in 53.8% of cases) were the dominant clinical characteristics of classic HS. Hypotension, tachypnea, vomiting, diarrhea, and biochemical biomarkers indicating mild-to-moderate rhabdomyolysis, acute kidney, liver, heart injury, and coagulopathy were frequent at the onset. Concomitantly, stress hormones (cortisol and catecholamines) and biomarkers of systemic inflammation and coagulation activation were increased. HS was fatal in 1 in 18 cases (pooled case fatality rate = 5.6% [95%CI: 4.6, 6.5]). ConclusionsThe findings of this review suggest that HS induces an early multiorgan injury that can progress rapidly to organ failure, culminating in death, if it is not recognized and treated promptly.

An evolutionary heat shock response (HSR) protects most living species, including humans, from heat-induced macromolecular damage. However, its role in the pathogenesis of heat stroke is unknown. We examined the whole genome transcriptome in peripheral blood mononuclear cells of a cohort of subjects exposed to the same high environmental heat conditions, who developed heat stroke (n = 19) versus those who did not (n = 19). Patients with heat stroke had a mean rectal temperature at admission of 41.7 ± 0.8°C, and eight were in deep coma (Glasgow Coma Score = 3). The transcriptome showed that genes involved in more than half of the entire chaperome were differentially expressed relative to heat stress control. These include the heat shock protein, cochaperone, and chaperonin genes, indicating a robust HSR. Differentially expressed genes also encoded proteins related to unfolded protein response, DNA repair, energy metabolism, oxidative stress, and immunity. The analysis predicted perturbations of the proteome network and energy production. Cooling therapy attenuated these alterations without complete restoration of homeostasis. We validated the significantly expressed genes by a real-time polymerase chain reaction. The findings reveal the molecular signature of heat stroke. They also suggested that a powerful HSR may not be sufficient to protect against heat injury. The overwhelming proteotoxicity and energy failure could play a pathogenic role. KEY POINTS: Most living species, including humans, have inherent heat stress response (HSR) that shields them against heat-induced macromolecular damage. The role of the HSR in subjects exposed to environmental heat who progressed to heat stroke versus those that did not is unknown. Our findings suggest that heat stroke induces a broad and robust HSR of nearly half of the total heat shock proteins, cochaperones, and chaperonin genes. Heat stroke patients exhibited inhibition of genes involved in energy production, including oxidative phosphorylation and ATP production. Significant enrichment of neurodegenerative pathways, including amyloid processing signalling, the Huntington's and Parkinson's disease signalling suggestive of brain proteotoxicity was noted. The data suggests that more than a powerful HSR may be required to protect against heat stroke. Overwhelming proteotoxicity and energy failure might contribute to its pathogenesis.

Context:Bariatric surgery has been shown to be effective in inducing complete remission of type 2 diabetes in adults with obesity. However, its efficacy in achieving complete diabetes remission remains variable and difficult to predict before surgery.Objective:We aimed to characterize bariatric surgery-induced transcriptome changes associated with diabetes remission and the predictive role of the baseline transcriptome.Methods:We performed a whole-genome microarray in peripheral mononuclear cells at baseline (before surgery) and 2 and 12 months after bariatric surgery in a prospective cohort of 26 adults with obesity and type 2 diabetes. We applied machine learning to the baseline transcriptome to identify genes that predict metabolic outcomes. We validated the microarray expression profile using a real-time polymerase chain reaction.Results:Sixteen patients entered diabetes remission at 12 months and 10 did not. The gene-expression analysis showed similarities and differences between responders and nonresponders. The difference included the expression of critical genes (SKT4, SIRT1, and TNF superfamily), metabolic and signaling pathways (Hippo, Sirtuin, ARE-mediated messenger RNA degradation, MSP-RON, and Huntington), and predicted biological functions (β-cell growth and proliferation, insulin and glucose metabolism, energy balance, inflammation, and neurodegeneration). Modeling the baseline transcriptome identified 10 genes that could hypothetically predict the metabolic outcome before bariatric surgery.Conclusion:The changes in the transcriptome after bariatric surgery distinguish patients in whom diabetes enters complete remission from those who do not. The baseline transcriptome can contribute to the prediction of bariatric surgery-induced diabetes remission preoperatively.

Placenta-derived stem cells (PDSCs), due to unique traits such as mesenchymal and embryonic characteristics and the absence of ethical constraints, are in a clinically and therapeutically advantageous position. To aid in stemness maintenance, counter pathophysiological stresses, and withstand post-differentiation challenges, stem cells require elevated protein synthesis and consequently augmented proteostasis. Stem cells exhibit source-specific proteostasis traits, making it imperative to study them individually from different sources. These studies have implications for understanding stem cell biology and exploitation in the augmentation of therapeutic applications. Here, we aim to identify the primary determinants of proteotoxic stress response in PDSCs. We generated heat-induced dose-responsive proteotoxic stress models of three stem cell types: placental origin cells, the placenta-derived mesenchymal stem cells (pMSCs), maternal origin cells, the decidua parietalis mesenchymal stem cells (DPMSCs), and the maternal–fetal interface cells, decidua basalis mesenchymal stem cells (DBMSCs), and measured stress induction through biochemical and cell proliferation assays. RT-PCR array analysis of 84 genes involved in protein folding and protein quality control led to the identification of Hsp70 members HSPA1A and HSPA1B as the prominent ones among 17 significantly expressed genes and with further analysis at the protein level through Western blotting. A kinetic analysis of HSPA1A and HSPA1B gene and protein expression allowed a time series evaluation of stress response. As identified by protein expression, an active stress response is in play even at 24 h. More prominent differences in expression between the two homologs are detected at the translational level, alluding to a potential higher requirement for HSPA1B during proteotoxic stress response in PDSCs.

New Findings What is the topic of this review? The status and potential role of novel biological markers (biomarkers) that can help identify the patients at risk of organ injury or long‐term complications following heatstroke. What advances does it highlight? Numerous biomarkers were identified related to many aspects of generalized heatstroke‐induced cellular injury and tissue damage, and heatstroke‐provoked cardiovascular, renal, cerebral, intestinal and skeletal muscle injury. No novel biomarkers were identified for liver or lung injury. Abstract Classic and exertional heatstroke cause acute injury and damage across numerous organ systems. Moreover, heatstroke survivors may sustain long‐term neurological, cardiovascular and renal complications with a persistent risk of death. In this context, biomarkers, defined as biological samples obtained from heatstroke patients, are needed to detect early organ injury, and predict outcomes to develop novel organ preservation therapeutic strategies. This narrative review provides preliminary insights that will guide the development and future utilization of these biomarkers. To this end, we have identified numerous biomarkers of widespread heatstroke‐associated cellular injury, tissue damage and repair (extracellular heat shock proteins 72 and 60, high mobility group box protein 1, histone H3, and interleukin‐1α), and other organ‐specific biomarkers including those related to the cardiovascular system (cardiac troponin I, endothelium‐derived factors, circulation endothelial cells, adhesion molecules, thrombomodulin and von Willebrand factor antigen), the kidneys (plasma and urinary neutrophil gelatinase‐associated lipocalin), the intestines (intestinal fatty acid‐binding protein 2), the brain (serum S100β and neuron‐specific enolase) and skeletal muscle (creatine kinase, myoglobin). No specific biomarkers have been identified so far for liver or lung injury in heatstroke. Before translating the identified biomarkers into clinical practice, additional preclinical and clinical prospective studies are required to further understand their clinical utility, particularly for the biomarkers related to long‐term post‐heatstroke health outcomes.

Background During critical illness in humans, the effects of caloric restriction on the inflammatory response are not well understood. The aim of this study is to examine the associations of caloric restriction, inflammatory response profiles and outcomes in critically ill patients. Methods This is a sub-study of the PermiT trial (Permissive Underfeeding or Standard Enteral Feeding in Critically Ill Adults Trial- ISRCTN68144998). Serum samples were collected on study days 1, 3, 5, 7 and 14 and analyzed for a panel of 29 cytokines. We used principal component analysis to convert possibly correlated variables (cytokine levels) into a limited number of linearly uncorrelated variables (principal components). We constructed repeated measures mixed linear models to assess whether permissive underfeeding compared to standard feeding was associated with difference cytokine levels over time. Results A total of 72 critically ill patients were enrolled in this study (permissive underfeeding n = 36 and standard feeding n = 36). Principal component analysis identified 6 components that were responsible for 78% of the total variance. When adjusted to principal components, permissive underfeeding was not associated with 90-day mortality (adjusted odds ratio 1.75, 95% confidence interval 0.44, 6.95, p = 0.43) or with incident renal replacement therapy. The cytokines did not differ with time between permissive underfeeding and standard feeding groups. Conclusions The association of permissive underfeeding compared to standard feeding with mortality was not influenced by the inflammatory profile. Permissive underfeeding compared to standard feeding was not associated with differences in the serum levels of cytokines in critically ill patients.

The molecular mechanisms by which individuals subjected to environmental heat stress either recover or develop heat-related complications are not well understood. We analysed the changes in blood mononuclear gene expression patterns in human volunteers exposed to extreme heat in a sauna (temperature of 75.7 ± 0.86 °C). Our analysis reveals that expression changes occur rapidly with no significant increase in core temperature and continue to amplify one hour after the end of heat stress. The reprogramed transcriptome was predominantly inhibitory, as more than two-thirds of the expressed genes were suppressed. The differentially expressed genes encoded proteins that function in stress-associated pathways; including proteostasis, energy metabolism, cell growth and proliferation, and cell death, and survival. The transcriptome also included mitochondrial dysfunction, altered protein synthesis, and reduced expression of genes -related to immune function. The findings reveal the human transcriptomic response to heat and highlight changes that might underlie the health outcomes observed during heat waves.