Insights into pathophysiology and therapeutic strategies for heat stroke: Lessons from a baboon model.

Heat 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.

Proteomics Analysis of Proteotoxic Stress Response in In-Vitro Human Neuronal Models.

Heat stroke, a hazardous hyperthermia-related illness, is characterized by CNS injury, particularly long-lasting brain damage. A root cause for hyperthermic neurological damage is heat-induced proteotoxic stress through protein aggregation, a known causative agent of neurological disorders. Stress magnitude and enduring persistence are highly correlated with hyperthermia-associated neurological damage. We used an untargeted proteomic approach using liquid chromatography-tandem mass spectrometry (LC-MS/MS) to identify and characterize time-series proteome-wide changes in dose-responsive proteotoxic stress models in medulloblastoma [Daoy], neuroblastoma [SH-SY5Y], and differentiated SH-SY5Y neuron-like cells [SH(D)]. An integrated analysis of condition-time datasets identified global proteome-wide differentially expressed proteins (DEPs) as part of the heat-induced proteotoxic stress response. The condition-specific analysis detected higher DEPs and upregulated proteins in extreme heat stress with a relatively conservative and tight regulation in differentiated SH-SY5Y neuron-like cells. Functional network analysis using ingenuity pathway analysis (IPA) identified common intercellular pathways associated with the biological processes of protein, RNA, and amino acid metabolism and cellular response to stress and membrane trafficking. The condition-wise temporal pathway analysis in the differentiated neuron-like cells detects a significant pathway, functional, and disease association of DEPs with processes like protein folding and protein synthesis, Nervous System Development and Function, and Neurological Disease. An elaborate dose-dependent stress-specific and neuroprotective cellular signaling cascade is also significantly activated. Thus, our study provides a comprehensive map of the heat-induced proteotoxic stress response associating proteome-wide changes with altered biological processes. This helps to expand our understanding of the molecular basis of the heat-induced proteotoxic stress response with potential translational connotations.

Whole genome transcriptomic reveals heat stroke molecular signatures in humans.

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.

Classic heat stroke in a desert climate: A systematic review of 2632 cases.

BACKGROUND: Although 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. OBJECTIVES: A 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. METHODS: We 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. RESULTS: Forty-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°C [95% confidence interval (CI): 41.9, 42.1], range 40-44.8°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]). CONCLUSIONS: The 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.

Heat-Induced Proteotoxic Stress Response in Placenta-Derived Stem Cells (PDSCs) Is Mediated through HSPA1A and HSPA1B with a Potential Higher Role for HSPA1B.

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.

Biomarkers of heatstroke-induced organ injury and repair.

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 S100ß 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.

Interferon-induced transmembrane protein-3 genetic variant rs12252 is associated with COVID-19 mortality.

Interferon-induced membrane proteins (IFITM) 3 gene variants are known risk factor for severe viral diseases. We examined whether IFITM3 variant may underlie the heterogeneous clinical outcomes of SARS-CoV-2 infection-induced COVID-19 in large Arab population. We genotyped 880 Saudi patients; 93.8% were PCR-confirmed SARS-CoV-2 infection, encompassing most COVID-19 phenotypes. Mortality at 90 days was 9.1%. IFITM3-SNP, rs12252-G allele was associated with hospital admission (OR = 1.65 [95% CI; 1.01-2.70], P = 0.04]) and mortality (OR = 2.2 [95% CI; 1.16-4.20], P = 0.01). Patients less than 60 years old had a lower survival probability if they harbor this allele (log-rank test P = 0.002). Plasma levels of IFNγ were significantly lower in a subset of patients with AG/GG genotypes than patients with AA genotype (P = 0.00016). Early identification of these individuals at higher risk of death may inform precision public health response.

Obesity and COVID-19: what makes obese host so vulnerable?

The disease (COVID-19) novel coronavirus pandemic has so far infected millions resulting in the death of over a million people as of Oct 2020. More than 90% of those infected with COVID-19 show mild or no symptoms but the rest of the infected cases show severe symptoms resulting in significant mortality. Age has emerged as a major factor to predict the severity of the disease and mortality rates are significantly higher in elderly patients. Besides, patients with underlying conditions like Type 2 diabetes, cardiovascular diseases, hypertension, and cancer have an increased risk of severe disease and death due to COVID-19 infection. Obesity has emerged as a novel risk factor for hospitalization and death due to COVID-19. Several independent studies have observed that people with obesity are at a greater risk of severe disease and death due to COVID-19. Here we review the published data related to obesity and overweight to assess the possible risk and outcome in Covid-19 patients based on their body weight. Besides, we explore how the obese host provides a unique microenvironment for disease pathogenesis, resulting in increased severity of the disease and poor outcome.

Evidence of a wide gap between COVID-19 in humans and animal models: a systematic review.

BACKGROUND: Animal models of COVID-19 have been rapidly reported after the start of the pandemic. We aimed to assess whether the newly created models reproduce the full spectrum of human COVID-19. METHODS: We searched the MEDLINE, as well as BioRxiv and MedRxiv preprint servers for original research published in English from January 1 to May 20, 2020. We used the search terms (COVID-19) OR (SARS-CoV-2) AND (animal models), (hamsters), (nonhuman primates), (macaques), (rodent), (mice), (rats), (ferrets), (rabbits), (cats), and (dogs). Inclusion criteria were the establishment of animal models of COVID-19 as an endpoint. Other inclusion criteria were assessment of prophylaxis, therapies, or vaccines, using animal models of COVID-19. RESULT: Thirteen peer-reviewed studies and 14 preprints met the inclusion criteria. The animals used were nonhuman primates (n = 13), mice (n = 7), ferrets (n = 4), hamsters (n = 4), and cats (n = 1). All animals supported high viral replication in the upper and lower respiratory tract associated with mild clinical manifestations, lung pathology, and full recovery. Older animals displayed relatively more severe illness than the younger ones. No animal models developed hypoxemic respiratory failure, multiple organ dysfunction, culminating in death. All species elicited a specific IgG antibodies response to the spike proteins, which were protective against a second exposure. Transient systemic inflammation was observed occasionally in nonhuman primates, hamsters, and mice. Notably, none of the animals unveiled a cytokine storm or coagulopathy. CONCLUSIONS: Most of the animal models of COVID-19 recapitulated mild pattern of human COVID-19 with full recovery phenotype. No severe illness associated with mortality was observed, suggesting a wide gap between COVID-19 in humans and animal models.

Feasibility of Using Convalescent Plasma Immunotherapy for MERS-CoV Infection, Saudi Arabia.

We explored the feasibility of collecting convalescent plasma for passive immunotherapy of Middle East respiratory syndrome coronavirus (MERS-CoV) infection by using ELISA to screen serum samples from 443 potential plasma donors: 196 patients with suspected or laboratory-confirmed MERS-CoV infection, 230 healthcare workers, and 17 household contacts exposed to MERS-CoV. ELISA-reactive samples were further tested by indirect fluorescent antibody and microneutralization assays. Of the 443 tested samples, 12 (2.7%) had a reactive ELISA result, and 9 of the 12 had reactive indirect fluorescent antibody and microneutralization assay titers. Undertaking clinical trials of convalescent plasma for passive immunotherapy of MERS-CoV infection may be feasible, but such trials would be challenging because of the small pool of potential donors with sufficiently high antibody titers. Alternative strategies to identify convalescent plasma donors with adequate antibody titers should be explored, including the sampling of serum from patients with more severe disease and sampling at earlier points during illness.

Beyond heatwaves: A nuanced view of temperature-related mortality.

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.

Escalating climate-related health risks for Hajj pilgrims to Mecca.

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°C (Mann-Kendall P < 0.0001) and 0.2°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.

Clinical characteristics, sepsis interventions and outcomes in the obese patients with septic shock: an international multicenter cohort study.

INTRODUCTION: Data are sparse as to whether obesity influences the risk of death in critically ill patients with septic shock. We sought to examine the possible impact of obesity, as assessed by body mass index (BMI), on hospital mortality in septic shock patients. METHODS: We performed a nested cohort study within a retrospective database of patients with septic shock conducted in 28 medical centers in Canada, United States and Saudi Arabia between 1996 and 2008. Patients were classified according to the World Health Organization criteria for BMI. Multivariate logistic regression analysis was performed to evaluate the association between obesity and hospital mortality. RESULTS: Of the 8,670 patients with septic shock, 2,882 (33.2%) had height and weight data recorded at ICU admission and constituted the study group. Obese patients were more likely to have skin and soft tissue infections and less likely to have pneumonia with predominantly Gram-positive microorganisms. Crystalloid and colloid resuscitation fluids in the first six hours were given at significantly lower volumes per kg in the obese and very obese patients compared to underweight and normal weight patients (for crystalloids: 55.0 ± 40.1 ml/kg for underweight, 43.2 ± 33.4 for normal BMI, 37.1 ± 30.8 for obese and 27.7 ± 22.0 for very obese). Antimicrobial doses per kg were also different among BMI groups. Crude analysis showed that obese and very obese patients had lower hospital mortality compared to normal weight patients (odds ratio (OR) 0.80, 95% confidence interval (CI) 0.66 to 0.97 for obese and OR 0.61, 95% CI 0.44 to 0.85 for very obese patients). After adjusting for baseline characteristics and sepsis interventions, the association became non-significant (OR 0.80, 95% CI 0.62 to 1.02 for obese and OR 0.69, 95% CI 0.45 to 1.04 for very obese). CONCLUSIONS: The obesity paradox (lower mortality in the obese) documented in other populations is also observed in septic shock. This may be related in part to differences in patient characteristics. However, the true paradox may lie in the variations in the sepsis interventions, such as the administration of resuscitation fluids and antimicrobial therapy. Considering the obesity epidemic and its impact on critical care, further studies are warranted to examine whether a weight-based approach to common therapeutic interventions in septic shock influences outcome.

Diagnosing and managing heat exhaustion: insights from a systematic review of cases in the desert climate of Mecca.

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.

Human tolerance to extreme heat: evidence from a desert climate population.

BACKGROUND: Ambient temperatures exceeding 40 °C are projected to become common in many temperate climatic zones due to global warming. Therefore, understanding the health effects of continuous exposure to high ambient temperatures on populations living in hot climatic regions can help identify the limits of human tolerance. OBJECTIVE: We studied the relationship between ambient temperature and non-accidental mortality in the hot desert city of Mecca, Saudi Arabia, between 2006 and 2015. METHODS: We used a distributed lag nonlinear model to estimate the mortality-temperature association over 25 days of lag. We determined the minimum mortality temperature (MMT) and the deaths that are attributable to heat and cold. RESULTS: We analyzed 37,178 non-accidental deaths reported in the ten-year study period among Mecca residents. The median average daily temperature was 32 °C (19-42 °C) during the same study period. We observed a U-shaped relationship between daily temperature and mortality with an MMT of 31.8 °C. The total temperature-attributable mortality of Mecca residents was 6.9% (-3.2; 14.8) without reaching statistical significance. However, extreme heat, higher than 38 °C, was significantly associated with increased risk of mortality. The lag structure effect of the temperature showed an immediate impact, followed by a decline in mortality over many days of heat. No effect of cold on mortality was observed. IMPACT STATEMENT: High ambient temperatures are projected to become future norms in temperate climates. Studying populations familiar with desert climates for generations with access to air-conditioning would inform on the mitigation measures to protect other populations from heat and on the limits of human tolerance to extreme temperatures. We studied the relationship between ambient temperature and all-cause mortality in the hot desert city of Mecca. We found that Mecca population is adapted to high temperatures, although there was a limit to tolerance to extreme heat. This implies that mitigation measures should be directed to accelerate individual adaptation to heat and societal reorganization.

Association of Ambient Temperature with Mortality in Resident and Multiethnic Transient Populations in a Desert Climate, 2006-2014.

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°C (19°C-37°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°C lower for pilgrims in comparison with the MMT for Mecca residents (23.5°C vs. 26.0°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.

Transcriptome Changes and Metabolic Outcomes After Bariatric Surgery in Adults With Obesity and Type 2 Diabetes.

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 (ß-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.

Profiling the Hsp70 Chaperone Network in Heat-Induced Proteotoxic Stress Models of Human Neurons.

Heat stroke is among the most hazardous hyperthermia-related illnesses and an emerging threat to humans from climate change. Acute brain injury and long-lasting brain damage are the hallmarks of this condition. Hyperthermic neurological manifestations are remarkable for their damage correlation with stress amplitude and long-term persistence. Hyperthermia-induced protein unfolding, and nonspecific aggregation accumulation have neurotoxic effects and contribute to the pathogenesis of brain damage in heat stroke. Therefore, we generated heat-induced, dose-responsive extreme and mild proteotoxic stress models in medulloblastoma [Daoy] and neuroblastoma [SH-SY5Y] and differentiated SH-SY5Y neuronal cells. We show that heat-induced protein aggregation is associated with reduced cell proliferation and viability. Higher protein aggregation in differentiated neurons than in neuroblastoma precursors suggests a differential neuronal vulnerability to heat. We characterized the neuronal heat shock response through RT-PCR array analysis of eighty-four genes involved in protein folding and protein quality control (PQC). We identify seventeen significantly expressed genes, five of which are Hsp70 chaperones, and four of their known complementing function proteins. Protein expression analysis determined the individual differential contribution of the five Hsp70 chaperones to the proteotoxic stress response and the significance of only two members under mild conditions. The co-expression analysis reveals significantly high co-expression between the Hsp70 chaperones and their interacting partners. The findings of this study lend support to the hypothesis that hyperthermia-induced proteotoxicity may underlie the brain injury of heat stroke. Additionally, this study presents a comprehensive map of the Hsp70 network in these models with potential clinical and translational implications.

Tissue factor/factor VIIa pathway mediates coagulation activation in induced-heat stroke in the baboon.

OBJECTIVE: Excessive activation of coagulation, which can culminate in overt disseminated intravascular coagulation, is a prominent feature of heat stroke. However, neither the mechanism that initiates the coagulation activation nor its pathogenic role is known. We examined whether the tissue factor/factor VIIa complex initiates the coagulation activation in heat stroke and, if so, whether upstream inhibition of coagulation activation through its neutralization may minimize cellular injury and organ dysfunction. We also examined whether coagulation inhibition influences heat stroke-induced fibrinolytic and inflammatory responses. DESIGN: Randomized controlled study. SETTING: Comparative Medicine Department, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia. SUBJECTS: Baboons (Papio Hamadryas). INTERVENTIONS: Twelve anesthetized baboons assigned randomly to recombinant nematode anticoagulant protein c2, a powerful inhibitor of tissue factor/factor VIIa-dependent coagulation (n = 6), or a control group (n = 6) were heat-stressed in a prewarmed neonatal incubator at 44-47°C until systolic blood pressure fell <90 mm Hg, signaling the onset of severe heat stroke. Recombinant nematode anticoagulant protein c2 was administered as a single intravenous dose of 30 µg/kg body weight at onset of heat stroke. The control group received an equivalent volume of sterile saline intravenously. MEASUREMENTS AND MAIN RESULTS: Heat stroke was associated with coagulation activation and fibrin formation as evidenced by the increased plasma thrombin-antithrombin complexes, endogenous thrombin potential, and D-dimer levels. Recombinant nematode anticoagulant protein c2 induced significant inhibition of thrombin generation and fibrin formation. Inhibition of coagulation in recombinant nematode anticoagulant protein c2-treated animals did not influence either fibrinolysis (assessed by tissue plasminogen activator, plasmin-α2-antiplasmin complexes, and plasminogen activator inhibitor) or the release of pro- and anti-inflammatory cytokines. No difference in markers of cell injury and organ dysfunction was observed between recombinant nematode anticoagulant protein c2-treated and control groups. CONCLUSIONS: Tissue factor/factor VIIa-dependent pathway initiates coagulation activation in induced-heat stroke in the baboon without an effect on fibrinolysis and inflammation. The findings suggest also that coagulation activation is not a prerequisite of cell injury and organ dysfunction.