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Background: Clinical prediction models (CPMs) estimate an individual's risk of current or future outcome events, using information available about the individual at the time of prediction. While most CPMs are developed to predict a single outcome event, many clinical decisions require considering the risks of multiple outcome events. For example, decision-making for anticoagulation therapy involves assessing an individual's risks of both blood clot and bleeding, while decision-making around interventions for multimorbidity prevention requires an understanding of the risks of developing multiple long-term conditions. However, determining when and how to incorporate multiple outcomes into CPMs remains challenging. This article aims to raise awareness of multiple outcome prediction and present clinical examples where such prediction is essential to help inform individual decision-making., Main Text: A range of analytical methods are available to develop multiple-outcome CPMs, but there are frequent malapropisms and heterogeneity in terminology across this literature, making it difficult to identify/compare possible methods. Selecting the appropriate method should depend on the intended risk estimand-the type of predicted risks that we wish the CPM to estimate-but this is often not defined or reported. Using clinical examples and a decision-analytical perspective, we present a taxonomy of risk estimands to frame different clinical contexts requiring multiple-outcome CPMs. We outline four levels of risk estimands: (i) single-outcome risk, (ii) competing-outcome risk, (iii) composite-outcome risk, and (iv) risk of multiple outcome combinations. We demonstrate how a decision-analytical and utility-theory lens can help define the risk estimand for a given clinical scenario, based on the model's intended use., Conclusions: Clearly defining and reporting the risk estimand is essential for all prediction model studies. A decision-analytical framework aids in selecting the most appropriate estimand for a given prediction task and in determining when and how to incorporate multiple outcomes into CPM development., Competing Interests: Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Visiting an air-conditioned location during heat exposure reduces physiological strain, however the effects on gastrointestinal barrier dysfunction and renal ischemia remain unexplored. We compared serum protein responses during a 9-h heat exposure (40.3°C, 9.3% relative humidity) in 17 older adults without cooling (control) and 19 older adults with a cooling break (~23°C) during hours 5 and 6 (cooling). IFABP and sCD14 increased similarly across groups. NGAL was 3.2 pg/mL [1.9, 6.1] lower in the cooling group during heat exposure. A 2-h cooling centre exposure did not ameliorate gastrointestinal barrier dysfunction, but did a reduce a surrogate marker of renal ischemia.

Purpose: Brain-derived neurotrophic factor (BDNF) is a neuroprotective growth factor that increases in young adults during short, intense bouts of passive heat stress. However, this may not reflect the response in heat-vulnerable populations exposed to air temperatures more consistent with indoor overheating during hot weather and heatwaves, especially as the BDNF response to acute stressors may diminish with increasing age. We therefore evaluated the ambient and body temperature-dependent responses of BDNF in older adults during daylong passive heating., Methods: Sixteen older adults (6 females; aged 66-78 years) completed 8-h exposure to four randomized ambient conditions simulating those experienced indoors during hot weather and heatwaves in continental climates: 22 °C (air-conditioning; control), 26 °C (health-agency-recommended indoor temperature limit), 31 °C, and 36 °C (non-airconditioned home); all 45% relative humidity. To further investigate upstream mechanisms of BDNF regulation during thermal strain, we also explored associations between BDNF and circulating heat shock protein 70 (HSP70; taken as an indicator of the heat shock response)., Results: Circulating BDNF was elevated by ~ 28% (1139 [95%CI: 166, 2112] pg/mL) at end-exposure in the 36 °C compared to the 22 °C control condition (P = 0.026; 26 °C-and 31 °C-22 °C differences: P ≥ 0.090), increasing 90 [22, 158] pg/mL per 1 °C rise in ambient temperature (linear trend: P = 0.011). BDNF was also positively correlated with mean body temperatures (P = 0.013), which increased 0.12 [0.10, 0.13]°C per 1 °C rise in ambient temperature (P < 0.001). By contrast, serum HSP70 did not change across conditions (P ≥ 0.156), nor was it associated with BDNF (P = 0.376)., Conclusion: Our findings demonstrate a progressive increase in circulating BDNF during indoor overheating in older adults., Competing Interests: Declarations. Conflict of interest: The authors have no conflicts of interest, financial or otherwise, to declare., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Although activation of autophagy is vital for cellular survival during exposure to ambient heat and exercise, it remains unclear if autophagic activity differs between these heat stress conditions and if aging mediates this response. Young [ n = 10, mean (SD): 22 (2) yr] and older males [ n = 10, 70 (5) yr] performed 30 min of semi-recumbent cycling (70% maximal oxygen uptake). On a separate day, participants were immersed in warm water for 30 min, with the water temperature adjusted to induce the same increase in core temperature (rectal) as the prior exercise bout. Proteins associated with autophagy, inflammation, apoptosis, and the heat shock response (HSR) were assessed in peripheral blood mononuclear cells via Western blot before and after each exposure and during a 6-h seated recovery in a temperate environment (∼22°C). No differences in core temperature occurred at end-exposure to exercise or passive heating in either group (both, P ≥ 0.999). Older adults exhibited greater autophagic regulation (significant LC3-II accumulation) to exercise when compared with passive heating at all time points (all, P ≤ 0.022). However, passive heating alone may have impaired autophagy (elevated p62; P = 0.044). Pro-inflammatory IL-6 was elevated during both conditions ( P < 0.001) in older adults. Conversely, greater autophagic initiation (i.e., beclin-2) occurred in young adults at end-exercise and 3-h recovery when compared with passive heating (both, P ≤ 0.024). The HSR and apoptotic responses were similar between conditions in both groups. Although brief exercise stimulates autophagy, exposure to ambient heat stress of an equivalent heat load may underlie autophagic dysregulation in older adults. NEW & NOTEWORTHY We show that a short-duration (30-min) bout of vigorous-intensity exercise stimulates autophagy in young and older males when performed in a temperate environment. However, when exposed to an equivalent heat load as achieved during the prior exercise bout to elicit the same relative increase in core temperature via warm-water immersion, autophagic dysregulation occurs in older but not younger males.

Nitric oxide synthase (NOS) is an important mediator of cutaneous vasodilation during exercise-heat stress. We recently reported that pharmacological activation of transient receptor potential ankyrin 1 (TRPA1) channel mediates cutaneous vasodilation via NOS-dependent mechanisms under nonheat stress-resting conditions. Here, we hypothesized that TRPA1 channel activation would contribute to cutaneous vasodilation during exercise in the heat via NOS-dependent mechanisms. To assess this response, we first conducted TRPA1 channel antagonist verification substudy (10 young adults and 5 women) wherein 1 mM ASP7663 (TRPA1 channel agonist) increased cutaneous vascular conductance (CVC; cutaneous blood flow divided by mean arterial pressure) and this response was blocked by ∼50% with 100 μM HC030031, a known TRPA1 channel antagonist. Subsequently, 12 young adults (5 women) completed two bouts of 30-min moderate-intensity cycling (45% of their predetermined peak oxygen uptake) in the heat (35°C). During the first exercise, CVC was evaluated at four dorsal forearm skin sites perfused with a 5% DMSO, whereas in the second bout, all sites were treated with either 1 ) a 5% DMSO (control), 2 ) 100 µM HC030031, 3 ) 20 mM l-NAME, a nonselective NOS inhibitor, or 4 ) combination of both. No between-site differences in CVC were measured during the first exercise ( P > 0.182). During the second exercise, HC030031 alone had no effect on CVC relative to the control (all P > 0.104). Both l-NAME and HC030031 + l-NAME reduced CVC (all P < 0.001), with the combined treatment showing a greater reduction (all P < 0.001). We showed that TRPA1 channels mediate cutaneous vasodilation during exercise-heat stress only when NOS is inhibited. NEW & NOTEWORTHY We demonstrated that the administration of TRPA1 channel antagonist HC030031 only appears to attenuate cutaneous vasodilation during exercise in the heat when nitric oxide synthase (NOS) is inhibited. TRPA1 channels may function as a "backup system" to maintain cutaneous vasodilation when NOS-dependent vasodilation is compromised during exercise in the heat.

Recent evidence from modelling and laboratory-based studies showed that electric fans are ineffective at lowering core temperature in older adults at air temperatures of 36°C. However, their influence on self-reported environmental symptoms and mood-state during daylong use in hot indoor environments remains unclear. Eighteen older adults (8 females, median [interquartile range]; 72 [67-76 years]) completed three randomized 8-hour heat exposures (36°C, 45% relative humidity) with a fan generating air speeds of 0 (no fan, Control), 2, or 4 m/s at the front of the body positioned 1-m away. Participants were seated throughout, except for 4 x 10-min periods of simulated activities of daily living (stepping [~2.25 METs]). Core temperature, mean skin temperature, and heart rate areas under the curve (AUC, hours 0-8) were calculated to assess cumulative physiological strain. Total symptom scores (68-item environmental symptoms questionnaire) as well as total mood disturbance and energy index (40-item profile of mood states questionnaire) were evaluated at end-heating (adjusted for pre-exposure). Core temperature, mean skin temperatures, and heart rate AUCs were not different between conditions (all P≥0.087). Total symptom scores were 0.89-fold [0.81,0.97] lower with fan use (combined across speeds) compared to no fan (P=0.009). Energy index scores were 2.4 points [0.8,4.0] higher with fan use compared to no fan (P=0.004). However, mood disturbance was not significantly different between conditions (P=0.345). Our exploratory analysis show that fans can reduce self-reported symptoms and increase perceived energy levels in older adults in overheated indoor environments, despite no meaningful attenuation of physiological strain.

Objectives: Knowledge and risk perception are driving factors for initiating appropriate health-protective actions during extreme heat events (EHEs). We sought to examine the (1) current knowledge of heat as a health threat, (2) perception of personal vulnerability to heat, (3) role of heat warnings and heat alert and response systems in initiating heat mitigating practices, and (4) opinions of community preparedness among heat-vulnerable older adults, as well as explore factors that may influence these concepts., Design: Cross-sectional survey., Setting: Canada., Participants: Individuals aged 50 years or older., Main Outcome Measures: The number of respondents and percentage of the total sample were calculated based on individual response rates to each question. To explore factors that may have influenced the respondents' understanding of heat health knowledge, awareness, and risk perception, a bootstrapped least absolute shrinkage and selection operator regression was conducted., Results: 1027 respondents (69% female, median age: 68 years) from 10 provinces/territories. Most felt knowledgeable about heat stress (74%), but many indicated that greater effort is needed to increase public awareness of EHE (64%). Self-reported responsiveness to heat alerts was also high (88%) despite many respondents reporting a low level of self-perceived risk (66%) and characteristics of heat susceptibility (eg, age, comorbidities)., Conclusions: In our sample of older Canadians, various factors influenced knowledge, perceived heat vulnerability, responsiveness to heat alerts, and perception of community preparedness. These findings can help inform public heat preparedness initiatives to ensure they align with the needs of older Canadians., Competing Interests: The authors have no funding disclosures or other conflicts of interest to report., (Copyright © 2025 Wolters Kluwer Health, Inc. All rights reserved.)

This study compares the efficacy of machine learning models to traditional biophysical models in predicting rectal (T re ) and skin (T sk ) temperatures of older adults (≥60 years) during prolonged heat exposure. Five machine learning models were trained on data using 4-fold cross validation from 162 day-long (8-9h) sessions involving 76 older adults across six environments, from thermoneutral to heatwave conditions. These models were compared to three biophysical models: the JOS-3 model, the Gagge two-node model, and an optimised two-node model. Our findings show that machine learning models, particularly ridge regression, outperformed biophysical models in prediction accuracy. The ridge regression model achieved a Root-Mean Squared Error (RMSE) of 0.27 °C for T re , and 0.73 °C for T sk . Among the best biophysical models, the optimised two-node model achieved an RMSE of 0.40 °C for T re , while JOS-3 achieved an RMSE of 0.74 °C for T sk . Of all models, ridge regression had the highest proportion of participants with T re RMSEs within clinically meaningful thresholds at 70% (<0.3 °C) and the highest proportion for T sk at 88% (<1.0 °C), tied with the JOS-3 model. Our results suggest machine learning models better capture the complex thermoregulatory responses of older adults during prolonged heat exposure. The study highlights machine learning models' potential for personalised heat risk assessments and real-time predictions. Future research should expand upon training datasets, incorporate more dynamic conditions, and validate models in real-world settings. Integrating these models into home-based monitoring systems or wearable devices could enhance heat management strategies for older adults., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Brain-derived neurotrophic factor (BDNF) is a growth factor with a range of neurological, cardioprotective, and metabolic health benefits. While passive heat stress has been observed to increase circulating BDNF, the BDNF response to a given stressor may be attenuated with increasing age. To investigate the influence of age on the BDNF response to heat stress, we compared BDNF responses to daylong (9-hours) exposure to hot ambient conditions (40°C, 9% relative humidity) between 19 young (range: 19-31 years; 9 female) and 37 older adults (61-78 years; 12 female). We also explored whether cumulative thermal strain (area under the curve of rectal and mean body temperatures) impacted comparisons. Serum BDNF concentrations were assessed at pre- and end-exposure using enzyme-linked immunosorbent assays. Circulating BDNF concentrations increased from baseline in both groups (P<0.001), but end-exposure concentrations were 2594 [1555, 3633] pg/mL lower in older than young adults (P<0.001). This age-related difference persisted, albeit to a lesser magnitude, after accounting for the lower pre-exposure BDNF levels in older adults (baseline-adjusted between-group difference: 1648 [667, 2630] pg/mL; P<0.001). Additionally, the BDNF response was not related to indices of thermal strain (P≥0.562), and baseline-adjusted between-group differences were not appreciably altered by adjusting for area under the curve of rectal (1769 [714, 2825] pg/mL; P=0.002) or mean body temperatures (1745 [727, 2763] pg/mL; P=0.001). Our study is the first to demonstrate an age-related reduction in the BDNF response to prolonged passive heat exposure, which informs our wider understanding of how environmental stressors influence BDNF responses in older adults.

Background: Cold fluid ingestion is recommended during work to maintain hydration status and physiological function. While monitoring the physiological strain index (PSI) during work in the heat is recommended, it is logistically challenging. Subjective estimates, i.e., perceptual strain index (PeSI), are thought to reflect PSI. However, it remains unclear if cold fluid influences an individual's perception of heat strain., Methods: Twenty young adults (10 females) performed four 15-min bouts of moderate-intensity (200 W/m 2 ) cycling in the heat (40°C, 13% RH), each separated by 15-min rest. On separate days, participants consumed 2 boluses consisting of 5.2 g/kg of cold (0°C) or warm fluid (37.5°C) before the first and third work bout. Rectal temperature (Tc) and heart rate (HR) were recorded to calculate PSI (0-10 scale). Rating of perceived exertion (RPE) and thermal sensation (TS) were recorded to calculate PeSI (0-10 scale). Tc, HR, TS, and RPE were compared between experimental trials and across work bouts via two-way ANOVAs. Relation between PSI, PeSI and fluid temperature were evaluated via linear mixed models. Mean bias (95% limits of agreement [LoA]) between PSI and PeSI was assessed via Bland-Altman analysis., Findings: Tc, HR, TS and RPE were not influenced by fluid temperature (P ≥ 0.09), nor was the relation between PeSI and PSI (P = 0.11). Mean bias [95% LoA] between PSI and PeSI was greater in cold (-2.1 [-5.7 - 1.5]) compared to the warm fluid condition (-1.8 [-4.8 - 1.2], P = 0.008)., Conclusion: While the relation between PeSI and PSI was not influenced by beverage temperature the agreement between measures was worsened following cold fluid ingestion., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare: support for the submitted work from Engineering and Physical Sciences Research Council, National Institute for Health and Care Research, Cancer Research UK, US National Center for Advancing Translational Sciences, Vanderbilt Institute for Clinical and Translational Research, details in the funding section. No financial relationships with any organisations that might have an interest in the submitted work in the previous three years; RDR receives royalties for the textbooks “Prognosis Research in Healthcare” and “Individual Participant Data Meta-Analysis”. RDR and GSC are Statistical Editors for the BMJ for which they receive consulting fees.

Background: Child sexual assault (CSA) is associated with mental health (MH) difficulties, both as a risk factor and as a consequence. Research is lacking on predictive factors that indicate which children attending a Sexual Assault Referral Centre (SARC) are more likely to have pre-existing MH difficulties., Objectives: (1) To identify the prevalence of pre-existing MH difficulties across children attending Saint Marys SARC in Manchester. (2) To develop and internally validate a risk prediction model for children attending SARC with pre-existing MH difficulties, which could be used to triage such patients., Methods: Our primary outcome was any history of self-reported MH difficulty and/or current psychiatric medication. We developed the predictive model for this primary outcome using logistic regression. From a list of 7 candidate predictors for potential inclusion in the model, we used stepwise selection to determine the final variables in the model. Calibration and discrimination of the model was assessed using bootstrap internal validation., Results: The analysis cohort included 492 cases of CSA (aged over 11 years). Of these, 218 cases (44.31 %) had the primary outcome. After applying variable selection, the developed prediction model included 4 predictors of MH difficulties (age, gender, location of alleged assault, and time between alleged assault and SARC attendance), and achieved good performance, upon internal validation, in terms of both calibration (calibration-in-the-large of -0.01 [-0.186, 0.162], calibration slope of 0.77 [0.52, 1.15]) and discrimination (AUC of 0.59 [0.56, 0.61])., Conclusions: Being able to predict which children attending a SARC are likely to have MH difficulties would enable proactive tailoring of interventions and swift referrals. A timely response is known to have a positive impact on children's MH outcomes., Competing Interests: Declaration of competing interest None., (Copyright © 2025. Published by Elsevier Ltd.)

Abstract: Objective: We investigated the impact of workplace heat and cold on work time loss. Methods: Field experiments in different industrial sectors were conducted in multiple countries across all seasons between 2016 and 2024. Hundreds of workers were video-recorded and their full shifts (n = 603) were analyzed on a second-by-second basis (n = 16,065,501 sec). Environmental data were recorded using portable weather stations. The Workplace Environmental Labor Loss (WELL) functions were developed to describe work time loss due to workplace temperature. Results: The WELL functions revealed a U-shaped relationship whereby the least work time loss is observed at 18 °C (64 °F), and increases for every degree above or below this optimal temperature. Conclusions: The WELL functions quantify the impact of workplace temperature on work time loss, extending to temperatures previously believed to be unaffected., Competing Interests: Conflict of Interest for All Authors: NONE DECLARED Acknowledgments:Sources of Support: The authors report no competing interests that are directly or indirectly related to this work submitted for publication. We wish to thank the Qatar Ministry of Administrative Development, Labour and Social Affairs, as well as the Supreme Committee for Delivery and Legacy for their organizational support throughout the studies conducted in Qatar. This research was funded by the European Union’s Horizon 2020 research and innovation programme (project HEAT-SHIELD; Grant agreement No 668786) and the International Labour Organization (Contract Number: 40262271/1). There are no relevant financial or other relationships that might be perceived as leading to a conflict of interest in relation to this work. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Author Contributions: Conceptualization, L.G.I and A.D.F.; methodology, L.G.I., A.D.F., G.P.K., G.H., I.B.M., and L.N.; validation, L.G.I. and A.D.F.; formal analysis, L.G.I. and A.D.F.; investigation, L.G.I., L.T., K.M., G.G., G.A., and A.D.F.; resources, L.G.I. and A.D.F.; data curation, L.G.I.; writing—original draft preparation, L.G.I. and A.D.F.; writing—review and editing, All authors; visualization, L.G.I. and A.D.F.; funding acquisition, A.D.F. All authors have read and agreed to the published version of the manuscript. Data Availability: The data supporting the findings of this study are available upon reasonable request from the corresponding authors. EQUATER Network Reporting Guidelines: This study was reported in accordance with the STROBE guidelines for observational studies (STROBE checklist is available as Supplementary Digital Content). AI Statement: No AI was utilized at any stage during research, development, design, data collection, and manuscript preparation. The authors used Grammarly to proofread for grammar and spelling errors., (Copyright © 2025 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American College of Occupational and Environmental Medicine.)

This study explores the multifaceted challenges experienced by individuals with schizophrenia during extreme heat, highlighting the interplay between individual factors, social dynamics, and environmental influences. Despite making up only 1% of the Canadian population, individuals diagnosed with schizophrenia comprised 16% (n = 97) of the deaths during the 2021 heat dome in Western Canada. However, to date, there exists scant qualitative research that explore the direct experiences and the intricacies of intersecting factors faced by individuals with schizophrenia during extreme heat events. This study aims to explore experiences of heat by those living with schizophrenia, including social, behavioural and physiological vulnerability factors that may exacerbate heat-related risks. Between October 2023 and February 2024, semi-structured interviews were conducted with 35 people with a clinical diagnosis of schizophrenia from in-patient and community settings. Participants had experienced the 2021 Heat Dome, or other extreme heat events, in a community setting within British Columbia, Canada. A descriptive form of thematic analysis that prioritizes participants' experiences was used to identify and explore patterns in the interview transcripts. Participants' narratives underscore how some symptoms of schizophrenia - such as paranoia and delusional thinking - may hinder participants' ability to seek relief from the heat and interpret bodily sensations accurately. Social isolation, compounded by societal stigma, acts as a significant barrier to accessing support networks and public resources for coping with extreme temperatures. Additionally, participants described feeling deterred from seeking medical care or public resources due to past negative experiences and social stigma. Findings illustrate various factors that contribute to the disproportionate impact of extreme heat on individuals diagnosed with schizophrenia, encapsulating both schizophrenia-specific biomedical factors as well as social vulnerability associated with their diagnosis. These findings can inform the development of a multidimensional approach that transcends individual responsibility and addresses the systemic and structural determinants of health., Competing Interests: Declaration of competing interest The authors declare they have no conflicts of interest related to this work to disclose., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The assessment of adrenergic modulation of sweating as assessed via pharmacologic administration of α- and β-adrenergic receptor blockers during exercise has yielded mixed findings. However, the underlying mechanisms for this disparity remain unresolved. We investigated the effects of separate and combined blockade of α- and β-adrenergic receptors on forearm sweating induced by a 30-min moderate-intensity exercise bout ( n = 17, protocol 1 ) and the administration of adrenergic agonists epinephrine and norepinephrine ( n = 16, protocol 2 ) in the heat. Adrenergic receptor blockade was induced via the separate and combined iontophoretic administration of terazosin (α-adrenergic receptor antagonist) and propranolol (β-adrenergic receptor antagonist) on forearm skin. Bretylium, a noradrenergic sympathetic nerve inhibitor, was also administered separately in protocol 1 . In protocol 1 , relative to the separate administration of propranolol, terazosin alone or in combination with propranolol attenuated exercise sweating to a similar extent (both P ≤ 0.037), although the effect was reduced relative to that observed with bretylium treatment ( P < 0.001). In protocol 2 , administration of propranolol increased norepinephrine- ( P = 0.029) but not epinephrine-induced sweat rate. The combined administration of terazosin reversed this response, attenuating sweating ( P < 0.001) to a greater extent than terazosin treatment alone ( P = 0.030). Altogether, we showed that although β-adrenergic receptors may interact with α-adrenergic receptors pharmacologically, it does not appear to modulate exercise-induced sweating on the forearm. Furthermore, α- but not β-adrenergic receptors independently modulate the regulation of forearm sweating during exercise in the heat. Finally, the bretylium-induced reduction in forearm sweat rate during exercise likely occurs independently of α- and β-adrenergic receptors. NEW & NOTEWORTHY Pharmacological stimulation of α- and β-adrenergic receptors produces sweating in vivo. Still, the separate and interactive roles of these adrenergic receptors during exercise and pharmacological adrenergic stimulation in the heat remain unknown. We showed that β-adrenergic receptors may interact with α-adrenergic receptors pharmacologically, but it does not modulate exercise-induced sweating. The α-adrenergic receptors independently modulate sweating during exercise in the heat. We provide important new insights into our understanding of the mechanisms regulating human sweating.

While cold acclimation can enhance thermoregulation in humans, the potential to improve cellular cold tolerance remains unknown. Thus, this work aims to evaluate the effect of a 7-day cold-water acclimation on the cytoprotective mechanism of autophagy in young males. Further, this work assesses changes in cellular cold tolerance by employing hypothermic ex vivo (whole blood) cooling prior to and following acclimation. Peripheral blood mononuclear cells are isolated before and after cold exposures on days 1, 4, and 7 of acclimation and following ex vivo cooling. Proteins associated with autophagy, apoptosis, the heat shock response, and inflammation are analyzed via Western blotting. Indicators of autophagic dysfunction paired with increased apoptotic signaling are prevalent at the beginning of acclimation. At the end of acclimation, autophagic activity increased while apoptotic and inflammatory signaling decreased. Although an elevated heat shock response is observed following cold exposure, this does not change throughout the acclimation. Further, improvements of autophagic activity are observed during ex vivo cooling along with a reduction of apoptotic signaling, albeit still elevated compared to basal levels. This work shows that 7-day cold acclimation elicits improvements in cellular cold tolerance in young males through enhanced autophagic responses concomitant with reductions in apoptotic signaling., (© 2024 The Author(s). Advanced Biology published by Wiley‐VCH GmbH.)

Achieving net-zero global emissions of carbon dioxide (CO 2 ), with declining emissions of other greenhouse gases, is widely expected to halt global warming. CO 2 emissions will continue to drive warming until fully balanced by active anthropogenic CO 2 removals. For practical reasons, however, many greenhouse gas accounting systems allow some 'passive' CO 2 uptake, such as enhanced vegetation growth owing to CO 2 fertilization, to be included as removals in the definition of net anthropogenic emissions. By including passive CO 2 uptake, nominal net-zero emissions would not halt global warming, undermining the Paris Agreement. Here we discuss measures to address this problem, to ensure residual fossil fuel use does not cause further global warming: land management categories should be disaggregated in emissions reporting and targets to better separate the role of passive CO 2 uptake; where possible, claimed removals should be additional to passive uptake; and targets should acknowledge the need for Geological Net Zero, meaning one tonne of CO 2 permanently restored to the solid Earth for every tonne still generated from fossil sources. We also argue that scientific understanding of Net Zero provides a basis for allocating responsibility for the protection of passive carbon sinks during and after the transition to Geological Net Zero., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. Springer Nature Limited.)

Objectives: To give an overview of methods for updating artificial intelligence (AI)-based clinical prediction models based on new data., Study Design and Setting: We comprehensively searched Scopus and Embase up to August 2022 for articles that addressed developments, descriptions, or evaluations of prediction model updating methods. We specifically focused on articles in the medical domain involving AI-based prediction models that were updated based on new data, excluding regression-based updating methods as these have been extensively discussed elsewhere. We categorized and described the identified methods used to update the AI-based prediction model as well as the use cases in which they were used., Results: We included 78 articles. The majority of the included articles discussed updating for neural network methods (93.6%) with medical images as input data (65.4%). In many articles (51.3%) existing, pretrained models for broad tasks were updated to perform specialized clinical tasks. Other common reasons for model updating were to address changes in the data over time and cross-center differences; however, more unique use cases were also identified, such as updating a model from a broad population to a specific individual. We categorized the identified model updating methods into four categories: neural network-specific methods (described in 92.3% of the articles), ensemble-specific methods (2.5%), model-agnostic methods (9.0%), and other (1.3%). Variations of neural network-specific methods are further categorized based on the following: (1) the part of the original neural network that is kept, (2) whether and how the original neural network is extended with new parameters, and (3) to what extent the original neural network parameters are adjusted to the new data. The most frequently occurring method (n = 30) involved selecting the first layer(s) of an existing neural network, appending new, randomly initialized layers, and then optimizing the entire neural network., Conclusion: We identified many ways to adjust or update AI-based prediction models based on new data, within a large variety of use cases. Updating methods for AI-based prediction models other than neural networks (eg, random forest) appear to be underexplored in clinical prediction research., Plain Language Summary: AI-based prediction models are increasingly used in health care, helping clinicians with diagnosing diseases, guiding treatment decisions, and informing patients. However, these prediction models do not always work well when applied to hospitals, patient populations, or times different from those used to develop the models. Developing new models for every situation is neither practical nor desired, as it wastes resources, time, and existing knowledge. A more efficient approach is to adjust existing models to new contexts ('updating'), but there is limited guidance on how to do this for AI-based clinical prediction models. To address this, we reviewed 78 studies in detail to understand how researchers are currently updating AI-based clinical prediction models, and the types of situations in which these updating methods are used. Our findings provide a comprehensive overview of the available methods to update existing models. This is intended to serve as guidance and inspiration for researchers. Ultimately, this can lead to better reuse of existing models and improve the quality and efficiency of AI-based prediction models in health care., Competing Interests: Declaration of competing interest There are no competing interests for any author., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

An ever-increasing number of workplaces are becoming heat-exposed due to rising temperature extremes. However, a comprehensive review of Canadian safety materials available to support workplaces in managing this critical hazard has not previously been conducted. We undertook a review and a content analysis of heat stress materials on safety-based ministry, association, and agency websites in Canada (n = 155) to identify content related to heat stress (n = 595). Each document was qualitatively analyzed using NVivo. The most dominant components identified were heat stress control measures (n = 492, 83%), training and education (n = 414, 70%), workplaces and workers at risk (n = 361, 61%), exposure limits and monitoring practices (n = 344, 58%), and emergency response and reporting (n = 249, 42%). However, the content within these programming components was highly variable. While we found that organizations across Canada provide heat stress content, there was evidence of inconsistencies and considerable gaps in the availability of material and the strategies presented to control the critical risk posed by heat., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Introduction: During the summer of 2021, western Canada experienced a historic and deadly extreme heat event. Simultaneously, toxic drug use and overdoses related to high-risk use of opioids and polysubstance use continued to rise across the country. However, the combined impacts of these intersecting public health crises remain poorly understood as relevant data sources are limited in Canada., Methods: We explored news media articles (n = 86, 3%) discussing toxic drug use, overdose-related deaths and the 2021 Heat Dome which were identified in a systematic review of Canadian online news media (e.g., newspaper articles, radio broadcasts) from five subscription news databases and an extensive grey literature search (n = 2909). The analyzed articles were published before, during and after the 2021 Heat Dome, and were qualitatively coded and thematically analyzed in NVivo to identify patterns of meaning across the dataset., Results: Four main themes were identified within our media-based analysis: (I) the reported impact of toxic drug use on human thermoregulation and behavioural adaptation; (II) the reported demand of intersecting crises on the health system; (III) barriers and stigma reported to influence an individual's access to or use of heat mitigation behaviours and services; and (IV) the reported impact of extreme heat on the public health response to drug poisoning emergencies., Conclusion: With increasing temperature extremes and a rising tide of toxic drug use and overdoses, our findings illustrate that there is a need for further research to better understand the combined impacts when toxic drug use, overdose-related deaths, and extreme heat coincide., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2025 Tetzlaff et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Sleep deprivation has been associated with impaired thermoregulatory function. However, whether these impairments translate to changes in whole-body heat exchange during exercise-heat stress remains unknown. Therefore, following either a night of normal sleep or 24 h of sleep deprivation, 10 young men (mean (SD): 23 (3) years) completed three 30-min bouts of semi-recumbent cycling at increasing fixed rates of metabolic heat production (150, 200, 250 W/m 2 ), each separated by a 15-min rest in dry heat (40 °C, ~ 13% relative humidity). Rates (W/m 2 ) of whole-body total heat exchange (dry + evaporative) were measured continuously and expressed as peak responses [mean of the final 5-min of exercise at the highest metabolic heat production (250 W/m 2 )]. Body heat storage was quantified as the temporal summation of heat production and loss. Core temperature, indexed by rectal temperature, was measured continuously. Relative to normal sleep, sleep deprivation did not modify whole-body heat exchange (evaporative (-6 [-18, 5] W/m 2 ; P = 0.245), or dry (7 [-5, 19] W/m 2 ; P = 0.209; sleep deprivation-normal sleep mean difference [95%CIs]) and therefore total heat loss (1 [-14, 15] W/m 2 ; P = 0.917). There were no differences in either the change in body heat storage (-9 [-67, 49] kJ; P = 0.732) or change in core temperature (0.1 [-0.1, 0.3] °C; P = 0.186) between conditions. Overall, we showed that 24-h sleep deprivation did not influence whole-body dry or evaporative heat exchange, resulting in no differences in total whole-body heat exchange or body heat storage in young adults during exercise under hot-dry conditions., Competing Interests: Declarations. Conflict of interest: No conflicts of interest, financial or otherwise, are declared by the author(s)., (© 2025. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

With mines extending deeper and rising surface temperatures, workers are exposed to hotter environments. This study aimed to characterize heat stress and strain in the Canadian mining industry and evaluate the utility of the Heat Strain Score Index (HSSI), combined with additional self-reported adverse health outcomes. An exploratory web-based survey was conducted among workers ( n  = 119) in the Canadian mining industry. The survey included 74 questions on workers' risk perception, strategies for heat stress management, and the HSSI-a validated tool to classify workplace heat stress based on various workplace factors and indicators of heat strain. Most workers reported that heat stress is an occupational hazard associated with their duties and tasks (89%). Based on the HSSI, 22% of respondents were classified as high risk, 42% at moderate risk, and 36% at low risk for heat stress and heat strain. Those with higher HSSI scores self-reported more heat-related adverse signs and symptoms with a higher prevalence of self-reported heat-related illness ( p  < 0.01). Despite workers reporting various self-initiated practices (e.g., drinking water) and management-enforced heat mitigation practices (e.g., rest breaks), many workers reported still having experienced signs or symptoms of heat stress (86%) and heat-related illnesses (37%). The study found elevated heat stress and strain levels among a sample of workers in the Canadian mining industry despite workers employing various heat-mitigating strategies. Heat stress management programs considering mining-specific factors and challenges are needed to safeguard worker health and safety.

We evaluated enterocyte damage (IFABP), microbial translocation (sCD14), and inflammatory responses (TNF-α, IL-6, CRP) in 16 older adults (66-78 years) during 8 hours rest in conditions simulating homes maintained at 22°C (control), the 26°C indoor temperature upper limit proposed by health agencies, and homes without air-conditioning during heatwaves (31°C, 36°C). Relative to 22°C, IFABP was elevated ~181 pg/mL after exposure to 31°C (P=0.07), and by ~378 pg/mL (P<0.001) after exposure to 36°C. No differences were observed for sCD14, TNF-α, IL-6, or CRP (all P≥0.26). Our data supports recommendations to maintain indoor temperatures ≤26°C to preserve gastrointestinal barrier integrity in heat-vulnerable persons.

There is increasing use of digital tools to monitor people with psychosis and schizophrenia remotely, but using this type of data is challenging. This systematic review aimed to summarise how studies processed and analysed data collected through digital devices. In total, 203 articles collecting passive data through smartphones or wearable devices, from participants with psychosis or schizophrenia were included in the review. Accelerometers were the most common device (n = 115 studies), followed by smartphones (n = 46). The most commonly derived features were sleep duration (n = 50) and time spent sedentary (n = 41). Thirty studies assessed data quality and another 69 applied data quantity thresholds. Mixed effects models were used in 21 studies and time-series and machine-learning methods were used in 18 studies. Reporting of methods to process and analyse data was inconsistent, highlighting a need to improve the standardisation of methods and reporting in this area of research., Competing Interests: Competing interests: S. Bu and J.A. are Directors and shareholders of CareLoop Health Ltd., a spin of from the University of Manchester to develop and market digital solutions for remote monitoring using smartphones for mental health conditions, currently schizophrenia, and postnatal depression. The remaining authors declare no competing interests., (© 2025. The Author(s).)

Abstract: This article provides an overview of the current evidence on the epidemiology, overlapping risk factors, and pathophysiology of cardiovascular disease (CVD) in patients with cancer. It explores the cardiotoxic effects of anticancer therapy and their impact on prognosis. Although cancer survival rates have improved over the last two decades, the risk of CVD has risen over time in patients with cancer. CVD and cancer share similar risk factors and a common pathophysiology involving inflammation. Many chemotherapeutic agents used to treat cancer are associated with cardiovascular complications (such as heart failure, myocardial infarction, and thrombosis). Current evidence indicates a significant burden of CVD in patients with cancer, particularly in the first year following cancer diagnosis, with elevated risk persisting beyond this period. This short- and long-term risk of CVD may vary depending on the cancer type and treatment regimen. Early identification of potential cardiovascular risk in patients with cancer, can lead to more favorable clinical and survival outcomes. Given the acute and long-term consequences, patients with cancer require increased cardiovascular care and lifestyle optimization. This article offers valuable insights into the cardiovascular burden and needs of patients with cancer. It is intended for a general medical research readership interested in the intersection of cardiology and oncology., (Copyright © 2024 The Chinese Medical Association, produced by Wolters Kluwer, Inc. under the CC-BY-NC-ND license.)

Purpose: Exercise-induced heat acclimation can mitigate age-related reductions in heat-loss capacity, though performing repeated bouts of strenuous exercise in the heat may be untenable for many older adults. While short-term passive heat acclimation (e.g., ≤7 days of warm-water immersion) enhances whole-body heat loss in young adults, evidence of its efficacy in older adults is lacking. Thus, we examined whether 7-days warm-water immersion would improve whole-body heat loss in older adults., Methods: Twelve habitually active older men (median [IQR] age: 68 [64-73] years; peak oxygen uptake (V̇O2peak): 34.1 [29.4-36.1] mLO2·kg-1·min-1) completed 7 consecutive days of ~90-minutes warm-water immersion (~40 °C) with core (rectal) temperature clamped at ~38.5 °C for the final 60 minutes. Before and after the warm-water immersion intervention, whole-body total (evaporative + dry) heat loss was measured via direct calorimetry during three, 30-minute bouts of cycling at increasing fixed rates of metabolic heat production (150, 200, 250 W·m-2), each separated by 15-minutes rest, in a hot-dry environment (40 °C, ~13% relative humidity). Rectal temperature and heart rate were measured continuously., Results: Following 7 days of warm-water immersion, whole-body total heat loss was elevated by 23 [95% confidence interval: 14, 31] W·m-2 across exercise bouts (acclimation-effect: P < 0.001; interaction: P = 0.598). This was paralleled by reductions in core temperature and heart rate of 0.3 [0.2, 0.4] °C and 11 [8, 14] beats·min-1 (both, acclimation-effect: P < 0.001; interaction: P = 0.288), respectively., Conclusions: Seven consecutive days of warm-water immersion improved whole-body heat loss and reduced core temperature and cardiovascular strain across light-to-vigorous intensity exercise in habitually active older men. Passive heat acclimation may be an efficacious alternative to exercise-heat acclimation to improve heat-loss capacity. Studies are warranted to assess effectiveness in more heat-vulnerable populations., Competing Interests: Conflict of Interest and Funding Source: This study was supported by the Natural Sciences and Engineering Council of Canada (all funds held by Dr. Glen P. Kenny-RGPIN-2020-03891); G.P.K is supported by a University of Ottawa Industry Research Chair. K.T.J, F.K.O, R.D.M, B.J.R, N.J.K, N.V.K, and J.J.M are supported by the Human and Environmental Physiology Research Unit, University of Ottawa. R.D.M was supported by a Canadian Institutes of Health Research Postdoctoral Fellowship. F.K.O and J.J.M were supported by a Mitacs Accelerate Fellowship (IT30924). A.D.F is supported by the University of Thessaly, Greece. The authors declare no conflicts of interest., (Copyright © 2025 by the American College of Sports Medicine.)

The process of autophagy is vital in maintaining normal cellular function, especially during exposure to elevated states of physiological stress associated with exercise and hot ambient temperatures. Although prior observations are primarily limited to responses in males, the autophagic response to acute physiological stress in females represents a considerable knowledge gap. Therefore, we assessed autophagy and related pathways of cellular stress in peripheral blood mononuclear cells (PBMCs) from 20 healthy young [ n = 10, mean (SD): aged 23 yr (3)] and older [ n = 10, aged 69 yr (3)] females in response to 30 min of semi-recumbent high-intensity cycling exercise (70% of predetermined maximal oxygen consumption) in temperate (25°C) and hot (40°C) ambient conditions (15% relative humidity). Mean body temperature (rectal and skin) was measured throughout, whereas cellular responses were evaluated before and after exercise, including up to 6 h of seated recovery. Proteins associated with autophagy and related pathways were assessed via Western blot. Mean body temperature was elevated after exercise in both conditions, with significant elevations observed after exercise in the heat (all, P ≤ 0.05). Although young females displayed signs of elevated autophagic activity [elevations in microtubule-associated light chain 3B (LC3)-II and beclin-2] in response to exercise performed in both temperate and hot ambient conditions (all, P ≤ 0.05), responses were attenuated in older females. This was accompanied by elevations in chaperone-mediated autophagy in young but not in older females in response to exercise independent of ambient temperature. Our findings indicate exercise, with and without ambient heat exposure may stimulate the autophagic response in young but not in older females. NEW & NOTEWORTHY We show for the first time that an acute bout (30 min) of high-intensity intensity exercise stimulates autophagy in young females irrespective of ambient heat exposure. However, older females did not display the same increase in autophagy as their younger counterparts when high-intensity exercise was performed in temperate or hot ambient conditions. Consequently, older females may be at an elevated risk of heat-induced cellular damage during exertional heat stress.

Background: The RESECT-90 model was developed to predict 90-day mortality for patients undergoing lung resection but hasn't been externally validated. The aim of this study was to validate the RESECT-90 clinical prediction model using multicentre patient data from across the United Kingdom (UK)., Materials and Methods: Data from 12 UK thoracic surgery centers for patients undergoing lung resection between 2016 and 2020 with available 90-day mortality status were used to externally validate the RESECT-90 model. Measures of discrimination (area under the receiving operator characteristic curve [AUC]) and calibration (calibration slope, calibration intercept and flexible calibration plot) were assessed as measures of model performance. Model recalibration was also performed by updating the original model intercept and coefficients., Results: A total of 12,241 patients were included. Overall 90-day mortality was 2.9% (n = 360). Acceptable model discrimination was demonstrated (AUC 0.74 [0.73, 0.75]). Calibration varied between centers with some evidence of overall model miscalibration (calibration slope 0.80 [0.66, 0.95] and calibration intercept 0.40 [0.29, 0.52]) despite acceptable appearances of the flexible calibration plot. The model was subsequently recalibrated, after which all measures of calibration indicated excellent performance., Conclusions: After external validation and recalibration using a large contemporary cohort of patients undergoing surgery in multiple geographical locations across the UK, the RESECT-90 model demonstrated satisfactory statistical performance for the prediction of 90-day mortality after lung resection. Whilst the recalibrated model will require ongoing validation, the results of this study suggest that routine use of the RESECT-90 model in UK thoracic surgery practice should be considered., Competing Interests: Disclosure The authors have stated that they have no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: Maximum heart rate (HRmax) is commonly used to estimate exercise intensity. Since direct measurement of HRmax is not always practical, prediction equations were developed. However, most equations have not been properly validated in adults at low and high risk of cardiovascular disease (CVD). We sought to: 1) assess the accuracy of commonly used equations to predict HRmax among adults at low and high CVD risk and, 2) determine if SuperLearner (SL) modeling combining base machine algorithms could improve HRmax prediction., Methods: A total of 1208 participants (61.6 ± 7.3 yr; 62.7% male) were included. HRmax was measured during a maximal cardiorespiratory exercise test. Predicted HRmax was estimated using the following published equations: Fox, Åstrand, Tanaka, Gelish and Gulati, and a SL model. Bland-Altman analyses as well as performance indicators such as root mean squared error (RMSE) and Lin's Concordance Correlation Coefficient were performed., Results: All predicted HRmax-derived equations were positively associated with measured HRmax (women: r = 0.31; men: r = 0.46, P ≤ 0.001) but to a greater extent using a SL model (women: r = 0.47; men: r = 0.59, P ≤ 0.001). Overall, all equations tended to overestimate measured HRmax, with a RMSE which varied between 10.4 and 12.3 bpm. Although the SL model outperformed other equations, with no significant difference between measured and predicted HRmax, RMSE remained high (11.3 bpm). Lack of accuracy was mainly observed among adults with low aerobic fitness and with CVD risk factors, such as obesity, diabetes, and hypertension., Conclusions: We showed that commonly used equations and the SL model have insufficient accuracy to predict HRmax among adults. The performance of the prediction equations varied considerably according to the population clinical characteristics such as the presence of CVD risk factors or a low aerobic fitness., (Copyright © 2024 by the American College of Sports Medicine.)

Cytomegalovirus (CMV) infections continue to be associated with significant morbidity and mortality following solid organ transplantation and haemopoietic stem cell transplantation. Advances in understanding the biology of CMV in the immunosuppressed host will translate into improved management approaches and better clinical outcomes. Updated definitions of resistant and refractory CMV infections will lead to more consistent reporting of CMV outcomes, better inform appropriate antiviral strategies and influence clinical trial design. Improved knowledge of the immunological control of CMV in the immunosuppressed host has led to novel diagnostics, emerging therapeutic cellular therapies and the development of an informed rationale for prophylactic and pre-emptive strategies. As the boundaries of transplantation are extended, new patterns of CMV infection are being recognised. Finally, recent studies support the use of novel antiviral therapies in transplant recipients in the appropriate clinical setting. In this review, we provide an update on important new and emerging concepts in the management of CMV in immunosuppressed transplant recipients., (© 2024 Royal Australasian College of Physicians.)

Introduction: Due to rising temperature extremes, workplaces are seeking new solutions, such as using personal cooling garments (PCG) to mitigate and manage workplace heat exposure. This systematic review sought to assess the physiological and perceptual effects of PCGs on workers in standard work clothing performing moderate-to-heavy intensity tasks in hot environments., Methods: A peer-reviewed search strategy was conducted in MEDLINE, Embase, CINAHL, Scopus, Global Health, and Business Source Complete with no language or time limits. A meta-analysis using a realist evaluation framework was then performed to evaluate the effectiveness of the PCGs., Results: Thirty-three studies with 764 participants (98% male; average 21 ± 34 participants per study), conducted primarily in a laboratory setting (76%) were included. The studies were 193 ± 190 min in duration and consisted of a moderate-to-heavy work effort of 3.3 ± 1.0 METs in hot ambient conditions (temperature: 35.9 ± 3.3°C, 51.4 ± 12.1% relative humidity, wet bulb globe temperature [WBGT] 31.2 ± 2.6°C). The PCGs (n = 67) facilitated heat exchange through conduction (n = 39), evaporation (n = 4), convection (n = 2), radiation (n = 2), or hybrid combinations (n = 20). Conductive and hybrid PCGs offered the greatest thermoregulatory benefit, whereby core temperature (T c ) and heart rate (HR) reductions were consistently observed (Conductive: T c : -0.3°C, HR: -12 bpm; Hybrid: T c :-0.2°C, HR: -10 bpm), while PCGs directed at enhancing evaporative and radiative heat exchange had no or minimal effect on the physiological outcomes assessed (i.e., T C  < 0.1°C, HR: < 0.7 bpm)., Conclusion: While the PCGs had a positive overall effect, conductive options offered the most consistent benefit to workers. WBGT, clothing insulation, and duration of wear significantly affected some physiological and perceptual outcomes., (© 2024 The Author(s). American Journal of Industrial Medicine published by Wiley Periodicals LLC.)

Background: With the growing threat posed by extreme heat, heat-health messaging communicated by public health authorities is critical for raising community awareness and action. This study sought to (i) identify what heat-health content is shared online by Canadian public health authorities and (ii) analyse the material to develop an understanding of the content included within the resources., Study Design: Qualitative content analysis., Methods: We reviewed public health authority websites in Canada (n = 99) and extracted all available heat-health content. Content analysis of each resource was performed using descriptive codes related to three categories - populations at greater risk, actions to reduce risk and awareness and knowledge., Results: Within the public health authority websites searched, 417 webpages and online resources were identified (range: 1-43). Over half of the material came from regional health authorities (56 %), primarily located in Ontario and British Columbia (60 %). At least one population at greater risk of heat stress (e.g., older adults, children) (range: 0-24) was mentioned in 59 % of the materials, 81 % mentioned at least one action or behaviour to reduce risk (e.g., stay hydrated) (range: 0-40), and 91 % provided material related to raising awareness and knowledge (range: 0-12)., Conclusions: Although a wide array of webpages and online resources were identified, the material content and availability varied considerably across authorities and provinces and territories. These results provide important insights into the composition of heat-health webpages and online resources within Canada and can help guide relevant revisions and additions to the existing heat-health materials., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Objectives: Heat-health communication initiatives are a key public health protection strategy. Therefore, understanding the potential challenges that all Canadians and specific groups, such as those facing literacy barriers and non-native language speakers, may experience in accessing or interpreting information, is critical., Methods: This study reviewed and evaluated the language availability, readability, suitability, and comprehensibility of heat-related webpages and online resources ( n = 417) published on public health authority websites in Canada ( n  = 73). Six validated readability scales and a comprehensibility instrument were used., Results: Most content was presented in English (90 %); however, only 7 % of the online resources were available in more than one language. The average reading grade level of the content (grade 8) exceeded the recommended level (grade 6), and only 22 % of the content was deemed superior for suitability and comprehensibility., Conclusions: Our study evaluating web-based materials about extreme heat published by Canadian health authorities provides evidence that the current language availability, readability, suitability, and comprehensibility may be limiting the capacity for members of the public to discern key messaging., Innovation: To ensure all Canadians can access and interpret information related to heat-health protection, public health authorities may consider translating their materials into additional languages and incorporating a readability evaluation to improve public understanding., Competing Interests: The authors report there are no competing interests to declare., (© 2024 The Author(s).)

Tuberculosis remains a leading cause of death by infectious disease. The long treatment regimen and the spread of drug-resistant strains of the causative agent Mycobacterium tuberculosis (Mtb) necessitates the development of new treatment options. In a phenotypic screen, nitrofuran-resorufin conjugate 1 was identified as a potent sub-micromolar inhibitor of whole cell Mtb. Complete loss of activity was observed for this compound in Mtb mutants affected in enzyme cofactor F 420 biosynthesis (fbiC), suggesting that 1 undergoes prodrug activation in a manner similar to anti-tuberculosis prodrug pretomanid. Exploration of the structure-activity relationship led to the discovery of novel resorufin analogues that do not rely on the deazaflavin-dependent nitroreductase (Ddn) bioactivation pathway for their antimycobacterial activity. These analogues are of interest as they work through an alternative, currently unknown mechanism that may expand our chemical arsenal towards the treatment of this devastating disease., (© 2024 The Author(s). ChemMedChem published by Wiley-VCH GmbH.)

Purpose: To investigate whether macular perfusion density (PD) changes measured over time by optical coherence tomography angiography (OCTA) are detectable before progressive macular ganglion cell layer (GCL) thinning in early glaucoma., Methods: This prospective longitudinal cohort study involved patients with early open-angle glaucoma and healthy subjects imaged by OCT and OCTA every 4 months. GCL thickness and macular PD were evaluated in 16 tiles in the macula. We estimated baseline percentage losses of GCL thickness or macular PD in glaucoma patients with age-corrected normative values derived from the healthy subjects. Additionally, the threshold slope separating glaucoma patients from healthy subjects with 90% specificity was used to determine the number of patients with steeper slopes than the threshold slope., Results: Eighty patients with glaucoma and 42 healthy subjects were included. In eight tiles (50%), patients with a significant macular PD slope had a significantly greater baseline percentage loss of GCL thickness relative to macular PD compared to patients without a significant macular PD slope. Furthermore, in 15 tiles (94%), a greater baseline percentage loss of GCL thickness relative to PD was significantly correlated with faster PD slopes. In contrast, only one tile (6%) showed these significant trends for GCL slopes. The number of patients with faster GCL slopes than threshold slopes was significantly larger than patients with faster PD slopes in 12 tiles (75%)., Conclusions: A decrease in GCL thickness precedes a measurable decrease in macular PD. Early glaucomatous progression is more frequently detectable with changes in GCL thickness compared to macular PD.

Background: To mitigate health risks associated with occupational heat stress, workers are advised to adhere to a work-rest regimen, and hydrate regularly. However, it remains unclear if beverage temperature influences whole-body heat exchange during work-rest cycles, and if responses differ in older workers who have a blunted heat loss capacity., Methods: Ten young (mean [SD]: 22 [3] years) and 10 older (60 [4] years) males performed four 15-min bouts of moderate-intensity cycling at a fixed rate of metabolic heat production (200 W·m -2 ), each interspersed by 15-min rest in dry heat (40°C, ~12% relative humidity). On separate days, participants consumed either ice-slurry (~0°C), standardized to provide a heat transfer capacity of 75 kJ·m -2 , or an identical mass of warm fluid (37.5°C) before the first and third exercise bouts. Evaporative and dry heat exchange (direct calorimetry) and metabolic heat production (indirect calorimetry) were measured continuously to determine cumulative heat storage (summation of heat loss and heat gain) over the entire protocol. Rectal temperature was also measured continuously., Results: Relative to warm fluid, ice-slurry ingestion reduced cumulative heat storage in young (69 [181] vs. 216 [94] kJ) and older males (90 [104] vs. 254 [140] kJ, main effect: p < 0.01), but was unaffected by age (p = 0.49). However, rectal temperature was unaffected by beverage temperature in both groups (all p ≥ 0.15)., Conclusion: We show that cold fluid ingestion is an appropriate administrative control for both young and older males as it can mitigate increases in body heat content during moderate-intensity work-rest cycles in dry heat., (© 2024 The Author(s). American Journal of Industrial Medicine published by Wiley Periodicals LLC.)

We evaluated reactive oxygen species (ROS) modulation of cutaneous vasodilation during local and whole body passive heating in young and older adults. Cutaneous vascular conductance normalized to maximum vasodilation (%CVC max ) was assessed in young and older adults (10/group) using laser-Doppler flowmetry at four dorsal forearm sites treated with 1 ) Ringer solution (control), 2 ) 100 µM apocynin (NADPH oxidase inhibitor), 3 ) 10 µM allopurinol (xanthine oxidase inhibitor), or 4 ) 10 µM tempol (superoxide dismutase mimetic), via intradermal microdialysis during local ( protocol 1 ) and whole body heating ( protocol 2 ). In protocol 1 , forearm skin sites were set at 33°C during baseline and then progressively increased to 39°C and 42°C (30 min each). In protocol 2 , participants were immersed in warm water (35°C, midsternum) with the experimental forearm above water level, and local skin sites were maintained at 34°C. Bath temperature was increased (∼40°C) to clamp core temperature at 38.5°C for 60 min. In protocol 1 , there were significant treatment site by age interactions for the 39°C ( P = 0.015) and 42°C ( P = 0.004) plateaus; however no significant effects were observed after post hoc adjustment. In protocol 2, there was a significant treatment site by age interaction ( P < 0.001), where %CVC max in older adults was 11.0% [7.4, 14.6] higher for apocynin ( P < 0.001), 8.9% [5.3, 12.5] higher for allopurinol ( P < 0.001), and 4.8% [1.3, 8.4] higher for tempol ( P = 0.016) sites relative to the control site. ROS derived from NADPH oxidase and xanthine oxidase attenuate cutaneous vasodilation in older adults during passive whole body heating, but not during local skin heating, with negligible effects on their young counterparts for either heating modality. NEW & NOTEWORTHY We found that local infusion of apocynin or allopurinol improved cutaneous vasodilator responses to passive whole body heating (but not local skin heating) in healthy older adults. These findings indicate that impaired microvascular responses to whole body heating with primary aging are linked to augmented production of reactive oxygen species (ROS) from NADPH oxidase and xanthine oxidase. This study sheds new light on the specific ROS pathways that modulate age-related changes in cutaneous microvascular responses to heating.

Heart rate variability (HRV) has shown potential as a tool for monitoring thermal strain, but there is limited data to support its efficacy in older adults during prolonged heat exposures. We compared HRV between young (19-31 years, n  = 20) and older (61-78 years, n  = 39) adults during 9 h of heat exposure (40 °C, 9% RH). We also explored whether heart rate (HR) and/or HRV could be used to distinguish older adults who achieved elevated thermal strain, defined as either (1) an increase in core temperature >1.0 °C (occurring in 39%, 15/39) or (2) a reduction in systolic blood pressure >10 mm Hg (occurring in 67%, 26/39). Percentage of age-predicted maximal HR and percentage of heart rate reserve (HRR) were higher, whereas standard deviation of normal RR intervals, the square root of the mean of squared differences between successive RR intervals (RMSSD), high frequency power (HF), and cardiac vagal index (CVI) were lower in older compared to young adults during heat exposure ( P  ≤ 0.004). In older adults, increases in core temperature were correlated with percentage of age-predicted maximal HR, percentage of HRR, RMSSD, and CVI ( P  ≤ 0.031), whereas changes in systolic blood pressure were not significantly associated with HR or HRV indices ( P  ≥ 0.327). Receiver operating characteristic curve analysis indicated that HR and HRV indices had generally poor ability to identify older adults with elevated thermal strain (area under the curve ≤0.65). Age-related differences in HRV, consistent with vagal withdrawal among older adults, remained during daylong heat exposure, but marked heterogeneity of response likely contributed to HRV providing limited discriminatory value in identifying changes in core temperature or blood pressure in older adults., Competing Interests: The authors declare there are no competing interests.

This corrects the article doi: 10.25270/jic/21.00036.

Foot immersion and neck cooling are recommended cooling strategies for protecting heat-vulnerable persons during heat waves. While we recently showed that these strategies do not limit core temperature increases in older adults during prolonged heat exposure, we did observe small reductions in heart rate. Expanding on these findings, we examined the effects of foot immersion with and without neck cooling on cardiac autonomic function. Seventeen adults (9 females; 65-81 years) underwent 3 randomized, 6 h exposures to 38 °C and 35% relative humidity with: no cooling (control), foot immersion (20 °C water), or foot immersion with a wet towel (20 °C) around the neck. Cardiac autonomic responses were measured at baseline and end-exposure. These included heart rate variability, cardiac and systolic blood pressure responses to standing, indexed via the 30:15 ratio and supine-to-standing systolic pressure change, respectively, and baroreflex sensitivity during repeated sit-to-stand maneuvers. The 30:15 ratio was 0.04 [95% CI: 0.01, 0.07] greater with foot immersion and neck cooling (1.08 (SD: 0.04)) relative to control (1.04 (0.06); P  = 0.018). Similarly, standing systolic blood pressure was elevated 9 [0, 17] mmHg with foot immersion and neck cooling ( P  = 0.043). That said, neither difference remained statistically significant after adjusting for multiplicity ( P adjusted  ≥ 0.054). No differences in 30:15 ratio or standing systolic blood pressure were observed with foot immersion alone, while heart rate variability and baroreflex sensitivity were unaffected by either cooling intervention. While foot immersion with neck cooling potentially improved cardiac autonomic responses in older adults exposed to simulated indoor overheating, these effects were small and of questionable clinical importance., Competing Interests: GPK, RDM, JJM, PB, and RJS reported receiving grants from the Canadian Institutes of Health Research and Health Canada. No other disclosures are declared by the authors.

While monitoring physiological strain is recommended to safeguard workers during heat exposure, it is logistically challenging. The perceptual strain index (PeSI) is a subjective estimate thought to reflect the physiological strain index (PSI) that requires no direct monitoring. However, advanced age and chronic diseases (hypertension/type 2 diabetes [T2D]) influence the perception of heat stress, potentially limiting the utility of the PeSI. We therefore assessed whether the relation and agreement between the PeSI and PSI during simulated work in various environmental conditions is modified by age and T2D/hypertension. Thirteen young adults and 37 older adults without ( n  = 14) and with T2D ( n  = 10) or hypertension ( n  = 13) walked on a treadmill (∼200 W/m 2 ) for 180 min or until termination (volitional fatigue, rectal temperature ≥39.5 °C) in 16, 24, 28, and 32 °C wet-bulb globe temperatures. Rectal temperature and heart rate were recorded to calculate PSI (0-10 scale). Rating of perceived exertion and thermal sensation were recorded to calculate PeSI (0-10 scale). The relation between hourly PSI and PeSI was assessed via linear mixed models. Mean bias (95% limits of agreement [LoA]) between PSI and PeSI was assessed via Bland-Altman analysis. PSI increased with PeSI ( p  < 0.001), but the slope of this relation was not different between young and older adults ( p  = 0.189) or as a function of chronic disease (within older adults; p  = 0.183). The mean bias between PSI and PeSI was small (0.02), but the 95% LoA was wide (-3.3-3.4). Together, a linear relation between PeSI and PSI was observed but agreement between these measures varied considerably across individuals and thus PeSI should not be used as a surrogate marker of PSI. Caution should be taken when utilizing the PeSI to estimate physiological strain on workers.

Background: Capsule sponge testing, using an oesophageal cell collection device with biomarkers, was implemented nationally across Scotland in 2020 for symptomatic reflux patients referred to secondary care for non-urgent endoscopy. The aim was to use capsule sponge testing as a triage tool to reduce pressures on the endoscopy service during COVID-19, focus endoscopy resources on those most likely to have pathology and streamline the patient pathway. This prospective cohort study presents the first real-world results and evaluates the clinical application of capsule sponge testing in symptomatic reflux disease based on endoscopic biopsy results., Methods: Over a 32-month period, all patients undergoing capsule sponge testing for investigation of reflux symptoms across 11 Scottish health boards were identified from prospectively maintained databases. Individual patient records were interrogated to collect baseline demographics, capsule sponge test result (TFF3/atypia/p53) and ongoing clinical management. Further analysis was performed on patients who subsequently underwent upper gastrointestinal (UGI) endoscopy., Results: 1385 tests were performed for reflux symptoms in 1305 patients. The median follow-up time was 20 months (IQR 12-27). 1103/1385 tests (79.6%) were negative for biomarkers. 913/1305 (70.0%) patients were discharged with no additional investigation required. 355/1305 patients (27.2%) underwent UGI endoscopy due to a positive or insufficient result or ongoing symptoms. With insufficient tests excluded, 52/314 patients (16.6%) had intestinal metaplasia (IM) on endoscopic biopsies, which strongly correlated with positive biomarkers (88.5% vs. 11.5%; p < 0.001), including 1 case of dysplasia. 10/1103 sponge negative patients (0.9%) had biopsies demonstrating IM (n = 6) or malignancy (n = 4): 1 patient was diagnosed with oesophageal adenocarcinoma 27 months later and 3 patients had gastric malignancy, which relies on symptom assessment to direct to endoscopy since the capsule sponge is an oesophageal test., Conclusions: Capsule sponge testing is effectively at identifying the 30% of symptomatic reflux patients requiring further investigation with UGI endoscopy and aiding the diagnosis of Barrett's oesophagus in clinical practice. Judicious follow-up of the discharged group will be critical to validate the ongoing use of capsule sponge testing long-term., Competing Interests: Declarations. Ethics approval and consent to participate: Ethical approval was obtained via local information governance teams in each health board, in addition to Public Benefit and Privacy (PBPP) approval on a national level from the Caldicott guardian (NHS Scotland Public Benefit and Privacy Panel for Health and Social Care; NHS Scotland). This was approved with the need for individual patient consent waived due to the retrospective nature of data collection and for the purposes of service development as per NHS Scotland PBPP for Health and Social Care. All patients signed a National Health Service (NHS) consent form prior to the procedure. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Acenes are notable for their optoelectronic properties and applications in organic electronics. Starphenes are structurally related molecules possessing three acene arms that radiate linearly from a central benzene ring (i. e., linearly annellated triphenylenes). Large starphenes have been prepared using convergent syntheses involving transition metal catalyzed cyclotrimerizations of either preformed acenes or arynes. Here, we report a one-pot divergent synthesis of a 13-ring triquinone that is readily converted to a [4.4.4]tridecastarphene derivative. The one-pot procedure involves the sequential reactions of three 1,4-anthraquinones with o-quinodimethane derivatives that are generated sequentially from a stable, trisulfone precursor. The resulting [4.4.4]tridecastarphene derivative bearing p-(t-butyl)phenyl substituents was characterized by 1 H NMR, 13 C NMR and UV-vis spectroscopies, as well as mass spectrometry, cyclic voltammetry and differential pulse voltammetry. Theoretical and experimental studies reveal a relatively high-lying HOMO orbital (about -4.70 to -4.86 eV) and a relatively small HOMO-LUMO gap (2.1 eV), suggesting utility as a p-type organic semiconductor. Our [4.4.4]tridecastarphene derivative photooxidizes in a CH 2 Cl 2 solution exposed to ambient light and air with a half-life of 150 minutes at room temperature, but shows no sign of degradation after 12 months in the solid-state. Our [4.4.4]tridecastarphene derivative also shows excellent solubility in a number of organic solvents including dichloromethane, chloroform and toluene, potentially enabling printed electronic applications., (© 2024 Wiley-VCH GmbH.)

Background: Elevated body mass index (BMI) ≥25 kg/m 2 is a major preventable cause of cancer. A single BMI measure does not capture the degree and duration of exposure to excess BMI. We investigate associations between adulthood overweight-years, incorporating exposure time to BMI ≥25 kg/m 2, and cancer incidence, and compare this with single BMI., Methods: In this cohort study and individual participant data meta-analysis, we obtained data from the ABACus 2 Consortium, consisting of four US cohorts: Atherosclerosis Risk in Communities (ARIC) study (1987-2015), Women's Health Initiative (WHI; 1991 to 2005 [main study], to 2010 [Extension 1], and to 2020 [Extension 2]), Prostate, Lung, Colorectal, Ovarian Cancer Screening (PLCO) Trial (1993-2009), NIH-AARP Diet and Health Study (1996-2011), and one European cohort, the European Prospective Investigation into Cancer and Nutrition (EPIC; participants enrolled in 1990 and administrative censoring was centre-specific). Participants with at least 3 BMI measurements and complete cancer follow-up data were included. We calculated overweight-years: degree of overweight (BMI ≥25 kg/m 2 ) multiplied by the duration of overweight (years). Using random effects two-stage individual participant data meta-analyses, associations between cancer and overweight-years, single BMI, cumulative overweight degree and duration, measured at the same time and captured over a median of 41 years in men and 39 years in women, were evaluated with Cox proportional hazards models. Models were age-adjusted or multivariable (MV) adjusted for baseline age, ethnicity, alcohol, smoking and hormone replacement therapy (HRT). Harrell's C-statistic of metrics were compared. This study is registered at PROSPERO, CRD42021238270., Findings: 720,210 participants, including 312,132 men and 408,078 women, were followed up for cancer incidence over a median 9.85 years (interquartile range (IQR) 8.03, 11.67) in men and 10.80 years (IQR 6.05, 15.55) in women. 12,959 men (4.15%) and 36,509 women (8.95%) were diagnosed with obesity-related cancer. Hazard ratios for obesity-related cancers in men, per 1 standard deviation (SD) overweight-years were 1.15 (95% CI: 1.14, 1.16, I 2 : 0) age-adjusted and 1.15 (95% CI: 1.13, 1.17, I 2 : 0%) MV-adjusted and per 1SD increment in single BMI were 1.17 (95% CI: 1.16, 1.18, I 2 : 0) age-adjusted and 1.16 (95% CI: 1.15, 1.18, I 2 : 0%) MV-adjusted. The HR for overweight-years in women per 1 SD increment was 1.08 (95% CI: 1.04, 1.13, I 2 : 82%) age-adjusted and 1.08 (95% CI: 1.04, 1.13, I 2 : 83%) MV-adjusted and per 1SD increment in single BMI was 1.10 (95% CI: 1.07, 1.14, I 2 : 72%) age-adjusted and 1.11 (95% CI: 1.07, 1.15, I 2 : 79%) MV-adjusted. C-statistics for overweight-years and single BMI for obesity-related cancers were 0.612 (95% CI: 0.578, 0.646) and 0.611 (95% CI: 0.578, 0.644) respectively for men and 0.566 (95% CI: 0.534, 0.598) and 0.573 (95% CI: 0.546, 0.600) for women., Interpretation: Adulthood degree and duration of excess BMI were associated with cancer risk. Both factors should be considered in cancer prevention strategies and policies. This study only focused on adulthood exposure to excess BMI, so the minimal differences in the predictive performance between adiposity metrics may be due to underestimation of cumulative excess BMI exposure., Funding: Cancer Research UK, the Manchester NIHR Biomedical Research Centre, the National Cancer Institute, the National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services, U.S. Department of Health and Human Services, the Intramural Research Program of the National Cancer Institute, the International Agency for Research on Cancer, Imperial College London, European Commission (DG-SANCO), the Danish Cancer Society, Ligue Contre le Cancer, Institut Gustave-Roussy, Mutuelle Générale de l'Education Nationale, Institut National de la Santé et de la Recherche Médicale, Deutsche Krebshilfe, Deutsches Krebsforschungszentrum, German Federal Ministry of Education and Research, the Hellenic Health Foundation, Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy and National Research Council, Dutch Ministry of Public Health, Welfare, and Sports, Netherlands Cancer Registry, LK Research Funds, Dutch Prevention Funds, Dutch Zorg Onderzoek Nederland, World Cancer Research Fund, Statistics Netherlands, Health Research Fund, Instituto de Salud Carlos III, regional Spanish governments of Andalucía, Asturias, Basque Country, Murcia, and Navarra, the Catalan Institute of Oncology, Swedish Cancer Society, Swedish Scientific Council, and Region Skåne and Region Västerbotten, and the Medical Research Council., Competing Interests: NH, MS, GPM, RS, CEM, FR, AT, AKH, HF, MJG, and AGR declare no competing interests. EAP received a National Institutes of Health research grant; an award made to Johns Hopkins University for the manuscript. MN received funding for the paper from the National Heart Lung and Blood Institute, National Institutes of Health to the Institution (Fred Hutchinson Cancer Center). MN receives funding as the Deputy Editor of, Journal of Nutrition. CJ received the American Cancer Society's support for the present manuscript and the following grants or contracts to the institution, Johns Hopkins University, from the National Institutes of Health, Prostate Cancer Foundation, The Ralph Lauren Corporate Foundation, Department of Defense., (© 2024 The Authors.)

Background and Aims: Risk stratification of sudden cardiac death after myocardial infarction and prevention by defibrillator rely on left ventricular ejection fraction (LVEF). Improved risk stratification across the whole LVEF range is required for decision-making on defibrillator implantation., Methods: The analysis pooled 20 data sets with 140 204 post-myocardial infarction patients containing information on demographics, medical history, clinical characteristics, biomarkers, electrocardiography, echocardiography, and cardiac magnetic resonance imaging. Separate analyses were performed in patients (i) carrying a primary prevention cardioverter-defibrillator with LVEF ≤ 35% [implantable cardioverter-defibrillator (ICD) patients], (ii) without cardioverter-defibrillator with LVEF ≤ 35% (non-ICD patients ≤ 35%), and (iii) without cardioverter-defibrillator with LVEF > 35% (non-ICD patients >35%). Primary outcome was sudden cardiac death or, in defibrillator carriers, appropriate defibrillator therapy. Using a competing risk framework and systematic internal-external cross-validation, a model using LVEF only, a multivariable flexible parametric survival model, and a multivariable random forest survival model were developed and externally validated. Predictive performance was assessed by random effect meta-analysis., Results: There were 1326 primary outcomes in 7543 ICD patients, 1193 in 25 058 non-ICD patients ≤35%, and 1567 in 107 603 non-ICD patients >35% during mean follow-up of 30.0, 46.5, and 57.6 months, respectively. In these three subgroups, LVEF poorly predicted sudden cardiac death (c-statistics between 0.50 and 0.56). Considering additional parameters did not improve calibration and discrimination, and model generalizability was poor., Conclusions: More accurate risk stratification for sudden cardiac death and identification of low-risk individuals with severely reduced LVEF or of high-risk individuals with preserved LVEF was not feasible, neither using LVEF nor using other predictors., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Although the demand for allografts continuously surpasses the supply, the majority of lungs offered for transplant are declined based on various factors, including donor age. This in turn sustains the wait-list mortality of patients with end-stage pulmonary disease., Methods: In this single-center, observational cohort study, we investigated the impact of donor age on graft survival. We additionally compared our center's data to data reported to the International Society for Heart and Lung Transplantation (ISHLT) Thoracic Organ Transplant Registry. Kaplan-Meier method was used to describe overall graft survival. Multivariate Cox proportional hazards regression was used to assess clinical features associated with graft loss., Results: Between January 2010 and December 2023, Alfred performed 1,101 single and double lung transplants and the combined ISHLT cohort totaled 32,200 transplants. At Alfred, grafts originating from donors ≥65 years were used in 13.3% of lung transplant cases and univariate analysis showed no impact of donor age ≥65 on graft survival (hazard ratio [HR] 0.86, p = 0.34). In the combined cohort, North America had a lower proportion of donors aged ≥65 years compared to Europe and the Alfred (2.4% vs 9.8% vs 13.3%, p < 0.001). The univariate analysis showed a negative impact of donor age ≥65 on graft survival (HR 1.16, p < 0.001). However, this did not hold in a multivariate model (HR 1.06, p = 0.298) when adjusted for center experience and recipient characteristics., Conclusions: Donor age might impact outcomes to a lesser degree than previously suggested. Therefore, appropriately assessed age-extended lungs should be routinely considered for lung transplantation., Competing Interests: Disclosure statement A.M.D. reports grants from the University Hospital Basel, and Lungitude Foundation, lecture honoraria from AstraZeneca, GSK and Sanofi, travel support from OrPha Swiss, MSD and Janssen, and advisory board participation with Gebro Pharma, Janssen and MSD outside submitted work. M.P. reports the positions as ESHLT Treasurer and board member for Scandiatransplant, roles within ISHLT Thoracic Transplant Registry, and ERS 8.02 Group, an institutional grant from PulmonX, consulting fees from rhyme medical, Takeda, Zambon, and TTF, lecture honoraria from AstraZeneca outside submitted work. B.J.L., H.V.S., M.A.P., K.V., S.L.E., G.P.W., and G.I.S. have nothing to report. We would like to thank Dr Wida Cherikh, principal biostatistician and manager of the United Network of Organ Sharing Research Department, for reviewing our manuscript and Dr Zakary Doherty, research fellow at Monash University, for his support with the data analysis. Andrei Darie would like to thank the University of Basel and Freiwillige Akademische Gesellschaft Basel for the research grants supporting the present work., (Copyright © 2024 International Society for the Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)