Global and Regional Cardiovascular Mortality Attributable to Nonoptimal Temperatures Over Time.

BACKGROUND: The association between nonoptimal temperatures and cardiovascular mortality risk is recognized. However, a comprehensive global assessment of this burden is lacking. OBJECTIVES: The goal of this study was to assess global cardiovascular mortality burden attributable to nonoptimal temperatures and investigate spatiotemporal trends. METHODS: Using daily cardiovascular deaths and temperature data from 32 countries, a 3-stage analytical approach was applied. First, location-specific temperature-mortality associations were estimated, considering nonlinearity and delayed effects. Second, a multivariate meta-regression model was developed between location-specific effect estimates and 5 meta-predictors. Third, cardiovascular deaths associated with nonoptimal, cold, and hot temperatures for each global grid (55 km × 55 km resolution) were estimated, and temporal trends from 2000 to 2019 were explored. RESULTS: Globally, 1,801,513 (95% empirical CI: 1,526,632-2,202,831) annual cardiovascular deaths were associated with nonoptimal temperatures, constituting 8.86% (95% empirical CI: 7.51%-12.32%) of total cardiovascular mortality corresponding to 26 deaths per 100,000 population. Cold-related deaths accounted for 8.20% (95% empirical CI: 6.74%-11.57%), whereas heat-related deaths accounted for 0.66% (95% empirical CI: 0.49%-0.98%). The mortality burden varied significantly across regions, with the highest excess mortality rates observed in Central Asia and Eastern Europe. From 2000 to 2019, cold-related excess death ratios decreased, while heat-related ratios increased, resulting in an overall decline in temperature-related deaths. Southeastern Asia, Sub-Saharan Africa, and Oceania observed the greatest reduction, while Southern Asia experienced an increase. The Americas and several regions in Asia and Europe displayed fluctuating temporal patterns. CONCLUSIONS: Nonoptimal temperatures substantially contribute to cardiovascular mortality, with heterogeneous spatiotemporal patterns. Effective mitigation and adaptation strategies are crucial, especially given the increasing heat-related cardiovascular deaths amid climate change.

Effects of the interaction between cold spells and fine particulate matter on mortality risk in Xining: a case-crossover study at high altitude.

Background: With global climate change, the health impacts of cold spells and air pollution caused by PM2.5 are increasingly aggravated, especially in high-altitude areas, which are particularly sensitive. Exploring their interactions is crucial for public health. Methods: We collected time-series data on meteorology, air pollution, and various causes of death in Xining. This study employed a time-stratified case-crossover design and conditional logistic regression models to explore the association between cold spells, PM2.5 exposure, and various causes of death, and to assess their interaction. We quantitatively analyzed the interaction using the relative excess odds due to interaction (REOI), attributable proportion due to interaction (AP), and synergy index (S). Moreover, we conducted stratified analyses by average altitude, sex, age, and educational level to identify potential vulnerable groups. Results: We found significant associations between cold spells, PM2.5, and various causes of death, with noticeable effects on respiratory disease mortality and COPD mortality. We identified significant synergistic effects (REOI>0, AP > 0, S > 1) between cold spells and PM2.5 on various causes of death, which generally weakened with a stricter definition of cold spells and longer duration. It was estimated that up to 9.56% of non-accidental deaths could be attributed to concurrent exposure to cold spells and high-level PM2.5. High-altitude areas, males, the older adults, and individuals with lower educational levels were more sensitive. The interaction mainly varied among age groups, indicating significant impacts and a synergistic action that increased mortality risk. Conclusion: Our study found that in high-altitude areas, exposure to cold spells and PM2.5 significantly increased the mortality risk from specific diseases among the older adults, males, and those with lower educational levels, and there was an interaction between cold spells and PM2.5. The results underscore the importance of reducing these exposures to protect public health.

Cold waves and fine particulate matter in high-altitude Chinese cities: assessing their interactive impact on outpatient visits for respiratory disease.

BACKGROUND: Extreme weather events like heatwaves and fine particulate matter (PM2.5) have a synergistic effect on mortality, but research on the synergistic effect of cold waves and PM2.5 on outpatient visits for respiratory disease, especially at high altitudes in climate change-sensitive areas, is lacking. METHODS: we collected time-series data on meteorological, air pollution, and outpatient visits for respiratory disease in Xining. We examined the associations between cold waves, PM2.5, and outpatient visits for respiratory disease using a time-stratified case-crossover approach and distributional lag nonlinear modeling. Our analysis also calculated the relative excess odds due to interaction (REOI), proportion attributable to interaction (AP), and synergy index (S). We additionally analyzed cold waves over time to verify climate change. RESULTS: Under different definitions of cold waves, the odds ratio for the correlation between cold waves and outpatient visits for respiratory disease ranged from 0.95 (95% CI: 0.86, 1.05) to 1.58 (1.47, 1.70). Exposure to PM2.5 was significantly associated with an increase in outpatient visits for respiratory disease. We found that cold waves can synergize with PM2.5 to increase outpatient visits for respiratory disease (REOI > 0, AP > 0, S > 1), decreasing with stricter definitions of cold waves and longer durations. Cold waves' independent effect decreased over time, but their interaction effect persisted. From 8.1 to 21.8% of outpatient visits were due to cold waves and high-level PM2.5. People aged 0-14 and ≥ 65 were more susceptible to cold waves and PM2.5, with a significant interaction for those aged 15-64 and ≥ 65. CONCLUSION: Our study fills the gap on how extreme weather and PM2.5 synergistically affect respiratory disease outpatient visits in high-altitude regions. The synergy of cold waves and PM2.5 increases outpatient visits for respiratory disease, especially in the elderly. Cold wave warnings and PM2.5 reduction have major public health benefits.

Cold hypersensitivity in the hands and feet is associated with erectile dysfunction in young Taiwanese men.

Cold hypersensitivity in the hands and feet (CHHF) is a protective or predisposing factor for many diseases; however, the relationship between CHHF and erectile dysfunction (ED) remains unclear. We aimed to investigate associations between CHHF and ED among young men of Southeast Asian origin. In this cross-sectional study, sexually active Taiwanese men aged 20-40 years were enrolled via an online questionnaire comprising general demographic information, comorbidities, subjective thermal sensations of their hands and feet in the past 6 months, and their erectile function using the International Index of Erectile Function-5 (IIEF-5). Participants who reported cold sensation of hands and feet were classified to have CHHF; those with IIEF-5 score ≤ 21 were considered to have ED. Total 54.2% and 27.9% of participants had ED and CHHF, respectively. Men with CHHF were significantly younger, had lower body mass index and IIEF-5 scores (p < 0.001), and a lower prevalence of diabetes mellitus (p = 0.033) along with higher prevalence of ED, psychiatric disorders, and insomnia (p < 0.001). After adjusting for predisposing factors of ED, CHHF (odds ratio 1.410, 95% confidence interval 1.159-1.714; p = 0.001) remained an independent predictor of ED. Thus, CHHF is independently associated with ED, affecting more than a quarter of young Taiwanese men. Autonomic dysregulation and subclinical endothelial dysfunction may be common pathophysiologies of CHHF and ED.

Ovarian PERK/NRF2/CX43/StAR/progesterone pathway activation mediates female reproductive dysfunction induced by cold exposure.

Ambient air temperature is a key factor affecting human health. Female reproductive disorders are representative health risk events under low temperature. However, the mechanism involving in cold-induced female reproductive disorders remains largely unknown. Female mice were intermittently exposed to cold conditions (4 °C) to address the health risk of low temperature on female reproductive system. Primary granulosa cells (GCs) were prepared and cultured under low temperature (35 °C) or exposed to ß3-adrenoreceptor agonist, isoproterenol, to mimic the condition of cold exposure. Western-blot, RT-PCR, co-IP, ELISA, pharmacological inhibition or siRNA-mediated knockdown of target gene were performed to investigate the possible role of hormones, gap conjunction proteins, and ER stress sensor protein in regulating female reproductive disorders under cold exposure. Cold exposure induced estrous cycle disorder and follicular dysplasia in female mice, accompanying with abnormal upregulation of progesterone and its synthetic rate-limiting enzyme, StAR, in the ovarian granulosa cells. Under the same conditions, an increase in connexin 43 (CX43) expressions in the GCs was also observed, which contributed to elevated progesterone levels in the ovary. Moreover, ER stress sensor protein, PERK, was activated in the ovarian GCs after cold exposure, leading to the upregulation of downstream NRF2-dependent CX43 transcription and aberrant increase in progesterone synthesis. Most importantly, blocking PERK expression in vivo significantly inhibited NRF2/CX43/StAR/progesterone pathway activation in the ovary and efficiently rescued the prolongation of estrous cycle and the increase in follicular atresia of the female mice induced by cold stress. We have elucidated the mechanism of ovarian PERK/NRF2/CX43/StAR/progesterone pathway activation in mediating female reproductive disorder under cold exposure. Targeting PERK might be helpful for maintaining female reproductive health under cold conditions.

Silent information regulator 2 deficiency exacerbates chronic cold exposure-induced colonic injury and p65 activation in mice.

Cold is a common stressor that threatens colonic health by affecting internal homeostasis. From the literature, Silent information regulator 2 (SIRT2) may have important roles during cold stress, but this conjecture requires investigation. To address this knowledge gap, we investigated the effects of SIRT2 on colonic injury in chronically cold-exposure mice. In a previous study, we showed that SIRT2 regulated p65 activation after cold exposure. In the current study, mice were exposed to 4 °C for 3 h/day for 3 weeks to simulate a chronic cold exposure environment. Chronic cold exposure shortened colon length, disrupted tight junctions in colonic epithelial tissue, and disordered colonic flora. Chronic cold exposure also increased p65 acetylation levels, promoted nuclear factor (NF)-κB activation, and increased the expression of its downstream pro-inflammatory factors, while SIRT2 knockdown aggravated the consequences of tissue structure disruption and increased inflammatory factors brought about by chronic cold exposure to some extent, but could alleviate the downregulation of colonic tight junction-related proteins to some extent. We also observed direct SIRT2 regulatory effects toward p65, and in Caco-2 cells treated with lipopolysaccharide (LPS), SIRT2 knockdown increased p65 acetylation levels and pro-inflammatory factor expression, while SIRT2 overexpression reversed these phenomena. Therefore, SIRT2 deletion exacerbated chronic cold exposure-induced colonic injury and p65 activation in mice. Mechanistically, p65 modification by SIRT2 via deacetylation may affect NF-κB signaling. These findings suggest that SIRT2 is a key target of colonic health maintenance under chronic cold exposure conditions.

The law that came in from the cold.

As winter draws on it is timely to look at ways in which nurses in the community may be faced with problems, expected and unexpected, when their patients are particularly affected by cold conditions and at the precautions which need to be taken to avoid or lessen adverse effects on their health. As in the case of heat-related risks to health, examined in an earlier article, so too in the case of cold those most at risk are elderly patients and those who are vulnerable due to a pre-existing condition affecting health even in a more clement climate. Cold weather attracts extra legal responsibilities which are examined in this article.

Managing cold intolerance after hand injury: A systematic review.

OBJECTIVES: This systematic review seeks to understand whether cold intolerance (CI) improves with time and if there is any role for management strategies such as behavioural therapy, surgery, or pharmacotherapy. METHODS: Two independent reviewers used a predefined search strategy to query MEDLINE, PubMed, Embase, CINAHL, Cochrane Library, Web of Science and Google Scholar databases. Articles written in English, Studies of interventions (such as pharmacotherapy or behavioural therapy) for cold intolerance in adult patients with a history of hand injury along with prevalence over time were included for review. RESULTS: Seventeen studies were included, with twelve prognostic studies of the effect of time on CI, four studies of self management/behavioural therapies, and a single study of surgical treatment of neuromas. No studies of pharmacotherapies were identified for inclusion in the hand injury literature. Most studies (76.4%) were either prevalence or prospective cohort studies; no level I or II evidence studies were included. CONCLUSIONS: Cold intolerance does not resolve over time for the vast majority of patients. Behavioral and self-management studies have low efficacy and studies presented had a high risk of bias. There is a lack of evidence for the use of pharmacotherapy in CI and this could be considered for future studies.

Personalised cooler dialysate for patients receiving maintenance haemodialysis (MyTEMP): a pragmatic, cluster-randomised trial.

BACKGROUND: Haemodialysis centres have conventionally provided maintenance haemodialysis using a standard dialysate temperature (eg, 36·5°C) for all patients. Many centres now use cooler dialysate (eg, 36·0°C or lower) for potential cardiovascular benefits. We aimed to assess whether personalised cooler dialysate, implemented as centre-wide policy, reduced the risk of cardiovascular-related death or hospital admission compared with standard temperature dialysate. METHODS: MyTEMP was a pragmatic, two-arm, parallel-group, registry-based, open-label, cluster-randomised, superiority trial done at haemodialysis centres in Ontario, Canada. Eligible centres provided maintenance haemodialysis to at least 15 patients a week, and the medical director of each centre had to confirm that their centre would deliver the assigned intervention. Using covariate-constrained randomisation, we allocated 84 centres (1:1) to use either personalised cooler dialysate (nurses set the dialysate temperature 0·5-0·9°C below each patient's measured pre-dialysis body temperature, with a lowest recommended dialysate temperature of 35·5°C), or standard temperature dialysate (36·5°C for all patients and treatments). Patients and health-care providers were not masked to the group assignment; however, the primary outcome was recorded in provincial databases by medical coders who were unaware of the trial or the centres' group assignment. The primary composite outcome was cardiovascular-related death or hospital admission with myocardial infarction, ischaemic stroke, or congestive heart failure during the 4-year trial period. Analysis was by intention to treat. The study is registered at ClinicalTrials.gov, NCT02628366. FINDINGS: We assessed all of Ontario's 97 centres for inclusion into the study. Nine centres had less than 15 patients and one director requested that four of their seven centres not participate. 84 centres were recruited and on Feb 1, 2017, these centres were randomly assigned to administer personalised cooler dialysate (42 centres) or standard temperature dialysate (42 centres). The intervention period was from April 3, 2017, to March 31, 2021, and during this time the trial centres provided outpatient maintenance haemodialysis to 15 413 patients (about 4·3 million haemodialysis treatments). The mean dialysate temperature was 35·8°C in the cooler dialysate group and 36·4°C in the standard temperature group. The primary outcome occurred in 1711 (21·4%) of 8000 patients in the cooler dialysate group versus 1658 (22·4%) of 7413 patients in the standard temperature group (adjusted hazard ratio 1·00, 96% CI 0·89 to 1·11; p=0·93). The mean drop in intradialytic systolic blood pressure was 26·6 mm Hg in the cooler dialysate group and 27·1 mm Hg in the standard temperature group (mean difference -0·5 mm Hg, 99% CI -1·4 to 0·4; p=0·14). INTERPRETATION: Centre-wide delivery of personalised cooler dialysate did not significantly reduce the risk of major cardiovascular events compared with standard temperature dialysate. The rising popularity of cooler dialysate is called into question by this study, and the risks and benefits of cooler dialysate in some patient populations should be clarified in future trials. FUNDING: Canadian Institutes of Health Research, Heart and Stroke Foundation of Canada, Ontario Renal Network, Ontario Strategy for Patient-Oriented Research Support Unit, Dialysis Clinic, Inc., ICES (formerly known as the Institute for Clinical Evaluative Sciences), Lawson Health Research Institute, and Western University.

Preservation of Adrenoceptor and Endothelin Receptor Mediated Vasoconstriction and of Endothelium-Dependent Relaxation after Cold Storage of Explanted Blood Vessels for ex vivo Analyses.

INTRODUCTION: Adrenoceptor and endothelin (ET) receptor-mediated vasoconstriction as well as endothelium-dependent vasodilation of human saphenous veins were compared before and after 20 h of cold storage. METHODS: Contractile responses to potassium chloride (KCl), norepinephrine (NE), and ET-1 as well as vasodilator responses to acetylcholine (ACh) were evaluated. RESULTS: Storage in HEPES-supplemented Dulbecco's modified Eagle's medium (HDMEM) diminished KCl induced contractile forces to 71% (p = 0.002) and NE induced contractions to 80% (p = 0.037), in contrast to HEPES-supplemented Krebs-Henseleit solution (HKH) and TiProtec solution. KCl-normalized NE contractions were not affected by storage. NE EC50 values were slightly lower (7.1E-8 vs. 7.5E-8, p = 0.019) after storage in HKH, with no changes after storage in the other solutions. Endothelium-dependent responses to ACh were not affected by storage. ET-1 induced contractions were attenuated after storage in HDMEM (77%, p = 0.002), HKH (75%, p = 0.020), and TiProtec (73%, p = 0.010) with no changes in normalized constrictions. ET-1 EC50 values were not affected by storage. CONCLUSION: Loss of contractility after storage in HDMEM may reflect the lower content of dextrose. There was no specific attenuation of adrenoceptor, ET-receptor, or ACh receptor mediated signal transduction after storage in any of the media. HKH or TiProtec are equally suitable cold storage solutions for ex vivo measurements.

Protective effects of Banhasasim-tang, a herbal medicine, against cold restraint stress-induced gastric ulcers.

Banhasasim-tang (BST), a herbal medicine, has been used for nausea and fever from cold damage. This study aimed to investigate the protective effects of BST in cold restraint stress-induced gastric ulcers. Male Sprague Dawley rats were orally treated with various doses of BST including 0.25, 0.5, 1, 3, 6, 9, 12 and 18g/kg based on the human daily intake dose. After treatment once per day for 3 days, rats were restrained into the cold stress chamber for 12h at 4°C to induce gastric ulcers. Gastric hemorrhagic ulcer area was evaluated and serum adrenocorticotropic hormone (ACTH), corticosterone, epinephrine and dopamine levels were determined. Compared to cold stress-induced gastric ulcer rats, hemorrhage ulcer areas were reduced in BST-treated stomach tissues at all concentrations. Increased serum ACTH, corticosterone and epinephrine levels were significantly decreased by BST treatment in cold stress-induced gastric ulcer rats. Moreover, there were increments of serum dopamine levels in 3 and 6g/kg of BST-treated groups. Taken together, BST positively ameliorated cold restraint stress-induced gastric hemorrhage with decrease in serum stress-related biomarkers such as ACTH, corticosterone, epinephrine and dopamine. The 3-6-fold of human daily intake dose of BST exhibited protective effects as a herbal medicine for gastric ulcers.

Aquaphotomics Research of Cold Stress in Soybean Cultivars with Different Stress Tolerance Ability: Early Detection of Cold Stress Response.

The development of non-destructive methods for early detection of cold stress of plants and the identification of cold-tolerant cultivars is highly needed in crop breeding programs. Current methods are either destructive, time-consuming or imprecise. In this study, soybean leaves' spectra were acquired in the near infrared (NIR) range (588-1025 nm) from five cultivars genetically engineered to have different levels of cold stress tolerance. The spectra were acquired at the optimal growing temperature 27 °C and when the temperature was decreased to 22 °C. In this paper, we report the results of the aquaphotomics analysis performed with the objective of understanding the role of the water molecular system in the early cold stress response of all cultivars. The raw spectra and the results of Principal Component Analysis, Soft Independent Modeling of Class Analogies and aquagrams showed consistent evidence of huge differences in the NIR spectral profiles of all cultivars under normal and mild cold stress conditions. The SIMCA discrimination between the plants before and after stress was achieved with 100% accuracy. The interpretation of spectral patterns before and after cold stress revealed major changes in the water molecular structure of the soybean leaves, altered carbohydrate and oxidative metabolism. Specific water molecular structures in the leaves of soybean cultivars were found to be highly sensitive to the temperature, showing their crucial role in the cold stress response. The results also indicated the existence of differences in the cold stress response of different cultivars, which will be a topic of further research.

Health risk of extreme low temperature on respiratory diseases in western China.

Previous studies have reported that daily average temperature is connected with respiratory diseases (RD), but proof is limited for the influence of the extreme low temperature on RD in Lanzhou, a northwestern China of temperate area. Generalized additive model (GAM) was built in this work to describe the relationship between daily mean temperature and RD in Lanzhou, China from 2012 to 2017. The results indicated that the exposure-response curve was inverse J-shaped, showing the lower the temperature, the larger the relative risk (RR). The RR of daily emergency room (ER) admissions in P5 extreme low temperature (the temperature below the fifth percentile, etc.) was larger than that in P10. The P5 extreme low temperature has the strongest effect at lag 0, and the RRs were 1.043 (95% CI: 1.030, 1.055) for the total, 1.031 (95% CI: 1.015, 1.046) for males and 1.058 (95% CI: 1.039, 1.077) for females. For different age groups, the largest RRs were 1.026 (95% CI: 1.013, 1.039) for the children (age < 16 years) at lag 5, 1.057 (95% CI: 1.030, 1.085) for the young adults (aged 16-45 years), 1.060 (95% CI: 1.023, 1.099) for the middle-aged (aged 46-60 years) and 1.121 (95% CI: 1.077, 1.166) for the elderly group of age > 60 years. Meanwhile, females and the elderly were more vulnerable to extreme temperature. The results could strengthen the scientific evidence of effects of extreme low temperature on RD in temperate areas.

Assessment of the architecture and integrity of frozen-thawed testicular tissue from (pre)pubertal boys with cancer.

BACKGROUND: Testicular tissue freezing is proposed for fertility preservation to (pre)pubertal boys with cancer before highly gonadotoxic treatment. Studies accurately comparing human (pre)pubertal testicular tissue quality before freezing and after thawing are exceptional. No study has reported this approach in a systematic manner and routine care. OBJECTIVES: To assess the impact of a control slow freezing protocol on testicular tissue architecture and integrity of (pre)pubertal boys after thawing. MATERIALS AND METHODS: (Pre)pubertal boys (n = 87) with cancer from 8 Reproductive Biology Laboratories of the French CECOS network benefited from testicular tissue freezing before hematopoietic stem cell transplantation. Seminiferous tubule cryodamage was determined histologically by scoring morphological alterations and by quantifying intratubular spermatogonia and the expression of DNA replication and repair marker in frozen-thawed testicular fragments. RESULTS: A significant increase in nuclear and epithelial score alterations was observed after thawing (p < 0.0001). The global lesional score remained lower than 1.5 and comparable to fresh testicular tissue. The number of intratubular spermatogonia and the expression of DNA replication and repair marker in spermatogonia and Sertoli cells did not vary significantly after thawing. These data showed the good preservation of the seminiferous tubule integrity and architecture after thawing, as previously reported in our studies performed in prepubertal mice and rats. DISCUSSION: The current study reports, for the first time, the development of a semi-quantitative analysis of cryodamage in human (pre)pubertal testicular tissue, using a rapid and useful tool that can be proposed in routine care to develop an internal and external quality control for testicular tissue freezing. This tool can also be used when changing one or several parameters of the freezing-thawing procedure. CONCLUSION: Control slow freezing protocol without seeding maintains the seminiferous tubule architecture and integrity, the concentration of spermatogonia and the expression of DNA replication and repair marker in spermatogonia and Sertoli cells after thawing.

Resting Energy Expenditure and Cold-induced Thermogenesis in Patients With Overt Hyperthyroidism.

CONTEXT: Thyroid hormone (TH) is crucial for the adaptation to cold. OBJECTIVE: To evaluate the effect of hyperthyroidism on resting energy expenditure (REE), cold-induced thermogenesis (CIT) and changes in body composition and weight. METHODS: This was a prospective cohort study at the endocrine outpatient clinic of a tertiary referral center. Eighteen patients with overt hyperthyroidism were included. We measured REE during hyperthyroidism, after restoring euthyroid TH levels and after 3 months of normal thyroid function. In 14 of the 18 patients, energy expenditure (EE) was measured before and after a mild cold exposure of 2 hours and CIT was the difference between EEcold and EEwarm. Skin temperatures at 8 positions were recorded during the study visits. Body composition was assessed by dual X-ray absorption. RESULTS: Free thyroxine (fT4) and free triiodothyronine (fT3) decreased significantly over time (fT4, P = .0003; fT3, P = .0001). REE corrected for lean body mass (LBM) decreased from 42 ±â€…6.7 kcal/24 hour/kg LBM in the hyperthyroid to 33 ±â€…4.4 kcal/24 hour/kg LBM (-21%, P < .0001 vs hyperthyroid) in the euthyroid state and 3 months later to 33 ±â€…5.2 kcal/24 hour/kg LBM (-21%, P = .0022 vs hyperthyroid, overall P < .0001). fT4 (P = .0001) and fT3 (P < 0.0001) were predictors of REE. CIT did not change from the hyperthyroid to the euthyroid state (P = .96). Hyperthyroidism led to increased skin temperature at warm ambient conditions but did not alter core body temperature, nor skin temperature after cold exposure. Weight regain and body composition were not influenced by REE and CIT during the hyperthyroid state. CONCLUSION: CIT is not increased in patients with overt hyperthyroidism.