Heat-related mortality and ambulance transport after a power outage in the Tokyo metropolitan area.

Background: Air conditioners can prevent heat-related illness and mortality, but the increased use of air conditioners may enhance susceptibility to heat-related illnesses during large-scale power failures. Here, we examined the risks of heat-related illness ambulance transport (HIAT) and mortality associated with typhoon-related electricity reduction (ER) in the summer months in the Tokyo metropolitan area. Methods: We conducted event study analyses to compare temperature-HIAT and mortality associations before and after the power outage (July to September 2019). To better understand the role of temperature during the power outage, we then examined whether the temperature-HIAT and mortality associations were modified by different power outage levels (0%, 10%, and 20% ER). We computed the ratios of relative risks to compare the risks associated with various ER values to the risks associated without ER. Results: We analyzed the data of 14,912 HIAT cases and 74,064 deaths. Overall, 93,200 power outage cases were observed when the typhoon hit. Event study results showed that the incidence rate ratio was 2.01 (95% confidence interval [CI] = 1.42, 2.84) with effects enduring up to 6 days, and 1.11 (95% CI = 1.02, 1.22) for mortality on the first 3 days after the typhoon hit. Comparing 20% to 0% ER, the ratios of relative risks of heat exposure were 2.32 (95% CI = 1.41, 3.82) for HIAT and 0.95 (95% CI = 0.75, 1.22) for mortality. Conclusions: A 20% ER was associated with a two-fold greater risk of HIAT because of summer heat during the power outage, but there was little evidence for the association with all-cause mortality.

Seasonality of mortality under climate change: a multicountry projection study.

BACKGROUND: Climate change can directly impact temperature-related excess deaths and might subsequently change the seasonal variation in mortality. In this study, we aimed to provide a systematic and comprehensive assessment of potential future changes in the seasonal variation, or seasonality, of mortality across different climate zones. METHODS: In this modelling study, we collected daily time series of mean temperature and mortality (all causes or non-external causes only) via the Multi-Country Multi-City Collaborative (MCC) Research Network. These data were collected during overlapping periods, spanning from Jan 1, 1969 to Dec 31, 2020. We projected daily mortality from Jan 1, 2000 to Dec 31, 2099, under four climate change scenarios corresponding to increasing emissions (Shared Socioeconomic Pathways [SSP] scenarios SSP1-2.6, SSP2-4.5, SSP3-7.0, and SSP5-8.5). We compared the seasonality in projected mortality between decades by its shape, timings (the day-of-year) of minimum (trough) and maximum (peak) mortality, and sizes (peak-to-trough ratio and attributable fraction). Attributable fraction was used to measure the burden of seasonality of mortality. The results were summarised by climate zones. FINDINGS: The MCC dataset included 126 809 537 deaths from 707 locations within 43 countries or areas. After excluding the only two polar locations (both high-altitude locations in Peru) from climatic zone assessments, we analysed 126 766 164 deaths in 705 locations aggregated in four climate zones (tropical, arid, temperate, and continental). From the 2000s to the 2090s, our projections showed an increase in mortality during the warm seasons and a decrease in mortality during the cold seasons, albeit with mortality remaining high during the cold seasons, under all four SSP scenarios in the arid, temperate, and continental zones. The magnitude of this changing pattern was more pronounced under the high-emission scenarios (SSP3-7.0 and SSP5-8.5), substantially altering the shape of seasonality of mortality and, under the highest emission scenario (SSP5-8.5), shifting the mortality peak from cold seasons to warm seasons in arid, temperate, and continental zones, and increasing the size of seasonality in all zones except the arid zone by the end of the century. In the 2090s compared with the 2000s, the change in peak-to-trough ratio (relative scale) ranged from 0·96 to 1·11, and the change in attributable fraction ranged from 0·002% to 0·06% under the SSP5-8.5 (highest emission) scenario. INTERPRETATION: A warming climate can substantially change the seasonality of mortality in the future. Our projections suggest that health-care systems should consider preparing for a potentially increased demand during warm seasons and sustained high demand during cold seasons, particularly in regions characterised by arid, temperate, and continental climates. FUNDING: The Environment Research and Technology Development Fund of the Environmental Restoration and Conservation Agency, provided by the Ministry of the Environment of Japan.

Identification of differentially methylated regions associated with both liver fibrosis and hepatocellular carcinoma.

BACKGROUND: Liver fibrosis is a major risk factor for hepatocellular carcinoma (HCC). We have previously reported that differentially methylated regions (DMRs) are correlated with the fibrosis stages of metabolic dysfunction-associated steatotic liver disease (MASLD). In this study, the methylation levels of those DMRs in liver fibrosis and subsequent HCC were examined. METHODS: The methylation levels of DMRs were investigated using alcoholic cirrhosis and HCC (GSE60753). The data of hepatitis C virus-infected cirrhosis and HCC (GSE60753), and two datasets (GSE56588 and GSE89852) were used for replication analyses. The transcriptional analyses were performed using GSE114564, GSE94660, and GSE142530. RESULTS: Hypomethylated DMR and increased transcriptional level of zinc finger and BTB domain containing 38 (ZBTB38) were observed in HCC. Hypermethylated DMRs, and increased transcriptional levels of forkhead box K1 (FOXK1) and zinc finger CCCH-type containing 3 (ZC3H3) were observed in HCC. The methylation levels of DMR of kazrin, periplakin interacting protein (KAZN) and its expression levels were gradually decreased as cirrhosis progressed to HCC. CONCLUSIONS: Changes in the methylation and transcriptional levels of ZBTB38, ZC3H3, FOXK1, and KAZN are important for the development of fibrosis and HCC; and are therefore potential therapeutic targets and diagnostic tools for cirrhosis and HCC.

Fluctuating risk of acute kidney injury-related mortality for four weeks after exposure to air pollution: A multi-country time-series study in 6 countries.

BACKGROUND: Recent studies have reported that air pollution is related to kidney diseases. However, the global evidence on the risk of death from acute kidney injury (AKI) owing to air pollution is limited. Therefore, we investigated the association between short-term exposure to air pollution-particulate matter ≤ 2.5 µm (PM2.5), ozone (O3), and nitrogen dioxide (NO2)-and AKI-related mortality using a multi-country dataset. METHODS: This study included 41,379 AKI-related deaths in 136 locations in six countries during 1987-2018. A novel case time-series design was applied to each air pollutant during 0-28 lag days to estimate the association between air pollution and AKI-related deaths. Moreover, we calculated AKI deaths attributable to non-compliance with the World Health Organization (WHO) air quality guidelines. RESULTS: The relative risks (95% confidence interval) of AKI-related deaths are 1.052 (1.003, 1.103), 1.022 (0.994, 1.050), and 1.022 (0.982, 1.063) for 5, 10, and 10 µg/m3 increase in lag 0-28 days of PM2.5, warm-season O3, and NO2, respectively. The lag-distributed association showed that the risk appeared immediately on the day of exposure to air pollution, gradually decreased, and then increased again reaching the peak approximately 20 days after exposure to PM2.5 and O3. We also found that 1.9%, 6.3%, and 5.2% of AKI deaths were attributed to PM2.5, warm-season O3, and NO2 concentrations above the WHO guidelines. CONCLUSIONS: This study provides evidence that public health policies to reduce air pollution may alleviate the burden of death from AKI and suggests the need to investigate the several pathways between air pollution and AKI death.

Prediction of outcomes in patients with metabolic dysfunction-associated steatotic liver disease based on initial measurements and subsequent changes in magnetic resonance elastography.

BACKGROUND: The prognosis of metabolic dysfunction-associated steatotic liver disease (MASLD) is strongly associated with liver fibrosis. We aimed to investigate whether liver stiffness measurement (LSM) and changes in LSM (ΔLSM) on magnetic resonance elastography (MRE) can predict clinical events in patients with MASLD. METHODS: We included 405 patients with MASLD who underwent at least two MREs. The patients were divided into five groups corresponding to fibrosis stages (0-4) based on initial LSM and classified as progressors (ΔLSM ≥ 19%) or non-progressors (ΔLSM < 19%) based on the difference between the first and last LSM. RESULTS: The mean follow-up period was 72.6 months, and the mean interval between MREs was 23.5 months. There were 52 (12.8%) progressors and 353 (87.2%) non-progressors. The initial LSM was significantly associated with the cumulative probabilities of decompensated cirrhosis, hepatocellular carcinoma (HCC), liver-related events, extrahepatic malignancies, and overall mortality but not with cardiovascular disease. Progressors had significantly higher hazard ratios (HRs) for decompensated cirrhosis, HCC, and liver-related events but not for extrahepatic malignancies, cardiovascular disease, or overall mortality. Among patients without cirrhosis, the HR for developing cirrhosis among progressors was 60.15. Progressors had a significantly higher risk of liver-related events, even in the low initial LSM (fibrosis stage 0-2) subgroups. CONCLUSIONS: Both initial LSM and ΔLSM can predict liver-related events in patients with MASLD, even for low initial LSM. This integrated assessment can allow more detailed risk stratification compared with single LSM assessments and identify high-risk patients with MASLD among those previously considered as low risk.

A Nationwide Comparative Analysis of Temperature-Related Mortality and Morbidity in Japan.

BACKGROUND: The impact of temperature on morbidity remains largely unknown. Moreover, extensive evidence indicates contrasting patterns between temperature-mortality and temperature-morbidity associations. A nationwide comparison of the impact of temperature on mortality and morbidity in more specific subgroups is necessary to strengthen understanding and help explore underlying mechanisms by identifying susceptible populations. OBJECTIVE: We performed this study to quantify and compare the impact of temperature on mortality and morbidity in 47 prefectures in Japan. METHODS: We applied a two-stage time-series design with distributed lag nonlinear models and mixed-effect multivariate meta-analysis to assess the association of temperature with mortality and morbidity by causes (all-cause, circulatory, and respiratory) at prefecture and country levels between 2015 and 2019. Subgroup analysis was conducted by sex, age, and regions. RESULTS: The patterns and magnitudes of temperature impacts on morbidity and mortality differed. For all-cause outcomes, cold exhibited larger effects on mortality, and heat showed larger effects on morbidity. At specific temperature percentiles, cold (first percentile) was associated with a higher relative risk (RR) of mortality [1.45; 95% confidence interval (CI): 1.39, 1.52] than morbidity (1.33; 95% CI: 1.26, 1.40), as compared to the minimum mortality/morbidity temperature. Heat (99th percentile) was associated with a higher risk of morbidity (1.30; 95% CI: 1.28, 1.33) than mortality (1.04; 95% CI: 1.02, 1.06). For cause-specific diseases, mortality due to circulatory diseases was more susceptible to heat and cold than morbidity. However, for respiratory diseases, both cold and heat showed higher risks for morbidity than mortality. Subgroup analyses suggested varied associations depending on specific outcomes. DISCUSSION: Distinct patterns were observed for the association of temperature with mortality and morbidity, underlying different mechanisms of temperature on different end points, and the differences in population susceptibility are possible explanations. Future mitigation policies and preventive measures against nonoptimal temperatures should be specific to disease outcomes and targeted at susceptible populations. https://doi.org/10.1289/EHP12854.

Enhancing health resilience in Japan in a changing climate.

Climate change poses significant threats to human health, propelling Japan to take decisive action through the Climate Change Adaptation Act of 2018. This Act has led to the implementation of climate change adaptation policies across various sectors, including healthcare. In this review, we synthesized existing scientific evidence on the impacts of climate change on health in Japan and outlined the adaptation strategies and measures implemented by the central and local governments. The country has prioritized tackling heat-related illness and mortality and undertaken various adaptation measures to mitigate these risks. However, it faces unique challenges due to its super-aged society. Ensuring effective and coordinated strategies to address the growing uncertainties in vulnerability to climate change and the complex intersectoral impacts of disasters remains a critical issue. To combat the additional health risks by climate change, a comprehensive approach embracing adaptation and mitigation policies in the health sector is crucial. Encouraging intersectoral communication and collaboration will be vital for developing coherent and effective strategies to safeguard public health in the face of climate change.

Net impact of air conditioning on heat-related mortality in Japanese cities.

BACKGROUND: Air conditioning (AC) presents a viable means of tackling the ill-effects of heat on human health. However, AC releases additional anthropogenic heat outdoors, and this could be detrimental to human health, especially in urban communities. This study determined the excess heat-related mortality attributable to anthropogenic heat from AC use under various projected global warming scenarios in seven Japanese cities. The overall protection from AC use was also measured. METHODS: Daily average 2-meter temperatures in the hottest month of August from 2000 to 2010 were modeled using the Weather Research and Forecasting (WRF) model with BEP+BEM (building effect parameterization and building energy model). Risk functions for heat-mortality associations were generated with and without AC use from a two-stage time series analysis. We coupled simulated August temperatures and heat-mortality risk functions to estimate averted deaths and unavoidable deaths from AC use. RESULTS: Anthropogenic heat from AC use slightly augmented the daily urban temperatures by 0.046 °C in Augusts of 2000-2010 and up to 0.181 °C in a future with 3 °C urban warming. This temperature rise was attributable to 3.1-3.5 % of heat-related deaths in Augusts of 2000-2010 under various urban warming scenarios. About 36-47 % of heat-related deaths could be averted by air conditioning use under various urban warming scenarios. DISCUSSION: AC has a valuable protective effect from heat despite some unavoidable mortality from anthropogenic heat release. Overall, the use of AC as a major adaptive strategy requires careful consideration.

Combined, elobixibat, and colestyramine reduced cholesterol toxicity in a mouse model of metabolic dysfunction-associated steatotic liver disease.

BACKGROUND: Cholesterol levels and bile acid metabolism are important drivers of metabolic dysfunction-associated steatohepatitis (MASH) progression. Using a mouse model, we investigated the mechanism by which cholesterol exacerbates MASH and the effect of colestyramine (a bile acid adsorption resin) and elobixibat (an apical sodium-dependent bile acid transporter inhibitor) concomitant administration on bile acid adsorption and MASH status. METHODS: Mice were fed a high-fat high-fructose diet with varying concentrations of cholesterol to determine changes in fatty liver according to liver status, water intake, defecation status, insulin resistance, bile acid levels, intestinal permeability, atherosclerosis (in apolipoprotein E knockout mice), and carcinogenesis (in diethylnitrosamine mice). Using small interfering ribonucleic acid (siRNA), we evaluated the effect of sterol regulatory element binding protein 1c (SREBP1c) knockdown on triglyceride synthesis and fatty liver status following the administration of elobixibat (group E), colestyramine (group C), or both (group EC). RESULTS: We found greater reductions in serum alanine aminotransferase levels, serum lipid parameters, serum primary bile acid concentrations, hepatic lipid levels, and fibrosis area in EC group than in the monotherapy groups. Increased intestinal permeability and watery diarrhea caused by elobixibat were completely ameliorated in group EC. Group EC showed reduced plaque formation rates in the entire aorta and aortic valve of the atherosclerosis model, and reduced tumor counts and tumor burden in the carcinogenesis model. CONCLUSIONS: Excessive free cholesterol in the liver can promote fatty liver disease. Herein, combination therapy with EC effectively reduced free cholesterol levels in MASH model mice. Our study provides strong evidence for combination therapy as an effective treatment for MASH.

Interactive effects of ambient fine particulate matter and ozone on daily mortality in 372 cities: two stage time series analysis.

OBJECTIVE: To investigate potential interactive effects of fine particulate matter (PM2.5) and ozone (O3) on daily mortality at global level. DESIGN: Two stage time series analysis. SETTING: 372 cities across 19 countries and regions. POPULATION: Daily counts of deaths from all causes, cardiovascular disease, and respiratory disease. MAIN OUTCOME MEASURE: Daily mortality data during 1994-2020. Stratified analyses by co-pollutant exposures and synergy index (>1 denotes the combined effect of pollutants is greater than individual effects) were applied to explore the interaction between PM2.5 and O3 in association with mortality. RESULTS: During the study period across the 372 cities, 19.3 million deaths were attributable to all causes, 5.3 million to cardiovascular disease, and 1.9 million to respiratory disease. The risk of total mortality for a 10 µg/m3 increment in PM2.5 (lag 0-1 days) ranged from 0.47% (95% confidence interval 0.26% to 0.67%) to 1.25% (1.02% to 1.48%) from the lowest to highest fourths of O3 concentration; and for a 10 µg/m3 increase in O3 ranged from 0.04% (-0.09% to 0.16%) to 0.29% (0.18% to 0.39%) from the lowest to highest fourths of PM2.5 concentration, with significant differences between strata (P for interaction <0.001). A significant synergistic interaction was also identified between PM2.5 and O3 for total mortality, with a synergy index of 1.93 (95% confidence interval 1.47 to 3.34). Subgroup analyses showed that interactions between PM2.5 and O3 on all three mortality endpoints were more prominent in high latitude regions and during cold seasons. CONCLUSION: The findings of this study suggest a synergistic effect of PM2.5 and O3 on total, cardiovascular, and respiratory mortality, indicating the benefit of coordinated control strategies for both pollutants.

Lysosomal cholesterol overload in macrophages promotes liver fibrosis in a mouse model of NASH.

Accumulation of lipotoxic lipids, such as free cholesterol, induces hepatocyte death and subsequent inflammation and fibrosis in the pathogenesis of nonalcoholic steatohepatitis (NASH). However, the underlying mechanisms remain unclear. We have previously reported that hepatocyte death locally induces phenotypic changes in the macrophages surrounding the corpse and remnant lipids, thereby promoting liver fibrosis in a murine model of NASH. Here, we demonstrated that lysosomal cholesterol overload triggers lysosomal dysfunction and profibrotic activation of macrophages during the development of NASH. ß-cyclodextrin polyrotaxane (ßCD-PRX), a unique supramolecule, is designed to elicit free cholesterol from lysosomes. Treatment with ßCD-PRX ameliorated cholesterol accumulation and profibrotic activation of macrophages surrounding dead hepatocytes with cholesterol crystals, thereby suppressing liver fibrosis in a NASH model, without affecting the hepatic cholesterol levels. In vitro experiments revealed that cholesterol-induced lysosomal stress triggered profibrotic activation in macrophages predisposed to the steatotic microenvironment. This study provides evidence that dysregulated cholesterol metabolism in macrophages would be a novel mechanism of NASH.

Rapid increase in the risk of heat-related mortality.

Heat-related mortality has been identified as one of the key climate extremes posing a risk to human health. Current research focuses largely on how heat mortality increases with mean global temperature rise, but it is unclear how much climate change will increase the frequency and severity of extreme summer seasons with high impact on human health. In this probabilistic analysis, we combined empirical heat-mortality relationships for 748 locations from 47 countries with climate model large ensemble data to identify probable past and future highly impactful summer seasons. Across most locations, heat mortality counts of a 1-in-100 year season in the climate of 2000 would be expected once every ten to twenty years in the climate of 2020. These return periods are projected to further shorten under warming levels of 1.5 °C and 2 °C, where heat-mortality extremes of the past climate will eventually become commonplace if no adaptation occurs. Our findings highlight the urgent need for strong mitigation and adaptation to reduce impacts on human lives.

Positive Association of Aggression with Ambient Temperature.

Background: Relatively little attention has been paid to the potential effects of rising temperatures on changes in human behavior that lead to health and social consequences, including aggression. This study investigated the association between ambient temperature and aggression using assault death data from Seoul, South Korea (1991-2020). Methods: We conducted a time-stratified case-crossover analysis based on conditional logistic regression to control for relevant covariates. The exposure-response curve was explored, and stratified analyses were conducted by season and sociodemographic characteristics. Results: The overall risk of assault deaths significantly increased by 1.4% per 1°C increase in ambient temperature. A positive curvilinear relationship was observed between ambient temperature and assault deaths, which flattened out at 23.6°C during the warm season. Furthermore, risk increases were higher in males, teenagers, and those with the least education. Conclusion: This study highlighted the importance of understanding the impact of rising temperatures on aggression in the context of climate change and public health.

Effect modification of the association between temperature variability and hospitalization for cardiovascular disease by comorbid diabetes mellitus: A nationwide time-stratified case-crossover analysis.

AIMS: We aimed to explore the association between short-term exposure to temperature variability (TV), and cardiovascular hospitalization stratified by the presence of comorbid diabetes. METHODS: We collected data on nationwide hospitalization for cardiovascular diseases and daily weather conditions during 2011-2018 in Japan. TV was calculated as the standard deviation of daily minimum and maximum temperatures within 0-7 lag days. We applied a two-stage time-stratified case-crossover design to estimate the association between TV and cardiovascular hospitalization with and without comorbid diabetes, adjusting for temperature and relative humidity. Furthermore, specific cardiovascular disease causes, demographic characteristics, and seasons were used for stratification. RESULTS: In 3,844,910 hospitalizations for cardiovascular disease, each 1 °C increase in TV was associated with a 0.44% (95% CI: 0.22%, 0.65%) increase in the risk of cardiovascular admission. We observed a 2.07% (95% CI: 1.16%, 2.99%) and 0.61% (95% CI: -0.02%, 1.23%) increase per 1 °C in risk of heart failure admission in individuals with and those without diabetes, respectively. The higher risk among individuals with diabetes was mostly consistent in the analyses stratified by age, sex, body mass index, smoking status, and season. CONCLUSION: Comorbid diabetes may increase susceptibility to TV in relation to acute cardiovascular disease hospitalization.

Prediction of climate change impacts on heatstroke cases in Japan's 47 prefectures with the effect of long-term heat adaptation.

One of the negative consequences of increased air temperatures due to global warming is the associated increase in heat-related mortality and morbidity. Studies that focused on future predictions of heat-related morbidity do not consider the effect of long-term heat adaptation measures, nor do they use evidence-based methods. Therefore, this study aimed to predict the future heatstroke cases for all 47 prefectures of Japan, by considering long-term heat adaptation by translating current geographical differences in heat adaptation to future temporal heat adaptation. Predictions were conducted for age groups of 7-17, 18-64, and ≥65 years. The prediction period was set to a base period (1981-2000), mid-21st century (2031-2050), and the end of the 21st century (2081-2100). We found that the average heatstroke incidence (number of patients with heatstroke transported by ambulance per population) in Japan under five representative climate models and three greenhouse gas (GHG) emissions scenarios increased by 2.92- for 7-17 years, 3.66- for 18-64 years, and 3.26-fold for ≥65 years at the end of the 21st century without heat adaptation. The corresponding numbers were 1.57 for 7-17 years, 1.77 for 18-64 years, and 1.69 for ≥65 years with heat adaptation. Furthermore, the average number of patients with heatstroke transported by ambulance (NPHTA) under all climate models and GHG emissions scenarios increased by 1.02- for 7-17 years, 1.76- for 18-64 years, and 5.50-fold for ≥65 years at the end of 21st century without heat adaptation, where demographic changes were considered. The corresponding numbers were 0.55 for 7-17 years, 0.82 for 18-64 years, and 2.74 for ≥65 years with heat adaptation. The heatstroke incidence, as well as the NPHTA, substantially decreased when heat adaptation was considered. Our method could be applicable to other regions across the globe.

Mortality Risk of Hot Nights: A Nationwide Population-Based Retrospective Study in Japan.

BACKGROUND: The health effects of heat are well documented; however, limited information is available regarding the health risks of hot nights. Hot nights have become more common, increasing at a faster rate than hot days, making it urgent to understand the characteristics of the hot night risk. OBJECTIVES: We estimated the effects of hot nights on the cause- and location-specific mortality in a nationwide assessment over 43 y (1973-2015) using a unified analytical framework in the 47 prefectures of Japan. METHODS: Hot nights were defined as days with a) minimum temperature ≥25°C (HN25) and b) minimum temperature ≥95th percentile (HN95th) for the prefecture. We conducted a time-series analysis using a two-stage approach during the hot night occurrence season (April-November). For each prefecture, we estimated associations between hot nights and mortality controlling for potential confounders including daily mean temperature. We then used a random-effects meta-analytic model to estimate the pooled cumulative association. RESULTS: Overall, 24,721,226 deaths were included in this study. Nationally, all-cause mortality increased by 9%-10% [HN25 relative risk (RR)=1.09, 95% confidence interval (CI): 1.08, 1.10; HN95th RR=1.10, 95% CI: 1.09, 1.11] during hot nights in comparison with nonhot nights. All 11 cause-specific mortalities were strongly associated with hot nights, and the corresponding associations appeared to be acute and lasted a few weeks, depending on the cause of death. The strength of the association between hot nights and mortality varied among prefectures. We found a higher mortality risk from hot nights in early summer in comparison with the late summer in all regions. CONCLUSIONS: Our findings support the evidence of mortality impacts from hot nights in excess of that explicable by daily mean temperature and have implications useful for establishing public health policy and research efforts estimating the health effects of climate change. https://doi.org/10.1289/EHP11444.

M-PAST score is better than MAST score for the diagnosis of active fibrotic nonalcoholic steatohepatitis.

BACKGROUND: Clinical trials enroll patients with active fibrotic nonalcoholic steatohepatitis (NASH) (nonalcoholic fatty liver disease [NAFLD] activity score ≥ 4) and significant fibrosis (F ≥ 2); however, screening failure rates are high following biopsy. We developed new scores to identify active fibrotic NASH using FibroScan and magnetic resonance imaging (MRI). METHODS: We undertook prospective primary (n = 176), retrospective validation (n = 169), and University of California San Diego (UCSD; n = 234) studies of liver biopsy-proven NAFLD. Liver stiffness measurement (LSM) using FibroScan or magnetic resonance elastography (MRE), controlled attenuation parameter (CAP), or proton density fat fraction (PDFF), and aspartate aminotransferase (AST) were combined to develop a two-step strategy-FibroScan-based LSM followed by CAP with AST (F-CAST) and MRE-based LSM followed by PDFF with AST (M-PAST)-and compared with FibroScan-AST (FAST) and MRI-AST (MAST) for diagnosing active fibrotic NASH. Each model was categorized using rule-in and rule-out criteria. RESULTS: Areas under receiver operating characteristic curves (AUROCs) of F-CAST (0.826) and M-PAST (0.832) were significantly higher than those of FAST (0.744, p = 0.004) and MAST (0.710, p < 0.001). Following the rule-in criteria, positive predictive values of F-CAST (81.8%) and M-PAST (81.8%) were higher than those of FAST (73.5%) and MAST (70.0%). Following the rule-out criteria, negative predictive values of F-CAST (90.5%) and M-PAST (90.9%) were higher than those of FAST (84.0%) and MAST (73.9%). In the validation and UCSD cohorts, AUROCs did not differ significantly between F-CAST and FAST, but M-PAST had a higher diagnostic performance than MAST. CONCLUSIONS: The two-step strategy, especially M-PAST, showed reliability of rule-in/-out for active fibrotic NASH, with better predictive performance compared with MAST. This study is registered with ClinicalTrials.gov (number, UMIN000012757).

Association between ambient temperature and cause-specific cardiovascular disease admissions in Japan: A nationwide study.

BACKGROUND: Substantial evidence suggests that non-optimal temperatures can increase the risk of cardiovascular disease (CVD) mortality and morbidity; however, limited studies have reported inconsistent results for hospital admissions depending on study locations, which also lack national-level investigations on cause-specific CVDs. METHODS: We performed a two-stage meta-regression analysis to examine the short-term associations between temperature and acute CVD hospital admissions by specific categories [i.e., ischemic heart disease (IHD), heart failure (HF), and stroke] in 47 prefectures of Japan from 2011 to 2018. First, we estimated the prefecture-specific associations using a time-stratified case-crossover design with a distributed lag nonlinear model. We then used a multivariate meta-regression model to obtain national average associations. RESULTS: During the study period, a total of 4,611,984 CVD admissions were reported. We found cold temperatures significantly increased the risk of total CVD admissions and cause-specific categories. Compared with the minimum hospitalization temperature (MHT) at the 98th percentile of temperature (29.9 °C), the cumulative relative risks (RRs) for cold (5th percentile, 1.7 °C) and heat (99th percentile, 30.5 °C) on total CVD were 1.226 [95% confidence interval (CI): 1.195, 1.258] and 1.000 (95% CI: 0.998, 1.002), respectively. The RR for cold on HF [RR = 1.571 (95% CI: 1.487, 1.660)] was higher than those of IHD [RR = 1.119 (95% CI: 1.040, 1.204)] and stroke [RR = 1.107 (95% CI: 1.062, 1.155)], comparing to their cause-specific MHTs. We also observed that extreme heat increased the risk of HF with RR of 1.030 (95% CI: 1.007, 1.054). Subgroup analysis showed that the age group ≥85 years was more vulnerable to these non-optimal temperature risks. CONCLUSIONS: This study indicated that cold and heat exposure could increase the risk of hospital admissions for CVD, varying depending on the cause-specific categories, which may provide new evidence to reduce the burden of CVD.