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Objectives: In this study, we evaluated the association between working hours and cancer risk in the Japanese population, which has not been evaluated., Methods: Using a cohort database from a Japan Public Health Center-based Prospective Study, we evaluated 26 738 participants (16 351 men and 10 387 women), who responded to a questionnaire about working hours and followed these participants from 1993-1994 to 2013. Participants were divided into four groups according to working hours (≤6, 7-8, 9-10, ≥11 h/day). The hazard ratio (HR) and 95% confidence interval (CI) of each cancer incidence were calculated using a multivariable-adjusted Cox proportional hazard model., Results: During 488 383 person-years of follow-up, 481 patients with newly diagnosed cancers were identified. There was no clear association between long working hours and overall cancer, lung cancer, and stomach cancer risks. Long working hours tended to increase prostate cancer risk in men and breast cancer risk in women, although the difference was not statistically significant. Increased liver cancer risk with short working hours (HR [95% CI]; 3.15 [1.44-6.88] in the ≤6 h/day group vs. 7-8 h/day) was observed. Colorectal cancer also tended to increase risk in short working hours, however, there were not statistically significance., Conclusions: In this population, long working hours were not associated with cancer risk with statistically significance. The association between short working hours and liver cancer risk was observed, probably due to the reverse causation of liver cancer., (© 2022 The Authors. Journal of Occupational Health published by John Wiley & Sons Australia, Ltd on behalf of The Japan Society for Occupational Health.) more...

Patients with traumatic brain injury (TBI) are severely injured patients who require timely, efficient, and specialized care. The effectiveness of helicopter emergency medical services (HEMS) for patients with TBI remains unclear. This study aimed to compare the mortality of patients with TBI transported by HEMS and ground ambulance using propensity score-matching analysis, and to analyze the effects of HEMS in various subpopulations. We conducted a retrospective analysis of the Japan Trauma Data Bank. The study period was from January 2004 to December 2018. The participants were divided into two groups: the helicopter group (patients transported by HEMS) and ground group (patients transported by ground ambulance). The principal outcome was death at hospital discharge. In total, 58,532 patients were eligible for analysis (ground group, n  = 54,820 [93.7%]; helicopter group, n  = 3712 [6.3%]). Helicopter transport decreased patient mortality at hospital discharge (adjusted odds ratio [OR], 0.83; 95% confidence interval [CI], 0.74-0.92). In propensity score-matched patients, the proportion of deaths at hospital discharge was lower in the helicopter (18.76%) than in the ground (21.21%) group (crude OR, 0.86; 95% CI, 0.77-0.96). The mortality rate in the helicopter group was significantly reduced in many subpopulations, especially in cases of severe TBI with a decreased level of consciousness or higher Injury Severity Score (ISS; Japan Coma Scale score 2 [adjusted OR, 0.60; 95% CI, 0.45-0.80] and ISS ≥50 [adjusted OR, 0.69; 95% CI, 0.48-0.99]). Although the study design was non-randomized, our findings in patients with TBI showed that HEMS conferred a mortality benefit over ground ambulance. more...

While the age-standardized mortality rate in Japan is decreasing for all cancers as a whole, this is not the case for some major site-specific cancers. We descriptively compared trends in all-cancer and site-specific cancer mortality in Japan and selected countries. Data on age-standardized cancer mortality rates in six countries (Japan, the USA, the UK, Canada, Australia and the Republic of Korea) in 1980-2016 were obtained from the World Health Organization mortality database. While stomach and liver cancer mortality rates in Japan and Korea were initially much higher than those in non-Asian countries, they have rapidly decreased over the long term. By contrast, colorectal, pancreatic and cervical cancer mortality rates in Japan, which were initially lower than those in other countries, have increased such that they are now similar or higher than the rates in non-Asian countries. For male lung cancer, Japan's initially lower mortality rate is now comparable to that in non-Asian countries as a result of slower decline. Meanwhile, the mortality rate of female breast cancer in Japan and Korea has increased and is nearing the rates observed in non-Asian countries, which by contrast have shown a steady decrease. Thus, while Japan has been successful in reducing the burden of stomach and liver cancers, it is falling behind in reducing the mortality rate of screening-related cancers such as colorectal, female breast and cervical cancers. Control measures for these cancers need to be strengthened., (© The Author(s) 2021. Published by Oxford University Press.) more...

Background and Aim: In Japan, screening colonoscopy for colorectal cancer is expected to reduce colorectal cancer mortality, although its complication rate has not been sufficiently examined. The aim of this study is to analyze severe complications due to colonoscopy., Methods: As a study population, we retrospectively used commercially anonymized health insurance claims data covering 5.71 million patients from January 2005 to August 2018. We extracted patients who received colonoscopy with lesions resection or without treatment. Main outcomes were rates of hemorrhage, perforation, fatal events, and their risk factors., Results: Among 341 852 colonoscopy without treatment in 260 128 patients (mean age: 49.6 ± 11.7 years), the rates of hemorrhage, perforation, and fatal events were 0.0059% (95% confidence interval [CI] 0.0031-0.0085), 0.0032% (95% CI 0.0011-0.0052), and 0.00029% (95% CI 0-0.0012), respectively. Regarding hemorrhage, compared with the rate for patients <50 years old (0.0050%), the rates for those 50-59, 60-69, and ≥70 years old were 0.0095% (P = 0.17), 0.0031% (P = 0.17), and 0%, respectively. Regarding perforation, compared with patients <50 years old (0.0056%), the rates for those 50-59, 60-69, and ≥70 years old were 0%, 0.0015% (P = 0.99), and 0.0102% (P = 0.99), respectively. A multivariate analysis for risk factors showed no significant findings for hemorrhage and perforation without treatment. Among 123 087 colonoscopy with lesions resection in 102 058 patients (mean age: 53.7 ± 9.3 years), the rates of hemorrhage, perforation, and fatal events were 0.136% (95% CI 0.1157-0.1572), 0.033% (95% CI 0.0228-0.0437), and 0.00081% (95% CI 0-0.0035), respectively., Conclusions: The analysis using health insurance claims data demonstrated the safety of colonoscopy., (© 2021 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.) more...

Aim: Vasopressors are frequently incorporated into severe traumatic brain injury management algorithms. However, evidence regarding their clinical effectiveness is lacking. We undertook a nationwide retrospective cohort study to determine the association between vasopressor use and mortality in patients with severe traumatic brain injury., Methods: Data were collected between January 2004 and December 2018 from the Japanese Trauma Data Bank, which includes data from 272 emergency hospitals in Japan. Adults aged 16 years and over with severe traumatic brain injury but without major extracranial injuries were examined. A severe traumatic brain injury was defined based on a Glasgow Coma Scale score of 3-8 on admission. Multivariable analysis and propensity score matching were carried out. Statistical significance was assessed using 95% confidence intervals., Results: In total, 10,295 patients were eligible for analysis, with 654 included in the vasopressor group and 9,641 included in the nonvasopressor group. The proportion of deaths at hospital discharge was higher in the vasopressor group than in the nonvasopressor group (81.80% [535/654] versus 40.24% [3,880/9,641]). This finding was confirmed in a multivariable logistic regression analysis (adjusted odds ratio, 5.37; 95% confidence interval, 4.23-6.81). Among propensity score-matched patients adjusted for severity, the proportion of deaths at hospital discharge remained higher in the vasopressor group than in the nonvasopressor group (81.87% [533/651] versus 56.22% [366/651]) (odds ratio, 3.52; 95% confidence interval, 2.73-4.53)., Conclusion: The study results suggest that vasopressor use in patients with severe isolated traumatic brain injury is associated with a higher mortality at hospital discharge., Competing Interests: Approval of the research protocol: The protocol for this research project has been approved by a suitably constituted Ethics Committee of the institution and it conforms to the provisions of the Declaration of Helsinki. Committee of Osaka University Graduate School of Medicine (Osaka, Japan), Approval No. 16260. Informed consent: The requirement for written informed consent was waived due to the retrospective nature of the study. Personal identifiers were removed from the Japanese Trauma Data Bank registry before data extraction in this study. Registry and the registration no. of the study/trial: N/A. Animal studies: N/A. Conflict of interest: None., (© 2021 The Authors. Acute Medicine & Surgery published by John Wiley & Sons Australia, Ltd on behalf of Japanese Association for Acute Medicine.) more...

Background: B vitamins and methionine are essential substrates in the one-carbon metabolism pathway involved in DNA synthesis and methylation. They may have essential roles in cancer development. We aimed to evaluate the associations of dietary intakes of vitamin B12, vitamin B6, folate, and methionine with the risk of esophageal cancer (EC) using data from the Japan Public Health Center-based Prospective Study., Methods: We included 87,053 Japanese individuals who completed a food frequency questionnaire and were followed up from 1995-1998 to 2013 and 2015. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated by Cox proportional-hazard regression across quintiles of dietary intakes of B vitamins and methionine., Results: After 1,456,678 person-years of follow-up, 427 EC cases were documented. The multivariable HR (95% CI) of incident EC in the highest versus lowest quintile of dietary intake of vitamin B12 was 1.75 (1.13-2.71; p-trend=0.01). Stratification analysis based on alcohol consumption showed that higher dietary intakes of vitamin B12 and methionine were associated with an increased risk of EC among never-drinkers; HRs (95% CIs) were 2.82 (1.18-6.74; p-trend=0.009; p-interaction=0.18) and 3.45 (1.32-9.06; p-trend=0.003; p-interaction 0.02) for vitamin B12 and methionine, respectively. Meanwhile, there was no association between vitamin B12 and methionine intake with the risk of EC among drinkers. There were no associations between dietary intake of folate or vitamin B6 and the risk of EC., Conclusion: Dietary intake of vitamin B12 was positively associated with the risk of EC in the Japanese population., (© 2021. The Author(s).) more...

Introduction: The COVID-19 pandemic caused by SARS-CoV-2 has now affected tens of millions of people globally. It is the hope that vaccines against SARS-CoV-2 will deliver a comprehensive solution to this global pandemic; however, this will require extensive national vaccination programs. Ultimately, clinical conditions and even sudden unexplained death will occur around the time of vaccination, thus a distinction needs to be made between events that are causally related to the vaccine or temporally related to vaccination. This study aimed to estimate the background occurrence of 43 clinical conditions in the Japanese population., Methods: A retrospective cohort study was conducted from 2013 to 2019 using data from two large healthcare claims databases (MDV and JMDC) in Japan. The estimated number of new cases and incidence were calculated based on the actual number of new cases identified in the databases. The PubMed and Ichushi-web databases, as well as grey literature such as guidelines and government statistics, were also searched to identify any publications related to incidence of these conditions in Japan., Results and Conclusion: The estimates of the number of total cases and incidence were similar for the MDV and JMDC databases for some diseases. In addition, some estimates were similar to those in the scientific literature. For example, from the MDV and JMDC databases, estimates of incidence of confirmed Bell's palsy in 2019 were 41.7 and 47.9 cases per 100,000 population per year, respectively. These estimates were of the same order from the scientific publication. Determining whether clinical conditions occurring around the time of vaccination are causally or only temporally related to vaccination will be critical for public health decision makers as well as for the general public. Comparison of background occurrence at the population level may provide some additional objective evidence for the evaluation of temporality or causality., Competing Interests: Tomotaka Sobue has received consultancy fees from AstraZeneca, Janssen and Pfizer Inc. Haruhisa Fukuda has received research support from Pfizer Inc. and Eisai, lecture fees from Pfizer Inc. and Merck & Co., and consultancy fees from Astellas, BD, Eli Lilly, Abbott and Novartis. Tetsuya Matsumoto received lecture fees and/or consultant fees from Pfizer Inc. and Merck & Co.; he is also a program supervisor for the Japan Agency for Medical Research and Development, and a member of the advisory board for the Pharmaceuticals and Medical Devices Agency. Bennett Lee and Shuhei Ito are employees of Pfizer Japan Inc. and hold stock/stock options of Pfizer Inc. Satoshi Iwata received lecture fees from Taisho Toyama Pharmaceutical Co., Ltd., Pfizer Japan Inc., Astellas Pharma Inc., Japan Vaccine Co., Ltd. and Meiji Seika Pharma Co., Ltd.; he has also been a member of an advisory board of drug reassessment and antimicrobials for husbandry for the Ministry of Health, Labour and Welfare, and a member of the advisory board for the Pharmaceuticals and Medical Devices Agency. more...

Aim: The epidemiological characteristics, in-hospital treatments and outcomes of coronavirus disease 2019 among older patients have not been fully evaluated in Japan., Methods: In this retrospective observational study carried out in Osaka Prefecture, Japan, we enrolled patients aged ≥60 years with laboratory-confirmed coronavirus disease 2019 from January to November 2020. The main outcome was mortality during the observation period, based on the Infectious Diseases Control Law. Cox regression analysis was used to evaluate the association between epidemiological factors and mortality among older patients with coronavirus disease 2019., Results: Older patients accounted for 21.5% (3192/14 846) of the registered patients with coronavirus disease 2019. The number of patients according to age was as follows: 60-69 years, 1140 (35.7%); 70-79 years, 1058 (33.1%); 80-89 years, 749 (23.5%); and ≥90 years, 245 (7.7%). The proportion of deaths during the observation period was 8.5% (271/3192). The proportion of deaths increased with increasing age category (from 1.9% to 20.4%, P for trend <0.001). In multivariable Cox regression analysis, patients aged 70-79, 80-89 and ≥90 years had higher hazard ratios and 95% confidence intervals of death (2.62 [1.63-4.23], 5.99 [3.77-9.50] and 10.24 [6.03-17.40], respectively) than those aged 60-69 years. Factors such as male sex, presence of comorbidities, cluster cases in medical institutions and moderate/severe symptoms at diagnosis were also associated with mortality., Conclusions: This study shows the epidemiological characteristics of older patients with coronavirus disease 2019 in Osaka Prefecture, Japan. The proportion of deaths was 8.5% in total and increased with increasing age. Geriatr Gerontol Int 2021; 21: 629-635., (© 2021 Japan Geriatrics Society.) more...

Purpose: Nine bladder cancer (BCa) cases were reported among aromatic amine-exposed male workers at a factory manufacturing organic dye/pigment intermediates in Japan. We aimed to evaluate the characteristics of aromatic amine-exposed workers by cross-sectional observation, and the risk of BCa by assessing the standardized incidence ratio (SIR)., Methods: In the cross-sectional study, our subjects were: 9 BCa patients, 36 aromatic amine-exposed non-patients, and 79 non-exposed workers from 3 factories. We evaluated the subjects' medical history, urinalysis, qualitative determination of nuclear matrix protein 22, and urinary cytology. For SIR assessment, 98 aromatic amine-exposed workers from 1 factory were included, and the Japanese general male population was used as a referent population. Since no direct aromatic amine-exposure data were available, we calculated surrogate exposure levels using information on job sites, exposure potency, and duration., Results: Coexistent aromatic amines were ortho-toluidine (OT), aniline, para-toluidine, ortho-anisidine, 2,4-xylidine, and ortho-chloroaniline. The prevalence rates of cystitis and bladder lesion-related symptoms in both BCa patients and aromatic amine-exposed non-patient workers were significantly higher than those of non-exposed workers. Overall, the SIR for BCa in OT-exposed workers was 56.8 (95% CI 27.7-104.3) and apparent dose-response relationships were revealed between the SIR and the surrogate exposure level in the 0-10-year lagged analyses. Overall, SIRs in other aromatic amine-exposed workers were also significantly high but no or unclear dose-response relationships were observed., Conclusions: We conclude that OT may be responsible for the increased risk of BCa. Regular monitoring of bladder lesion-related symptoms is essential for the early identification of BCa., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH, DE part of Springer Nature.) more...

Surgeons and medical staff attend academic meetings several times a year. However, there is insufficient evidence on the influence of the "meeting effect" on traumatic brain injury (TBI) treatments and outcomes. Using the Japan Trauma Data Bank, we analyzed the data of TBI patients admitted to the hospital from 2004 to 2018 during the national academic meeting days of the Japanese Association for Acute Medicine, the Japanese Society of Intensive Care Medicine, the Japanese Association for the surgery of trauma, the Japan Society of Neurotraumatology and the Japan Neurosurgical Society. The data of these patients were compared with those of TBI patients admitted 1 week before and after the meetings. The primary outcome was in-hospital death. We included 7320 patients in our analyses, with 5139 and 2181 patients admitted during the non-meeting and meeting days, respectively; their in-hospital mortality rates were 15.7% and 14.5%, respectively. No significant differences in in-hospital mortality were found (adjusted odds ratio, 0.93; 95% confidence interval, 0.78-1.11). In addition, there were no significant differences in in-hospital mortality during the meeting and non-meeting days by the type of national meeting. In Japan, it is acceptable for medical professionals involved in TBI treatments to attend national academic meetings without impacting the outcomes of TBI patients., (© 2021. The Author(s).) more...

Background: Among the many factors that may influence traumatic brain injury (TBI) progression, sex is one of the most controversial. The objective of this study was to investigate sex differences in TBI-associated morbidity and mortality using data from the largest trauma registry in Japan., Methods: This retrospective, population-based observational study included patients with isolated TBI, who were registered in a nationwide database between 2004 and 2018. We excluded patients with extracranial injury (Abbreviated Injury Scale score ≥ 3) and removed potential confounding factors, such as non-neurological causes of mortality. Patients were stratified by age and mortality and post-injury complications were compared between males and females., Results: A total of 51,726 patients with isolated TBI were included (16,901 females and 34,825 males). Mortality across all ages was documented in 12.01% (2030/16901) and 12.76% (4445/34825) of males and females, respectively. The adjusted odds ratio (OR) of TBI mortality for males compared to females was 1.32 (95% confidence interval [CI], 1.22-1.42]. Males aged 10-19 years and ≥ 60 years had a significantly higher mortality than females in the same age groups (10-19 years: adjusted OR, 1.97 [95% CI, 1.08-3.61]; 60-69 years: adjusted OR, 1.24 [95% CI, 1.02-1.50]; 70-79 years: adjusted OR, 1.20 [95% CI, 1.03-1.40]; 80-89 years: adjusted OR, 1.50 [95% CI, 1.31-1.73], and 90-99 years: adjusted OR, 1.72 [95% CI, 1.28-2.32]). In terms of the incidence of post-TBI neurologic and non-neurologic complications, the crude ORs were 1.29 (95% CI, 1.19-1.39) and 1.14 (95% CI, 1.07-1.22), respectively, for males versus females. This difference was especially evident among elderly patients (neurologic complications: OR, 1.27 [95% CI, 1.14-1.41]; non-neurologic complications: OR, 1.29 [95% CI, 1.19-1.39])., Conclusions: In a nationwide sample of patients with TBI in Japan, males had a higher mortality than females. This disparity was particularly evident among younger and older generations. Furthermore, elderly males experienced more TBI complications than females of the same age. more...

Current detergent or ether-disrupted split vaccines (SVs) for influenza do not always induce adequate immune responses, especially in young children. This contrasts with the whole virus particle vaccines (WPVs) originally used against influenza that were immunogenic in both adults and children but were replaced by SV in the 1970s due to concerns with reactogenicity. In this study, we re-evaluated the immunogenicity of WPV and SV, prepared from the same batch of purified influenza virus, in cynomolgus macaques and confirmed that WPV is superior to SV in priming potency. In addition, we compared the ability of WPV and SV to induce innate immune responses, including the maturation of dendritic cells (DCs) in vitro. WPV stimulated greater production of inflammatory cytokines and type-I interferon in immune cells from mice and macaques compared to SV. Since these innate responses are likely triggered by the activation of pattern recognition receptors (PRRs) by viral RNA, the quantity and quality of viral RNA in each vaccine were assessed. Although the quantity of viral RNA was similar in the two vaccines, the amount of viral RNA of a length that can be recognized by PRRs was over 100-fold greater in WPV than in SV. More importantly, 1000-fold more viral RNA was delivered to DCs by WPV than by SV when exposed to preparations containing the same amount of HA protein. Furthermore, WPV induced up-regulation of the DC maturation marker CD86 on murine DCs, while SV did not. The present results suggest that the activation of antigen-presenting DCs, by PRR-recognizable viral RNA contained in WPV is responsible for the effective priming potency of WPV observed in naïve mice and macaques. WPV is thus recommended as an alternative option for seasonal influenza vaccines, especially for children., 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 © 2021 Elsevier Ltd. All rights reserved.) more...

The epidemiological and clinical characteristics, treatments, and outcomes of patients with coronavirus disease 2019 (COVID-19) who are admitted to the intensive care unit (ICU) have not been adequately evaluated in Japan. We analyzed the registry data of 205 patients with COVID-19 admitted to the ICU between February and November 2020, in Osaka Prefecture, Japan. A Cox proportional hazards model was used to assess the association between epidemiological factors and mortality among ICU patients. Of the 205 ICU patients, 161 (78.5%) were men and 149 (72.7%) were older than 60 years. A total of 117 patients (57.1%) had comorbidities. The most common symptoms at diagnosis were mild ( n = 131, 63.9%). A total of 187 patients (91.2%) received mechanical ventilation, and 32 patients (15.6%) required extracorporeal membrane oxygenation. Patients were followed up for a median of 25 days after ICU admission. A total of 147 patients (71.7%) were alive at discharge, and 58 patients (28.3%) died. The hazard ratio for mortality among patients aged >80 years was 6.02 (95% confidence interval: 2.10-17.25) in the multivariable model, which was higher than that among those aged ≤59 years. These results are useful for recognizing the clinical course of this infection in ICU patients. more...

The epidemiological information on characteristics, in-hospital treatments, and outcomes of the coronavirus disease 2019 (COVID-19) among pediatric patients has not been fully evaluated in Japan. This was a retrospective observational study conducted in the Osaka Prefecture, Japan, and we enrolled laboratory-confirmed COVID-19 patients aged ≤ 19 years old from January to November in 2020. Of 14,846 COVID-19 eligible patients, 1240 pediatric patients (8.4%) were registered during the study period; 329 were children aged 0-9 years (26.5%) and 911 were adolescents aged 10-19 years (73.5%). The majority of the patients exhibited mild symptoms at diagnosis (872, 70.3%), some were asymptomatic (296, 23.9%). Cluster infections occurred in child-care facilities (26, 7.9%) among children and in universities (27, 3.0%) and schools (18, 2.0%) among adolescents. The number of close-contact cases was 260 (69.0%) in children and 459 (50.4%) in adolescents. Sixty of the children (18.2%) and 90 of the adolescents (9.9%) were hospitalized. One patient received mechanical ventilation, and none underwent extracorporeal membrane oxygenation. One patient was admitted to the intensive care unit; there were no deaths. These results are useful for recognizing the clinical course from transmission route to outcomes of this infection in pediatric patients., Competing Interests: The authors declare no conflict of interest. more...

Aim: To assess the impact of the Summit on Financial Markets and the World Economy held in Osaka City, Japan (G20 Osaka Summit) on the emergency medical services (EMS) system., Methods: This study used the ORION database with its population-based registry of emergency patients comprising both ambulance and in-hospital records in Osaka Prefecture, Japan. The G20 Osaka Summit was held in Osaka City from 28 to 29 June, 2019. Changes in the EMS system and traffic regulations in Osaka were made during the period from 27 to 30 June, but we focused on the two summit days as the G20 period. The control periods comprised the same calendar days 1 week before and 1 week after the G20 period. We evaluated differences in the number of emergency transports, difficulties in obtaining hospital acceptance of patients, deaths among hospitalized emergency patients, and ambulance transport times between the two periods., Results: In total, 2,590 cases in the G20 period and 5,152 cases in the control periods were registered. The relative risk of cases during the G20 versus control periods was 1.01 (0.96-1.05). Significant decreases were observed in the number of traffic accidents as ambulance calls (relative risk = 0.77; 95% confidence interval, 0.64-0.91). There were no significant differences in difficulties in obtaining hospital acceptance or deaths among hospitalized emergency patients between the G20 and control periods. In addition, ambulance transport times during the G20 period were not significantly longer than those in the control periods., Conclusion: The G20 Osaka Summit did not adversely impact the provision of emergency medical care in the Osaka area., Competing Interests: Approval of the research protocol: The protocol was approved by the Ethics Committee of Osaka University as the corresponding institution (No. 15003). Informed consent: The requirement for informed consent of patients was waived. Registry and the registration no. of the study/trial: N/A. Animal studies: N/A. Conflict of interest: None., (© 2021 The Authors. Acute Medicine & Surgery published by John Wiley & Sons Australia, Ltd on behalf of Japanese Association for Acute Medicine.) more...

Background: Second primary cancers have impact on survival in patients who achieved cure for the first esophageal cancer. We, therefore, assessed the risk of incidence and mortality for second primary cancer by calculating standardized incidence ratio (SIR) and standardized mortality ratio (SMR) in patients with superficial or localized esophageal cancer without lymph node metastases as the first cancer (index cancer)., Methods: Data on cancer development and subsequent causes of deaths were collected from integrated database of the Osaka Cancer Registry and the Vital Statistics of Japan. Records with information on patients with index esophageal cancer diagnosed between 2004 and 2013 were extracted from the database. Then, SIR and SMR for second primary cancers that developed in other organ were calculated with the reference to the general population during the same period. All probability values are two-tailed., Results: Of 473,784 case records, 3022 cases of patients with index esophageal cancer were identified. Significantly higher SMRs/SIRs for cancers in mouth/pharynx, larynx, pancreas, and leukemia were confirmed with the values of 10.78/16.16, 8.56/6.44, 2.33/2.31, and 3.96/4.42, respectively. Significantly, higher SIRs for stomach, lung, and skin cancers were confirmed with the values of 2.84, 2.36, and 3.38, respectively, while SMRs were not significantly higher in these cancers., Conclusions: Significantly higher risks for mouth/pharynx, larynx, pancreas, and leukemia as second cancers were clarified. Careful surveillance for these cancers is required for esophageal cancer patients. more...

Antihypertensive drugs have been reported as both promotors and suppressors of cancers and this relationship has been known for several decades. We examined a large-scale prospective cohort study in Japan to assess the relationship between long-term antihypertensive drug use, for 10 y, and carcinogenesis. We divided participants into 4 categories according to the period of antihypertensive drug use, and calculated the hazard ratios (HRs), 95% confidence intervals (CIs), and P trends using the Cox proportional hazard model. In all cancers, there was a significant difference in the medication period and the adjusted HR, as well as a significant difference in the P trend. Furthermore, more than 10 y use of antihypertensive drugs significantly increased the adjusted HR in colorectal cancer (multivariable HR: 1.18, 95% CI: 1.01-1.37 in the >10 y use group; P for trend = .033) and renal cancer (multivariable HR: 3.76, 95% CI: 2.32-6.10 in the 5-10 y use group; multivariable HR: 2.14, 95% CI: 1.29-3.56 in the >10 y use group; P for trend < .001). The highest adjusted HR in renal cancer among antihypertensive drug users was observed in the analysis performed on patients in which the outcomes were calculated from 3 y after the 10-y follow-up survey and by sex. A large-scale cohort study in Japan suggested that long-term use of antihypertensive drugs may be associated with an increased incidence of colorectal and renal cancer., (© 2021 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.) more...

In Japan, the differences in characteristics, severity, and mortality of novel coronavirus disease (COVID-19) patients between the first and second surges of infections have not been fully understood. This study is a retrospective cohort study of COVID-19 patients confirmed between February 1 and August 31, 2020 in Osaka Prefecture, Japan. Publicly available information on patients was collected from the website of Osaka Prefecture. Patients were divided into two groups according to the date of the positive laboratory test result: the first surge (February 1 to May 22) and the second surge (May 23 to August 31). Patients' characteristics were compared between the two groups. A multivariable Cox proportional-hazards model was applied to compare severity and mortality between the two groups, where sex, age group at the onset date, city of residence, and days to test positive were adjusted. Hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated. A total of 8,541 patients included 1,780 and 6,761 patients in the first and second surges, respectively. Age at the onset date was younger in the second surge ( p < 0.001), and median of days from the onset date to the positive test date shortened from 7 to 6 days ( p < 0.001). The multivariable Cox proportional-hazards model revealed that both severity and mortality were lower in the second surge than in the first surge (severity: HR: 0.51 [0.39-0.67]; mortality: HR: 0.37 [0.25-0.56]). In conclusion, severity and mortality were lower in the second surge than in the first surge among COVID-19 patients in Osaka Prefecture, Japan., Competing Interests: The authors have no conflicts of interest to disclose., (2021, National Center for Global Health and Medicine.) more...

The effect of a history of cancer on the prognosis of patients with acute myocardial infarction (AMI) after percutaneous coronary intervention (PCI) is poorly understood.From the Osaka Acute Coronary Insufficiency Study (OACIS) registry in Osaka, Japan, we enrolled the case data of a total of 3499 patients with AMI treated with PCI between 1998 and 2014, of whom 462 had a cancer history (cancer group, 13.2%) and 3037 did not (non-cancer group, 86.8%). All of the cases were followed for up to five years from discharge.The Kaplan-Meier curve and multivariate analysis using Cox proportional hazards models revealed that all-cause mortality was significantly higher in the cancer group than in the non-cancer group (adjusted hazard ratio [HR], 2.43; P < 0.001). Deaths from cardiac, cancer, and other causes were treated as competing events, and competing analysis using the cumulative incidence function (CIF) and Fine-Gray model revealed that mortality due to cancer was higher in the cancer group than in the non-cancer group, whereas cardiac mortality was similar between the two groups. The incidences of cardiovascular events, including stroke, recurrent infarction, and heart failure requiring readmission, were also similar between the two groups, although the Kaplan-Meier analysis and univariate Cox proportional hazards model revealed that the incidence of stroke was higher in the cancer group than in the non-cancer group.A history of cancer increased all-cause and cancer mortality among patients with AMI treated with PCI, although it was not associated with cardiovascular events. more...

Prior studies reported the association of reproductive factors with breast cancer (BC), but the evidence is inconsistent. We conducted a pooled analysis of nine cohort studies in Japan to evaluate the impact of six reproductive factors (age at menarche/age at first birth/number of births/age at menopause/use of female hormones/breastfeeding) on BC incidence. We conducted analyses according to menopausal status at the baseline or at the diagnosis. Hazard ratio (HR) and 95% confidence interval (CI) were estimated by applying Cox proportional-hazards model in each study. These hazard ratios were integrated using a random-effects model. Among 187,999 women (premenopausal: 61,113, postmenopausal: 126,886), we observed 873 premenopausal and 1,456 postmenopausal cases. Among premenopausal women, use of female hormones significantly increased BC incidence (HR: 1.53 [1.04-2.25]). Although P value for trend was not significant for age at first birth and number of births (P for trend: 0.15 and 0.30, respectively), women giving first birth at ages ≥36 experienced significantly higher BC incidence than at ages 21-25 years, and women who had ≥2 births experienced significantly lower BC incidence than nulliparous women. Among postmenopausal women, more births significantly decreased BC incidence (P for trend: 0.03). Although P value for trend was not significant for age at first birth and age at menopause (P for trend: 0.30 and 0.37, respectively), women giving first birth at ages 26-35 years experienced significantly higher BC incidence than at ages 21-25 years, and women with age at menopause: ≥50 years experienced significantly higher BC incidence than age at menopause: ≤44 years. BC incidence was similar according to age at menarche or breastfeeding history among both premenopausal and postmenopausal women. In conclusion, among Japanese women, use of female hormones increased BC incidence in premenopausal women, and more births decreased BC incidence in postmenopausal women., (© 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.) more...

Acrylamide can be carcinogenic to humans. However, the association between the acrylamide and the risks of renal cell, prostate, and bladder cancers in Asians has not been assessed. We aimed to investigate this association in the Japan Public Health Center-based Prospective Study data in 88,818 Japanese people (41,534 men and 47,284 women) who completed a food frequency questionnaire in the five-year follow-up survey in 1995 and 1998. A validated food frequency questionnaire was used to assess the dietary acrylamide intake. Cox proportional hazard regression models were used to estimate hazard ratios and 95% confidence intervals (CIs). During a mean follow-up of 15.5 years (15.2 years of prostate cancer), 208 renal cell cancers, 1195 prostate cancers, and 392 bladder cancers were diagnosed. Compared to the lowest quintile of acrylamide intake, the multivariate hazard ratios for the highest quintile were 0.71 (95% CI: 0.38-1.34, p for trend = 0.294), 0.96 (95% CI: 0.75-1.22, p for trend = 0.726), and 0.87 (95% CI: 0.59-1.29, p for trend = 0.491) for renal cell, prostate, and bladder cancers, respectively, in the multivariate-adjusted model. No significant associations were observed in the stratified analyses based on smoking. Dietary acrylamide intake was not associated with the risk of renal cell, prostate, and bladder cancers. more...

Acrylamide, which is present in many daily foods, is a probable human carcinogen. In 2002, it was identified in several common foods. Subsequently, western epidemiologists began to explore the relationship between dietary acrylamide exposure and cancer risk; however, limited suggestive associations were found. This prospective study aimed to examine the association between dietary acrylamide intake and the risk of hematological malignancies, including malignant lymphoma (ML), multiple myeloma (MM), and leukemia. We enrolled 85,303 participants in the Japan Public Health Center-based Prospective study on diet and cancer as from 1995. A food frequency questionnaire that included data on acrylamide in all Japanese foods was used to assess dietary acrylamide intake. We applied multivariable adjusted Cox proportional hazards models to reckon hazard ratios (HRs) for acrylamide intake for both categorical variables (tertiles) and continuous variables. After 16.0 median years of follow-up, 326 confirmed cases of ML, 126 cases of MM, and 224 cases of leukemia were available for final multivariable-adjusted analysis. HRs were 0.87 (95% confidence interval [CI]: 0.64-1.18) for ML, 0.64 (95% CI: 0.38-1.05) for MM, and 1.01 (95% CI: 0.71-1.45) for leukemia. Our results implied that acrylamide may not be related to the risk of hematological malignancies. more...

Cervical cancer remains among the most common cancers in women worldwide and can be prevented by vaccination. The Ministry of Health, Labour and Welfare of Japan suspended active recommendation of regular human papillomavirus (HPV) vaccines in 2013 because of various symptoms including chronic pain and motor impairment. This nationwide case-control study from April 2013 to March 2017 targeted women aged 20-24 years old at cervical screening. We compared HPV vaccination exposure between those with abnormal and normal cytology. Abnormal cytology was classified based on the results of histological test and we calculated the odds ratio (OR) and 95% confidence interval (CI) of the above endpoints and vaccination exposure using the conditional logistic regression model and estimated vaccine effectiveness using the formula (1 - OR) × 100. A total of 2483 cases and 12 296 controls (one-to-five matching) were eligible in 31 municipalities in Japan. The distribution of histological abnormalities among cases was 797 CIN1 (including dysplasia) (32.1%), 165 CIN2 (6.7%), 44 CIN3 (1.8%), and eight squamous cell carcinoma (SCC) (0.3%). The OR of HPV vaccination compared with no vaccination for abnormal cytology, CIN1+, CIN2+, and CIN3+ versus controls was 0.42 (95% CI, 0.34-0.50), 0.42 (95% CI, 0.31-0.58), 0.25 (95% CI, 0.12-0.54), and 0.19 (95% CI, 0.03-1.15), respectively, equating to a vaccine effectiveness of 58.5%, 57.9%, 74.8%, and 80.9%, respectively. Eight patients had SCC, none was vaccinated. This nationwide case-control study in Japan demonstrated a substantial risk reduction in abnormal cytology and CIN among women who did versus those who did not receive HPV vaccination., (© 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.) more...

Objectives: To compare the mortality of Japanese athletes in the 1964 Tokyo Olympic Games with that of the Japanese population, and to elucidate factors associated with their mortality., Methods: We obtained from the Japan Sport Association study subjects' biographical information, information on lifestyles and medical data. Missing data were obtained from online databases. Standardised mortality ratio (SMR) was calculated to compare athletes' mortality with the Japanese population. Cox proportional hazards model was applied to estimate the HR for each category of body mass index (BMI), smoking history and handgrip strength. This analysis was limited to male athletes due to the small number of female athletes., Results: Among 342 (283 men, 59 women) athletes, deaths were confirmed for 70 (64 men, 6 women) athletes between September 1964 and December 2017. Total person years was 15 974.8, and the SMR was 0.64 (95% CI 0.50 to 0.81). Multivariate analysis performed on 181 male athletes. Mortality was significantly higher for BMI≥25 kg/m 2 than for 21-23 kg/m 2 (HR: 3.03, 95% CI 1.01 to 9.07). We found no statistically significant associations between smoking history and mortality; the HR (95% CI) for occasional and daily smokers were 0.82 (0.26 to 2.57) and 1.30 (0.55 to 3.03) compared with never smokers. We also found no statistically significant associations between handgrip strength and mortality (P for trend: 0.51)., Conclusion: Japanese athletes in the 1964 Tokyo Olympic Games lived longer than the Japanese population. BMI≥25 kg/m 2 was associated with higher mortality, but smoking history and handgrip strength were not associated with mortality., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.) more...

The levels of hemoglobin adducts of acrylamide (AA-Hb), a biomarker of acrylamide exposure, have not been reported for Japanese subjects. Herein, we determined the AA-Hb levels in a Japanese population and compared them with the estimated dietary intake from the duplicate diet method (DM) and a food frequency questionnaire (FFQ). One-day DM samples, FFQ, and blood samples were collected from 89 participants and analyzed for acrylamide. AA-Hb was analyzed using liquid chromatography tandem mass spectrometry and the N-alkyl Edman method. Participants were divided into tertiles of estimated acrylamide intake and geometric means (GMs) of AA-Hb adjusted for sex and smoking status. A stratified analysis according to smoking status was also performed. The average AA-Hb levels for all participants, never, past, and current smokers were 46, 38, 65, and 86 pmol/g Hb, respectively. GMs of AA-Hb levels in all participants were significantly associated with tertiles of estimated acrylamide intake from DM ( p for trend = 0.02) and FFQ ( p for trend = 0.04), although no association with smokers was observed. AA-Hb levels reflected smoking status, which were similar to values reported in Western populations, and they were associated with estimated dietary intake of acrylamide when adjusted for sex and smoking status. more...

Background: A better understanding of the epidemiology of pediatric out-of-hospital cardiac arrest (OHCA) occurring in nursery schools and kindergartens is indispensable to establish an evidence-based strategy for prevention and improved outcomes. This study aimed to describe the incidence, characteristics, and outcomes of pediatric OHCAs that occurred in certified nursery schools and kindergartens., Methods: Stop and Prevent cardIac aRrest, Injury, and Trauma in Schools (SPIRITS) is a study to construct and analyze a nationwide registry of pediatric OHCAs occurring in school settings in Japan. Using data from the SPIRITS registry, we assessed the incidence, characteristics, and outcomes of pediatric OHCAs that occurred in certified nursery schools/kindergartens between April 2008 and December 2016., Results: During the study period, 37 OHCA patients (31 in certified nursery schools and 6 in kindergartens) were confirmed. The overall incidence rate was 0.13 per 100,000 children per year. Among 37 patients, 57% (21/37) had an OHCA while napping and 35% (13/37) experienced OHCA that was witnessed by bystanders. Although public-access automated external defibrillator pads were applied by bystanders in 24% (9/37) of cases, only 1 patient actually received defibrillation. Overall, the proportion of 1-month survival with favorable neurological outcomes after OHCA was 19% (7/37). Among those with OHCA of non-medical origins, 60% (3/5) of patients experienced arrest caused by suffocation, 60% (3/5) by drowning, and 100% (1/1) by head injury. In contrast, no patient had 1-month favorable neurological outcomes among those with OHCA of medical origins such as presumed cardiac origin (0/17), sudden infant death syndrome (0/6), acute viral myocarditis (0/1), respiratory disease (0/1), and ventricular fibrillation (0/1)., Conclusions: In this population, the majority of pediatric OHCAs occurring in certified nursery schools/kindergartens had non-ventricular fibrillation rhythm, and their outcomes after OHCA of medical origin were poor., (Copyright © 2020. Published by Elsevier Ltd.) more...

Red meat or saturated fatty acid (SFA) intake has been reported to increase lung cancer (LC) risk in several western countries. However, in Asia, studies on the relationship between meat and SFA intake with LC incidence are still relatively insufficient, and their conclusions are inconsistent. We investigated the association of meat and SFA intake with LC incidence in a population-based prospective cohort study in Japan. Cox regression was used to estimate the hazard ratio (HR) and 95% confidence interval (CI) for LC risk according to meat intake and SFA intake. A total of 73 187 participants (32 934 men and 40 253 women) aged 45 to 74 years participated in our study. During the follow-up period of 1 151 839 person-years (median, 16.0 year) from 1995 to 2013 for Cohort I and from 1998 to 2013 for Cohort II, 1315 (901 men and 414 women) newly diagnosed cases of LC were identified. In men, we found an adverse association between total red meat intake (HR and 95% CI: 1.25 [1.02-1.53]; P trend = .008) and LC risk. Additionally, borderline statistically significant elevated risks of LC were seen with high intake of unprocessed red meat and processed red meat. However, no positive association between total red meat intake and LC risk was observed in women. In contrast, poultry and fish intake were not associated with LC risk in either men or women. We concluded that a high total intake of total red meat was associated with moderately elevated LC risk in men., (© 2020 UICC.) more...

Acrylamide is a probable carcinogen in humans. Few studies have assessed dietary acrylamide intake and the risk of pancreatic cancer; however, these studies are based on Western populations. Our purpose was to investigate the association of dietary acrylamide intake with the risk of pancreatic cancer utilizing data from the Japan Public Health Center-based Prospective Study. We evaluated the data of 89,729 participants aged 45-74 years, who replied to a questionnaire on past medical history and lifestyle habits from 1995-1998. Dietary acrylamide intake was estimated utilizing a validated food frequency questionnaire. We calculated the hazard ratios and 95% confidence intervals by using Cox proportional-hazards regression models. The average follow-up was 15.2 years, and 576 cases of pancreatic cancer were diagnosed. In the multivariate-adjusted model, an association between dietary acrylamide intake and pancreatic cancer risk was not demonstrated (hazard ratio for the highest vs. lowest quartile = 0.83, 95% confidence interval: 0.65-1.05, p for trend = 0.07). Furthermore, in the analyses stratified by sex, smoking status, coffee consumption, green tea consumption, alcohol consumption, and body mass index, no significant association was detected. Dietary acrylamide intake was not associated with the pancreatic cancer risk in Japanese individuals. more...

Skin cancer is the most frequently diagnosed cancer in the fair-skinned population. In recent years, the incidence of nonmelanoma skin cancer (NMSC) has been increasing worldwide. However, there is no epidemiological study on skin cancer in the Asian population. A prospective cohort study including 140 420 participants was initiated in 1990 for cohort Ⅰ and 1993 for cohort Ⅱ at baseline survey from 11 public health center (PHC) areas. Of these participants, 284 NMSC cases were diagnosed during the follow-up period (through 2012 in the Osaka PHC area and 2013 in the other PHC areas). The Cox proportional hazards model was used to estimate hazard ratios and 95% confidence intervals (CI) for NMSC incidence according to occupational type, lifestyle factors (alcohol consumption, coffee consumption, smoking status, physical activity, and body mass index), and family history of cancer. Among men, compared with indoor workers, outdoor workers were associated with 2.18 (95% CI, 1.17-4.04) higher risk of squamous cell carcinoma (SCC) but not of basal cell carcinoma (BCC). Furthermore, men who have a family history of cancer had 1.99 (95% CI, 1.10-3.62) higher SCC risk. In women, we did not observe any association between occupational type and the risk of SCC (1.26; 95% CI, 0.68-2.32) or BCC (0.74; 95% CI, 0.42-1.28). In conclusion, men who are outdoor workers or have a family history of cancer had an increased risk of SCC., (© 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.) more...

In Japan, a study using population-based cancer registry data from six prefectures revealed a difference in bladder cancer survival between men and women. However, the period of the study was limited to 1993-2006. The recent introduction of immune checkpoint inhibitors, which have proved to be effective for the treatment for bladder cancer, has led to a rising demand for analysis of long-term trends in net survival in order to accurately assess the effect of the new treatment. The aim of the present study was to examine long-term trends in sex difference in bladder cancer net survival using large-scale population-based cancer registry data from Osaka, Japan (17,500 cases from 1975 to 2009). We also evaluated sex difference in bladder cancer survival after adjustment for stage, histologic type, and other prognostic factors. We showed the long-term trend of five-year net survival for each stage and found that women had poorer five-year net survival than men for the whole study period. The risk of death from bladder cancer was higher among men than women even after adjusting for period at diagnosis, histologic type, stage, age group, and treatment (Excess hazard ratios: 1.17; 95% Confidence interval: 1.10-1.25)., (© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.) more...

In 1955, an outbreak of arsenic poisoning caused by the ingestion of arsenic-contaminated Morinaga Dry Milk occurred in western Japan. This study aimed to assess the mortality and cancer incidence risk among Japanese individuals who were poisoned during this time as infants. In total, 6223 survivors (mean age at enrollment, 27.5 y) who had ingested contaminated milk when they were aged ≤ 2 y participated in this study. Follow-up was conducted from 1982 to 2018 (mean follow-up duration, 30.3 y). Standardized mortality ratio (SMR) and standardized incidence ratio (SIR) were used to compare mortality and cancer incidence rates of subjects with the respective Japanese population rates, and 95% confidence intervals (95% CIs) of the SMR and SIR were also calculated. In total, 561 deaths and 524 new cancer cases were observed. A statistically significant increase in mortality rate was observed for all causes (SMR, 1.15; 1.01-1.19), nervous system disease (2.83, 1.62-4.19), respiratory disease (2.02, 1.37-2.62), genitourinary system disease (2.25, 1.10-3.73), and traffic accident (2.03, 1.14-3.04). In contrast, a significant decrease in cancer incidence rate was observed for all cancers (SIR, 0.96; 0.84-0.99), stomach cancer (0.77, 0.57-0.92), colon cancer (0.63, 0.41-0.85), rectum cancer (0.69, 0.43-0.95), and breast cancer (0.72, 0.52-0.89). Liver cancer showed a high mortality rate (SMR, 1.68; 1.06-2.31). In this study, after the long-term follow-up we revealed overall and cause-specific mortality and cancer incidence risk among survivors who ingested arsenic-contaminated dry milk as infants., (© 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.) more...

Introduction: The aim of this study was to investigate the effect of supplemental vibratory force on biomarkers of bone remodelling during orthodontic tooth movement, the rate of mandibular anterior alignment (RMAA), and compliance with a vibration device., Design, Settings, and Participants: Forty patients between the ages 15-35 undergoing fixed appliance treatment that presented to a university orthodontic clinic were randomly allocated to supplemental use of an intraoral vibrational device (n = 20, AcceleDent®) or fixed appliance only (n = 20). Salivary multiplex assay was completed to analyse the concentration of selected biomarkers of bone remodelling before treatment (T0) and at three following time points (T1, T2, T3), 4-6 weeks apart. Irregularity of the mandibular anterior teeth and compliance was assessed at the same trial time points. Data were analysed blindly on an intention-to-treat basis with descriptive statistics, Mann-Whitney U-test, Wilcoxon signed-rank test, and linear mixed effects regression modelling., Results: No difference in the changes in salivary biomarkers of bone remodelling and RMAA between groups at any time point over the trial duration was observed. No correlation was found between changes in irregularity and biomarker level from baseline to another time point. Lastly, there was no association between RMAA and compliance with the AcceleDent® device., Conclusions: Supplemental vibratory force during orthodontic treatment with fixed appliances does not affect biomarkers of bone remodelling or the RMAA., Limitations: The main limitation of the study was the small sample size and the large variability in the salivary biomarkers., Harms: No harms were observed during the duration of the trial., Protocol: The protocol was not published prior to trial commencement., Registration: The study was registered in Clinical Trials.gov (NCT02119455) first posted on April 2014., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Orthodontic Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.) more...

Little is known about the epidemiological characteristics of patients with coronavirus disease 2019 (COVID-19) in Japan. This is a retrospective observational study of COVID-19 patients; study was conducted from February 1 to May 31, 2020. We used publicly collected data on cases of COVID-19 confirmed by polymerase chain reaction (PCR) testing in Osaka Prefecture, Japan. We described the patient characteristics. The Cox proportional-hazards model was applied to evaluate the association between factors (sex, onset month, age group, city of residence) and mortality, and hazard ratios (HRs) with 95% confidence intervals were estimated. During the study period, 5.7% (1782/31,152) of individuals who underwent PCR testing for COVID-19 showed positive results. Among 244 patients with information on symptoms, the most common symptom was fever (76.6%), followed by cough (44.3%). Of the 1782 patients, 86 patients died. Compared with those aged 0-59 years, higher mortality was observed among those aged 60-69 years (HR: 12.02 [3.37-42.93]), 70-79 years (HR: 44.62 [15.16-131.30]), 80-89 years (HR: 68.38 [22.93-203.89]), and ≥90 years (HR: 144.71 [42.55-492.15]). In conclusion, in Osaka Prefecture, Japan, the most common symptom was fever, and older adults had higher mortality among COVID-19 patients. more...

There are limited real-world data on the treatment practices, outcomes, and safety of chemoradiotherapy (CRT) alone in potential candidates for immune checkpoint inhibitors (ICI) for unresectable non-small cell lung cancer (NSCLC). In this study, we analyzed the safety and efficacy of CRT in patients who underwent CRT and would satisfy the key eligibility criteria for maintenance therapy with durvalumab (eg, no progression after CRT) in real-world settings (m-sub) for unresectable Stage III NSCLC between 1 January 2013 and 31 December 2015 at 12 sites in Japan. The m-sub comprised 214 patients with a median follow-up of 31.6 months (range 1.9-65.8 months). Median overall survival (OS) and progression-free survival (PFS) from completing CRT were 36.4 months (95% confidence interval [CI] 28.1 months to not reached) and 9.5 months (95% CI 7.7-11.7 months), respectively. Consolidation chemotherapy did not influence OS or PFS. Median PFS was 16.9 vs 9.1 months in patients with vs without epidermal growth factor receptor (EGFR) mutations, with PFS rates of ~20% at 3-4 years. Pneumonitis was the most common adverse event (according to MedDRA version 21.0J), and about half of events were grade 1. Pneumonitis mostly occurred 10-24 weeks after starting CRT, peaking at 18-20 weeks. Esophagitis and dermatitis generally occurred from 0 to 4 weeks, peaking at 2-4 weeks after starting CRT. Pericarditis was rare and occurred sporadically. In conclusion, the results of the m-sub provide real-world insight into the outcomes of CRT, and will be useful for future evaluations of ICI maintenance therapy after CRT., (© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.) more...

Acrylamide has been studied for its carcinogenicity in experimental animals, causing tumors at several organ sites, and has been considered probably carcinogenic to humans as well. Given the small number of epidemiological studies that have been conducted, it is still uncertain whether the consumption of acrylamide is associated with liver cancer. Therefore, we investigated a study to determine the possible relationship between acrylamide intake and the risk of developing liver cancer in the Japanese population. A total of 85,305 participants, from the Japan Public Health Center-based Prospective Study, who provided a validated food-frequency questionnaire were enrolled between 1995 and 1998. During a median of 16.0 years follow-up, 744 new liver cancer cases were identified. Compared to the lowest tertile of acrylamide consumption (<4.8 µg/day), the multivariate hazard ratio (HR) for the highest tertile (≥7.6 µg/day) was 0.79 (95% confidence interval [CI] = 0.65-0.95) for liver cancer using multivariable model 1, adjusted for smoking status, body mass index (BMI), physical activity, medical history, and alcohol consumption; whereas the inverse relationship disappeared after additionally adjusting for coffee consumption in multivariable model 2 with HR of 1.08 (95% CI = 0.87-1.34) for the highest tertile. The effect of dietary acrylamide intake on the risk of liver cancer was not observed in the Japanese population. more...

Acrylamide, which forms in heat-treated foods with high carbohydrate content, is a probable human carcinogen. This study aimed to evaluate the association between dietary acrylamide intake and lung cancer using data from the Japan Public Health Center based Prospective Study. Our study included 85,303 participants who completed a food frequency questionnaire. Cox proportional hazards regression models were used to assess hazard ratios and 95% confidence intervals (CIs) after adjusting for confounders. After 14.3 years and 15.4 years of mean follow-up period, 1187 and 485 lung cancer cases were identified in men and women, respectively. The multivariable-adjusted hazard ratios of 10-µg/day increment in acrylamide intake were 1.01 (95% CI, 0.99-1.02) in men and 0.98 (95% CI, 0.95-1.02) in women. Compared with the lowest quartile of acrylamide intake, the hazard ratios for the highest quartile were 1.13 (95% CI, 0.95-1.33; p for trend = 0.12) in men and 1.03 (95% CI, 0.78-1.36; p for trend = 0.86) in women in the multivariable-adjusted model. Moreover, there was also no significant association observed in the stratified analysis for histological subtypes of lung cancer. This study demonstrated that dietary acrylamide intake was not associated with increased lung cancer risk in the Japanese population. more...

Background:  Chemotherapy may be a cause of cancer-associated stroke, but whether it increases stroke risk remains uncertain. We investigated how chemotherapy affects stroke risk in cancer patients., Methods:  Of 27,932 patients in a hospital-based cancer registry (which contains clinical data on all patients treated for cancer at Osaka University Hospital) screened between 2007 and 2015, medical records of 19,006 patients with complete data were investigated. A validated algorithm was used to identify stroke events within 2 years of cancer diagnosis. Patients were divided based on whether their initial treatment plan included chemotherapy. The association between chemotherapy and stroke was analyzed using the Kaplan-Meier method and stratified Cox regression., Results:  Of 19,006 patients, 5,887 (31%) were in the chemotherapy group. Stroke occurred in 44 (0.75%) and 51 (0.39%) patients in the chemotherapy and nonchemotherapy group, respectively. Kaplan-Meier curve analysis showed that patients in the chemotherapy group had a higher stroke risk than those in the nonchemotherapy group (hazard ratio [HR] 1.84; 95% confidence interval [CI] 1.23-2.75). However, this difference was insignificant after adjustment for cancer status using inverse probability of treatment weighting with propensity scores (HR 1.20; 95% CI 0.76-1.91). Similarly, in the stratified Cox regression model, chemotherapy was not associated with stroke after adjustment for cancer status (HR 1.26; 95% CI 0.78-2.03)., Conclusion:  In our study, the elevated stroke risk in cancer patients who received chemotherapy was presumably due to advanced cancer stage; chemotherapy was not associated with the increased risk of stroke., Competing Interests: None declared., (Georg Thieme Verlag KG Stuttgart · New York.) more...

The effect of post-cardiac arrest care in children with out-of-hospital cardiac arrest (OHCA) has not been adequately established, and the long-term outcome after pediatric OHCA has not been sufficiently investigated. We describe here detailed in-hospital characteristics, actual management, and survival, including neurological status, 90 days after OHCA occurrence in children with OHCA transported to critical care medical centers (CCMCs).We analyzed the database of the Comprehensive Registry of Intensive Care for OHCA Survival (CRITICAL) study, which is a multicenter, prospective observational data registry designed to accumulate both pre- and in-hospital data on OHCA treatments. We enrolled all consecutive pediatric patients aged <18 years who had an OHCA and for whom resuscitation was attempted and who were transported to CCMCs between 2012 and 2016.A total of 263 pediatric patients with OHCA were enrolled. The average age of the patients was 6.3 years, 38.0% were aged < 1 year, and 60.8% were male. After hospital arrival, 4.9% of these pediatric patients received defibrillation; 1.9%, extracorporeal life support; 6.5%, target temperature management; and 88.2% adrenaline administration. The proportions of patients with 90-day survival and a pediatric cerebral performance category (PCPC) score of 1 or 2 were 6.1% and 1.9%, respectively. The proportion of patients with a PCPC score of 1 or 2 at 90 days after OHCA occurrence did not significantly improve during the study period.The proportion of pediatric patients with a 90-day PCPC score of 1 or 2 transported to CCMCs was extremely low, and no significant improvements were observed during the study period. more...

Background: Due to concerns of carcinogenicity, it is necessary to assess long-term acrylamide exposure in individuals. Whether the available methods of estimating acrylamide intake can indicate long-term exposure remains unknown. We examined variations in the estimated dietary acrylamide intake of the Japanese population., Methods: The study included 240 participants aged 40-74 years who were a part of the Japan Public Health Center-based Prospective Study for the Next Generation (JPHC-NEXT). Twelve-day dietary records (DRs) were collected over a one-year period, and food frequency questionnaires (FFQs) were collected twice during the year. Dietary acrylamide intake was estimated from an acrylamide content database. Within-individual variations and between-individual variations were calculated using the random effects model. A linear regression analysis was performed to identify foods with large between-individual variations., Results: The ratios of within-individual variance to between-individual variation were 3.2 for men and 4.3 for women. Days of DRs required to estimate the usual individual intake within 20% of the true mean intake with 95% confidence were 60 days for men and 66 days for women. Coffee/cocoa, potato, and green tea contributed to between-individual variations, in that order, and seven foods contributed to 93% of the between-individual variation., Conclusions: Estimating the acrylamide intake using DRs requires an extended data collection period to estimate the intragroup ranking and habitual intake of individuals. Long-term exposure assessments should be based on methods with less potential for measurement errors, such as the use of biomarkers. more...

Background: The effect of meat and fish consumption on cancer risk has been well studied in humans. However, studies related to biliary tract cancer (BTC) are scarce., Methods: We examined the association between meat and fish consumption and the risk of BTC in a population-based prospective cohort study in Japan. HRs and 95% confidence intervals (CI) were estimated using the Cox proportional hazard model., Results: During 1995 and 1999, 43,177 men and 49,323 women ages 45 to 74 years were enrolled and followed up for 607,757.0 person-years (men) and 728,820.3 person-years (women) until 2012, during which time 217 male and 162 female BTC cases were identified. Higher total meat consumption was significantly associated with a decreased BTC risk in men (HR for the highest vs. lowest quartiles = 0.66; 95% CI, 0.44-0.98; P trend = 0.011) but not in women. Similar association was observed with red meat, but no association was observed with poultry. Fish was not associated with BTC risk. We further analyzed each BTC subtype to confirm the observed association with BTC. However, significant association with each BTC subtype was not observed, although a trend of decreased extrahepatic bile duct cancer risk was observed., Conclusions: BTC risk was lower among men who consumed more meat, particularly red meat, in Japan., Impact: This is the first prospective study that evaluated the relationship between meat and BTC. This may provide important suggestions to elucidate the etiology of BTC., (©2019 American Association for Cancer Research.) more...

Purpose : This study aimed to clarify the experiences of caregivers desiring to refuse life-prolonging treatment for their elderly parents at the end of life. Methods : A semi-structured interview was performed for four family caregivers who wanted to refuse life-prolonging treatment suggested by the physicians. Results : In this study, four caregivers who refused life-prolonging treatment suggested by the physicians for their elderly parents completed semi-structured interviews. The obtained data were analyzed in relation to the theme "Experiences of caregivers who desire to refuse life-prolonging treatment for their elderly parents at the end of life." As a result, 38 subcategories and 12 categories were extracted. Conclusions : Participants in this study initially had a negative view of life-prolonging treatment. However, they agonized over the decision when they received conflicting advice from the physicians. The participants indicated that physicians' advice and attitudes complicated their decisions to reject life-prolonging treatment for their elderly parents. more...

The incidence of breast cancer among Japanese women is substantially increasing. This study evaluated the effects of reproductive and lifestyle factors with respect to breast cancer overall and separately among pre- and postmenopausal women using data from the Three-Prefecture Cohort Study of Japan.A total of 33,410 women aged 40 to 79 years completed a self-administered questionnaire, which included items about menstrual and reproductive history and other lifestyle factors. The follow-up period was from 1984 to 1992 in Miyagi and 1985 to 2000 in Aichi Prefectures. We used Cox proportional hazards regression models to estimate hazards ratios (HRs) and 95% confidence intervals (CIs) after adjusting for confounding factors.After 9.8 mean years of follow-up, 287 cases of breast cancer were recorded. In the overall analysis, later menarche (≥16 years) and parity were significantly associated with a decreased risk of breast cancer, with HRs of 0.69 (95% CI 0.48-0.99) and 0.72 (95% CI 0.52-0.99), respectively. Further, there was a significant decline in the risk of breast cancer with increasing number of birth among parous women (P for trend = .010). On the contrary, a family history of breast cancer in the mother was significantly associated with an increased risk of breast cancer (HR 3.22, 95% CI 1.52-6.84). Analyses based on menopausal status at baseline indicated that height (≥160 cm) and weight (≥65 kg) were significantly associated with an increased risk of postmenopausal breast cancer, with HRs of 1.34 (95% CI 0.72-2.50) and 3.13 (95% CI 1.75-5.60), respectively. Risk associated with BMI significantly differs by menopausal status.Our findings suggest the important role of reproductive factors in the development of breast cancer in Japanese women; however, body mass index (BMI) may have different effects on breast cancer in Japanese women compared with western women. more...

Aim: To evaluate mortality among Japanese Olympic athletes compared with the general population and also evaluate their mortality based on total number of Olympics participation and intensity of sports disciplines., Methods: Information on biography, vital status, date of birth, date of death and latest follow-up date on Japanese Olympians was retrieved from six online databases and compared. Standardised mortality ratio (SMR) was estimated according to observation periods and years from last participation in the Olympics. To further evaluate the association between mortality and total number of Olympics participation/intensity of sports disciplines within the study population, rate ratios (RRs) adjusted by sex, observation period and attained age group were estimated by a Poisson regression model., Results: A total of 3381 Olympians were included in the analysis. The total person years was 94 076.82. The deaths of 153 (4.53%) Olympians were confirmed, and the overall SMR was 0.29 (95% CI, 0.25 to 0.34). SMRs categorised by years from last participation did not differ significantly. Higher mortality was observed among those who participated in the Olympics twice (RR: 1.52; 95% CI, 1.04 to 2.23) and three times or more (RR: 1.87; 95% CI, 1.08 to 3.25) compared with those who participated just once. Compared with combination of low static and low dynamic intensity category, higher mortality was observed in most combinations of middle-intensity or high-intensity categories., Conclusion: Japanese Olympians lived longer than the general population. More frequent participation in the Olympics and higher intensity of sports disciplines were associated with higher mortality., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.) more...

Oral mucositis is a common complication of cancer chemotherapy treatment. Because of the lack of relevant oral mucositis experimental models, it is not clear how chemotherapeutic agents injure the oral mucosa and if commensal microorganisms accelerate tissue damage. We developed an organotypic oral mucosa model that mimics cellular responses commonly associated with cytotoxic chemotherapy. The organotypic model consists of multilayer oral epithelial cells growing over a collagen type I matrix, with embedded fibroblasts. Treatment of organotypic constructs with the chemotherapeutic agent, 5-fluorouracil (5-FU), leads to major histopathologic changes resembling mucositis, such as DNA synthesis inhibition, increased apoptosis and cytoplasmic vacuolation. Candida albicans formed mucosal biofilms on these tissues and augmented the inflammatory responses to 5-FU. This model can be used in further mechanistic studies of oral mucositis and associated opportunistic infections., Competing Interests: Competing interestsNo competing interests., (Copyright © 2019 The Authors; exclusive licensee Bio-protocol LLC.) more...

Background: Acrylamide has been classified as a probable human carcinogen based chiefly on laboratory evidence. However, the influence of dietary acrylamide intake on risk of esophageal, gastric, and colorectal cancer has not been extensively studied. We aimed to evaluate the association between dietary acrylamide intake and esophageal, gastric, and colorectal cancer using data from the Japan Public Health Center-based Prospective Study., Methods: Our study included 87,628 participants who completed a food-frequency questionnaire at enrollment in 1990 and 1993. We used Cox proportional hazards regression models to estimate hazards ratios and 95% confidence intervals (CI) after adjusting for confounding factors., Results: After 15.5, 15.3, and 15.3 mean years of follow-up for esophageal, gastric, and colorectal cancer, we identified and analyzed 391 esophageal, 2,218 gastric, and 2,470 colorectal cancer cases, respectively. Compared with the lowest quintile of acrylamide intake, the multivariate HR for the highest quintile was 0.86 (95% CI, 0.53-1.39; P trend = 0.814), 0.84 (95% CI, 0.69-1.01; P trend = 0.301), and 0.93 (95% CI, 0.79-1.08; P trend = 0.165) for esophageal, gastric, and colorectal cancer, respectively, in the multivariable-adjusted model. Furthermore, no significant associations were observed when the participants were stratified by cancer subsites., Conclusions: In conclusion, this study demonstrated that dietary acrylamide intake was not associated with increased risk of esophageal, gastric, or colorectal cancer among the Japanese population., Impact: It is the first time to assess the effect of dietary acrylamide intake on risk of digestive system cancer in Asian populations., (©2019 American Association for Cancer Research.) more...

The International Cancer Research Partnership (ICRP) has developed a cancer research funding database since its establishment, with data gathered from the participating funnding organizations. We estimated and compared the total amount of cancer research funding from governmental organizations in the USA, the UK and Japan using ICRP and publicly available databases. We also discussed use of the ICRP database as a tool to consider the cancer research funding allocation at a national level. more...

Objectives: Urinary excretion of 2,5-hexanedione is currently used to estimate the exposure levels of hexane occurring to an individual during the previous work shift. However, because hexane exposures and urinary 2,5-hexanedione levels can vary considerably from day to day, and subchronic to chronic exposures to hexane are required to produce neuropathy, this biomarker may not accurately reflect the risk of an individual for developing hexane neuropathy. This investigation examines the potential of hexane-derived pyrrole adducts produced on globin and plasma proteins as markers for integrating cumulative exposures. Because the pyrrole markers incorporate bioactivation of hexane to 2,5-hexandione and the initial step of protein adduction involved in hexane-induced neuropathy, they potentially can serve as biomarkers of effect through reflecting pathogenetic events within the nervous system. Additionally, pyrrole formation is an irreversible reaction suggesting that hexane-derived protein pyrroles can be used to assess cumulative exposures to provide a better characterization of individual susceptibilities., Methods: To examine the utility of the proposed markers, blood samples were obtained from eleven workers who used hexane for granulating metal powders in a slurry to produce metal machining die tools and four non-exposed volunteers. Globin and plasma were isolated, and the proteins were digested using pepsin, reacted with Ehrlich's reagent and the level of pyrrole adducts were determined by absorbance at 530 nm. To determine the dose-response curve and dynamic range of the assay, erythrocytes were incubated with a range of 2,5-hexanedione concentrations and the net absorbance at 530 nm of isolated globin was measured., Results: Pyrrole was detected in both the globin and plasma samples of the workers exposed to hexane and the levels of pyrroles in plasma were positively correlated with the levels of pyrroles in globin for most of the workers., Conclusions: This investigation demonstrates that detectable levels of hexane-derived protein pyrrole adducts are produced on peripheral proteins following occupational exposures to hexane and supports the utility of measuring pyrroles for integrating cumulative exposures to hexane. more...

Background: Our objective was to assess the characteristics such as public-access defibrillation (PAD) by laypersons and the outcomes after pediatric out-of-hospital cardiac arrest by location in the PAD era., Methods: From a nationwide, prospective, population-based registry of out-of-hospital cardiac arrest patients in Japan, we enrolled consecutive pediatric patients aged ≤17 years before emergency medical service (EMS) arrival between 2013 and 2015. The primary outcome measure was 1-month survival, with favorable neurologic outcome defined as cerebral performance category 1 or 2. Factors associated with favorable neurologic outcome were assessed using multivariable logistic regression analysis., Results: Among 3991 eligible pediatric out-of-hospital cardiac arrests, the proportion of PAD was 0.2% (5/2888) at residence, 1.6% (2/125) in public areas, 0.9% (3/321) on streets/highways, 21.6% (11/51) at recreation/sports event areas, 46.1% (82/178) at education institutions, and 1.2% (5/428) in others. In the multivariable analysis, arrest witnessed by family members (adjusted odds ratio [AOR], 5.25; 95% confidence interval [CI], 3.22-8.58) and nonfamily members (AOR, 2.45; 95% CI, 1.26-4.77), first documented ventricular fibrillation (AOR, 12.29; 95% CI, 7.08-21.35), PAD (AOR, 2.63; 95% CI, 1.23-5.62), and earlier EMS response time (AOR for 1-min increment, 0.88; 95% CI, 0.81-0.94) were associated with improving outcome. As for locations, recreation/sports event areas (AOR, 3.43; 95% CI, 1.17-10.07) and education institutions (AOR, 3.03; 95% CI, 1.39-6.63) were also associated with favorable neurologic outcome., Conclusions: In Japan, where public-access automated external defibrillators are well disseminated, characteristics such as PAD and outcomes for pediatric out-of-hospital cardiac arrest before EMS arrival differed substantially by location., (Copyright © 2019 Elsevier B.V. All rights reserved.) more...

Background: Sudden cardiac death during exercise or sports is an important problem among young athletes and non-athletes. An understanding of the epidemiological features of sports-related out-of-hospital cardiac arrest (OHCA) among children is crucial for planning approaches for prevention and better outcomes of paediatric OHCAs. We assessed the characteristics and outcomes of sports-related OHCA among children at schools in Japan to prevent sports-related paediatric OHCA at schools., Methods: The Stop and Prevent cardIac aRrest, Injury, and Trauma in Schools (SPIRITS) is a nationwide, prospective, observational study linking databases of two nationally representative registries. Data on the characteristics and outcomes of sports-related paediatric OHCA at schools in Japan were obtained from these databases., Results: Between 2008 and 2015, 188 sports-related paediatric OHCAs due to presumed cardiac origin occurred. The greatest proportion of OHCA during or after sports was due to long-distance running (21.8%), followed by soccer/futsal (13.3%), basketball (12.2%), and baseball/rubber-ball baseball (11.2%). We also assessed the association between prehospital factors and one-month survival with favourable neurological outcome after sports-related OHCA. The proportions of ventricular fibrillation as the first documented rhythm, bystander cardiopulmonary resuscitation (CPR), and public-access defibrillation (PAD) were 87.8%, 87.2%, and 63.3%, respectively. Compared with the non-PAD group, the adjusted odds ratio (95% confidence interval) of the PAD group was 3.64 (1.78-7.45)., Conclusions: In Japan, 188 schoolchildren experienced OHCAs of cardiac origin occurring during or after sports activity at schools during the 8-year period. Increasing PAD is essential to enhance better neurological outcome after sports-related OHCA among students., (Copyright © 2019 Elsevier B.V. All rights reserved.) more...

Background: It is commonly believed that a full moon affects human behavior or the occurrence and outcome of various diseases; thus, the occurrence of out-of-hospital cardiac arrest (OHCA) might increase during full moon nights. Methods and Results: This nationwide, population-based observational study consecutively enrolled OHCA patients in Japan with attempted resuscitation between 2005 and 2016. The primary outcome measure was the occurrence of OHCA. Based on the double-control method, assuming Poisson sampling, we evaluated the average number of OHCA events that occurred on full moon nights compared with that which occurred on control nights, which included events that occurred on the same calendar days 1 week before and after the full moon nights. A total of 29,552 OHCA that occurred on 148 full moon nights and 58,707 OHCA that occurred on 296 control nights were eligible for analysis. The occurrence of OHCA did not differ between full moon and control nights (199.7 vs. 198.3 per night; relative risk [RR], 1.007; 95% CI: 0.993-1.021). On subgroup analysis, compared with control nights, the RR of OHCA occurrence were 1.013 (95% CI: 0.994-1.032, P=0.166) and 0.998 (95% CI: 0.977-1.020, P=0.866) for cardiac and non-cardiac origins, respectively. Conclusions: In this population, there was no significant difference in OHCA occurrence between full moon and control nights., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2019, THE JAPANESE CIRCULATION SOCIETY.) more...