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The major genetic group of Toxoplasma gondii, known as type I, generally displays high lethality in laboratory Mus musculus (mouse) strains, with few exceptions. However, because rodents are the primary reservoir hosts for T. gondii, if this characteristic manifests in the wild, type I strains would be extinct. Therefore, we hypothesized that populations of wild rodents capable of harboring type I T. gondii asymptomatically exist globally and are not limited to a few localized areas, as previously thought. The strength of mouse resistance to T. gondii is known to depend on the affinity of the mouse-expressed immunity-related GTPases B2 (IRGB2) protein for the T. gondii-expressed rphoptry protein 5B (ROP5B) protein. Therefore, the Irgb2 gene sequences of 12 individuals mice captured at two animal farms in Gifu Prefecture, and on an island in Okinawa Prefecture, Japan were determined, and subjected to a molecular phylogenetic analysis together with those of various mouse strains worldwide. The Irgb2 gene of M. musculus individuals captured on one farm and one island showed diverse sequences. The sequences from two individual mice captured in an animal farm formed a single clade with a wild mouse derived CAST/EiJ strain, known for its exceptional resistance to type I T. gondii lethality. These results suggest that M. musuculus individuals resistant to the Type I T. gondii strain may be present in Japan, in addition to the previously known populations in South Asia, Thailand and India.

Background: The study aim was to elucidate the effect of the 2024 Noto Peninsula earthquake on outpatient chemotherapy treatment of cancer survivors at Kanazawa Medical University Hospital (KMUH), Japan., Methods: Medical and nursing records for January 4-31, 2024, from KMUH were retrospectively collected, and data for 286 participants were analyzed., Results: Of the 286 participants, 95.1% were able to attend their first scheduled appointment. Of the 12 (4.2%) who could not attend because of the earthquake, 7 (58.3%) rescheduled their appointments. A total of 8 participants (2.8%) were unable to attend their second scheduled appointment in January, despite being able to attend their first appointment; 3 (37.5%) of these participants reported that they were unable to attend their appointments because of the effect of the earthquake. Chemotherapy was not administered to 53 (18.5%) participants who did attend, mainly owing to neutropenia, progressive disease, rash, and anemia. Evacuation information was available for 25 participants (8.7%); of these, 8 (28.6%) evacuated to their homes, 7 (25.0%) to public shelters, and 4 (14.3%) to apartments near the hospital. Disaster status information was obtained from 62 participants (21.7%), and indicated experiences such as home damage, water outages, and relying on transportation assistance from family to attend appointments., Conclusions: Most cancer survivors receiving chemotherapy at KMUH were able to maintain outpatient visits. However, a few could not attend because of the earthquake. Further studies are needed to provide more detailed information on the effect of disasters on cancer survivors and the potential factors underlying non-attendance at medical appointments., (© 2024. The Author(s).)

Objectives: Hikikomori is commonly defined as a social condition in which individuals avoid social participation and relationships beyond their family members by confining themselves to a room or their house for 6 months or longer. Hikikomori has been predominantly considered a problem among young people; however, as the population is ageing, hikikomori has also emerged as a social issue among adults. Nevertheless, no comparative studies have examined the differences in the factors associated with hikikomori among teenagers/young adults and middle-aged/older adults. Thus, this phenomenon has not been thoroughly examined, and it remains unclear whether the risk factors vary between teenagers/young adults and middle-aged/older adults. Based on the Japan Cabinet Office's definition of hikikomori, this cross-sectional study evaluated the prevalence and related factors of hikikomori among the working age population (15-64 years), utilising univariate and multivariate analyses. The study also compared differences in the prevalence of and factors related to hikikomori between teenagers/young adults and middle-aged/older adults., Methods: We distributed self-administered questionnaires to individual participants and their families between 24 December 2020 and 18 January 2021., Results: Data from an anonymised sample of 3,092 individuals (split into two groups of 15-39 and 40-64 years) were subjected to analysis. The results revealed a hikikomori prevalence of 2.3% in the target population; the prevalence rate was 2.12% among individuals aged 15 to 39 years and 2.42% among those aged 40 to 64 years. The analysis demonstrated strong correlations between hikikomori and several factors, including unemployment, truancy, a history of psychiatric consultation or hospitalisation, being male and the absence of ibasho , which is defined as a place where individuals can feel peace, security, acceptance and belonging. The factors associated with hikikomori differed between teenagers/young adults and middle-aged/older adults., Conclusion: Our findings, thus, contribute to existing research by providing a comparative analysis of risk factors across different age groups.

Background: Mirtazapine blocks 5-hydroxytryptamine type (5-HT) 2A , 5-HT 2C , 5-HT 3 and histamine H 1 receptors, similarly to olanzapine. This study aimed to investigate the efficacy and safety of mirtazapine plus granisetron and dexamethasone for carboplatin (CBDCA)-induced nausea and vomiting in patients with thoracic cancers., Methods: We conducted a prospective, open-label, single-arm, multicenter, phase II trial in four institutions in Japan. Registered patients were moderately to highly emetogenic chemotherapy-naïve, and were scheduled to receive CBDCA at area under the curve (AUC) ≥ 4 mg/mL per minute. Patients received mirtazapine 15 mg/day orally at bedtime for four consecutive days, in combination with granisetron and dexamethasone. Primary endpoint was complete response (CR; no emesis and no use of rescue medication) rate during the delayed period (24-120 h)., Results: Between July 2022 and July 2023, 52 patients were enrolled, and 48 patients were evaluated. CR rates in the delayed (24-120 h), overall (0-120 h), and acute periods (0-24 h) were 83.3%, 83.3%, and 100%, respectively. No grade 3 or higher treatment-related adverse events were observed except for one patient who had grade 3 dry mouth as evaluated by Common Terminology Criteria for Adverse Events version 5.0., Conclusions: Prophylactic antiemetic therapy with mirtazapine plus granisetron and dexamethasone shows promising efficacy and an acceptable safety profile. This three-drug combination appears to be a reasonable treatment approach in patients with thoracic cancers receiving a CBDCA-based regimen at AUC ≥ 4 mg/mL per minute., Competing Interests: Declaration of competing interest Dr. Iihara has received personal fees from Taiho, Chugai, Yakult, Astellas, Eli Lilly, Daiichi Sankyo, AstraZeneca, Nippon Kayaku, Ono, and Nippon Boehringer Ingelheim and consulting fees for their institution from Taiho and Eisai outside the submitted work. Dr. Morita has received personal fees from AstraZeneca, Bristol Myers Squibb, Chugai, Daiichi Sankyo, Amgen, Eli Lilly, Takeda, Taiho, Thermo Fisher, Nihon Kayaku, MSD, Novartis, Pfizer outside the submitted work. Ms. Hirose has received personal fees from Eli Lilly, Eisai, Merck, Chugai, and Nippon Kayaku outside the submitted work. Dr. Kawazoe has received grants for their institution from Eli Lilly outside the submitted work. Dr. Fukunaga has received personal fees from Boehringer Ingelheim, Novartis, Sanofi, GlaxoSmithKline, AstraZeneca, and Kyorin outside the submitted work and grants for their institution from Boehringer Ingelheim and Chugai outside the submitted work. Dr. Fukunaga has received personal fees from Boehringer Ingelheim, Novartis, Sanofi, GlaxoSmithKline, AstraZeneca, and Kyorin outside the submitted work and grants for their institution from Boehringer Ingelheim and Chugai outside the submitted work. Dr. Suzuki has received personal fees from Toa Eiyo, Asahi Kasei, Daiichi Sankyo, Pfizer, Eisai, Nippon Shinyaku, Celltrion Healthcare Japan, Otsuka, Sandoz, Tsumura, Nipro, Taiho, Kyowa-Kirin, Nippon Chemiphar, Japan Blood Products Organization, Takeda, and Nippon Boehringer Ingelheim and grants for their institution from Nippon Kayaku, Asahi Kasei, Chugai, Taiho, Daiichi Sankyo, Japan Blood Products Organization, Mochida, and Sun Pharma outside the submitted work. Other authors do not have conflict of interest., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Objectives: Endoscopic submucosal dissection (ESD) for superficial esophageal squamous cell carcinoma (ESCC) is performed for the treatment of lesions with varied backgrounds and factors. However, the predictive factors associated with the technical difficulty of ESD remain unknown in patients with varied lesions. Therefore, this study aimed to identify the predictive factors associated with the technical difficulty of ESD for ESCC using a retrospective cohort., Methods: This multicenter, retrospective study was conducted in 10 hospitals in Japan. Consecutive patients who underwent esophageal ESD between January 2013 and December 2019 were enrolled. Lesions of subepithelial tumors, adenocarcinoma, and adenoma were excluded. Difficult lesions were defined as ESD requiring a long procedure time (≥120 min), perforation development, piecemeal resection, or discontinued ESD. In the present study, the clinical factors were assessed to identify the technical difficulty of ESD using univariate and multivariate analyses., Results: Among 1708 lesions treated with esophageal ESD, eight subepithelial tumors, 44 adenocarcinomas, and two adenomas were excluded. Finally, 1505 patients with 1654 lesions were analyzed, and 217 patients with 217 lesions (13.1%) were classified as patients with difficult lesions. In multivariate analysis, the predictive factors associated with the technical difficulty of ESD were as follows: tumors with varices, tumors with diverticulum, antiplatelet use (discontinued), circumference of tumor (≥1/2), preoperative tumor size ≥30 mm, trainee, and nonhigh-volume center., Conclusion: This multicenter retrospective study identified the predictive factors associated with the technical difficulty of ESD for ESCC with varied backgrounds and factors., (© 2023 Japan Gastroenterological Endoscopy Society.)

Introduction: EndoTrac is a line-attached sheath-type traction device that enables us to control the direction and the force of traction during endoscopic submucosal dissection (ESD). The efficacy of EndoTrac for gastric ESD has not been fully verified., Methods and Analysis: The G-Trac study is a multicentre (nine general hospitals and two university hospitals in Japan) collaborative trial assessing the efficacy of EndoTrac for gastric ESDs. Patients with superficial gastric neoplasms will be enrolled and randomly assigned to undergo either conventional ESD or EndoTrac ESD. Allocation will be stratified according to tumour location, operator experience and tumour diameter at an allocation rate of 1:1. The type of endoknife used will be confirmed before randomisation. The primary outcome, procedure time, will be compared between the groups in both intention-to-treat and per-protocol analyses using the Wilcoxon rank sum test. The efficacy-related, safety-related and device-related outcomes will be assessed in the secondary analysis. The planned sample size of the 142 patients in the two groups will enable us to detect a difference with a power of 80% by using the Wilcoxon rank sum test, assuming an effect size of 0.54, asymptotic relative efficiency of 0.864 and a two-sided type 1 error rate of 5%., Ethics and Dissemination: This trial was approved by the certified review board of Kobe University (22 December 2022). The results from this trial will be disseminated through peer-review journals, presentations at national and international conferences, and data sharing with other researchers., Trial Registration Number: jRCT1052220166., Competing Interests: Competing interests: Takashi Toyonaga has received royalties from Top for the development of the EndoTrac. The other authors declare no conflicts of interest regarding this article., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Accurate evaluation of tumor invasion depth is essential to determine the appropriate treatment strategy for patients with superficial esophageal cancer. The pretreatment tumor depth diagnosis currently relies on the magnifying endoscopic classification established by the Japan Esophageal Society (JES). However, the diagnostic accuracy of tumors involving the muscularis mucosa (MM) or those invading the upper third of the submucosal layer (SM1), which correspond to Type B2 vessels in the JES classification, remains insufficient. Previous retrospective studies have reported improved accuracy by considering additional findings, such as the size and macroscopic type of the Type B2 vessel area, in evaluating tumor invasion depth. Therefore, this study aimed to investigate whether incorporating the size and/or macroscopic type of the Type B2 vessel area improves the diagnostic accuracy of preoperative tumor invasion depth prediction based on the JES classification., Methods: This multicenter prospective observational study will include patients diagnosed with MM/SM1 esophageal squamous cell carcinoma based on the Type B2 vessels of the JES classification. The tumor invasion depth will be evaluated using both the standard JES classification (standard-depth evaluation) and the JES classification with additional findings (hypothetical-depth evaluation) for the same set of patients. Data from both endoscopic depth evaluations will be electronically collected and stored in a cloud-based database before endoscopic resection or esophagectomy. This study's primary endpoint is accuracy, defined as the proportion of cases in which the preoperative depth diagnosis matched the histological depth diagnosis after resection. Outcomes of standard- and hypothetical-depth evaluation will be compared., Discussion: Collecting reliable prospective data on the JES classification, explicitly concerning the B2 vessel category, has the potential to provide valuable insights. Incorporating additional findings into the in-depth evaluation process may guide clinical decision-making and promote evidence-based medicine practices in managing superficial esophageal cancer., Trial Registration: This trial was registered in the Clinical Trials Registry of the University Hospital Medical Information Network (UMIN-CTR) under the identifier UMIN000051145, registered on 23/5/2023., (© 2024. The Author(s).)

Background: Mycobacterium lentiflavum is a slow-growing nontuberculous mycobacterium that is widely distributed in soil and water systems, but it is sometimes pathogenic to humans. Although cases of M. lentiflavum infections are rare, 22 isolates of M. lentiflavum were identified at a single hospital in Japan. We suspected a nosocomial outbreak; thus, we conducted transmission pattern and genotype analyses., Methods: Cases of M. lentiflavum isolated at Kushiro City General Hospital in Japan between May 2020 and April 2021 were analyzed. The patient samples and environmental culture specimens underwent whole-genome sequencing (WGS). Additionally, we retrospectively collected clinical data from patient medical records., Results: Altogether, 22 isolates of M. lentiflavum were identified from sputum and bronchoalveolar lavage samples. Clinically, the instances with M. lentiflavum isolates were considered contaminants. In the WGS analysis, 19 specimens, including 18 patient samples and 1 environmental culture from the hospital's faucet, showed genetic similarity. The frequency of M. lentiflavum isolation decreased after we prohibited the use of taps where M. lentiflavum was isolated., Conclusions: WGS analysis identified that the cause of M. lentiflavum pseudo-outbreak was the water used for patient examinations, including bronchoscopy.

The purpose of this study was to investigate the factors related to Japanese nurses' desire to quit their jobs during the Omicron wave of the coronavirus disease 2019 pandemic. We distributed an original, self-administered questionnaire to nurses at 3 facilities that accepted patients with coronavirus disease 2019 in Ishikawa Prefecture, Japan. Of the 625 nurses, 152 responded (24.3%); after excluding 3 men to rule out the effects of sex, responses for 81 (53.3%) nurses were analyzed. In total, 49 (60.5%) nurses expressed a desire to quit their current job. After controlling for the effects of age and years of experience, factors related to the desire to quit the current job included having fewer than 2 years of experience (odds ratio [OR] 9.08, 95% confidence interval [CI] 1.69-48.87), feeling anxiety at work (OR 4.59, 95% CI 1.01-20.81), being afraid to go to work (OR 4.10, 95% CI 1.20-21.69), and experiencing difficulty talking to people (OR 10.26, 95% CI 1.48-70.99). Nurse managers should regularly screen nurses who have fewer than 2 years of experience, feel anxiety at work, are afraid to go to work, and find it difficult to talk to people. Early action may prevent the turnover of nurses during a public health emergency., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Porcine reproductive and respiratory syndrome (PRRS) is an infectious swine disease caused by the PRRS virus (PRRSV) that results in economic loss to the pig-rearing industry. To study PRRSV infection in wild boars and pigs, we conducted a serological survey in Gifu Prefecture, Japan, from 2020 to 2021. Three out of 453 (0.7%) wild boar sera were positive for PRRSV antibodies in a commercial ELISA. However, given that PRRSV RNA was not detected in these three wild boars and the specificity and sensitivity of the test kit, these are considered as false positives. Although seropositive pigs were found in multiple pig farms in the study area, the role of wild boars as a source of PRRS to pig farms appeared to be minimal.

Infectious bronchitis virus (IBV) is the causative agent of infectious bronchitis (IB) in chickens. There is a correlation between cross-protection and percentage of similarity between nucleotide sequences encoding the S1 subunit, which is responsible for generating neutralizing and serotype-specific antibodies. Therefore, RT-PCR is commonly used to amplify the IBV-S1 gene following DNA sequencing in order to predict the efficacy of vaccines against IBV strains. We successfully enhanced the sensitivity for detection of the IBV-S1 gene by second PCR after purification of the 1st RT-PCR product. Using that method, we obtained detailed information on the prevalence of IBV on poultry farms in Gifu Prefecture, Japan. The IBV-S1 gene detection method used in the current study will enable accurate information on the prevalence of IBV in Japan to be obtained.

Background: Increasing proportions of smokers in Japan smoke <10 cigarettes per day (CPD). Yet, the health risks of low-intensity smoking in Asia are poorly understood., Methods: We performed a pooled analysis of 410 294 adults from nine population-based prospective cohort studies participating in the Japan Cohort Consortium. Cigarette-use data were collected at each study baseline in 1983-1994. Study-specific hazard ratios (HRs) and 95% confidence intervals (CIs) for all-cause and cause-specific mortality were calculated using multivariable-adjusted Cox regression by CPD among current smokers and by age at cessation among former smokers, with never smokers as the referent group. Pooled HRs and CIs were computed using a random-effect model., Results: The smoking prevalence was 54.5% in men and 7.4% in women. About 15.5% of male and 50.4% of female current smokers smoked 1-10 CPD (low-intensity). Both male and female low-intensity smokers had higher all-cause mortality risks than never smokers. Risks were further higher with increasing CPD in a dose-response manner. HRs (95% CIs) were 1.27 (0.97-1.66), 1.45 (1.33-1.59) and 1.49 (1.38-1.62) for 1-2, 3-5 and 6-10 CPD, respectively, in men; 1.28 (1.01-1.62), 1.49 (1.34-1.66) and 1.68 (1.55-1.81) for 1-2, 3-5 and 6-10 CPD, respectively, in women. Similar associations were observed for smoking-related causes of death. Among former low-intensity smokers, younger age at cessation was associated with lower mortality risk., Conclusions: Smoking very low amounts was associated with increased mortality risks in Japan. All smokers should quit, even if they smoke very few CPD., (Published by Oxford University Press on behalf of the International Epidemiological Association 2021. This work is written by US Government employees and is in the public domain in the US.)

Background: Little research has been done on post-exposure prophylaxis (PEP) for COVID-19. This study was done to determine if maoto, a traditional herbal medicine commonly used for diseases with symptoms similar to those of COVID-19, can be repurposed for post-exposure prophylaxis to prevent the spread of nosocomial infection with SARS-CoV-2., Methods: A cohort analysis was done of the data of 55 health care workers (HCWs) whether to get infected with SARS-CoV-2 in a Japanese hospital experiencing a COVID-19 cluster in April of 2021. Of these subjects, maoto granules for medical use were prescribed for PEP to 42 HCWs and taken for three days in mid-April. Controls were 13 HCWs who rejected the use of maoto. Polymerase chain reaction was performed routinely once or twice a week or when a participant presented with symptoms of COVID-19., Result: There were no background differences between the maoto and control groups by profession, sex, or mean age. No severe adverse reactions were observed. During the observation period of 1 week, significantly fewer subjects were diagnosed with COVID-19 in the maoto group (N = 3, 7.1%) than in the control group (N = 6, 46.2%). The prophylactic effectiveness of maoto was 84.5%., Conclusion: Oral administration of maoto is suggested to be effective as PEP against nosocomial COVID-19 infection., (Copyright © 2022 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Objective: In the past, it was believed that unilateral hearing loss has a minimal impact on the speech and language development in children. However, several studies have suggested that some school-age children with unilateral hearing loss have learning impairments in language. In the present study, we first examined whether preschool-age children with unilateral severe-to-profound hearing loss (UHL) have delays in the development of receptive vocabulary and verbal intelligence. In the follow-up study, we tested the children again after school admission. The objective of the present study was to reveal the development of receptive vocabulary and verbal intelligence from preschool to school years in children with UHL., Methods: Fifteen Japanese preschool-age children with UHL and a control group of 20 age-matched Japanese children with bilateral normal hearing (NH), who were examined because articulation disorder was suspected, were enrolled in this study. The development of receptive vocabulary and verbal intelligence was evaluated using the Picture Vocabulary Test-Revised (PVT-R) and the Wechsler Intelligence Scale, respectively. The present retrospective study was approved by the Committee for Medical Ethics of Tokushima University Hospital (#3801)., Results: The scaled score (SS) of the PVT-R and verbal intelligence quotient (VIQ)/verbal comprehension index (VCI), but not performance intelligence quotient/perceptual reasoning index in children with UHL were significantly lower than those in the control children with NH at preschool-age. The SS of the PVT-R and VIQ/VCI in children with UHL significantly improved after school admission. In the subgroup analysis, the SS of the PVT-R in the lower receptive vocabulary group of children with UHL at preschool-age was significantly increased after school admission, but the SS in the normal and higher receptive vocabulary group of children with UHL at preschool-age were still around the standardized mean of SS after school admission., Conclusion: These findings suggest that the development of receptive vocabulary and verbal intelligence was delayed in preschool-age children with UHL and that most of them caught up to exhibit normal language ability after school admission., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest in this study., (Copyright © 2021 Japanese Society of Otorhinolaryngology-Head and Neck Surgery, Inc. Published by Elsevier B.V. All rights reserved.)

Lake Sinai virus (LSV), an RNA virus, is suspected to be associated with poor health in honeybees (Apis mellifera). We examined LSV in 26 specimens of healthy honeybees and 44 specimens of wild arthropods in the Gifu Prefecture, Japan. LSV was found more frequently in honeybee specimens (11/26, 42.3%) than in wild arthropod specimens (1/44, 2.3%) (P<0.01). Phylogenetic and nucleotide sequence analysis revealed two lineages: LSV3 in honeybees, and LSV4 in both honeybees and wild arthropods. To our knowledge, this is the first report of LSV prevalence in honeybees and wild arthropods in Japan.

Background: Since June 2013, Japan has suspended proactive recommendation of human papillomavirus (HPV) vaccination due to self-reported diverse symptoms, including pain and motor dysfunction, as possible serious adverse events following immunization. Although these symptoms may be seen in adolescents without HPV vaccination, their frequency, taking into account disease severity, has not been examined., Methods: A two-stage, descriptive, nationwide epidemiological survey was conducted in 2016, with a 6-month target period from July 1 to December 31, 2015, to estimate the prevalence and incidence of diverse symptoms among Japanese adolescents without HPV vaccination. Participants were 11,037 medical departments in hospitals selected nationwide by stratified random sampling. Eligible patients had to satisfy four criteria: (1) aged 12-18 years upon visiting hospital; (2) having at least one of four symptoms/disorders (pain or sensory dysfunction, motor dysfunction, autonomic dysfunction, or cognitive impairment); (3) symptoms/disorders persisting for at least 3 months; and (4) both criteria (2) and (3) influence attendance at school or work. We then extracted data of patients with diverse symptoms similar to those after HPV vaccination while considering opinions of doctors in charge., Results: Estimated 6-month period prevalence of diverse symptoms among girls aged 12-18 years without HPV vaccination was 20.2 per 100,000. Annual incidence was estimated to be 7.3 per 100,000., Conclusion: Adolescent Japanese girls without HPV vaccination also visited hospitals with diverse symptoms similar to those following HPV vaccination. Our findings predict the medical demands for coincident diverse symptoms, which are temporally associated with but not caused by HPV vaccination of Japanese adolescents.

Viral infection damages honeybee colony health. Viruses can be carried by queen bees and apicultural production materials when imported from foreign countries. We investigated seven honeybee viruses in worker bees (Apis mellifera) from 26 healthy apiaries in Gifu, Japan between 2018 and 2019. Black queen cell virus (BQCV) was detected in 23 (88.5%) of the apiaries, followed by Israeli acute paralysis virus (42.3%), deformed wing virus (DWV) (38.5%), and sacbrood virus (3.8%). In phylogenetic analysis, BQCV and DWV in Gifu were related to those in China and South Korea. Additionally, a high prevalence of BQCV was observed among worker bees in BQCV-positive colonies. Therefore, BQCV horizontal transmission among worker bees may contribute to the high prevalence of BQCV in Gifu.

Background and Aim: The current prevalence of hepatitis C virus infection and hepatitis C virus-associated mortality in Japan falls short of the World Health Organization goal of viral hepatitis elimination by 2030. We aimed to evaluate the trends in hepatitis C virus-associated mortality in Japan., Methods: This nationwide observational study used the Japanese Vital Statistics from 1998 to 2017 and included all Japanese hepatitis C virus-associated deaths (84 936) of adults aged ≥ 40 years. We calculated the crude and age-standardized mortality rates per 100 000 persons by age and sex. Joinpoint regression analysis was used to identify significant changing points in trends and to estimate the annual percentage changes and the average annual percentage changes for the entire study period., Results: The crude mortality rate per 100 000 persons (annual death number) increased from 5.5 (3548) in 1998 to 7.0 (4843) in 2005 and decreased to 4.0 (3095) in 2017. By 2017, the crude mortality rates per 100 000 persons among men and women had dropped to 3.6 and 4.3, respectively. The age-standardized mortality rate was higher in women than in men. The average annual percentage change was -3.8% (95% confidence interval: -5.0 to -2.5). The declining trend was more rapid in men (-4.5%, 95% confidence interval: -5.3 to -3.6) than in women (-2.7%, 95% confidence interval: -3.8 to -1.6)., Conclusions: Trends in hepatitis C virus-associated mortality rates have declined in an accelerating manner in Japan, especially among men., (© 2021 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Toxoplasma gondii is a globally wide-spread parasite that infects almost all species of mammals and birds, including humans. We studied the spatial distribution of individual T. gondii-seropositive wild boar in Gifu Prefecture (10,621 km 2 ), Japan. Altogether, 744 wild boars were captured at 663 points around human settlements in Gifu Prefecture. Serum samples were collected after recording the exact capture locations, along with each wild boar's body length and sex. We then used a commercial enzyme-linked immunosorbent assay kit for swine to measure anti-T. gondii antibodies in these animals. Among the 744 wild boars, 169 tested positive for T. gondii (22.7%). No significant difference in T. gondii seroprevalence was observed between the mountainous northern region with high winter snow cover and the mild-wintered geographical plain of the southern part of the prefecture. In contrast, 8 of the 11 wild boars that were captured in a public park surrounded by residential areas showed T. gondii seropositivity (72.7%), a value significantly higher than those of the wild boar populations in the other prefecture areas. This in-depth analysis, which spans the big city suburbs and rural areas of a whole prefecture, explains the seroprevalence of zoonotic T. gondii in wild boar and has public health implications., (© 2021. The Author(s).)

Wild birds are recognized as disseminators of antimicrobial-resistant (AMR) bacteria into the environment. Here, we isolated AMR indicator bacteria from 198 Great Cormorant cloacal swabs collected in Shiga (n=90), Oita (n=52), Gifu (n=29), and Gunma (n=27) Prefectures, Japan, in 2018 and 2019. In total, 198 Aeromonas spp. and 194 Escherichia spp. were isolated, and their antimicrobial susceptibility was examined. Aeromonas spp. were resistant to colistin (8.6%), nalidixic acid (4%), and other antimicrobials (<2%), with 3.0% positivity for mcr-3. Escherichia spp. showed resistance to colistin (3.1%), ampicillin (2.6%), tetracycline (2.1%), and other antimicrobials (<2%). This study shows the presence of AMR bacteria in Great Cormorants, indicating that these birds potentially disseminate AMR bacteria.

Although alcohol consumption is reported to increase the incidence of breast cancer in European studies, evidence for an association between alcohol and breast cancer in Asian populations is insufficient. We conducted a pooled analysis of eight large-scale population-based prospective cohort studies in Japan to evaluate the association between alcohol (both frequency and amount) and breast cancer risk with categorization by menopausal status at baseline and at diagnosis. Estimated hazard ratios (HR) and 95% confidence intervals were calculated in the individual cohorts and combined using random-effects models. Among 158 164 subjects with 2 369 252 person-years of follow-up, 2208 breast cancer cases were newly diagnosed. Alcohol consumption had a significant association with a higher risk of breast cancer in both women who were premenopausal at baseline (regular drinker compared to nondrinker: HR 1.37, 1.04-1.81, ≥23 g/d compared to 0 g/d: HR 1.74, 1.25-2.43, P for trend per frequency category: P = .017) and those who were premenopausal at diagnosis (≥23 g/d compared to 0 g/d: HR 1.89, 1.04-3.43, P for trend per frequency category: P = .032). In contrast, no significant association was seen in women who were postmenopausal at baseline or at diagnosis, despite a substantial number of subjects and long follow-up period. Our results revealed that frequent and high alcohol consumption are both risk factors for Asian premenopausal breast cancer, similarly to previous studies in Western countries. The lack of a clear association in postmenopausal women in our study warrants larger investigation in Asia., (© 2021 UICC.)

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.)

Smoking has been consistently associated with the risk of colorectal cancer (CRC) in Western populations; however, evidence is limited and inconsistent in Asian people. To assess the association of smoking status, smoking intensity and smoking cessation with colorectal risk in the Japanese population, we performed a pooled analysis of 10 population-based cohort studies. Study-specific hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox's proportional hazards model and then pooled using a random-effects model. Among 363 409 participants followed up for 2 666 004 person-years, 9232 incident CRCs were identified. In men, compared with never smokers, ever smokers showed higher risk of CRC. The HRs (95% CI) were 1.19 (1.10-1.29) for CRC, 1.19 (1.09-1.30) for colon cancer, 1.28 (1.13-1.46) for distal colon cancer and 1.21 (1.07-1.36) for rectal cancer. Smoking was associated with risk of CRC in a dose-response manner. In women, compared with never smokers, ever smokers showed increased risk of distal colon cancer (1.47 [1.19-1.82]). There was no evidence of a significant gender difference in the association of smoking and CRC risk. Our results confirm that smoking is associated with an increased risk of CRC, both overall and subsites, in Japanese men and distal colon cancer in Japanese women., (© 2020 Union for International Cancer Control.)

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.)

What Is Known and Objective: Recently, opportunities for pharmacists to have face-to-face conversations with cancer patients have increased in Japan. The aim of this study was to investigate the difficulties experienced by Japanese pharmacists when communicating with cancer patients., Methods: We interviewed 7 pharmacists at Okayama University Hospital (Japan), using the semi-structured interview method. The obtained data were qualitatively analysed. A questionnaire was also filled out by 50 Japanese pharmacists to determine the difficulties they faced when communicating with cancer patients., Results and Discussion: The difficulties experienced by pharmacists when communicating with cancer patients were classified into the following three domains: (a) coping with patients' negative emotions, (b) questions beyond the scope of pharmacists' expertise and (3) how to manage patients and their families. Factor analysis indicated that the main difficulties pharmacists experienced were coping with patients' negative emotions and questions that were beyond the scope of their expertise. However, pharmacists were unlikely to experience difficulties in communicating additional information regarding anticancer drugs. Hospital pharmacists in Japan had some difficulties in communicating with cancer patients. In particular, many pharmacists felt that they could not sufficiently manage patients' negative emotions and answer questions beyond the scope of their expertise, such as questions about life expectancy or prognosis., What Is New and Conclusions: The current study showed that pharmacists experienced three types of difficulties when communicating with cancer patients: coping with patients' negative emotions, questions beyond the scope of their expertise and how to manage patients and their families. These results might facilitate the development of interventions that aim to improve patient-pharmacist communications in Japan., (© 2020 John Wiley & Sons Ltd.)

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.)

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.

Background: The association of alcohol drinking with bladder cancer risk remains unclear in East Asian populations. Aldehyde dehydrogenase 2 (ALDH2) enzyme oxidizes alcohol-metabolized carcinogenic acetaldehyde into acetate. It is well known that the inactive ALDH2 carriers, specific to East Asian populations, have an increased risk of several cancer types because of increased exposure to acetaldehyde after alcohol consumption. The aim of this study was to examine the association between alcohol drinking and bladder cancer risk using data from ten population-based prospective cohort studies in Japan, where approximately 40% of the population has inactive ALDH2 enzyme., Methods: We analyzed 340,497 Japanese participants with average follow-up of 13.4 years. The association between alcohol drinking and bladder cancer risk was evaluated using Cox regression models within each study, and random-effects models were used to estimate pooled hazard ratios (HRs) with corresponding 95% confidence intervals (CIs)., Results: During 4,729,071 person-years, 936 men and 325 women were newly diagnosed with bladder cancer. Our results showed no evidence of significant association between alcohol drinking and bladder cancer risk even among men who consumed alcohol of ≥69 g/week, with HR of 1.02 (95% CI, 0.79-1.33). The null result was observed consistently among women., Conclusions: Our findings do not support an association between alcohol drinking and bladder cancer risk in the Japanese, at least without consideration of the polymorphisms of alcohol-metabolizing enzymes.

Background: Globally, the number of deaths is estimated to increase to 74 million per year by 2030. Place of death (PoD) is increasingly being recognized as an important aspect of end-of-life care. However, recent trends in PoD in Japan, one of the super-aged societies, are unknown. Objective: To analyze trends in PoD in Japan over two decades. Design: Population-based retrospective observational study. Setting: All deaths reported in Japan, 1998-2017. PoD was defined as hospital, nursing home, or own home. Results: All Japanese decedents (∼22.6 million) over the past 20 years were analyzed. The proportion of hospital deaths was consistently high (>80%), with a significant decreasing trend from the mid-2000s. Although the proportion of deaths at home decreased in the first half of the study period, they later increased. There was a low proportion of deaths in nursing homes compared to other places of death; however, the proportion increased continually throughout the study period, particularly among women. In 2015, more women died in nursing homes than at home. Although the proportion of hospital deaths declined in the second half of the study period, their overall number continued to increase, reflecting an increase in total deaths in Japan. Conclusions: This study highlighted rapid changes in trends in PoD in Japan, and the need to consider affordable end-of-life care in Japan as well as other countries with aging populations. The findings from this long-term epidemiological study provide important insights on this issue.

Objectives: Appropriate antibiotic prescriptions for outpatients with acute respiratory tract infections (ARTIs) are urgently needed in Japan. However, the empirical proof of this need is under-documented. Therefore, we aimed to determine antibiotic prescription rates, and the proportions of antibiotic classes prescribed for Japanese patients with ARTIs., Methods: We analysed health insurance claims data over 2013-2015 among Japanese patients aged <75 years and determined the following indicators: 1) visit rates for patients with ARTIs and antibiotic prescription rates per 1000 person-years, and 2) proportion of visits by antibiotic-prescribed patients with ARTIs. We defined broad-spectrum antibiotics using the WHO Anatomical Therapeutic Chemical classification 4 level codes., Results: Among 8.65 million visits due to ARTIs at 6859 hospitals and 62,024 physicians' offices, the visit rate and antibiotic prescription rate per 1000 person-years were 990.6 (99% confidence interval [CI], 989.4-991.7) and 532.4 (99% CI, 531.6-533.3), respectively. The visit rates for patients aged 0-17, 18-59, and 60-74 years were 2410.0 (99% CI, 2407.2-2412.9), 683.6 (99% CI, 682.7-684.6), and 682.1 (99% CI, 678.2-686.0), and antibiotic prescription rates were 1093.3 (99% CI, 1091.4-1095.2), 434.1 (99% CI, 433.4-434.9), and 353.4 (99% CI, 350.7-356.1), respectively. The overall proportion of antibiotic prescriptions for ARTI visits was 52.7% and 91.3% of the antibiotics prescribed were broad-spectrum., Conclusions: Both the visit rates and antibiotic prescription rates for ARTIs were high in this Japanese cohort. The proportion of antibiotic prescriptions exceeded that recommended in the clinical guidelines. Thus, there might be a scope for reducing the current antibiotic prescription rate in Japan., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020. Published by Elsevier Ltd.)

The prognosis of cardiac light-chain (AL) amyloidosis is considered to be very poor. We studied the treatment efficacy and outcomes by retrospectively analyzing the clinical results of 45 patients with cardiac AL amyloidosis treated at our hospital between September 2008 and March 2016. The group of patients analyzed included 29 males and 16 females with a median age of 68 years. Their baseline median NT-proBNP, cTnT, and dFLC were 3167 pg/ml, 0.080 ng/ml, and 286.17 mg/l, respectively. Twenty-eight patients were in Cardiac Stage (CS) III and 17 patients were in Revised Prognostic Stage (RPS) IV. At the median follow-up of 10 months, the median overall survival (OS) was 16 months and 3-year OS was 35.9%. The patients in CS III showed significantly poorer survival rate than those in CS I or II (3-year OS: 12.2% vs. 65.8%, p = 0.0115) and the patients in RPS IV showed significantly poorer survival rate than those in RPS I, II, or III (3-year OS: 11.0% vs. 53.3%, p = 0.000914). Regardless of the therapeutic approaches, patients who achieved hematological CR or cardiac organ response demonstrated significantly improved prognosis. Therefore, achievement of hematological and organ responses is important in the treatment of cardiac AL amyloidosis.

Periodic paralysis (PP) is a rare disease caused by abnormal excitability of the sarcolemma, resulting in the episodic weakness in extremities. Two major subtypes have been identified: primary/familial PP showing Mendelian inheritance of a mutation in the ion channel genes expressed in skeletal muscle, and secondary/sporadic PP which does not show Mendelian inheritance. Thyrotoxic periodic paralysis (TPP) contributes to the majority of secondary PP cases in Asians and Latin Americans, suggesting that genetic factors may underlie the pathogenesis. In contrast, sporadic periodic paralysis (SPP) has no familial history and no secondary factors. The genetic features associated with SPP in Japanese patients remain unexplored. Here, we investigate whether nine single nucleotide variants (SNVs), rs623011, rs312691, rs393743, rs312692, rs312736, rs992072, rs312732, rs723498, and rs312707, found in TPP and/or SPP in other Asian populations are also associated with Japanese SPP cases. The study cohort included 43 Japanese periodic paralysis patients with no mutations in causative genes (SCN4A, CACNA1S, and KCNJ2), no myotonia, and with euthyroid function. The results showed disease susceptibility for all nine SNVs in our Japanese SPP cohort. One of them, rs312691, was newly confirmed to show susceptibility to SPP. Our results suggest the genetic background underlies periodic paralysis., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: There is a knowledge gap about advanced airway management (AAM) after pediatric out-of-hospital cardiac arrest (OHCA) in the prehospital setting. We assessed which AAM strategy would be associated with an increased chance of survival after pediatric OHCA., Methods: A nationwide population-based observational study was conducted using the Japanese government-led registry data of OHCA. Pediatric OHCA patients (aged 1-17 years) who received prehospital AAM via endotracheal intubation (ETI) or supraglottic airway (SGA) insertion by emergency medical service (EMS) personnel from 2011 to 2017 were included. Patients who received ETI were compared with those who received SGA insertion. The primary outcome was one-month survival after OHCA., Results: A total of 967 patients (mean [SD] age, 12.2 [5.1] years; 66.6% male) were included; 113 received ETI, and 854 received SGA insertion. Among the total cohort, 118 (12.2%) survived one month after OHCA. In the propensity score-matched cohort, no difference was observed in one-month survival between the ETI and SGA insertion groups: 13 of 113 patients (11.5%) vs 12 of 113 patients (10.6%); RR, 1.08; 95%CI, 0.52-2.27. This lack of association between AAM strategy and survival was observed across a variety of subgroup and sensitivity analyses, and also for neurologically favorable survival (P = 0.5611) in the propensity score-matched analysis., Conclusions: In Japan, among pediatric OHCA patients, there was no significant difference in one-month survival between prehospital ETI and SGA insertion by EMS personnel. Although an adequately powered randomized controlled trial is needed, EMS personnel may choose their familiar strategy when prehospital AAM was performed during pediatric OHCA., (Copyright © 2020 Elsevier B.V. All rights reserved.)

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.)

Bovine leukemia virus (BLV) infects cattle worldwide and causes B-cell lymphoma in cattle. BLV has been identified in human breast and lung cancer and in blood, but the association of BLV and human cancer is controversial. In this study, we investigated the existence of BLV in 145 Japanese human blood cell lines and 54 human cancer cell lines, using a new highly sensitive PCR assay that can amplify even one copy of BLV using LTR primers different from those in previous studies on BLV provirus in breast cancer. All samples were found negative for BLV provirus, suggesting that BLV is unlikely to infect humans.

Introduction: Acute bacterial infectious diseases are major causes for outpatient visits for young children. Pivalate-conjugated antibiotics (PCAs) are frequently prescribed for these situations in Japan, while several literatures have shown a potential risk of hypoglycemia associated with PCAs. This study aimed to evaluate the incidence of PCA-induced hypoglycemia in children, compared with other oral beta-lactam antibiotics., Methods: This retrospective cohort study using a Japanese medical and pharmacy claims database was performed on children aged 1 month to 5 years old with at least once prescription of PCAs or other oral beta-lactam antibiotics from January 2011 to December 2013. Hypoglycemia was defined based on diagnostic codes or the prescription of 10% or 20% glucose injection. We examined the prevalence of hypoglycemic events and performed multivariate analysis to investigate the risk of hypoglycemia with PCAs compared with the control oral beta-lactam antibiotics., Results: We identified 179,594 eligible patients in this population. In the PCA and control groups, there were 454,153 and 417,287 prescriptions and 3356 (0.74%, 95% confidence intervals [CI] 0.71-0.76) and 2605 (0.62%, 95% CI 0.60-0.65) hypoglycemic events, respectively. Multivariate analysis revealed that PCAs were associated with hypoglycemia (adjusted odds ratios [OR] 1.18, 95% CI 1.12-1.24), and even a shorter duration of PCAs prescribing (≤7 days) was significantly associated with hypoglycemia (adjusted OR 1.17, 95% CI 1.11-1.24)., Conclusion: These results suggest that in young children PCA use, even for a short period, is a risk factor of hypoglycemia., (Copyright © 2019 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Dementia is a major public health concern in ageing societies. Although the population of Japan is among the most aged worldwide, long-term trends in the place of death (PoD) among patients with dementia is unknown. In this Japanese nationwide observational study, we analysed trends in PoD using the data of patients with dementia who were aged ≥65 years and died during 1999-2016. Trends in the crude death rates and PoD frequencies were analysed using the Joinpoint regression model. Changes in these trends were assessed using the Joinpoint regression analysis in which significant change points, the annual percentage change (APC) and average APCs (AAPC) in hospitals, homes, or nursing homes were estimated. During 1999-2016, the number of deaths among patients with dementia increased from 3,235 to 23,757 (total: 182,000). A trend analysis revealed increased mortality rates, with an AAPC of 8.2% among men and 9.3% among women. Most patients with dementia died in the hospital, although the prevalence of hospital deaths decreased (AAPC: -1.0%). Moreover, the prevalence of nursing home deaths increased (AAPC: 5.6%), whereas the prevalence of home deaths decreased (AAPC: -5.8%). These findings support a reconsideration of the end-of-life care provided to patients with dementia.

Objectives: Fall-related mortality among older adults is a major public health issue, especially for ageing societies. This study aimed to investigate current trends in fall-related mortality in Japan using nationwide population-based data covering 1997-2016., Design: We analysed fall-related deaths among older persons aged ≥65 years using the data provided by the Japanese Ministry of Health, Labour and Welfare., Results: The crude and age-standardised mortality rates were calculated per 100 000 persons by stratifying by age (65-74, 75-84 and ≥85 years) and sex. To identify trend changes, a joinpoint regression model was applied by estimating change points and annual percentage change (APC). The total number of fall-related deaths in Japan increased from 5872 in 1997 to 8030 in 2016, of which 78.8% involved persons aged ≥65 years. The younger population (65-74 years) showed continuous and faster-decreasing trends for both men and women. Average APC among men aged ≥75 years did not decrease. Among middle-aged and older women (75-84 and ≥85 years) decreasing trends were observed. Furthermore, the age-adjusted mortality rate of men was approximately twice that of women, and it showed a faster decrease for women., Conclusions: Although Japanese healthcare has shown improvement in preventing fall-related deaths over the last two decades, the crude mortality for those aged over 85 years remains high, indicating difficulty in reducing fall-related deaths in the super-aged population. Further investigations to uncover causal factors for falls in older populations are required., 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.)

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.

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.

Background: Oral anticoagulants use has increased rapidly, internationally. Here we look at risks and benefits, based on Japanese data, of therapy with low risk non-valvular atrial fibrillation patients., Objectives: Using a health insurance claims data set we assessed: (i) oral anticoagulants usage in Japan, and (ii) efficacy and safety of dabigatran compared with warfarin, in Japanese patients with non-valvular atrial fibrillation, aged 18-74 years., Methods: We identified 4380 non-valvular atrial fibrillation patients treated with anticoagulants between 1 January 2005, and 28 February 2014, and estimated the adjusted hazard ratio for stroke or systemic embolism, and any hemorrhagic event (Cox proportional hazards regression model with stabilized inverse probability treatment weighting)., Results: The data included 101 989 anticoagulant prescriptions for 4380 patients, of which direct oral anticoagulants increased to 40.0% of the total by the end of the study. After applying exclusion criteria, 1536 new non-valvular atrial fibrillation patients were identified, including 1071 treated with warfarin and 465 with dabigatran. Mean ages were 56.11 ± 9.70 years for warfarin, and 55.80 ± 9.65 years for dabigatran. The adjusted hazard ratio (95% confidence interval), comparing dabigatran with warfarin, was 0.48 (0.25-0.91) for stroke or systemic embolism, and 0.91 (0.60-1.39) for any hemorrhage including intracranial and gastrointestinal., Conclusions: Number of patients prescribed direct oral anticoagulants steadily increased, and incidence of all-cause bleeding related to dabigatran was similar to warfarin, in our study population of younger non-valvular atrial fibrillation patients. Dabigatran, compared with warfarin, generally reduced risk of all-cause stroke and systemic embolism., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Red meat and processed meat have been suggested to increase risk of colorectal cancer (CRC), especially colon cancer. However, it remains unclear whether these associations differ according to meat subtypes or colon subsites. The present study addressed this issue by undertaking a pooled analysis of large population-based cohort studies in Japan: 5 studies comprising 232 403 participants (5694 CRC cases) for analysis based on frequency of meat intake, and 2 studies comprising 123 635 participants (3550 CRC cases) for analysis based on intake quantity. Study-specific hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using the Cox proportional hazards model and then pooled using the random effect model. Comparing the highest vs lowest quartile, beef intake was associated with an increased risk of colon cancer in women (pooled HR 1.20; 95% CI, 1.01-1.44) and distal colon cancer (DCC) risk in men (pooled HR 1.30; 95% CI, 1.05-1.61). Frequent intake of pork was associated with an increased risk of distal colon cancer in women (pooled HR 1.44; 95% CI, 1.10-1.87) for "3 times/wk or more" vs "less than 1 time/wk". Frequent intake of processed red meat was associated with an increased risk of colon cancer in women (pooled HR 1.39; 95% CI, 0.97-2.00; P trend = .04) for "almost every day" vs "less than 1 time/wk". No association was observed for chicken consumption. The present findings support that intake of beef, pork (women only), and processed red meat (women only) might be associated with a higher risk of colon (distal colon) cancer in Japanese., (© 2019 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Dramatic progress in targeted therapy and immunotherapy has been changing clinical practices in lung cancer. With the accumulation of clinical practice, it has become clear that pre-existing interstitial pneumonia (IP) could be a risk factor for drug-induced lung injury, which has enhanced awareness regarding the difficulty in treating lung cancer with comorbid IP. Unfortunately, there is only low-grade evidence in the field of lung cancer with comorbid IP, because almost all clinical trials exclude such patients. There have been very few specialized clinical trials for patients with lung cancer and underlying IPs thus far. Therefore, it is necessary to treat such cases empirically or to give up on the treatment itself. Considering these circumstances, establishing how to treat lung cancer with comorbid IP is an urgent issue. This paper is a summary of the official statement reported by the Diffuse Lung Disease/Thoracic Oncology Assembly and the Japanese Respiratory Society (JRS) in 2017, which attempts to approach lung cancer with comorbid IP systematically., (Copyright © 2019 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Background: Coffee and green tea, two popular drinks in the Japanese, have recently drawn much attention as potential protective factors against the occurrence of liver cancer., Methods: We systematically reviewed epidemiologic studies on coffee, green tea and liver cancer among Japanese populations. Original data were obtained by searching the MEDLINE (PubMed) and Ichushi databases, complemented with manual searches. The evaluation was performed in terms of the magnitude of association in each study and the strength of evidence ('convincing', 'probable', 'possible', or 'insufficient'), together with biological plausibility., Results: We identified four cohort and four case-control studies on coffee and liver cancer and six cohort and one case-control studies on green tea and liver cancer. All cohort and case-control studies on coffee reported a weak to strong inverse association, with a summary relative risk (RR) for one cup increase being 0.72 (95% confidence interval [CI] 0.66-0.79). Conversely, all studies but two cohort studies on green tea reported no association, with a corresponding summary RR of 0.99 (95% CI 0.97-1.01, P = 0.37)., Conclusion: Coffee drinking 'probably' decreases the risk of primary liver cancer among the Japanese population whereas the evidence on an association between green tea and liver cancer is 'insufficient' in this population., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The aim of our study was to assess the association between green tea consumption and all-cause and cause-specific mortality in a pooled analysis of eight Japanese population-based cohort studies. Pooled hazard ratios (HR) and 95% confidence intervals (CI), derived from random effects models, were used to evaluate the associations between green tea consumption, based on self-report at baseline, and risk of all-cause and cause-specific mortality. During a mean follow-up of 17.3 years, among 313,381 persons, 52,943 deaths occurred. Compared with individuals who consumed < 1 cup/day, those in the highest consumption category (≥ 5 cups/day) had a decreased risk of all-cause mortality [the multivariate-adjusted HR was 0.90 (95% CI 0.87-0.94) for men and 0.82 (0.74-0.90) for women]. A similar inverse association was observed for heart disease mortality [HR 0.82 (0.75-0.90) for men, and 0.75 (0.68-0.84) for women], and cerebrovascular disease mortality [HR 0.76 (0.68-0.85) for men, and 0.78 (0.68-0.89) for women]. Among women, green tea consumption was associated with decreased risk of total cancer mortality: 0.89 (0.83-0.96) for the 1-2 cups/day category and 0.91 (0.85-0.98) for the 3-4 cups/day category. Results for respiratory disease mortality were [HR 0.75 (0.61-0.94)] among 3-4 cup daily consumers and [HR 0.66 (0.55-0.79)] for ≥ 5 cups/day. Higher consumption of green tea is associated with lower risk for all-cause mortality in Japanese, especially for heart and cerebrovascular disease. Moderate consumption decreased the risk of total cancer and respiratory disease mortality in women.

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.)

Background: Management of anticoagulants for patients undergoing polypectomy is still controversial. Cold snare polypectomy (CSP) is reported to cause less bleeding than hot snare polypectomy (HSP)., Objective: To compare outcomes between continuous administration of anticoagulants (CA) with CSP (CA+CSP) and periprocedural heparin bridging (HB) with HSP (HB+HSP) for subcentimeter colorectal polyps., Design: Multicenter, parallel, noninferiority randomized controlled trial. (University Hospital Medical Information Network Clinical Trials Registry: UMIN000019355)., Setting: 30 Japanese institutions., Patients: Patients receiving anticoagulant therapy (warfarin or direct oral anticoagulants) who had at least 1 nonpedunculated subcentimeter colorectal polyp., Intervention: Patients were randomly assigned to undergo HB+HSP or CA+CSP and followed up 28 days after polypectomy., Measurements: The primary end point was incidence of polypectomy-related major bleeding (based on the incidence of poorly controlled intraprocedural bleeding or postpolypectomy bleeding requiring endoscopic hemostasis). The prespecified inferiority margin was -5% (CA+CSP vs. HB+HSP)., Results: A total of 184 patients were enrolled: 90 in the HB+HSP group, 92 in the CA+CSP group, and 2 who declined to participate after enrollment. The incidence of polypectomy-related major bleeding in the HB+HSP and CA+CSP groups was 12.0% (95% CI, 5.0% to 19.1%) and 4.7% (CI, 0.2% to 9.2%), respectively. The intergroup difference for the primary end point was +7.3% (CI, -1.0% to 15.7%), with a 0.4% lower limit of 2-sided 90% CI, demonstrating the noninferiority of CA+CSP. The mean procedure time for each polyp and the hospitalization period were longer in the HB+HSP than in the CA+CSP group., Limitation: An open-label trial assessing 2 factors (anticoagulation approach and polypectomy procedure type) simultaneously., Conclusion: Patients having CA+CSP for subcentimeter colorectal polyps who were receiving oral anticoagulants did not have an increased incidence of polypectomy-related major bleeding, and procedure time and hospitalization were shorter than in those having HB+HSP., Primary Funding Source: Japanese Gastroenterological Association.

Background: Detailed prospective evaluation of cigarette smoking associated with pancreatic cancer risk in large Asian populations is limited. The aim of this study was to examine this association in a Japanese population, with a particular focus on evaluating sex differences., Methods: We performed a pooled analysis of 10 population-based cohort studies. We calculated study-specific HRs and 95% confidence intervals (CI) using Cox proportional hazards regression, and then estimated summary HRs by pooling these estimates with a random effects model., Results: During 4,695,593 person-years of follow-up in 354,154 participants, 1,779 incident pancreatic cancer cases were identified. We observed an increased pancreatic cancer risk for current smoking compared with never smoking in both males [HR (95% CI), 1.59 (1.32-1.91)] and females [HR (95% CI), 1.81 (1.43-2.30)]. Significant risk elevations for former smoking and small cumulative dose of ≤20 pack-years (PY) were observed only among females, regardless of environmental tobacco smoke exposure. Trend analysis indicated significant 6% and nonsignificant 6% increases in pancreatic cancer risk for every 10 PYs in males and females, respectively. Risk became comparable with never smokers after 5 years of smoking cessation in males. In females, however, we observed no risk attenuation by smoking cessation., Conclusions: This study supports the well-known association between smoking and pancreatic cancer and indicates potential sex differences in a Japanese population. Quitting smoking would be beneficial for pancreatic cancer prevention, especially in males., Impact: Pancreatic cancer risk is increased with cumulative smoking exposure and decreased with smoking cessation, with potential sex differences., (©2019 American Association for Cancer Research.)

Background & Aims: Many studies have suggested that fish intake is associated with protection from risk of atherosclerotic diseases; however, this association with aortic diseases has not been elucidated worldwide. We hypothesized that fish intake is inversely associated with mortality from aortic diseases (aortic dissection and aneurysm)., Methods: The study was conducted as a pooled analysis of original data from a maximum of 8 cohort studies, comprising a total of 366,048 community-based men and women who had no history of cardiovascular disease or cancer. In each cohort, we used Cox proportional hazards regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for mortality from aortic dissection, aneurysm and total aortic disease according to the frequency of fish intake and estimated summary HRs derived from each study., Results: Nonlinear inverse associations were found between fish intake and total aortic disease. Compared with persons who ate fish 1-2 times/week, persons who seldom ate fish had higher mortality from total aortic disease (multivariable-adjusted pooled HR = 1.93; 95% CI, 1.13-3.31). Higher mortality was not seen in those who ate fish 1-2 times/month. A similar pattern was observed for aortic dissection. Regarding aortic aneurysm, both persons who seldom ate fish and those who ate fish 1-2 times/month had higher mortality (HR = 1.99; 95% CI, 0.90-4.40 and HR = 1.86; 95% CI, 0.87-3.98, respectively)., Conclusions: Persons who seldom ate fish had higher mortality from aortic dissection, aneurysm, and total aortic diseases., (Copyright © 2018 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Background: In this age of antimicrobial resistance, unnecessary use of antibiotics to treat non-bacterial acute respiratory tract infections (ARTIs) and inappropriate use of antibiotics in treating bacterial ARTIs are public health concerns., Purpose: Our aim is to identify the pattern of oral antibiotic prescriptions for outpatients with ARTIs in Japan., Methods: We analysed health insurance claims data of patients (aged ≤74 years) from 2013 to 2015, to determine the pattern of antibiotic prescriptions for outpatient ARTIs and calculated the proportion of each antibiotic., Results: Data on 4.6 million antibiotic prescriptions among 1559394 outpatients with ARTIs were analysed. The most commonly prescribed classes of antibiotics included cephalosporins (41.9%), macrolides (32.8%) and fluoroquinolones (14.7%). The proportion of first-, second- and third-generation cephalosporins was 1.0%, 1.7% and 97.3%, respectively. Fluoroquinolones accounted for a quarter of the prescriptions for ARTIs in patients aged >20 years. In contrast, penicillins accounted for just 8.0% of the total number of antibiotic prescriptions for ARTIs., Conclusions: According to clinical guidelines, penicillins are first-line antibiotics against ARTIs. However, third-generation cephalosporins, macrolides and fluoroquinolones are more frequently prescribed in Japan. Although we could not assess the extent to which appropriate antibiotics are selected, our results support the necessity of improving antibiotic choices in the treatment of ARTIs., (© The Author(s) 2018. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)