Labour Sciences Research Grant Research Articles

Expert consensus on vaccination in patients with inflammatory bowel disease in Japan

Immunosuppressive therapies can affect the immune response to or safety of vaccination in patients with inflammatory bowel disease (IBD). The appropriateness of vaccination should be assessed prior to the initiation of IBD treatment because patients with IBD frequently undergo continuous treatment with immunosuppressive drugs. This consensus was developed to support the decision-making process regarding appropriate vaccination for pediatric and adult patients with IBD and physicians by providing critical information according to the published literature and expert consensus about vaccine-preventable diseases (VPDs) [excluding cervical cancer and coronavirus disease 2019 (COVID-19)] in Japan. This consensus includes 19 important clinical questions (CQs) on the following 4 topics: VPDs (6 CQs), live attenuated vaccines (2 CQs), inactivated vaccines (6 CQs), and vaccination for pregnancy, childbirth, and breastfeeding (5 CQs). These topics and CQs were selected under unified consensus by the members of a committee on intractable diseases with support by a Health and Labour Sciences Research Grant. Physicians should provide necessary information on VPDs to their patients with IBD and carefully manage these patients’ IBD if various risk factors for the development or worsening of VPDs are present. This consensus will facilitate informed and shared decision-making in daily IBD clinical practice.

Associations of soluble fms-like tyrosine kinase-1 with cardiovascular events and stroke in patients with atrial fibrillation and suspected or known coronary artery disease: the EXCEED-J study

Abstract Background Atrial fibrillation (AF) increases the risk of stroke. Soluble fms-like tyrosine kinase-1 (sFlt-1), a vascular endothelial growth factor (VEGF) antagonist, has been suggested as a marker of endothelial dysfunction, which are associated with both AF and coronary artery disease (CAD). Recently, we demonstrated that sFlt-1 is independently associated with major adverse cardiovascular (CV) events (MACE) in patients with suspected or known CAD. However, the prognostic utility of sFlt-1 in patients with AF remains unknown. Methods Using data from a multicenter, prospective cohort of 3255 patients with suspected or known CAD, we investigated whether AF modifies the prognostic utility of sFlt-1. Heparin-free serum levels of sFlt-1, N-terminal pro-brain natriuretic peptide, high-sensitivity cardiac troponin-I, high-sensitivity C-reactive protein, cystatin C, neutrophil gelatinase-associated lipocalin, VEGF, and placental growth factor were measured in 324 patients with AF and 2931 patients without AF. The primary outcome was MACE defined as a composite of CV death, nonfatal myocardial infarction, and nonfatal stroke. The secondary outcomes were all-cause death, CV death, stroke, heart failure (HF) hospitalization, and coronary/peripheral artery revascularization. The biomarkers were natural log-transformed for use as continuous variables. Results After adjustment for potential clinical confounders including anticoagulant drug use, sFlt-1 was significantly associated with MACE (hazard ratio for 1 standard deviation increase [HR], 1.55; 95% confidence interval [CI], 1.14–2.08), CV death (HR, 1.68; 95% CI, 1.10–2.48), and stroke (HR, 1.89; 95% CI, 1.16–3.10), but not with all-cause death (HR, 1.32; 95% CI, 0.99–1.73), HF hospitalization (HR, 0.97; 95% CI, 0.73–1.25), or revascularization (HR, 0.99; 95% CI, 0.74–1.28) in patients with AF, whereas sFlt-1 was significantly associated with MACE (HR, 1.19; 95% CI, 1.02–1.37), all-cause death (HR, 1.19; 95% CI, 1.05–1.34), CV death (HR, 1.26; 95% CI, 1.03–1.48), and HF hospitalization (HR, 1.26; 95% CI, 1.11–1.42), but not with stroke (HR, 1.06; 95% CI, 0.81–1.33) or revascularization (HR, 1.01; 95% CI, 0.95–1.07) in patients without AF. Among other biomarkers, only VEGF was significantly associated with MACE (HR, 1.55; 95% CI, 1.02–2.44), and no biomarkers were significantly associated with CV death or stroke in patients with AF. sFlt-1 added incremental prognostic information for MACE (P=0.005 for net reclassification improvement [NRI], P=0.026 for integrated discrimination improvement [IDI]) and stroke (P=0.034 for NRI, P=0.018 for IDI), but not for CV death (P=0.021 for NRI, P=0.134 for IDI), to the model with potential clinical confounders in patients with AF. Conclusions sFlt-1 independently predicted MACE and stroke in patients with AF and suspected or known CAD. sFlt-1 may serve as a novel prognostic biomarker to stratify the risk of MACE and stroke in patients with AF. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Health Labour Sciences Research Grant (2013-2014), AMED (2015-2017, Grant Number JP17ek0210008)

Elimination of HIV transmission in Japanese MSM with combination interventions

SummaryBackgroundJapan has a concentrated HIV epidemic, with the majority of transmission among men who have sex with men (MSM). This study aimed to explore the effect of behavioral and biomedical interventions on the HIV epidemic and forecast the time required to eliminate HIV transmission among Japanese MSM.MethodsA deterministic compartmental model was built to estimate and forecast the HIV epidemic among Japanese MSM from 2010 to 2050. Elimination of HIV transmission among MSM was defined as incidence less than 1/1000 person-years. The time required for eliminating HIV transmission under different scenarios was calculated.FindingsUnder the current policies, HIV transmission cannot be eliminated by 2050. Both behavioral and biomedical interventions can achieve elimination of HIV among MSM by 2050 with annual number of sexual partners among high-risk MSM less than 9, or with condom use rate above 65%, or with testing and treatment rate above 80%, or with more than 10% PrEP coverage rate. Under comprehensive interventions, HIV elimination will be achieved in 2032, 2025 and 2024 using weak, moderate and strong intervention combinations, respectively.InterpretationBoth behavioural and biomedical interventions can achieve elimination of HIV among MSM by 2050, but comprehensive interventions can accelerate the realization of this goal with higher feasibility.FundingThis study was funded by a Health and Labor Sciences Research Grant (Research on HIV/AIDS) from The Ministry of Health Labour and Welfare (21HB0701) and National Natural Science Foundation of China (No. 81773543 and 81973150), and the KC Wong Education Foundation.

The looming health hazard: A wave of HPV-related cancers in Japan is becoming a reality due to the continued suspension of the governmental recommendation of HPV vaccine

The looming health hazard: A wave of HPV-related cancers in Japan is becoming a reality due to the continued suspension of the governmental recommendation of HPV vaccine

Impact of atrial fibrillation on soluble fms-like tyrosine kinase-1 and cardiovascular events in patients with suspected or known coronary artery disease: the EXCEED-J study

Abstract Background Soluble fms-like tyrosine kinase-1 (sFlt-1), a vascular endothelial growth factor (VEGF) antagonist, has been suggested as a marker of endothelial dysfunction. Circulating sFlt-1 levels are associated with adverse outcomes in patients with preeclampsia, chronic kidney disease, and heart failure. Atrial fibrillation (AF) and coronary artery disease (CAD) are both associated with endothelial dysfunction. However, whether sFlt-1 can predict cardiovascular (CV) events and whether AF modifies the relationship between sFlt-1 and CV events in patients with suspected or known CAD are unknown. Methods We performed a nationwide, multicenter, prospective cohort study to determine the prognostic value of sFlt-1 and other biomarkers in patients with suspected or known CAD undergoing elective angiography. Heparin-free fasting serum was collected from the peripheral vein to determine levels of sFlt-1, VEGF, placental growth factor, cystatin C, neutrophil gelatinase-associated lipocalin, N-terminal pro-brain natriuretic peptide (NT-proBNP), high-sensitivity cardiac troponin-I (hs-cTnI), and high-sensitivity C-reactive protein (hs-CRP). The primary outcome was 3-point major adverse CV events (3P-MACE) defined as a composite of CV death, nonfatal myocardial infarction, and nonfatal stroke. The secondary outcomes were all-cause death, CV death, and 5P-MACE defined as a composite of 3P-MACE, heart failure hospitalization, and coronary/peripheral artery revascularization. Results 3311 patients were consecutively enrolled between Nov 2013 and May 2017. After excluding 56 ineligible patients, 3255 patients (324 AF and 2931 non-AF) were followed up over 3 years (follow-up rate, 99%). During the follow-up, 156 patients developed 3P-MACE, 215 died from any cause, 82 died from cardiovascular disease, and 1361 developed 5P-MACE. The sFlt-1 level was significantly higher in AF compared to non-AF patients (p<0.001). Stepwise regression analysis revealed that the sFlt-1 level was independently associated with AF. After adjusting for potential clinical confounders, serum levels of sFlt-1, NT-proBNP, hs-cTnI and cystatin C, but not other biomarkers, were significantly associated with 3P-MACE in the entire cohort. These associations were still significant in non-AF patients, whereas only the sFlt-1 level was significantly associated with 3P-MACE in AF patients. Serum levels of sFlt-1, but not other biomarkers, were also significantly associated with CV death in AF patients. Among the biomarkers, only the hs-CRP level was significantly associated with all-cause death, and no biomarker was significantly associated with 5P-MACE in AF patients. Furthermore, sFlt-1 provided an incremental prognostic information for 3P-MACE to the model with potential clinical confounders in AF, but not in non-AF patients. Conclusions Serum levels of sFlt-1 were significantly associated with 3P-MACE in patients with suspected or known CAD. This association was pronounced in AF patients. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): The EXCEED-J study is supported by Health Labour Sciences Research Grant (2013-2014), AMED (2015-2017, Grant Number JP17ek0210008) and Grant-in-Aid for Clinical Research from the National Hospital Organization (2018-2020).

1086-P: A Retrospective Nationwide Surveillance on the First-Line Antidiabetic Medication for the Patients with Type 2 Diabetes in Japan

Background: To investigate the national trend in prescription of first-line non-insulin antidiabetic agents and the annual total medical costs since the first prescription in Japanese patients with type 2 diabetes. Materials and Methods: Using the National Database of Health Insurance Claims and Specific Health Check-ups of Japan (NDB), we calculated the proportion of each antidiabetic drug from fiscal year (FY) 2014 to 2017 and determined factors associated with drug selection in multivariable logistic regression analyses. The total medical costs (TMCs) in the first year after starting the drugs were calculated and factors associated with the costs were also determined. Results: Among 1,136,723 newly-prescribed patients, dipeptidyl peptidase-4 inhibitors (DPP4i) were most prescribed (65.1%) followed by biguanides (15.9%) and sodium-glucose co-transporter-2 inhibitors (SGLT2i) (7.6%). SGLT2i use increased markedly, as was biguanide gradually increased and other drug use decreased during the study period. Biguanides were not prescribed at all in 38.2% of non-certified facilities by the Japan Diabetes Society. TMCs [adjusted mean, 95% CI] were lowest in biguanides [$4638, 4591-4686] followed by thiazolidinediones [$4670, 4546-4794], moderate in SGLT2i [$5383, 5297-5468] and DPP4i [$5583, 5550-5617], highest in glucagon-like peptide 1 receptor agonist [$8596, 7532-9661] after adjusting for covariates including age and comorbidities. FY, age, gender, type of insurance, facility, number of beds, and comorbidities were associated with drug choice and medical costs in the model. There was wide regional variation in initial choice of antidiabetic drugs but not in the TMCs. Conclusions: Unlike in Europe and the US, DPP4i stands as a first-line treatment in Japan. The wide variation in the drug choice by facility and prefecture may suggest the need to create a new strategy such as algorithms that facilitate appropriate drug selection in Japan. Disclosure R. Bouchi: None. T. Sugiyama: None. A. Goto: None. K. Imai: None. N. Ihana-sugiyama: None. M. Ohsugi: Other Relationship; Self; Kyowa Kirin Co., Ltd., Research Support; Self; Abbott Japan Co., Ltd., Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly Japan K. K., Mitsubishi Tanabe Pharma Corporation, MSD K. K., Novartis Pharma K. K., Novo Nordisk Pharma Ltd., Sanofi K. K., Sumitomo Dainippon Pharma Co., Ltd. T. Yamauchi: Other Relationship; Self; Abbott Japan LLC, Astellas Pharma Inc., AstraZeneca K. K., Daiichi Sankyo Company, Limited, Eli Lilly Japan K. K., Kissei Pharmaceutical Co., Ltd., Kowa Company, Ltd., Kyorin Pharmaceutical Company, Limited, Kyowa Kirin Co., Ltd., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Nippon Boehringer Ingelheim Co. Ltd., Novo Nordisk Pharma Ltd., Ono Pharmaceutical Co., Ltd., Sanofi K. K., Sanwa Kagaku Kenkyusho, Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited, Research Support; Self; Aero Switch, Asahi Mutual Life Insurance Company, Bayer Yakuhin, Ltd., Mitsubishi Corporation Life Sciences Limited, NIPRO Medical Corporation, NTT Docomo Inc., Shionogi & Co., Ltd., Tosoh Corporation. T. Kadowaki: Other Relationship; Self; Asahi Mutual Life Insurance Company, MSD Corporation, Nippon Boehringer Ingelheim Co. Ltd., Novo Nordisk Pharma Ltd., Takeda Pharmaceutical Company Limited, Research Support; Self; Daiichi Sankyo Company, Limited, Eli Lilly Japan K. K., Kyowa Kirin Co., Ltd., Mitsubishi Tanabe Pharma Corporation, MSD Corporation, Novo Nordisk Pharma Ltd., Ono Pharmaceutical Co., Ltd., Sanofi K. K., Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Co., Speaker’s Bureau; Self; Astellas Pharma Inc., AstraZeneca, Daiichi Sankyo Company, Limited, Eli Lilly Japan K. K., Kowa Company, Ltd., Kyowa Kirin Co., Ltd., Mitsubishi Tanabe Pharma Corporation, MSD Corporation, Nippon Boehringer Ingelheim Co. Ltd., Novo Nordisk Pharma Ltd., Ono Pharmaceutical Co., Ltd., Sanofi K. K., Sanwa Kagaku Kenkyusho, Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd. K. Ueki: Advisory Panel; Self; Abbott Japan Co., Ltd., AstraZeneca K. K., Bayer Yakuhin, Ltd., Novo Nordisk Pharma Ltd., Poxel SA, Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo, Eli Lilly Japan K. K., Japan Agency for Medical Research and Development, Japan Society for the Promotion of Science, Kyowa Kirin Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk Pharma Ltd., Ono Pharmaceutical Co., Ltd., Sanofi K. K., Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited, Speaker’s Bureau; Self; Astellas Pharma Inc., AstraZeneca K. K., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo, Eli Lilly Japan K. K., Kyowa Kirin Co., Ltd., Mitsubishi Tanabe Pharma Corporation, MSD K. K., Ono Pharmaceutical Co., Ltd., Sanofi K. K., Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited. Funding Health and Labour Sciences Research Grants (20FA1016)

Coronavirus Disease 2019 Cluster Originating in a Primary School Teachers’ Room in Japan

Background: School closures are a subject of debate during the present coronavirus disease 2019 (COVID-19) pandemic. Because children are not the main driver of COVID-19 transmission in the community, school education must be prioritized in conjunction with appropriate infection prevention and control measures, as determined by local COVID-19 incidence.Methods: We investigated causes and transmission routes of a primary school cluster of COVID-19 that occurred during November and December 2020 in Niigata, Japan.Findings: In the cluster, the virus spread among teachers, then from teachers to students, and then to their family members. This primary school cluster comprised 26 infected patients and included teachers (13/33, 39%), students (9/211, 4%), and family members (4/65, 6%). The secondary attack rate from the three index teachers to the remaining 30 teachers was 33%; however, the rate to students was only 4%. Factors contributing to cluster formation include the fact that two of the index teachers continued working while symptomatic and that the environment and infection prevention measures in the teachers’ room were inadequate.Interpretation: To open schools safely and without interruption, adequate measures to prevent COVID-19 infection in schools should be emphasized not only for children but also for teachers and their work environment.Funding Information: Health and Labour Sciences Research Grants (20CA2035).Declaration of Interests: The authors have no competing interests to declare.Ethics Approval Statement: Because COVID-19 is designated as an infectious disease by the Prevention of Infectious Diseases and Medical Care for Patients with Infectious Diseases Act, investigations of outbreaks and contact tracing are led by the public health service of health centres, under the authority of the Department of Health and Welfare, Niigata Prefectural Office. We used anonymous and public data; thus, the requirement for informed consent was waived for this study. This study was approved by the Ethics Committee of Niigata University (2020-0499).

Smoking, Comorbidities, and Severity of Disease in Hospitalized COVID-19 Patients in Japan

Background: The aim of this study was to identify associations between smoking status and the severity of COVID-19 using a large-scale data registry of hospitalized COVID-19 patients in Japan (COVIREGI-JP) and to explore the reasons for the inconsistent results previously reported on this subject. Methods: The analysis included 17,702 COVID-19 inpatients aged 20-89 years (10,279 men and 7,423 women). We graded the severity of COVID-19 (grade 0 to 5) according to the most intensive treatment required during hospitalization. Associations of smoking status with severe grade 3/4/5 (invasive mechanical ventilation/extracorporeal membrane oxygenation/death) and separately with grade 5 (death) were analyzed using multiple logistic regression with grade 0 (no oxygen) as the control group. Results were expressed as odds ratios (OR) and 95% confidence intervals (CI) adjusted for age and other factors considering the potential intermediate effects of comorbidities.Findings: Among men, former smoking significantly increased the risk of grade 3/4/5 and grade 5, with age-adjusted ORs (95% CI) of 1·50 (1·18-1·90) and 1·65 (1·23-2·21), respectively. An additional adjustment for comorbidities weakened these ORs to 1·29 (1·00-1·66) and 1.41 (1·01-1·95), respectively. Similar results were seen for women. Current smoking did not significantly increase the risk of grade 3/4/5 and grade 5 in either sex.Interpretation: Smoking cessation should be recommended even if the observed relationship between current smoking and the severity of COVID-19 is null because current smoking increases the risks of future comorbidities due to different diseases that increase the risk of severe COVID-19.Funding Information: This research was funded by the Health and Labour Sciences Research grant (19HA1003, 20CA2031) and the National Center for Global Health and Medicine (20A-3002).Declaration of Interests: All authors report no conflict of interest.Ethics Approval Statement: This study was approved by the National Center for Global Health and Medicine (NCGM) ethics review (NCGM-G-003494-0).

Regional Disparity in Dental Care Utilization in Japan: Ecological Study Using the National Database of Health Insurance Claims

Background: We examined regional disparities in dental care utilization and their associations with dental care utilization and socioeconomic factors in Japan. Methods: Using the Fourth NBD Open Data Japan, a database for the universal healthcare insurance claims, we conducted an ecological study by analyzing 216 million pieces of aggregated data from April 2017 to March 2018. We used nine indicators to represent dental care utilization: outpatient visits, outreach services, cavity fillings, pulpectomies, dental calculus removals, periodontal surgeries, tooth extractions, dental bridges, and dentures. Standardized claim ratios (SCRs) for these indicators were calculated for Japan’s 47 prefectures, each of which was divided into three groups based on socioeconomic factors (i.e., average income per capita and the proportion of university enrollments). Kruskal-Wallis tests were performed among the three groups to examine the associations between the supply-adjusted nine indicators and the socioeconomic factors. Findings: The ratios between the maximum and minimum SCRs were 1·4 for outpatient visits, 19·3 for outreach services, and 17·6 for periodontal surgeries. Income level was negatively associated with dental bridges and dentures. Educational level was positively associated with outreach services and dental calculus removals, and negatively associated with pulpectomies, tooth extractions, dental bridges, and dentures. Interpretation: In Japan, regional disparities in dental care utilization exist for periodontal care and outreach services but are smaller for urgent and substantial dental care. Educational level appears to be a more important determining factor than income level in dental care utilization. Funding Statement: This work was supported in part by a Health and Labour Sciences Research Grant (Multidisciplinary research project on measures against lifestyle-related diseases such as cardiovascular diseases and diabetes mellitus) “Research study aimed at the development of new evaluation indices and new evaluation methods for the preservation of dental and oral health: Health service research aimed at reducing health disparities in Japan” received by the principal investigator, Nanako Tamiya (Grant number: H31-19FA1001). Declaration of Interests: Takahiro Mori: His appointment as an associate professor at the University of Tsukuba was sponsored by JMDC Inc. in the financial year 2018 (i.e., April 2018 – March 2019), by SMS CO., LTD. in the financial year 2019 (i.e., April 2019 – March 2020), and by FAST DOCTOR CO., LTD in the financial year 2020 (i.e., April 2020 – present). JMDC Inc., SMS CO., LTD, and FAST DOCTOR CO., LTD did not play any role in the conception, design, conduct, or reporting of this study. Sakata Nobuo: His appointment as an associate professor at the University of Tsukuba was sponsored by JMDC Inc. in the financial year 2020 (i.e., April 2020 – present). JMDC Inc. did not play any role in the conception, design, conduct, or reporting of this study. The other authors declare they have no competing interests. Ethics Approval Statement: This study was approved by the University of Tsukuba Medical Ethics Committee (date of approval: December 17, 2019; approval number: 1446).

Highly Specific Monoclonal Antibodies Against SARS-CoV-2 Nucleocapsid Antigen for Accurate Diagnosis of COVID-19

The ongoing COVID-19 pandemic is a major global public health concern. Although rapid point of care testing for detecting viral antigen is important for management the outbreak, none of current antigen detection kits provide a reliable diagnosis due to the lack of a specific monoclonal antibody (mAb) against SARS-CoV-2. In our current study, we produced mAbs exclusively react with SARS-CoV-2 and exhibited no cross-reactivity with other human coronaviruses including SARS-CoV. Molecular modeling revealed that the mAbs bound to epitopes present on the exterior surface of the nucleocapsid, encompassing their scope for detecting SARS-CoV-2 in clinical samples. We further selected the optimal pair of anti-SARS-CoV-2 NP mAbs for designing ELISA and immunochromatographic assay. An integrated bioinformatics analysis revealed that our mAbs could comprehensively detect divergent strains of SARS-CoV-2. Due to the high redundancy and absence of cross-reactivity, our newly developed mAbs would be instrumental for developing reliable diagnosis kits for COVID-19.Funding: This work was supported in part by Japan Agency for Medical Research and Development (AMED, Grant number: JP19fk0108110 and JP20he0522001), and by Health Labour Sciences research grant from The Ministry of Health Labour and Welfare.Conflict of Interest: The authors have no conflicts of interest directly relevant to the content of this article. YY, SK, KS and DA is a current employee of Kanto Chemical Co., Inc.Ethical Approval: This study was approved by the Institutional Review Board of Yokohama City University (IRB No. B200800106), and the protocols used in the study were approved by the ethicscommittee.

Findings from the First National Online Survey of Children's Well-Being During the COVID-19 Pandemic in Japan (CORONA-CODOMO Survey)

Background: The coronavirus disease 2019 (COVID-19) pandemic has changed people’s lives dramatically. Few data on the acute effects of the pandemic on children’s daily lives and well-being have been published to date. This study aimed to capture the effects on Japanese children during the peak of the outbreak and the national quarantine.Methods: We conducted a web-based, anonymous survey targeting Japanese children aged 7–17 years and parents/guardians of children aged 0–17 years. Eligible individuals were invited to the survey from April 30 to May 31, 2020. This self-report questionnaire examined daily life and behaviors, psychological symptoms (depression, anxiety, and stress), well-being, quality of life, and positive parenting or abusive behaviors during the quarantine.Findings: In our survey of 2,591 children and 6,116 parents/guardians, many aspects of children’s daily lives and well-being were affected by the pandemic. Nearly half of parents/guardians refrained from seeking medical care for the child’s symptoms. Sixty-two percent of children reported screen time exceeding 2 hours. Twenty percent of children reported abusive behaviors by family members, such as being yelled at, being threatened or insulted, and being slapped. Nine in ten parents/guardians of school-aged children reported their child had at least one acute stress symptom in the past month, such as irritable or aggressive behavior, sleep disorder, and poor concentration. Average mental health subscale scores from KINDL-R questionnaire on quality of life were lower than the national average for all grades.Interpretation: The COVID-19 pandemic had serious acute impacts on children’s daily lives, well-being, family relationships and health care utilisation including some impacts that are potentially long-lasting; thus, proactive interventions and services are needed, as well as longitudinal surveys.Funding Statement: This study was supported by the Health and Labour Sciences Research Grant in Japan and the Japan Science and Technology Agency JRAPID Grant.Declaration of Interests: All the authors declare no competing interests.Ethics Approval Statement: This study was approved by the institutional review board of the National Center for Child Health and Development on April 27, 2020 (approval number 2020- 21).

Intractable diffuse pulmonary diseases: Manual for diagnosis and treatment.

This manual has been compiled by a joint production committee with the Diffuse Lung Disease Assembly of the Japanese Respiratory Society (JRS) to provide a practical manual for the epidemiology, diagnosis, and treatment of intractable diffuse pulmonary diseases. The contents are based upon the results of research into these diseases by the Diffuse Pulmonary Diseases Study Group (principal researcher: Sakae Homma) supported by the FY2014-FY2016 Health and Labor Sciences Research Grant on Intractable Diseases. This manual focuses on: 1) pulmonary alveolar microlithiasis, 2) bronchiolitis obliterans, and 3) Hermansky-Pudlak Syndrome with interstitial pneumonia. As these are rare/intractable diffuse lung diseases (2 and 3 were first recognized as specified intractable diseases in 2015), there have not been sufficient epidemiological studies made, and there has been little progress in formulating diagnostic criteria and severity scales; however, the results of Japan's first surveys and research into such details are presented herein. In addition, the manual provides treatment guidance and actual cases for each disease, aiming to assist in the establishment of future modalities. The manual was produced with the goal of enabling clinicians specialized in respiratory apparatus to handle these diseases in clinical settings and of further advancing future research and treatment.

Exploratory Study of the Effectiveness of Granulocyte and Monocyte Adsorptive Apheresis Before Initiation of Steroids in Patients with Active Ulcerative Colitis During the COVID-19 Outbreak (EXPECT Study): A Multicenter Prospective Clinical Trial

Background: During the COVID-19 pandemic, safe treatment of inflammatory bowel disease is required. Granulocyte and monocyte adsorptive apheresis (GMA) has been used for therapy of steroid-dependent/refractory ulcerative colitis (UC) with few adverse events. Therefore, elucidating the effectiveness of GMA without steroids is important in the current situation. The aim of this study was to investigate the effectiveness of GMA in active UC patients who are not receiving steroids. Methods: A single-arm, open-label, and multicenter prospective clinical trial was conducted at ten facilities in Japan.UC patients who had insufficient responses to 5-aminosalicylic acid without steroids received GMA twice a week for five consecutive weeks. The primary and secondary endpoints were the induction of a response and endoscopic mucosal healing in the patients who achieved a response. Findings: A total of 67 patients were enrolled. The response rate of all patients who received GMA ten times was 58·2%. Of the 39 patients who achieved a response, 74·4% achieved endoscopically confirmed mucosal healing. Both the median Mayo score and ulcerative colitis endoscopic index of severity score were significantly decreased in the patients who achieved a response. The response rate of the patients who were suffering from their first episode was significantly higher than that of those with relapse-remitting UC (80·0% [16/20] vs. 48·9% [23/47], p=0·029). Undergoing the first episode of UC (odds ratio [OR]: 4·952, 95% confidence interval [CI]: 1·292-18·981, p>0.001) was defined as an independent predictor of a response. Interpretation: This study strongly suggest that GMA shows promising effectiveness in inducing remission in active UC patients who are not receiving steroid treatment. We expect that GMA can be made available during the COVID-19 pandemic. Trial Registration: UMIN registration No. 000013702 Funding Statement: Health and Labor Sciences Research Grants from the Ministry of Health, Labor and Welfare of Japan (Investigation and Research for intractable Inflammatory Bowel Disease to HN). Declaration of Interests: MM reports personal fees from Janssen Pharmaceutical K.K., and commercial research funding from AbbVie GK. and Nippon Kayaku Co., Ltd. SN reports receiving personal fees from EA Pharma Co., Ltd., AbbVie GK., Mitsubishi Tanabe Pharma Corporation, Janssen Pharmaceutical K.K., Mochida Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd. KH reports receiving research funding from EA Pharma Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Takeda Pharmaceutical Co., Ltd. HN reports receiving personal fees from AbbVie GK., Kissei Pharmaceutical Co., Ltd., Kyorin Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Janssen Pharmaceutical K.K., Takeda Pharmaceutical Co., Ltd., Pfizer Lnc., Cell gene Corporation., EA Pharma Co., Ltd., Zeria Pharmaceutical CO., Ltd., Mochida Pharmaceutical Co., Ltd., Nippon Kayaku Co., Ltd., Daiichi Sankyo Company, Limited., JIMRO Co., Ltd., as well as grants for commissioned/joint research from Hoya Group Pentax Medical, Boehringer Ingelheim GmbH, Bristol-Myers Squibb Company. All other authors declare no competing interests. Ethics Approval Statement: The protocol of the clinical trial was approved by the IRB at each institution. Informed consent to participate in the study was obtained from each participant before inclusion.

Evidence-based diagnosis and clinical practice guidelines for intestinal Beh\xe7et\u2019s disease 2020 edited by Intractable Diseases, the Health and Labour Sciences Research Grants

Behçet's disease (BD) is an intractable systemic inflammatory disease characterized by four main symptoms: oral and genital ulcers and ocular and cutaneous involvement. The Japanese diagnostic criteria of BD classify intestinal BD as a specific disease type. Volcano-shaped ulcers in the ileocecum are a typical finding of intestinal BD, and punched-out ulcers can be observed in the intestine or esophagus. Tumor necrosis factor inhibitors were first approved for the treatment of intestinal BD in Japan and have been used as standard therapy. In 2007 and 2014, the Japan consensus statement for the diagnosis and management of intestinal BD was established. Recently, evidence-based JSBD (Japanese Society for BD) Clinical Practice Guidelines for BD (Japanese edition) were published, and the section on intestinal BD was planned to be published in English. Twenty-eight important clinical questions (CQs) for diagnosis (CQs 1–6), prognosis (CQ 7), monitoring and treatment goals (CQs 8–11), medical management and general statement (CQs 12–13), medical treatment (CQs 14–22), and surgical treatment (CQs 23–25) of BD and some specific situations (CQs 26–28) were selected as unified consensus by the members of committee. The statements and comments were made following a search of published scientific evidence. Subsequently, the levels of recommendation were evaluated based on clinical practice guidelines in the Medical Information Network Distribution Service. The degree of agreement was calculated using anonymous voting. We also determined algorithms for diagnostic and therapeutic approaches for intestinal BD. The present guidelines will facilitate decision making in clinical practice.

Hematopoietic Stem-Cell Senescence and Myocardial Repair: Coronary Artery Disease Genotype/Phenotype Analysis of Post-MI Myocardial Regeneration Response Induced by CABG/CD133+ Bone Marrow Hematopoietic Stem Cell Treatment in RCT PERFECT Phase 3

Objective: Clonal hematopoiesis with mutational gene dysregulation of hematopoietic stem cell (HSC) precursors for immune or endothelial progenitor cell response is suspected to affect coronary artery disease bypass surgery (CABG) induced ischemic myocardial repair. Design: Transcriptome and variant expression analysis was studied in the phase 3 PERFECT (post MI CABG and CD133 + BMSC or Placebo) trial in myocardial regeneration responders (R, n=14; ∆LVEF +16% day 180/0) and non-responders (NR, n=9; ∆LVEF -1∙1% day 180/0), then validated in independent patient cohort (n=14) as well as under mouse SH2B3/LNK antisense or knockout deficient conditions. Findings: 1. Left ventricular functional recovery was accompanied by an increase in myocardial perfusion (R vs NR, p<0∙05). R differed from NR in a total of 161 genes in differential expression (n=23, q<0,05) and 872 genes in coexpression analysis (n=23, q<0,05). Machine Learning clustering analysis revealed distinct R vs NR preoperative gene-expression signature in peripheral blood. RvsNR ML-top selected genes were correlated to SH2B3 (p<0∙05). Mutation signature analysis performed by RNASeq revealed increased specific variants in NR vs R. (NR: 224 genes with 268 exon regions; R: 48 genes with 56 exon regions). 2. RvsNR ML-selected gene expression and phenotype was correlated to SH2B3 deficient mouse models. Competitive bone-marrow transplanted mice SH2B3/LNK silenced HSC clones displayed significant overgrowth of myeloid and immune cells in bone marrow, peripheral blood and tissue at day 160 after BMT. SH2B3/LNK-/- mice demonstrated enhanced cardiac repair through augmenting the kinetics of BM-derived EPCs, increased capillary density in ischemic myocardium and reduced left ventricular fibrosis with preserved cardiac function. 3. Validation analysis in 14 additional patients revealed 85% R vs NR prediction accuracy. Interpretation: Myocardial repair is affected by HSC gene response. Somatic mutation in adaptor proteins may alter response by clonal overgrowth as shown for SH2B3/LNK. ML guided predictions can be utilized to identify and predict pathological HSC response. Trial Registration: ClinicalTrials.gov NCT00950274 Funding Statement: German Ministry of Research and Education (BMBF): FKZ0312138A, FKZ031L0106C, EU ESF/IV-WM-B34-0011/08, ESF/IV-WM-B34-0030/10, and Miltenyi Biotec GmbH, Bergisch-Gladbach, Germany. Japanese Ministry of Health : Health and Labour Sciences Research Grant (H14-trans-001, H17-trans-002) Declaration of Interests: All authors declare no competing interests. Ethics Approval Statement: Approval by the Ethical committee, Rostock University Medical Center 2009; No. HV-2009-0012.

Clinical practice guidance for juvenile dermatomyositis (JDM) 2018-Update

Juvenile dermatomyositis is the most common type of juvenile idiopathic inflammatory myopathy mainly affecting the skin and proximal muscles. We have published the Japanese version of ‘Clinical practice guidance for juvenile dermatomyositis (JDM) 2018 ‘consisting of a review of articles in the field and evidence-informed consensus-based experts’ opinion on the treatment strategy in collaboration with The Pediatric Rheumatology Association of Japan and The Japan College of Rheumatology under the financial support by ‘Research on rare and intractable diseases, Health and Labor Sciences Research Grants’. This article is a digest version of the Japanese guidance.

Causal Effect of Physical Activity on Reducing the Risk of Dementia: Instrumental Variable Analysis Using 2013-16 Cohort Data from JAGES

Background: To examine the causal effect of physical activity on the risk of dementia, we conducted competing-risks survival analysis using the instrumental variable (IV) method. Residency in a snowy area was treated as an IV for frequency of physical activity. We obtained prospective cohort data from the Japan Gerontological Evaluation Study (JAGES). Methods: The baseline study was conducted in 23 municipalities in Japan from October to December 2013. Participants included 97,821 individuals aged 65 or older who completed the JAGES and were physically and cognitively independent at baseline. The incidence of dementia was ascertained by linking to registries of public long-term care insurance through 2016. During the mean follow-up of 3·2 years, we ascertained the incidence of dementia in 4,633 cases (4·7%). Findings: Through IV estimation, we found protective effects of physical activity at various levels of intensity on the risk of dementia: vigorous intensity (sub-distribution hazard ratio 0·62, 95% confidence interval 0·49 to 0·78), moderate intensity (0·69, 0·60 to 0·79), and light intensity (0·56, 0·47 to 0·68). Interpretations: Physical activity should be recommended for older adults to reduce the risk of dementia. Funding Statement: This study used data from the Japan Gerontological Evaluation Study (JAGES), which was supported by JSPS(Japan Society for the Promotion of Science) KAKENHI Grant Number (JP15H01972), Health Labour Sciences Research Grant (H28-Choju-Ippan-002), Japan Agency for Medical Research and Development (AMED) (JP17dk0110017, JP18dk0110027, JP18ls0110002, JP18le0110009), the Research Funding for Longevity Sciences from National Center for Geriatrics and Gerontology (29-42). Declaration of Interests: The authors state there are no conflicts of interest to declare. Ethics Approval Statement: This study was reviewed and approved by ethics committees at the University of Tokyo, Nihon Fukushi University, National Center for Geriatrics and Gerontology, and Chiba University.

1440PD - JIPANG study: Randomized phase III study of pemetrexed/cisplatin (PEM/Cis) versus vinorelbine /cisplatin (VNR/Cis) for completely resected p-stage II-IIIA non-squamous non-small cell lung cancer (Ns-NSCLC): Outcomes based on EGFR mutation status

BackgroundThe VNR/Cis chemotherapy doublet has been evaluated in prior positive adjuvant trials in patients with completely resected Ns-NSCLC, whereas no phase III study has so far evaluated PEM/Cis in this population. And there are few data regarding outcomes based on EGFR mutation (EGFRm) status in adjuvant chemotherapies. MethodsPatients with completely resected Ns-NSCLC were randomized in a 1:1 ratio to receive either PEM (500mg/m2, day 1)/Cis (75mg/m2, day 1) or VNR (25mg/m2, days 1 and 8)/Cis (80mg/m2, day 1), and stratified according to sex, age, pathologic stage, EGFRm status and institution. The primary endpoint was recurrence-free survival (RFS), and, the planned sample size was 800 patients in total (Trial Identifier, UMIN000006737). ResultsBetween March 2012 and August 2016, 804 patients were randomized. Of 784 for the efficacy analysis (389 in PEM/Cis and 395 in VNR/Cis), median age was 65/65 years; stage IIIA 52.2%/52.4%; adenocarcinoma, 95.9%/95.9%; and EGFR mutation, 24.1%/24.9%. With a median follow-up of 45.2 months (mo), median RFS was 38.9mo in PEM/Cis and 37.3mo in VNR/Cis with a hazard ratio (HR) of 0.98 (95% CI, 0.81--1.20; log-rank test, P=0.948), whereas HRs in patients with or without EGFRm were 1.38 (95% CI, 0.95--1.99) and 0.87 (95% CI, 0.69--1.09), respectively (Interaction, P=0.046). As for patients without EGFRm, median RFS was 65.2mo in PEM/Cis and 39.9mo in VNR/Cis. The overall survival rate at 3 years was 83.5% versus 87.2% with a HR of 0.98 (95% CI, 0.71 --1.35). Rates of treatment completion were 87.9% (PEM/Cis) and 72.7% (VNR/Cis), respectively (P<0.001). Incidences of grade 3 or 4 febrile neutropenia (11.6/0.3%, P<0.001), neutropenia (81.1/22.8%, P<0.001), and anemia (9.3/2.8%, P<0.001); any grade alopecia (30.1/12.8%, P<0.001). ConclusionsAlthough this phase III study did not meet the primary endpoint, PEM/CDDP had a similar efficacy to VNR/CDDP with a better tolerability as postoperative adjuvant chemotherapy for Ns-NSCLC patients. A significant interaction for RFS was found between treatment and EGFR mutation status. In patients without EGFR mutation, PEM/Cis seems to be a preferable regimen as the adjuvant chemotherapy. Clinical trial identificationUMIN000006737. Legal entity responsible for the studyThe authors. FundingHealth and Labor Sciences Research Grants, The Japan Agency of Medical Research and Development (AMED). DisclosureM. Tsuboi: Honoraria (self): AstraZeneca KK; Honoraria (self): Johnson & Johnson Japan; Honoraria (self): MSD; Honoraria (self): Chugai Pharmaceutical Co., Ltd.; Honoraria (self): Taiho Pharma; Honoraria (self): Eli Lilly Japan; Honoraria (self): Boehringer Ingelheim Japan; Honoraria (self): Ono Pharmaceutical Co., Ltd; Honoraria (self): Bristol-Myers Squibb KK; Honoraria (self): Daiichi-Sankyo; Honoraria (self): Covidien Japan; Honoraria (self): Teijin Pharma; Research grant / Funding (institution): Boehringer Ingelheim Japan. All other authors have declared no conflicts of interest.

CN37 - Estimation of HPQ-based absenteeism and presenteeism in cancer patients via ResearchKit

BackgroundAbsenteeism and presenteeism (A/P) are scales related to health problems and professional activity in patients and in healthy individuals. For cancer patients in the age of maximum labor productivity (18 to 65 years old), A/P are possibly affected by quality of care, type of cancer, and selection of treatments. The objectives of this study were to clarify via questionnaire the association between quality-of-life (QOL) and A/P, as well as the changes of A/P during clinical course in cancer patients. MethodsA/P were measured using the validated Japanese version of the World Health Organization Health and Work Performance Questionnaire (WHO-HPQ). QOL was measured using the 5-level EQ-5D version via a portable device with the Apple ResearchKit app. ResultsWe received 3983 survey results (healthy individuals, 297; cancer patients, 3686). Presenteeism was clearly different between cancer patients and healthy individuals (absolute/relative presenteeism: 59.3/0.93 and 65.8/1.01, respectively). Examination of the relationship between QOL and A/P using Spearman’s rank correlation coefficient analysis indicated that QOL is significantly correlated with relative presenteeism (r=0.40, P<0.001). The labor performance of pancreatic carcinoma patients was low (absolute/relative absenteeism: 68.7/0.29, absolute/relative presenteeism: 43.8/0.68). The A/P in patients with receiving chemotherapy were not maintained compared to in patients receiving surgical treatment (absolute/relative absenteeism: 39/8/0.16 vs. 17.8/0.02, p=0.04, absolute/relative presenteeism: 55.5/0.83 vs. 62.8/0.95, p<0.001, respectively). ConclusionsWHO-HPQ can be used to measure the labor performance in cancer patients. Moreover, A/P was strongly affected by type of cancers and selection of treatments. Legal entity responsible for the studyShunsuke Kondo. FundingProject Mirai Cancer Research Grants and Health Labour Sciences Research Grant. DisclosureAll authors have declared no conflicts of interest.

Mucin O-glycans facilitate symbiosynthesis to maintain gut immune homeostasis.

BackgroundThe dysbiosis of gut microbiota has been implicated in the pathogenesis of inflammatory bowel diseases; however, the underlying mechanisms have not yet been elucidated. Heavily glycosylated mucin establishes a first-line barrier against pathogens and serves as a niche for microbial growth.MethodsTo elucidate relationships among dysbiosis, abnormal mucin utilisation, and microbial metabolic dysfunction, we analysed short-chain fatty acids (SCFAs) and mucin components in stool samples of 40 healthy subjects, 49 ulcerative colitis (UC) patients, and 44 Crohn's disease (CD) patients from Japan.FindingsLevels of n-butyrate were significantly lower in stools of both CD and UC patients than in stools of healthy subjects. Correlation analysis identified seven bacterial species positively correlated with n-butyrate levels; the major n-butyrate producer, Faecalibacterium prausnitzii, was particularly underrepresented in CD patients, but not in UC patients. In UC patients, there were inverse correlations between mucin O-glycan levels and the production of SCFAs, such as n-butyrate, suggesting that mucin O-glycans serve as an endogenous fermentation substrate for n-butyrate production. Indeed, mucin-fed rodents exhibited enhanced n-butyrate production, leading to the expansion of RORgt+Treg cells and IgA-producing cells in colonic lamina propria. Microbial utilisation of mucin-associated O-glycans was significantly reduced in n-butyrate-deficient UC patients.InterpretationMucin O-glycans facilitate symbiosynthesis of n-butyrate by gut microbiota. Abnormal mucin utilisation may lead to reduced n-butyrate production in UC patients.FundJapan Society for the Promotion of Science, Health Labour Sciences Research Grant, AMED-Crest, AMED, Yakult Foundation, Keio Gijuku Academic Development Funds, The Aashi Grass Foundation, and The Canon Foundation.