Published papers

Current molecular quantitative trait locus catalogs are mostly at bulk resolution and centered on Europeans. Here, we constructed an immune cell atlas with single-cell transcriptomics of >1.5 million peripheral blood mononuclear cells, host genetics, plasma proteomics and gut metagenomics from 235 Japanese persons, including patients with coronavirus disease 2019 (COVID-19) and healthy individuals. We mapped germline genetic effects on gene expression within immune cell types and across cell states. We elucidated cell type- and context-specific human leukocyte antigen (HLA) and genome-wide associations with T and B cell receptor repertoires. Colocalization using dynamic genetic regulation provided better understanding of genome-wide association signals. Differential gene and protein expression analyses depicted cell type- and context-specific effects of polygenic risks. Various somatic mutations including mosaic chromosomal alterations, loss of Y chromosome and mitochondrial DNA (mtDNA) heteroplasmy were projected into single-cell resolution. We identified immune features specific to somatically mutated cells. Overall, immune cells are dynamically regulated in a cell state-dependent manner characterized with multiomic profiles.

Abstract Understanding the factors that influence people’s decisions regarding vaccination is essential to promote vaccination. We aimed to clarify the motivations for receiving booster vaccines. We conducted a paper-based questionnaire distributed during January–February 2022 involving students and faculty staff who received the first COVID-19 vaccination at the mass vaccination program during June–September 2021 at Keio University. A total of 1725 participants were enrolled, and all completed the survey. Among these, 64.9% reported a significant adverse event (AEs) affecting daily life after the second vaccine. “Fear of severe COVID-19 illness” (72.6%) was the most common reason for getting vaccinated, followed by “concern of infecting others” (68.4%) and “fear of COVID-19 infection itself” (68.3%). Television emerged as the most influential source of information (80%), followed by university information (50.2%) and social networking sites (42.8%). Multivariate analysis revealed “fear of severe COVID-19 illness”, “fear of COVID-19 infection itself”, and “trust in the efficacy and safety of the vaccines in general” were significantly correlated with willingness to receive paid vaccinations. The severity of AEs and source of information were not related to participants’ willingness to receive booster vaccinations. Participants with positive reasons for vaccination were more likely to accept a third dose.

Objectives Approximately half of Japanese men aged 20–49 years have purchased sexual services, but data concerning the use of commercial sex work (CSW) in Japan remain scarce. Methods We used online survey data from the National Inventory of Japanese Sexual Behavior conducted in 2022 (N=4000 Japanese men aged 20–49 years). We calculated the median number of paid sexual partners over the lifetime. We performed logistic regression analysis to determine the sociodemographic, anthropometric and attitudinal factors associated with any lifetime CSW use among men in Japan. Results The median number of paid sexual partners reported among men who had ever used CSW was 6 (IQR 3–17) across the lifetime; the corresponding value for those who had ever used CSW in the past year was 2 (IQR 1–4) over the last 12 months. In general, those reporting lifetime use of CSW were significantly more likely than their CSW-naïve counterparts to be older, be married, be heterosexual or bisexual, have higher income and have higher education. Those reporting higher self-rated attractiveness, high or low satisfaction with their sex lives, a desire to increase their frequency of sex and considering sex to be an important aspect of their lives were also found to have a higher likelihood of having used CSW. Conclusions High rates of CSW use in Japan likely reflect ease of access, low stigma with respect to use of sexual services and the diversity in the type of services offered. High-income, employed older men have more financial resources at their disposal to purchase services, which can be cost-prohibitive for part-time or unemployed young men with low incomes. These findings will serve as a launchpad for public health efforts directed at promoting safe sexual practices and improved sexually transmitted infection screening rates among users of CSW in Japan.

Fallopian tube carcinoma is frequently detected at an advanced stage, and its imaging findings and tumor marker profiles are often indistinguishable from those of ovarian or peritoneal carcinoma. Nontuberculous mycobacteria (NTM) are environmental acid-fast bacilli with increasing clinical significance in both immunocompromised and immunocompetent individuals. Infection of gynecologic organs is extremely rare. This report describes a case of fallopian tube NTM infection caused by Mycobacterium abscessus that mimicked fallopian tube carcinoma. An 87-year-old woman underwent fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) during routine surveillance, which revealed focal FDG uptake in the right adnexal region. Serum CA125 was elevated, and magnetic resonance imaging demonstrated findings suspicious for fallopian tube carcinoma. Primary debulking surgery was performed. Intraoperative frozen-section examination of the right adnexa revealed necrotizing granulomas without evidence of malignancy, raising suspicion of mycobacterial infection. Fresh specimens were submitted for microbiological evaluation. Culture identified Mycobacterium abscessus, establishing the diagnosis of fallopian tube NTM infection. The patient was asymptomatic and had no abscess formation. Complete surgical resection was achieved, and no antimicrobial therapy was administered. The patient remained recurrence-free at 1-year follow-up. This case highlights the difficulty of differentiating infectious granulomatous disease from malignancy based on imaging findings alone. Intraoperative frozen-section examination played a crucial role in prompting microbiological investigation and establishing the correct diagnosis.

Aggregatibacter actinomycetemcomitans is well-known as the pathogen of gingivitis or periodontitis, and discitis or vertebral osteomyelitis cases caused by this organism have rarely been reported. Ampicillin or amoxicillin has been used in the previously reported discitis cases however, no cases have been reported that is treated with levofloxacin. We report the first published case we chose levofloxacin to treat. We failed to perform the susceptibility testing because of the poor growth and fastidious nature of the organism, and the result of susceptibility of amoxicillin was unclear. Levofloxacin, which A. actinomycetemcomitans is usually susceptible to, can be an effective alternative oral antimicrobial agent in such cases.

PURPOSE: In 2021, we introduced a new simulation-based learning program focusing on a roleplay conference before patient discharge. This study aimed to evaluate the program's effectiveness and highlight the significance of cross-training in interprofessional education (IPE). METHODS: In September 2023, the program included 346 students (98 medical, 110 nursing, and 138 pharmacy students). The students' reflective writing was analyzed using inductive content analysis to describe their learning and perspectives. The original items, subcategories, and main categories were extracted. The simulation involved the students role-playing various healthcare professionals during a discharge-planning conference for a stroke patient. This allowed them to experience the challenges and dynamics of interprofessional collaboration. RESULTS: Student feedback emphasized the importance of understanding what constitutes a good healthcare team. A total of 203 items were grouped into eight main categories and 17 subcategories, including patient-centered care (related to the importance of patient-centered care, supporting patient decision-making, communicating with patients during conferences, and facilitating decision-making processes), contrasts in patient and interprofessional communication, conference communication (challenge of building consensus, the way to proceed conferences, importance of conference preparation, and process of information aggregation and realization of outcomes), mutual recognition and role contribution, building relationships (importance of daily interprofessional communication), understanding one's profession (reflection on one's own profession, understanding the roles of different professions, and communication within one's own professional context), recursion into learning (motivation for continuous learning and improvement), and understanding other professions (understanding the role and perspectives of other professions and recognizing professional differences). Specific feedback highlighted improved empathy and communication skills. Students recognized the value of each profession's contribution to patient care. Moreover, students reported a deeper appreciation of patient-centered approaches and the complexities of coordinating care across different healthcare roles. CONCLUSION: Simulated interprofessional team conferences using cross-training effectively taught junior students to understand the essence of a good healthcare team and the importance of a patient-centered approach. Cross-training significantly enhanced students' interprofessional competencies, communication skills, and empathy toward other professions. This case underscores the necessity of incorporating cross-training into IPE to prepare healthcare professionals for collaborative practice and improve patient outcomes. Future research should consider expanding the scope to include more diverse scenarios and longitudinal assessments to measure long-term impacts on professional practice.

SARS-CoV-2 whole-genome sequencing of samples from COVID-19 patients is useful for informing infection control. Datasets of these genomes assembled from multiple hospitals can give critical clues to regional or national trends in infection. Herein, we report a lineage summary based on data collected from hospitals located in the Tokyo metropolitan area. We performed SARS-CoV-2 whole-genome sequencing of specimens from 198 patients with COVID-19 at 13 collaborating hospitals located in the Kanto region. Phylogenetic analysis and fingerprinting of the nucleotide substitutions were performed to differentiate and classify the viral lineages. More than 90% of the identified strains belonged to Clade 20B, which has been prevalent in European countries since March 2020. Only two lineages (B.1.1.284 and B.1.1.214) were found to be predominant in Japan. However, one sample from a COVID-19 patient admitted to a hospital in the Kanto region in November 2020 belonged to the B.1.346 lineage of Clade 20C, which has been prevalent in the western United States since November 2020. The patient had no history of overseas travel or any known contact with anyone who had travelled abroad. Consequently, the Clade 20C strain belonging to the B.1.346 lineage appeared likely to have been imported from the western United States to Japan across the strict quarantine barrier. B.1.1.284 and B.1.1.214 lineages were found to be predominant in the Kanto region, but a single case of the B.1.346 lineage of clade 20C, probably imported from the western United States, was also identified. These results illustrate that a decentralized network of hospitals offers significant advantages as a highly responsive system for monitoring regional molecular epidemiologic trends.

INTRODUCTION: Clarithromycin (CAM), ethambutol (EB), and rifampicin (RFP) combination therapy is used to treat pulmonary Mycobacterium avium complex (MAC) infection; however, serum CAM concentration decreases due to RFP-mediated induction of CYP3A activity. Therefore, we investigated the pharmacokinetics of CAM, 14-hydroxy clarithromycin (14-OH CAM), EB, and RFP in patients receiving this three-drug combination therapy. METHODS: CAM monotherapy was started, EB was added 2 weeks later, and RFP was added 2 weeks after that. Serum CAM, 14-OH CAM, EB, and RFP concentrations were measured before and at 2, 4, 6, and 12 or 24 h after administration on days 14, 28, and 42, and pharmacokinetic parameters were calculated. RESULTS: Median area under the curve (AUC) of CAM decreased by 92.1% from 0 to 12 h after concomitant administration of RFP compared with CAM monotherapy [1.7 (interquartile range [IQR], 1.4-1.8) μg·h/mL vs. 21.5 (IQR, 17.7-32.3) μg·h/mL, respectively]. In contrast, median AUC of 14-OH CAM was not significantly different between concomitant administration of RFP [9.1 (IQR, 7.9-10.9) μg·h/mL] and CAM monotherapy [8.2 (IQR, 6.3-9.3) μg·h/mL]. AUCs of CAM and 14-OH CAM did not change in CAM+EB combination therapy. CONCLUSIONS: When RFP is combined with CAM in the treatment of pulmonary MAC infection, the blood concentration of CAM significantly decreased and that of the active metabolite 14-OH CAM increased, but not significantly. Our results suggest that combination therapy with CAM and RFP needs to be reconsidered and may require dose modification in the treatment of pulmonary MAC infection.

BACKGROUND: Nontuberculous mycobacterial (NTM) lung disease is one of a growing number of chronic health problems that is difficult to cure in aging societies. While it is important to be vigilant about associated comorbidities in order to provide better patient care, data on the prevalence of comorbidities stratified by country or region are scarce. We aimed to elucidate the comorbidities associated with NTM disease based on Japanese health insurance claims data. METHODS: Cross-sectional analyses were performed using the claims data for 2014 provided by the Japan Medical Data Center Co., Ltd. Patients aged 20-75 years with ≥3 claims associated with NTM disease were identified and matched to 10 sex-and-age-matched controls that had never made a claim for NTM disease. Thirty-one comorbidities previously suspected to be associated with NTM disease were selected, and the prevalence of these comorbidities compared between cases and controls. RESULT: Overall, 419 NTM patients (134 males and 285 females) and 4190 non-NTM controls were identified from the JMDC database. Aspergillosis, asthma, chronic heart failure, diffuse panbronchiolitis, gastroesophageal reflux, interstitial pneumonia, lung cancer, cancer other than breast, lung, ovary, or prostate cancer, and rheumatoid arthritis were associated with NTM disease in both males and females. Chronic obstructive pulmonary disease was associated with NTM in males while chronic kidney disease, osteoporosis, and Sjögren syndrome were associated with NTM in females. CONCLUSION: NTM disease was associated with multiple comorbidities that should be considered when providing medical care to individuals with NTM disease.

Background: Nosocomial spread of coronavirus disease 2019 (COVID-19) causes clusters of infection among high-risk individuals. Controlling this spread is critical to reducing COVID-19 morbidity and mortality. We describe an outbreak of COVID-19 in Keio University Hospital, Japan, and its control and propose effective control measures. Methods: When an outbreak was suspected, immediate isolation and thorough polymerase chain reaction (PCR) testing of patients and health care workers (HCWs) using an in-house system, together with extensive contact tracing and social distancing measures, were conducted. Nosocomial infections (NIs) were defined as having an onset or positive test after the fifth day of admission for patients and having high-risk contacts in our hospital for HCWs. We performed descriptive analyses for this outbreak. Results: Between March 24 and April 24, 2020, 27 of 562 tested patients were confirmed positive, of whom 5 (18.5%) were suspected as NIs. For HCWs, 52 of 697 tested positive, and 40 (76.9%) were considered NIs. Among transmissions, 95.5% were suspected of having occurred during the asymptomatic period. Large-scale isolation and testing at the first sign of outbreak terminated NIs. The number of secondary cases directly generated by a single primary case found before March 31 was 1.74, compared with 0 after April 1. Only 4 of 28 primary cases generated definite secondary infection; these were all asymptomatic. Conclusions: Viral shedding from asymptomatic cases played a major role in NIs. PCR screening of asymptomatic individuals helped clarify the pattern of spread. Immediate large-scale isolation, contact tracing, and social distancing measures were essential to containing outbreaks.

INTRODUCTION: In the novel coronavirus disease (COVID-19) pandemic era, it is essential to rule out COVID-19 effectively to prevent transmission in both communities and medical facilities. According to previous reports in high prevalence areas, CT screening may be useful in the diagnosis of COVID-19. However, the value of CT screening in low prevalence areas has scarcely been reported. METHODS: This report examines the diagnostic efficacy of CT screening before admission to a hospital in Tokyo. We conducted a retrospective analysis at Keio University Hospital from April 6, 2020, through May 29, 2020. We set up an outpatient screening clinic on April 6 for COVID-19, administering both PCR with nasopharyngeal swabs and chest CT for all patients scheduled for surgery under general anesthesia. RESULTS: A total of 292 asymptomatic patients were included in this study. There were three PCR-positive patients, and they all had negative CT findings, which revealed that both the sensitivity and positive predictive value of CT (PPV) were 0%. There were nine CT-positive patients; the specificity and the negative predictive value (NPV) were 96.9% and 98.9%, respectively. CONCLUSION: CT screening was not useful in low prevalence areas at this time in Tokyo, even with the inclusion of the most prevalent phase. Given that the utility of CT screening depends on disease prevalence, the criteria for performing CT screening based on the prevalence of COVID-19 should be established.

Patients with vancomycin-resistant Enterococcus (VRE) colonization should be managed in an isolation room with contact precautions. We herein report a patient whose colorectal carriage of VRE was successfully decolonized using concomitant bowel irrigation with polyethylene glycol, probiotics, and oral antimicrobials, linezolid and orally-administered daptomycin, for release from isolation and contact precautions. We therefore would like to suggest a potential strategy for managing patients with VRE colonization.