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Abstract Background Biliary atresia (BA) is an intractable disease of unknown cause that develops in the neonatal period. It causes jaundice and liver damage due to the destruction of extrahepatic biliary tracts,. We have found that heterozygous knockout mice of the SRY related HMG-box 17 (Sox17) gene, a master regulator of stem/progenitor cells in the gallbladder wall, exhibit a condition like BA. However, the precise contribution of hypoplastic gallbladder wall to the pathogenesis of hepatobiliary disease in Sox17 heterozygous embryos and human BA remains unclear. Methods We employed cholangiography and histological analyses in the mouse BA model. Furthermore, we conducted a retrospective analysis of human BA. Results We show that gallbladder wall hypoplasia causes abnormal multiple connections between the hilar hepatic bile ducts and the gallbladder-cystic duct in Sox17 heterozygous embryos. These multiple hilar extrahepatic ducts fuse with the developing intrahepatic duct walls and pull them out of the liver parenchyma, resulting in abnormal intrahepatic duct network and severe cholestasis. In human BA with gallbladder wall hypoplasia (i.e., abnormally reduced expression of SOX17), we also identify a strong association between reduced gallbladder width (a morphometric parameter indicating gallbladder wall hypoplasia) and severe liver injury at the time of the Kasai surgery, like the Sox17-mutant mouse model. Conclusions Together with the close correlation between gallbladder wall hypoplasia and liver damage in both mouse and human cases, these findings provide an insight into the critical role of SOX17-positive gallbladder walls in establishing functional bile duct networks in the hepatic hilus of neonates.

Abstract This was the first longitudinal study to analyze dental clinic wastewater to estimate asymptomatic SARS-CoV-2 infection trends in children. We monitored wastewater over a 14-month period, spanning three major COVID-19 waves driven by the Alpha, Delta, and Omicron variants. Each Saturday, wastewater was sampled at the Pediatric Dental Clinic of the only dental hospital in Japan’s Saitama Prefecture. The relationship between the weekly number of cases in Saitama Prefecture among residents aged

Abstract The study aimed to examine the association of expanded adverse childhood experiences (ACEs) with psychological distress in adulthood. The data from nation-wide online cohort was used for analysis. Community dwelling adults in Japan were included. The ACEs was assessed by 15 items of ACE-J, including childhood poverty and school bullying. Severe psychological distress was determined as the score of Kessler 6 over 13. Multivariable logistic regression analysis was conducted, by using sample weighting. A total of 28,617 participants were analyzed. About 75% of Japanese people had one or more ACEs. The prevalence of those with ACEs over 4 was 14.7%. Those with ACEs over 4 showed adjusted odds ratio = 8.18 [95% CI 7.14–9.38] for severe psychological distress. The prevalence of childhood poverty was 29% for 50–64 year old participants and 40% of 65 or older participants. The impact of childhood poverty on psychological distress was less than other ACEs in these age cohorts. Bullying was experienced 21–27% in young generations, but 10% in 65 or older participants. However, the impact on psychological distress in adulthood was relatively high in all age groups. ACEs have impacted mental health for a long time. Future research and practice to reduce ACEs are encouraged.

Abstract Background Recent advancements in and the proliferation of autonomous mobility technology, such as intelligent wheelchairs, have made it possible to provide mobility services for patients with reduced mobility due to musculoskeletal disorders. In the present study, we conducted a preliminary clinical study to assess the safety and feasibility of in-hospital autonomous transportation using a driverless mobility (wheelchair) for patients with musculoskeletal disorders. Methods From January to February 2022, 51 patients with musculoskeletal disorders exhibiting gait disturbance who presented to our institution were included in the present study. Driverless mobility rides were conducted over a straight-line distance of 100 m from the orthopaedic outpatient reception to the payment counter after the outpatient consultation. We assessed the quality of life using an EQ-5D-5 L index and pain using a VAS score before riding the mobility to investigate the patient’s condition. After the ride, a questionnaire survey was conducted to assess patient satisfaction on a 5-point scale. In addition, adverse events during the mobility ride were investigated. Results Overall satisfaction levels showed that 44 out of 51 (86%) patients rated the level as 3 or higher. There were no significant differences in the level of satisfaction based on the cause of disorders or EQ-5D-5 L Index. Among 19 patients who rated the level of satisfaction as 2–3, the ratio of postoperative patients and those with pain tended to be higher (p

A basic helix-loop-helix transcription factor, figα, is one of the earliest marker genes of oocyte differentiation in vertebrates. In the present study, we made figα knockout medaka by CRISPR/Cas9, expecting aborted progress of oogenesis, to see if differentiation of somatic ovarian tissues is affected. Figα knockout male gonads differentiated normally into testes with functional sperm. The females, on the other hand, were sterile; there are oocytes only up to pachytene. No growing oocytes in diplotene were found. The phenotype was already apparent at 10 days after hatching, when diplotene oocytes start to develop in the control. Furthermore, several putative target genes of figα were not expressed in the mutant female gonads. Previous studies showed that medaka lacking germ cells have morphologically abnormal gonads and female to male sex reversal occurred. Figα knockout female gonads differentiated morphologically into ovaries, suggesting that in medaka, figα knockout prevents oogenesis progress into diplotene stage, and ovarian differentiation do not need developed oocytes beyond pachytene stage. This ovarian phenotype reminded us of ''pachytene checkpoint'', which blocks meiotic progress into diplotene when chromosomal abnormalities are present. Therefore, we further analyzed phenotype of oocytes in the mutant ovaries. The number of oocytes at each meiotic stage suggested that oogenesis normally proceeded up to pachytene stage. The number of apoptotic oocytes in the knockout ovaries was small. Finally, we did not detect any abnormal pairings or unrepaired double-strand breaks by immunostaining. Taken together, figα knockout likely stop oocyte growth at or around pachytene via unknown mechanisms other than ''pachytene checkpoint'' and arrested oocytes remained in the ovary. This is in contrast to figα knockout mice where all oocytes underwent apoptosis quickly after birth.

Abstract Background Community-level group sports participation is a structural aspect of social capital that can potentially impact individual health in a contextual manner. This study aimed to investigate contextual relationship between the community-level prevalence of group sports participation and the risk of all-cause, cardiovascular disease (CVD), and cancer mortality in older adults. Methods In this 7-year longitudinal cohort study, data from the Japan Gerontological Evaluation Study, a nationwide survey encompassing 43,088 functionally independent older adults residing in 311 communities, were used. Cause of death data were derived from the Japanese governmental agency, The Ministry of Health, Labour and Welfare, for secondary use. “Participation” was defined as engaging in group sports for one or more days per month. To analyze the data, a two-level survival analysis was employed, and hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated. Results Among the participants, 5,711 (13.3%) deaths were identified, with 1,311 related to CVD and 2,349 to cancer. The average group sports participation rate was 28.3% (range, 10.0–52.7%). After adjusting for individual-level group sports participation and potential confounders, a higher community-level group sports participation rate was found to be significantly associated with a lower risk of both all-cause mortality (HR: 0.89, 95% CI: 0.83–0.95) and cancer mortality (HR: 0.89, 95% CI: 0.81–0.98) for every 10% point increase in the participation rate. For CVD mortality, the association became less significant in the model adjusted for all covariates (HR: 0.94, 95% CI: 0.82–1.09). Conclusions Our findings support the existence of a preventive relationship between community-level group sports participation and the occurrence of all-cause and cancer mortality among older individuals. Promoting group sports within communities holds promise as an effective population-based strategy for extending life expectancy, regardless of individual participation in these groups.

Objectives This study aims to describe the incidence, symptom clusters and determinants of post-acute COVID symptoms using data from the COVID RADAR app in the Netherlands.Design Prospective cohort.Setting General population in the Netherlands from April 2020 to February 2022.Participants A total of 1478 COVID RADAR app users, with data spanning 40 days before to 100 days after positive SARS-CoV-2 test.Outcome measures Incidence and duration of 10 new symptoms that developed during acute infection, defined as 10 days prior and 10 days after positive test. Clustering of these post-acute COVID symptoms and associations between factors known in the acute phase and 100-day symptom persistence.Results The most frequent post-acute symptoms were cough, loss of smell or taste and fatigue. At 100 days postinfection, 86 (8%) participants still experienced symptoms. Three post-acute COVID symptom clusters were identified: non-respiratory (headache and fatigue; 49% of participants with post-acute COVID symptoms); olfactory (15%) and respiratory (8%). Vaccination was associated with a lower risk of post-acute COVID symptoms 100 days after infection, although CIs were wide (OR: 0.5; 95% CI: 0.2 to 1.5), but not with non-respiratory symptoms (OR: 1.0; 95% CI: 0.3 to 4.4). Severe acute disease increased the risk of post-acute COVID symptoms (OR: 1.4; 95% CI: 1.2 to 1.5; per additional acute symptom).Conclusions In this cohort of infected community-dwelling app users, 5%–10% experienced post-acute COVID symptoms. The symptoms cluster in several distinct entities, which differ in incidence, patient characteristics and vaccination effects. This suggests multiple mechanisms underlying the development of post-acute COVID symptoms.

BackgroundAs the life expectancy of people living with human immunodeficiency virus (HIV) (PLWH) has improved, chronic disease burden and polypharmacy have increased in PLWH. Simplification of the antiretroviral therapy (ART) regimen for PLWH has become crucial. The real-world treatment patterns and medication persistence of the 2-drug single-tablet regimen (STR), dolutegravir/lamivudine (DTG/3TC), compared to bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) prescribed were investigated.MethodsThis retrospective, database study extracted data from a hospital-based medical claims database in Japan. The changes in ART distributions by year during the identification period between January 1, 2018 and December 31, 2021 were observed. Patients with disease record of HIV-1 infection and prescribed DTG/3TC or BIC/FTC/TAF as the first prescription of STR during the identification period were divided into two cohorts; DTG/3TC cohort and BIC/FTC/TAF cohort, respectively. Patient without medication records more than 3 months and no future data more than 6 months were excluded. Patients’ characteristics were compared between the DTG/3TC cohort and the BIC/FTC/TAF cohort by Mantel–Haenszel test to adjust for age. Medication persistence was compared between the two cohorts by evaluating the continuation rates using Kaplan–Meier methods, using the log-rank test to assess the difference between the Kaplan–Meier curves. The median time-to-first prescription was compared between the two cohorts by Kaplan–Meier methods.ResultsPrescriptions of DTG/3TC and BIC/FTC/TAF increased steadily from 2019 to 2021 after the release year of each STR. There was no significant difference in the time-to-first prescription (p = 0.3). A total of 959 patients were included, with 120 patients and 839 patients on DTG/3TC and BIC/FTC/TAF, respectively. The proportion of dyslipidemia at baseline was significantly higher in the DTG/3TC cohort than in the BIC/FTC/TAF cohort after adjusting for mean age (p = 0.002). There was no significant difference in medication persistence between the two cohorts (p = 0.91).ConclusionThis study showed that DTG/3TC was likely to be selected for elderly patients and those with chronic disease in real-world clinical practice, which seems in accordance with the treatment strategy recommended by guidelines. Comparable medication persistence was observed with both regimens, aligning with findings from other countries. The 2-drug single-tablet regimen DTG/3TC may be an important ART regimen for PLWH with multiple morbidities and polypharmacy in an aging society. Due to the limitations of the database, further research to assess viral loads, emergence of resistance and adverse events will be encouraged.

Background Ventricular repolarization time (ECG QT and JT intervals) is associated with malignant arrhythmia. Genome‐wide association studies have identified 230 independent loci for QT and JT; however, 50% of their heritability remains unexplained. Previous work supports a causal effect of lower serum calcium concentrations on longer ventricular repolarization time. We hypothesized calcium interactions with QT and JT variant associations could explain a proportion of the missing heritability. Methods and Results We performed genome‐wide calcium interaction analyses for QT and JT intervals. Participants were stratified by their calcium level relative to the study distribution (top or bottom 20%). We performed a 2‐stage analysis (genome‐wide discovery [N=62 532] and replication [N=59 861] of lead variants) and a single‐stage genome‐wide meta‐analysis (N=122 393, [European ancestry N=117 581, African ancestry N=4812]). We also calculated 2‐degrees of freedom joint main and interaction and 1‐degree of freedom interaction P values. In 2‐stage and single‐stage analyses, 50 and 98 independent loci, respectively, were associated with either QT or JT intervals (2‐degrees of freedom joint main and interaction P value

We fabricate a microelectromechanical systems (MEMS)-based device configuring the tunable air gap Fabry–Pérot filter (FPF) with a static gradient thickness filter on the same platform. The proposed double filter configuration offers a wavelength calibration approach that accurately estimates the air gap dimension in the tunable air gap FPF. The wavelength calibration is performed by utilizing the spectrally-selective and spatially-resolved transmission characteristics of the tunable air gap FPF and the static gradient thickness filter, respectively. The MEMS-compatible chip-level integration of the static gradient thickness filter facilitates device miniaturization to enable its use in handheld devices.

Abstract Multiple myeloma (MM) is an incurable B‐cell malignancy often accompanied by profound immunodeficiency. Lenalidomide (Len) is an immunomodulatory drug that exerts promising therapeutic effects on MM through the immune system. However, predictive markers related to the effects of Len treatment are not fully understood. This study aimed to identify candidate biomarkers for predicting the clinical efficacy of Len and dexamethasone (Ld) therapy through a comprehensive analysis of serum cytokines. The levels of 48 cytokines in the serum of patients with MM just before Ld therapy (n = 77), at the time of best response (n = 56), and at disease progression (n = 49) were measured and evaluated. Patients with high IL‐18 and M‐CSF levels showed significantly shorter progression‐free survival and overall survival (OS). In contrast, patients with high PDGF‐BB levels had longer survival. Moreover, low levels of G‐CSF, IL‐7, IL‐8, and SDF‐1α were associated with shorter OS after Ld therapy. During Ld therapy, pro‐inflammatory cytokines such as IL‐2Rα, IL‐18, and TNF‐α were decreased, while IFN‐γ was increased. IL‐4 and IL‐6 levels increased during disease progression. In conclusion, this study provides a better understanding of the association between cytokines and the efficacy of Ld therapy as well as the unique changes in cytokines related to inflammatory and immune responses during Ld therapy.