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Abstract Obtaining a fine approximation of a black-box function is important for understanding and evaluating innovative materials. Active learning aims to improve the approximation of black-box functions with fewer training data. In this study, we investigate whether active learning based on uncertainty sampling enables the efficient approximation of black-box functions in regression tasks using various material databases. In cases where the inputs are provided uniformly and defined in a relatively low-dimensional space, the liquidus surfaces of the ternary systems are the focus. The results show that uncertainty-based active learning can produce a better black-box function with higher prediction accuracy than that by random sampling. Furthermore, in cases in which the inputs are distributed discretely and unbalanced in a high-dimensional feature space, datasets extracted from materials databases for inorganic materials, small molecules, and polymers are addressed, and uncertainty-based active learning is occasionally inefficient. Based on the dependency on the material descriptors, active learning tends to produce a better black-box functions than random sampling when the dimensions of the descriptor are small. The results indicate that active learning is occasionally inefficient in obtaining a better black-box function in materials science.

Abstract There have been several reports of skin manifestations in patients with coronavirus disease 2019 (COVID-19). However, it is unclear whether severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA can be detected on the skin surface, including the sebum, of these patients. In this study, SARS-CoV-2 RNA was detected using real-time reverse-transcription polymerase chain reaction (RT-PCR) assay of skin surface lipids (SSLs) collected using an oil-blotting film from the faces of hospitalized patients with COVID-19. Human transcriptome analysis was also performed using the same samples. In facial SSLs of patients with COVID-19, the RT-PCR positivity rate was 84.6% (11/13 samples) within 5 days and 30.4% (7/23 samples) by 6–10 days of symptom onset. In the transcriptome analysis, the most characteristic SSL-RNA profile was the upregulation of interferon-stimulated gene (ISG)-related genes, such as ISG15, IFITM1, and MX1. This study presents an alternative technique using SSLs for non-invasive SARS-CoV-2 RNA detection and simultaneous analysis of human molecular pathogenesis in patients with COVID-19.

Abstract After traumatic events, simple cue-threat associative memories strengthen while episodic memories become incoherent. However, how the brain prioritises cue associations over episodic coding of traumatic events remains unclear. Here, we developed an original episodic threat conditioning paradigm in which participants concurrently form two memory representations: cue associations and episodic cue sequence. We discovered that these two distinct memories compete for physiological fear expression, reorganising overnight from an overgeneralised cue-based to a precise sequence-based expression. With multivariate fMRI, we track inter-area communication of the memory representations to reveal that a rebalancing between hippocampal- and prefrontal control of the fear regulatory circuit governs this memory maturation. Critically, this overnight re-organisation is altered with heightened trait anxiety. Together, we show the brain prioritises generalisable associative memories under recent traumatic stress but resorts to selective episodic memories 24 h later. Time-dependent memory competition may provide a unifying account for memory dysfunctions in post-traumatic stress disorders.

Abstract Targeted protein degradation is a groundbreaking modality in drug discovery; however, the regulatory mechanisms are still not fully understood. Here, we identify cellular signaling pathways that modulate the targeted degradation of the anticancer target BRD4 and related neosubstrates BRD2/3 and CDK9 induced by CRL2VHL- or CRL4CRBN -based PROTACs. The chemicals identified as degradation enhancers include inhibitors of cellular signaling pathways such as poly-ADP ribosylation (PARG inhibitor PDD00017273), unfolded protein response (PERK inhibitor GSK2606414), and protein stabilization (HSP90 inhibitor luminespib). Mechanistically, PARG inhibition promotes TRIP12-mediated K29/K48-linked branched ubiquitylation of BRD4 by facilitating chromatin dissociation of BRD4 and formation of the BRD4–PROTAC–CRL2VHL ternary complex; by contrast, HSP90 inhibition promotes BRD4 degradation after the ubiquitylation step. Consequently, these signal inhibitors sensitize cells to the PROTAC-induced apoptosis. These results suggest that various cell-intrinsic signaling pathways spontaneously counteract chemically induced target degradation at multiple steps, which could be liberated by specific inhibitors.

Abstract This study aimed to develop and validate a machine learning (ML) model tailored to the Korean population with type 2 diabetes mellitus (T2DM) to provide a superior method for predicting the development of cardiovascular disease (CVD), a major chronic complication in these patients. We used data from two cohorts, namely the discovery (one hospital; n = 12,809) and validation (two hospitals; n = 2019) cohorts, recruited between 2008 and 2022. The outcome of interest was the presence or absence of CVD at 3 years. We selected various ML-based models with hyperparameter tuning in the discovery cohort and performed area under the receiver operating characteristic curve (AUROC) analysis in the validation cohort. CVD was observed in 1238 (10.2%) patients in the discovery cohort. The random forest (RF) model exhibited the best overall performance among the models, with an AUROC of 0.830 (95% confidence interval [CI] 0.818–0.842) in the discovery dataset and 0.722 (95% CI 0.660–0.783) in the validation dataset. Creatinine and glycated hemoglobin levels were the most influential factors in the RF model. This study introduces a pioneering ML-based model for predicting CVD in Korean patients with T2DM, outperforming existing prediction tools and providing a groundbreaking approach for early personalized preventive medicine.

Abstract This retrospective observational study aimed to investigate the difference in 4-year outcomes of ranibizumab or aflibercept therapy for macular neovascularization (MNV) with high myopia between pathologic myopia (PM) and non-PM. This study was conducted at Kyoto University Hospital and included consecutive treatment-naïve eyes with active myopic MNV, in which a single intravitreal ranibizumab or aflibercept injection was administered, followed by a pro re nata (PRN) regimen for 4 years. Based on the META-PM study classification, eyes were assigned to the non-PM and PM groups. This study analyzed 118 eyes of 118 patients (non-PM group, 19 eyes; PM group, 99 eyes). Baseline, 1-year, and 2-year best-corrected visual acuity (BCVA) were significantly better in the non-PM group (P = 0.02, 0.01, and 0.02, respectively); however, the 3-year and 4-year BCVA were not. The 4-year BCVA course was similar in both groups. However, the total number of injections over 4 years was significantly higher in the non-PM than in the PM group (4.6 ± 2.6 vs. 2.9 ± 2.6, P = 0.001). Four-year BCVA significantly correlated only with baseline BCVA in both non-PM (P = 0.047, β = 0.46) and PM groups (P

Abstract Previous studies have examined the prevalence of allergic diseases in adolescents 1–2 years after the emergence of the COVID-19 pandemic. However, more data is needed to understand the long-term impact of COVID-19 on allergic diseases. Thus, we aimed to examine the trend of the atopic dermatitis prevalence in Korean adolescents before and during the COVID-19 pandemic across 14 years. Additionally, we analyze the risk factors of atopic dermatitis (AD) based on the results. The Korean Disease Control and Prevention Agency conducted the Korea Youth Risk Behavior Web-based Survey from 2009 to 2022, from which the data for this study were obtained. Prevalence trends were compared across subgroups, and the β difference (βdiff) was calculated. We computed odds ratios to examine changes in the disease prevalence before and during the pandemic. This study included a total of 917,461 participants from 2009 to 2022. The prevalence of atopic dermatitis increased from 6.79% (95% CI 6.66–6.91) in 2009–2011 to 6.89% (95% CI 6.72–7.05) in 2018–2019, then decreased slightly to 5.82% (95% CI 5.60–6.04) in 2022. Across the 14 years, middle school student status, low parent’s highest education level, low household income, non-alcohol consumption, non-smoker smoking status, no suicidal thoughts, and no suicide attempts were associated with increased risk of atopic dermatitis, while female sex, rural residence, high BMI, low school performance, low household income, and no feelings of sadness and despair was associated with a small increase. This study examined the prevalence of atopic dermatitis across an 18-year, and found that the prevalence increased in the pre-pandemic then decreased during the start of the pandemic and remained constant throughout the pandemic. This trend could be explained mainly by the large scale social and political changes that occurred during the COVID-19 pandemic.

Abstract Considering the significant burden of post-acute COVID-19 conditions among patients infected with SARS-CoV-2, we aimed to identify the risk of acute respiratory complications or post-acute respiratory sequelae. A binational population-based cohort study was conducted to analyze the risk of acute respiratory complications or post-acute respiratory sequelae after SARS-CoV-2 infection. We used a Korean nationwide claim-based cohort (K-COV-N; n = 2,312,748; main cohort) and a Japanese claim-based cohort (JMDC; n = 3,115,606; replication cohort) after multi-to-one propensity score matching. Among 2,312,748 Korean participants (mean age, 47.2 years [SD, 15.6]; 1,109,708 [48.0%] female), 17.1% (394,598/2,312,748) were infected with SARS-CoV-2. The risk of acute respiratory complications or post-acute respiratory sequelae is significantly increased in people with SARS-CoV-2 infection compared to the general population (acute respiratory complications: HR, 8.06 [95% CI, 6.92-9.38]; post-acute respiratory sequelae: 1.68 [1.62-1.75]), and the risk increased with increasing COVID-19 severity. We identified COVID-19 vaccination as an attenuating factor, showing a protective association against acute or post-acute respiratory conditions. Furthermore, while the excess post-acute risk diminished with time following SARS-CoV-2 infection, it persisted beyond 6 months post-infection. The replication cohort showed a similar pattern in the association. Our study comprehensively evaluates respiratory complications in post-COVID-19 conditions, considering attenuating factors such as vaccination status, post-infection duration, COVID-19 severity, and specific respiratory conditions.

Abstract Prior research has predominantly focused on the overall effects of the tobacco tax increase and the COVID-19 pandemic on adolescent smoking behavior. However, there is a need to examine both the immediate and sustained associations of these two factors on subgroups of adolescents, employing an interrupted time-series model. We aimed to investigate the immediate and sustained association of tobacco tax increase and the COVID-19 pandemic on adolescent smoking prevalence. This study utilized data from the Korea Youth Risk Behavior Web-Based Survey to analyze the prevalence of current smoking among all participants (CSP) and the prevalence of daily smoking among current smokers (DSP) of Korean adolescents (n = 1,159,995; mean, age 14.99; male 51.5%) over 18 years from 2005 to 2022. The study examined 18-year trends in CSP and DSP among Korean adolescents, emphasizing the influences of the 2015 tobacco tax increase and the COVID-19 pandemic, using β coefficients and their differences (βdiff) from an interrupted time-series ARIMA model. While CSP exhibited a decreasing trend, DSP exhibited an increasing trend. Tobacco tax increase was associated with both the short and long terms in smoking prevalence, however, the short-term association on prevalence (CSP, − 3.076 [95% CI, − 3.707 to − 2.445]; DSP, − 4.112 [95% CI, − 6.488 to − 1.735]) was stronger. The pandemic was associated with an immediate increase in DSP (9.345 [95% CI, 5.285–13.406]). These effects were strongest among adolescents from low economic status and those exposed to familial secondhand smoking. Supportive programs for adolescents in low-income families will help overcome the effects associated with the pandemic. As a tobacco tax increase was associated with a reduction in smoking prevalence, this could be one method to overcome the effects of the pandemic.

Abstract Several studies have evaluated immune checkpoint inhibitors (ICIs) for metastatic uveal melanoma; however, the efficacy of ICIs in the previous studies varied greatly. In this systematic review, we searched for prospective or retrospective studies on single or dual-ICIs for metastatic uveal melanoma treatment. A random-effect model meta-analysis with generic inverse-variance was conducted, and 36 articles representing 41 cohorts of 1414 patients with metastatic uveal melanoma were included. The pooled outcomes were as follows: objective response rate (ORR) was 5.6% (95% confidence interval [95%CI] 3.7–7.5%; I2, 36%), disease control rate (DCR) was 32.5% (95% CI 27.2–37.7%; I2, 73%), median progression-free survival was 2.8 months (95% CI 2.7–2.9 months; I2, 26%), and median overall survival (OS) was 11.2 months (95% CI 9.6–13.2 months; I2, 74%). Compared to single-agent ICI, dual ICI led to better ORR (single-agent: 3.4% [95% CI 1.8–5.1]; dual-agent: 12.4% [95% CI 8.0–16.9]; P

Abstract As mounting evidence suggests a higher incidence of adverse consequences, such as disruption of the immune system, among patients with a history of COVID-19, we aimed to investigate post-COVID-19 conditions on a comprehensive set of allergic diseases including asthma, allergic rhinitis, atopic dermatitis, and food allergy. We used nationwide claims-based cohorts in South Korea (K-CoV-N; n = 836,164; main cohort) and Japan (JMDC; n = 2,541,021; replication cohort A) and the UK Biobank cohort (UKB; n = 325,843; replication cohort B) after 1:5 propensity score matching. Among the 836,164 individuals in the main cohort (mean age, 50.25 years [SD, 13.86]; 372,914 [44.6%] women), 147,824 were infected with SARS-CoV-2 during the follow-up period (2020−2021). The risk of developing allergic diseases, beyond the first 30 days of diagnosis of COVID-19, significantly increased (HR, 1.20; 95% CI, 1.13−1.27), notably in asthma (HR, 2.25; 95% CI, 1.80−2.83) and allergic rhinitis (HR, 1.23; 95% CI, 1.15−1.32). This risk gradually decreased over time, but it persisted throughout the follow-up period (≥6 months). In addition, the risk increased with increasing severity of COVID-19. Notably, COVID-19 vaccination of at least two doses had a protective effect against subsequent allergic diseases (HR, 0.81; 95% CI, 0.68−0.96). Similar findings were reported in the replication cohorts A and B. Although the potential for misclassification of pre-existing allergic conditions as incident diseases remains a limitation, ethnic diversity for evidence of incident allergic diseases in post-COVID-19 condition has been validated by utilizing multinational and independent population-based cohorts.

Abstract Although functional dyspepsia (FD) is a common functional gastroduodenal disorder with a high socioeconomic burden, little is known about its global prevalence. Thus, we performed a comprehensive study to estimate long-term trends in the prevalence of FD. We searched PubMed/MEDLINE, Embase, and Google Scholar from 1990 to 2022 for population-based studies that reported the prevalence of FD in adults (≥ 18 years old) according to Rome I, II, III, or IV criteria. The prevalence of FD was extracted from included studies to obtain pooled prevalence with 95% confidence intervals (CI) and 95% prediction intervals. Subgroup analysis was performed according to certain characteristics, including geographic region. A total of 44 studies met the eligibility criteria, including 256,915 participants from 40 countries across six continents. The overall global pooled prevalence of FD was 8.4% (95% CI 7.4–.9.5). The prevalence was the highest in Rome I (11.9%; 95% CI 5.1–25.4) and lowest in Rome IV (6.8%; 95% CI 5.8–7.9). Developing countries showed a higher prevalence than developed countries (9.1% versus 8.0%), and prevalence was higher in women, irrespective of the definition used (9.0% versus 7.0%). The pooled prevalence gradually decreased from 1990 to 2020 (12.4% [8.2–18.3] in 1990–2002 versus 7.3% [6.1–8.7] in 2013–2020). The prevalence of FD differs by country, economic status, geographical region, and sex, and the global prevalence has been gradually declining. Despite the heterogeneity of sample population, our study estimates the current global burden of FD and provides information to heath care policy decisions.

Abstract Mobile phone applications (“apps”) are potentially an effective, low-burden method to collect patient-reported outcomes outside the clinical setting. Using such apps consistently and in a timely way is critical for complete and accurate data capture, but no studies of concurrent reporting by cancer patient–caregiver dyads have been published in the peer-reviewed literature. This study assessed app engagement, defined as adherence, timing, and attrition with two smartphone applications, one for adult cancer patients and one for their informal caregivers. This was a single-arm, pilot study in which adult cancer patients undergoing IV chemotherapy or immunotherapy used the DigiBioMarC app, and their caregivers used the TOGETHERCare app, for approximately one month to report weekly on the patients’ symptoms and wellbeing. Using app timestamp metadata, we assessed user adherence, overall and by participant characteristics. Fifty patient–caregiver dyads completed the study. Within the one-month study period, both adult cancer patients and their informal caregivers were highly adherent, with app activity completion at 86% for cancer patients and 84% for caregivers. Caregivers completed 86% of symptom reports, while cancer patients completed 89% of symptom reports. Cancer patients and their caregivers completed most activities within 48 h of availability on the app. These results suggest that the DigiBioMarC and TOGETHERCare apps can be used to collect patient- and caregiver-reported outcomes data during intensive treatment. From our research, we conclude that metadata from mobile apps can be used to inform clinical teams about study participants' engagement and wellbeing outside the clinical setting.

Abstract Despite drastic cellular changes during cleavage, a mitotic spindle assembles in each blastomere to accurately segregate duplicated chromosomes. Mechanisms of mitotic spindle assembly have been extensively studied using small somatic cells. However, mechanisms of spindle assembly in large vertebrate embryos remain little understood. Here, we establish functional assay systems in medaka (Oryzias latipes) embryos by combining CRISPR knock-in with auxin-inducible degron technology. Live imaging reveals several unexpected features of microtubule organization and centrosome positioning that achieve rapid, accurate cleavage. Importantly, Ran-GTP assembles a dense microtubule network at the metaphase spindle center that is essential for chromosome segregation in early embryos. This unique spindle structure is remodeled into a typical short, somatic-like spindle after blastula stages, when Ran-GTP becomes dispensable for chromosome segregation. We propose that despite the presence of centrosomes, the chromosome-derived Ran-GTP pathway has essential roles in functional spindle assembly in large, rapidly dividing vertebrate early embryos, similar to acentrosomal spindle assembly in oocytes.

Abstract Although food labeling on food packages is crucial for promoting a healthy diet, limited research has been conducted on how the COVID-19 pandemic (hereinafter “the pandemic”) has affected food labeling awareness. Therefore, this study aims to analyze the changes in trends in food labeling awareness, comprehension, and usage in South Korea during the pandemic. We utilized a nationwide, large-scale, and long-term dataset provided by the Korea Community Health Survey (KCHS) from 2014 to 2022 (total = 1,756,847 participants). This allowed the researchers to assess the long-term trends in the prevalence of food labeling awareness, comprehension, and usage. Furthermore, we investigated the factors associated with awareness specifically related to the pandemic. In total, 1,756,847 adults (54.19% women) participated in this study. The upward slope in overall food labeling awareness became less pronounced and even exhibited a downward slope during the pandemic (βdiff − 1.759; 95% CI − 1.874 to − 1.644). The upward slope in food labeling comprehension and usage became more pronounced during the pandemic (comprehension: βdiff 0.535; 95% CI 0.436–0.634; usage: βdiff 0.693; 95% CI 0.601–0.785). The vulnerability factors associated with lower food labeling awareness during the pandemic included older age, male, obesity, residing in rural areas, lower household income, lower educational level, smoking, and increased alcohol consumption. This study analyzed the 9-year trend in the prevalence of food labeling awareness, comprehension, and usage based on nationally representative data of adults in South Korea from 2014 to 2022. Our findings suggest that personalized nutrition strategies are needed to recognize vulnerable groups with risk factors and improve food labeling awareness among Korean adults during the pandemic.

Abstract This study aimed to analyze the trends and factors influencing the number of ophthalmic surgeries in Japan using the open data from the National Database of Health Insurance Claims and Specific Health Checkups of Japan published by the Ministry of Health, Labour and Welfare. We calculated the number of cataract, glaucoma, and vitreoretinal surgeries, categorized by sex, age, and surgical type, for the fiscal years (FY) 2014 to 2020. The number of cataract surgeries remained stable at approximately 1.45 million cases from FY 2014 to 2018, increased to nearly 1.6 million cases in FY 2019, and decreased to 1.45 million cases in FY 2020. Among glaucoma surgeries, surgical treatments were increased 1.8 times over 7 years, from 33,000 to 60,000 cases. Laser treatment remained steady at around 55,000 cases from FY 2014 to 2017 and then increased to approximately 60,000 cases. The number of vitreoretinal surgeries was increased 1.2 times from FY 2014 to 2019, from 120,000 to 140,000, and decreased to 130,000 by FY 2020. Trends in ophthalmic surgeries over the past 7 years may be influenced by population aging, minimally invasive surgery, and the coronavirus disease pandemic. These findings have implications on surgical decision-making and resource allocation.

Abstract The impact of the pandemic on hypertension management is unknown, particularly regarding changes in demographic risk factors. We conducted a comprehensive study between 1998 and 2021 on the long-term trends in hypertension prevalence in South Korea, including a comparison of the pre-pandemic and pandemic eras. Data from 1998 to 2021 of 108,687 Korean adults were obtained through a nationwide, large-scale, and serial study. We conducted a weighted complex sampling analysis on the estimates of national prevalence and compared the slope of hypertension prevalence before and during the pandemic to determine the trend dynamics. We included 108,687 participants over 24 years, 1998–2021. While the prevalence of patients with hypertension consistently increased before the pandemic from 25.51% [95% CI: 24.27–26.75] in 1998–2005 to 27.81% [95% CI: 26.97–28.66] in 2016–2019, the increasing slope in hypertension prevalence slowed during the pandemic period (28.07% [95% CI: 26.16–29.98] for 2021; βdiff, −0.012 [−0.023 to 0.000]). Hypertension awareness, treatment, control, and control rates among patients receiving treatment followed similar trends. Compared to the pre-pandemic era, individuals aged 19–59 years or male had significantly increased control rates among the treated patients during the pandemic. This study investigated long-term trends in hypertension prevalence, awareness, treatment, and control among Korean adults. The absence of a reduction in the health indicators associated with hypertension during the pandemic implies that medical services for individuals with hypertension remain unaffected.

Summary: Fear memories enhance survival especially when the memories guide defensive movements to minimize harm. Accordingly, fear memories and body movements have tight relationships in animals: Fear memory acquisition results in adapting reactive defense movements, while training active defense movements reduces fear memory. However, evidence in humans is scarce because their movements are typically suppressed in experiments. Here, we tracked adult participants’ body motions while they underwent ecologically valid fear conditioning in a 3D virtual space. First, with body motion tracking, we revealed that distinct spatiotemporal body movement patterns emerge through fear conditioning. Second, subsequent training to actively avoid threats with naturalistic defensive actions led to a long-term (24 h) reduction of physiological and embodied conditioned responses, while extinction or vicarious training only transiently reduced the responses. Together, our results highlight the role of body movements in human fear memory and its intervention.

Abstract Studies on the trends in the prevalence of rheumatoid arthritis (RA) and osteoarthritis (OA) are limited, particularly during the COVID-19 pandemic. This study aimed to analyze the temporal trend of RA and OA in South Korean adults from 1998 to 2021, including the COVID-19 pandemic period. The Korea National Health and Nutrition Examination Survey (KNHANES) data on adults aged ≥ 19 years were analyzed to investigate the prevalence of RA and OA from 1998 to 2021. The prevalence trends were compared by the years, and βdiff (β difference) was calculated. Odds ratios (ORs) were computed for each disease to examine changes in disease prevalence before and during the pandemic in order to determine the impact of the pandemic on disease prevalence. Among 163,221 Korean adults, the prevalence of RA and OA showed a steady decrease from 2005 (RA: from 1.91% in 2005–2007 to 1.55% in 2016–2019 and OA: from 9.75% in 2005–2007 to 8.27% in 2016–2019), but there was a slight increased after the onset of the COVID-19 pandemic (RA: from 1.23% in 2020 to 1.36% in 2021 and OA: from 8.04% in 2020 to 8.27% in 2021). Vulnerable groups, including participants aged ≥ 60 years (versus 19–60 years, ratio of ORs: 1.222; 95% CI 1.011–1.477), urban residents (ratio of ORs: 1.289; 95% CI 1.007–1.650), and participants with higher education level (ratio of ORs: 1.360; 95% CI 1.119–1.653) showed higher ORs of OA, whereas no particularly vulnerable population was observed for RA. Our findings provide an insight into the long-term trends of RA and OA among adult population and highlight a novel perspective on the impact of COVID-19 on disease prevalence.

Abstract Though vascular endothelial growth factors (VEGF) and other proangiogenic factors, such as angiopoietins (Ang), may be involved in the development of neovascular age-related macular degeneration (nvAMD), only drugs that inhibit the VEGF family are available for the treatment. The newly approved anti-VEGF drug faricimab, which also inhibits Ang-2, is expected to be effective in patients with AMD refractory to conventional anti-VEGF drugs. Therefore, we prospectively investigated the efficacy of faricimab in the treatment of aflibercept-refractory nvAMD. Patients with nvAMD who had been treated with aflibercept in the last year and required bimonthly injections were recruited. 25 eyes showed persistent exudative changes immediately before the faricimab injection (baseline). In these 25 eyes, switching to faricimab did not change visual acuity or central retinal thickness 2 months after the injection; however, 56% of eyes showed reduction or complete absorption of fluid. Notably, 25% of the eyes that showed dry macula at month 2 had no fluid recurrence for up to 4 months. These results indicate that faricimab could benefit some patients with aflibercept-refractory nvAMD.

Abstract Benefits of breastfeeding for both the mother and the child are well established, but a comprehensive and robust study to investigate the protective effect of breastfeeding and attenuated time effect stratified by cause of morbidity are lacking. This study is based on the nationwide birth cohort in Korea that includes data on all infants born from 2009 to 2015. Of 1,608,540 children, the median follow-up period was 8.41 years (interquartile range, 6.76-10.06). When compared to children with fully formula feeding, the hospital admission rate was 12% lower in those with partially breastfeeding and 15% lower in those with exclusive breastfeeding. The apparent protective effect of breastfeeding was reduced with increasing age. Our study provides potential evidence of the beneficial association of breastfeeding on subsequent hospital admissions. The protective effect declined over time as the children grew older. Encouraging any breastfeeding for at least the first 6 months among infants is an important public health strategy to improve overall child health.

Abstract Transplantation of human allogeneic induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) is a new, promising treatment for severe heart failure. However, immunorejection is a significant concern in allogeneic hiPSC-CM transplantation, requiring the administration of several immunosuppressive agents. An appropriate protocol for the administration of immunosuppressants may substantially affect the efficacy of hiPSC-CM transplantation in case of heart failure owing to allogeneic transplantation. In this study, we investigated the effect of immunosuppressant administration duration on the efficacy and safety of allogenic hiPSC-CM patch transplantation. We used a rat model of myocardial infarction to evaluate cardiac function using echocardiography six months after the transplantation of hiPSC-CM patches with immunosuppressant administration for either two or four months and compared them to control rats (sham operation, no immunosuppressant administration). Histological analysis performed at 6 months after hiPSC-CM patch transplantation revealed significant improvement in cardiac function in immunosuppressant-treated rats compared with those in the control group. Moreover, fibrosis and cardiomyocyte size was significantly reduced and the number of structurally mature blood vessels was significantly increased in the immunosuppressant-treated rats compared to control rats. However, there were no significant differences between the two immunosuppressant-treated groups. Our results show that prolonged administration of immunosuppressive agents did not enhance the effectiveness of hiPSC-CM patch transplantation, and therefore, highlight the importance of an appropriate immunological regimen for the clinical application of such transplantation.

Abstract Studies have shown the prevalence of mental health and obesity among adolescents is at increasing trend due to urbanisation and changes in lifestyle. This study is to investigate the level of stress and its impact on eating behaviour among Malaysian adolescents. A total of 797 multi-ethnic Malaysian secondary school student participated in this cross-sectional study. Data was collected two weeks prior to final year examination. A validated Cohen Perceived Stress Scale questionnaire was used to assess the stress level with subsample analysis of 261 participants’ saliva cortisol level. A validated Child Eating Behaviour questionnaire was used to explore eating behaviours. There were 29.1% adolescents having high stress with the mean saliva cortisol 3.8 nmol/L. A positive correlation was observed between perceived stress and emotional overeating; stronger among urban (r = 0.32), female (r = 0.31), underweight (r = 0.34) and moderately stressed adolescents (r = 0.24). In addition, a positive correlation was found between perceived stress and food responsiveness; strongest among Malay (r = 0.23), male (r = 0.24), underweight (r = 0.30) and adolescents with high perceived stress (r = 0.24). The perceived stress level prior to exam period affects the emotional eating and external eating patterns of adolescents.

Abstract To determine the clinical properties of pachychoroid neovasculopathy (PNV) that differ from conventional neovascular age-related macular degeneration (nAMD) and suggest that they are different clinical entities. To accomplish this, we reviewed the medical records of 100 consecutive patients diagnosed with nAMD. All of the patients were Japanese, and their mean age was 75.5 years. There were 72 men and 28 women. For the bilateral cases, only the right eye was analyzed. An eye was diagnosed with PNV when a macular neovascularization (MNV) was detected just above the dilated choroidal vessels. The Indocyanine green angiographic (ICGA) and en face optical coherence tomographic (OCT) images were used to assess the vertical symmetry of the medium and large choroidal vessels. The subfoveal choroidal thickness (SCT) was also measured manually in the OCT images. After reclassification, there were 29 (29%) patients with typical nAMD (25 with type 1 MNV, 4 with type 2 MNV), 43 (43%) with PNV, 21 (21%) with polypoidal choroidal vasculopathy, and 7 (7%) with retinal angiomatous proliferation. Of the 43 PNV, 17 (39.5%) had polypoidal lesions and 26 (60.5%) had no polypoidal lesions. The percentage of eyes with vertical asymmetry of the medium and large choroidal vessels was significantly greater in the 35 PNV (81.4%) than in the 16 non-PNV (28.1%; P

Abstract Little is known about the prevalence of chronic kidney disease (CKD) during the coronavirus disease 2019 (COVID-19) pandemic. We aimed to investigate the long-term trends in CKD prevalence from South Korea including the early pandemic. We used data from 108,152 Korean adults from 2007 to 2020 obtained from a representative longitudinal serial study. We defined CKD as a condition when the participant’s estimated glomerular filtration rate was

How has the genome duplication impacted the diversification of sexual characteristics in the teleost lineage? This study shows that androgen receptor ohnologs in medaka appear to have diverged in their roles for regulating morphological and behavioural sexual characteristics after loss from an ancestral role in spermatogenesis.

Over the past three decades, Sri Lanka has observed a substantial rise in landslide occurrences linked to intensified rainfall. However, the lack of comprehensive landslide inventories has hampered the development of effective risk analysis and simulation systems, requiring Sri Lanka to rely heavily on foreign-developed models, despite the difficulty of fully examining the similarities between the characteristics of landslides in Sri Lanka and the areas where the model has been developed. Satellite images have become readily available in recent years and have provided information about the Earth’s surface conditions over the past few decades. Thus, this study verifies the utility of satellite images as a cost-effective remote-sensing method to clarify the commonalities and differences in the characteristics of landslides in two regions Ikawa, Japan, and Sabaragamuwa, Sri Lanka, which exhibit different geological formations despite similar annual rainfall. Using Google Earth satellite images from 2013 to 2023, we evaluated land-slide density, types, and geometry. The findings reveal that Ikawa exhibits a higher landslide density and experiences multiple-type landslides. In contrast, both areas have similar initiation areas; however, Sabaragamuwa predominantly experiences single landslides that are widespread and mobile. The findings also reveal that various characteristics of landslides are mainly influenced by varied topography. Here, we confirmed that even in areas where comprehensive information on landslides is conventionally lacking, we can understand the characteristics of landslides by comparing landslide geometry between sites using satellite imagery.

Abstract Alzheimer’s disease (AD) is the most common neurodegenerative disease, and numerous recent findings suggest that several pathologic signs, including loss of muscle strength and mass, are also detected in these patients. In the present study, we evaluated muscle cross-sectional area (CSA), myonuclear number, satellite cell (SC) content, and myosin heavy chain (MyHC) types in an animal model of AD and examined the possible role of resistance training in controlling skeletal muscle size in this disease. Fifty-eight male rats were randomly divided into four groups: healthy-control (H-C), healthy-exercise (H-Ex), Alzheimer-control (A-C), and Alzheimer-exercise (A-Ex). AD was induced by the single injection of 1–42 amyloid into the CA1 region of the hippocampus (1 μl/site). The rats in H-Ex and A-Ex groups performed a 5-week resistance training period (17 sessions). The results indicated that AD induces significant skeletal muscle atrophy and reduces the myonuclear number and SC content in gastrocnemius muscle in both whole muscle cross-sections and isolated myofibers. Interestingly, we did not find any significant differences in the different MyHC distributions of AD animals compared with controls, while resistance training significantly increased the CSA of MyHC IIb fibers in both AD and healthy animals. Altogether, these observations suggest that the skeletal muscle of AD animals are more prone to atrophy and loss of myonuclear number and satellite cell content, while resistance training successfully restores these impairments.

Abstract SARS-CoV-2 continues to spread worldwide. Patients with COVID-19 show distinct clinical symptoms. Although many studies have reported various causes for the diversity of symptoms, the underlying mechanisms are not fully understood. Peripheral blood mononuclear cells from COVID-19 patients were collected longitudinally, and single-cell transcriptome and T cell receptor repertoire analysis was performed. Comparison of molecular features and patients’ clinical information revealed that the proportions of cells present, and gene expression profiles differed significantly between mild and severe cases; although even among severe cases, substantial differences were observed among the patients. In one severely-infected elderly patient, an effective antibody response seemed to have failed, which may have caused prolonged viral clearance. Naïve T cell depletion, low T cell receptor repertoire diversity, and aberrant hyperactivation of most immune cell subsets were observed during the acute phase in this patient. Through this study, we provided a better understanding of the diversity of immune landscapes and responses. The information obtained from this study can help medical professionals develop personalized optimal clinical treatment strategies for COVID-19.

Abstract To reveal optimal antibiotic prophylactic regimen for postoperative endophthalmitis (POE), we conducted systematic review and network meta-analysis. A total of 51 eligible original articles, including two randomized controlled trials, were identified. In total, 4502 POE cases occurred in 6,809,732 eyes (0.066%). Intracameral injection of vancomycin had the best preventive effect (odds ratio [OR] 0.03, 99.6% confidence interval [CI] 0.00–0.53, corrected P-value = 0.006, P-score = 0.945) followed by intracameral injection of cefazoline (OR 0.09, 99.6% CI 0.02–0.42, corrected P-value

GTP-triggered release from drug carriers has huge potential in cancer therapy but current carriers suffers from off target release due to ATP also acting as a trigger. Here, the authors report on the development of a microtubule capsule which is engineered to be responsive to only GTP not ATP and demonstrate targeted drug delivery.

Abstract There is a small body of evidence suggesting that unclean cooking fuel use may be associated with cognitive decline. However, to date, no study has investigated the association between unclean cooking fuel and mild cognitive impairment (MCI). Thus, we investigated the association between cooking fuel type or ventilation type and MCI among adults aged ≥ 65 years using nationally representative datasets from six low- and middle-income countries. Cross-sectional, community-based data from the World Health Organization (WHO) Study on global Ageing and adult health (SAGE) were analyzed. MCI was defined using the National Institute on Aging-Alzheimer's Association criteria. Unclean cooking fuel referred to kerosene/paraffin, coal/charcoal, wood, agriculture/crop, animal dung, and shrubs/grass. Multivariable logistic regression analysis was conducted to assess associations. Data on 13,623 individuals were analyzed [mean (SD) age 72.8 (11.0) years; 45.5% males]. Unclean cooking fuel (vs. clean cooking fuel) was associated with a significant 1.48 (95% CI = 1.08–2.03) times higher odds for MCI. Having no chimney or hood for cooking ventilation was also associated with significantly higher odds for MCI (OR = 1.88; 95% CI = 1.25–2.84). Unclean cooking fuel use and lack of chimney or hood for cooking ventilation were associated with higher odds for MCI. Findings support the implementation of the United Nations Sustainable Goal 7, which advocates affordable, reliable, sustainable, and modern energy for all, as this may also help reduce MCI and ultimately dementia.

Abstract To determine whether increasing thrombectomy-capable hospitals with moderate comprehensive stroke center (CSC) capabilities is a valid alternative to centralization of those with high CSC capabilities. This retrospective, nationwide, observational study used data from the J-ASPECT database linked to national emergency medical service (EMS) records, captured during 2013–2016. We compared the influence of mechanical thrombectomy (MT) use, the CSC score, and the total EMS response time on the modified Rankin Scale score at discharge among patients with acute ischemic stroke transported by ambulance, in phases I (2013–2014, 1461 patients) and II (2015–2016, 3259 patients). We used ordinal logistic regression analyses to analyze outcomes. From phase I to II, MTs increased from 2.7 to 5.5%, and full-time endovascular physicians per hospital decreased. The CSC score and EMS response time remained unchanged. In phase I, higher CSC scores were associated with better outcomes (1-point increase, odds ratio [95% confidence interval]: 0.951 [0.915–0.989]) and longer EMS response time was associated with worse outcomes (1-min increase, 1.007 [1.001–1.013]). In phase II, neither influenced the outcomes. During the transitional shortage of thrombectomy-capable hospitals, increasing hospitals with moderate CSC scores may increase nationwide access to MT, improving outcomes.

Abstract Optical coherence tomography angiography (OCTA) is a new technique for non-invasive imaging of blood vessels, allowing combined evaluation of both deep and surface vessels. The purpose of this study was to evaluate the post-trabeculectomy longitudinal changes in complete avascular area (CAA) of filtering blebs using anterior segment (AS-) OCTA and their association with surgical outcomes. This study included 57 eyes of 53 patients who had undergone trabeculectomy with mitomycin C. AS-OCTA images of filtering bleb were acquired at 3 and 6 months after trabeculectomy, and at 1 month in possible cases. CAAs, regions where complete blood flow was not depicted in AS-OCTA images, were evaluated for their presence, extent, and change over time. CAAs were detected in 37 eyes (65%) and 33 eyes (58%) at 3 and 6 months postoperatively, respectively. The extent of CAAs reduced over time after surgery in most cases. No parameters related to CAAs were significantly associated with surgical success (i.e., intraocular pressure (IOP) ≤ 12 mmHg and IOP reduction > 20% without medication). In conclusion, although it is difficult to predict surgical success by CAA itself, AS-OCTA may be useful for the objective evaluation of the vascularity of filtering blebs.

Systemic sclerosis (SSc) disease involves multisystem fibrosis and autoimmunity with limited treatment options. Here the authors demonstrate that IL-31 and IL-31RA are overexpressed in dermal fibroblasts from SSc patients and show that fibrosis and cytokine release can be reduced upon blocking of IL-31/IL-31RA.

Summary: Determinants of memory T cell longevity following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection remain unknown. In addition, phenotypes associated with memory T cell longevity, antibody titers, and disease severity are incompletely understood. Here, we longitudinally analyzed SARS-CoV-2-specific T cell and antibody responses of a unique cohort with similar numbers of mild, moderate, and severe coronavirus disease 2019 cases. The half-lives of CD4+ and CD8+ T cells were longer than those of antibody titers and showed no clear correlation with disease severity. When CD4+ T cells were divided into Th1-, Th2-, Th17-, and Tfh-like subsets, the Th17-like subset showed a longer half-life than other subsets, indicating that Th17-like cells are most closely correlated with T cell longevity. In contrast, Th2- and Tfh-like T cells were more closely correlated with antibody titers than other subsets. These results suggest that distinct CD4+ T cell subsets are associated with longevity and antibody responses.

Measurement(s) functional brain measurement Technology Type(s) 3 T MRI scanner • functional magnetic resonance imaging • Neurofeedback • machine learning Factor Type(s) type of task performed: visual, preference, perceptual, or memory task Sample Characteristic - Organism Homo sapiens Machine-accessible metadata file describing the reported data: https://doi.org/10.6084/m9.figshare.13578008

Summary: Double homeobox 4 (DUX4) is expressed at the early pre-implantation stage in human embryos. Here we show that induced human DUX4 expression substantially alters the chromatin accessibility of non-coding DNA and activates thousands of newly identified transcribed enhancer-like regions, preferentially located within ERVL-MaLR repeat elements. CRISPR activation of transcribed enhancers by C-terminal DUX4 motifs results in the increased expression of target embryonic genome activation (EGA) genes ZSCAN4 and KHDC1P1. We show that DUX4 is markedly enriched in human zygotes, followed by intense nuclear DUX4 localization preceding and coinciding with minor EGA. DUX4 knockdown in human zygotes led to changes in the EGA transcriptome but did not terminate the embryos. We also show that the DUX4 protein interacts with the Mediator complex via the C-terminal KIX binding motif. Our findings contribute to the understanding of DUX4 as a regulator of the non-coding genome.

PurposeStudies using functional magnetic resonance imaging and positron-emission tomography suggest that many regions of the brain are activated by such complex muscle activity. Although these studies demonstrated relative increases in blood flow in some brain regions with increased neural activity, whether or not the absolute value of cerebral blood flow increases has yet to be elucidated. It also remains unknown whether playing musical instruments affects cerebral blood flow. The aim of this study was to determine the impact of playing a musical instrument on blood flow velocity in the middle cerebral artery (MCAv) by using Doppler ultrasound to measure absolute values of arterial flow velocity.MethodsThirteen musicians performed three pieces of music with different levels of difficulty: play for the first time (FS), music in practice (PR) and already mastered (MS) on either piano or violin. MCAv was recorded continuously from 10 min before until 10 min after playing. Associations between the cerebral blood flow response and blood pressure and gas-exchange variables were examined.ResultsPR and MS significantly increased the MCAv. The blood pressure increased significantly in performances of all difficulty levels except for MS. There were no significant changes in exhaled gas variables during the performance.ConclusionThese findings suggest that playing a musical instrument increases MCAv, and that this change is influenced by the difficulty of the performance.

Polymorphisms in human leukocyte antigen (HLA) class I loci are known to have a great impact on disease progression in HIV-1 infection. Prevailing HIV-1 subtypes and HLA genotype distribution are different all over the world, and the HIV-1 and host HLA interaction could be specific to individual areas. Data on the HIV-1 and HLA interaction have been accumulated in HIV-1 subtype B- and C-predominant populations but not fully obtained in West Africa where HIV-1 subtype CRF02_AG is predominant. In the present study, to obtain accurate HLA typing data for analysis of HLA association with disease progression in HIV-1 infection in West African populations, HLA class I (HLA-A, -B, and -C) four-digit allele typing was performed in treatment-naïve HIV-1 infected individuals in Ghana (n = 324) by a super high-resolution single-molecule sequence-based typing (SS-SBT) using next-generation sequencing. Comparison of the SS-SBT-based data with those obtained by a conventional sequencing-based typing (SBT) revealed incorrect assignment of several alleles by SBT. Indeed, HLA-A*23:17, HLA-B*07:06, HLA-C*07:18, and HLA-C*18:02 whose allele frequencies were 2.5%, 0.9%, 4.3%, and 3.7%, respectively, were not determined by SBT. Several HLA alleles were associated with clinical markers, viral load and CD4+ T-cell count. Of note, the impact of HLA-B*57:03 and HLA-B*58:01, known as protective alleles against HIV-1 subtype B and C infection, on clinical markers was not observed in our cohort. This study for the first time presents SS-SBT-based four-digit typing data on HLA-A, -B, and -C alleles in Ghana, describing impact of HLA on viral load and CD4 count in HIV-1 infection. Accumulation of these data would facilitate high-resolution HLA genotyping, contributing to our understanding of the HIV-1 and host HLA interaction in Ghana, West Africa.

The loss of functional cells through immunological rejection after transplantation reduces the efficacy of regenerative therapies for cardiac failure that use allogeneic induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). Recently, mixed-chimera mice with donor-specific immunotolerance have been established using the RGI-2001 (liposomal formulation of α-galactosyl ceramide) ligand, which activates invariant natural killer T (iNKT) cells. The present study aimed to investigate whether mixed chimerism, established using RGI-2001, prolongs graft survival in allogeneic iPSC-CM transplantation. Mixed-chimera mice were established via combinatorial treatment with RGI-2001 and anti-CD154 antibodies in an irradiated murine bone marrow transplant model. Luciferase-expressing allogeneic iPSC-CMs were transplanted into mixed-chimera and untreated mice, followed by in vivo imaging. RGI-2001 enhanced iNKT cell activation in mice, and mixed chimerism was successfully established. In vivo imaging revealed that while the allografts were completely obliterated within 2 weeks when transplanted to untreated mice, their survivals were not affected in the mixed-chimera mice. Furthermore, numerous CD3+ cells infiltrated allografts in untreated mice, but fewer CD3+ cells were present in mixed-chimera mice. We conclude that mixed-chimera mice established using RGI-2001 showed prolonged graft survival after allogeneic iPSC-CM transplantation. This donor-specific immunotolerance might increase the efficacy of regenerative therapies for heart failure with allogeneic iPSC-CMs.

The loss of functional cells through immunological rejection after transplantation reduces the efficacy of regenerative therapies for cardiac failure that use allogeneic induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). Recently, mixed-chimera mice with donor-specific immunotolerance have been established using the RGI-2001 (liposomal formulation of α-galactosyl ceramide) ligand, which activates invariant natural killer T (iNKT) cells. The present study aimed to investigate whether mixed chimerism, established using RGI-2001, prolongs graft survival in allogeneic iPSC-CM transplantation. Mixed-chimera mice were established via combinatorial treatment with RGI-2001 and anti-CD154 antibodies in an irradiated murine bone marrow transplant model. Luciferase-expressing allogeneic iPSC-CMs were transplanted into mixed-chimera and untreated mice, followed by in vivo imaging. RGI-2001 enhanced iNKT cell activation in mice, and mixed chimerism was successfully established. In vivo imaging revealed that while the allografts were completely obliterated within 2 weeks when transplanted to untreated mice, their survivals were not affected in the mixed-chimera mice. Furthermore, numerous CD3+ cells infiltrated allografts in untreated mice, but fewer CD3+ cells were present in mixed-chimera mice. We conclude that mixed-chimera mice established using RGI-2001 showed prolonged graft survival after allogeneic iPSC-CM transplantation. This donor-specific immunotolerance might increase the efficacy of regenerative therapies for heart failure with allogeneic iPSC-CMs.

Purpose Studies using functional magnetic resonance imaging and positron-emission tomography suggest that many regions of the brain are activated by such complex muscle activity. Although these studies demonstrated relative increases in blood flow in some brain regions with increased neural activity, whether or not the absolute value of cerebral blood flow increases has yet to be elucidated. It also remains unknown whether playing musical instruments affects cerebral blood flow. The aim of this study was to determine the impact of playing a musical instrument on blood flow velocity in the middle cerebral artery (MCAv) by using Doppler ultrasound to measure absolute values of arterial flow velocity. Methods Thirteen musicians performed three pieces of music with different levels of difficulty: play for the first time (FS), music in practice (PR) and already mastered (MS) on either piano or violin. MCAv was recorded continuously from 10 min before until 10 min after playing. Associations between the cerebral blood flow response and blood pressure and gas-exchange variables were examined. Results PR and MS significantly increased the MCAv. The blood pressure increased significantly in performances of all difficulty levels except for MS. There were no significant changes in exhaled gas variables during the performance. Conclusion These findings suggest that playing a musical instrument increases MCAv, and that this change is influenced by the difficulty of the performance.

Polymorphisms in human leukocyte antigen (HLA) class I loci are known to have a great impact on disease progression in HIV-1 infection. Prevailing HIV-1 subtypes and HLA genotype distribution are different all over the world, and the HIV-1 and host HLA interaction could be specific to individual areas. Data on the HIV-1 and HLA interaction have been accumulated in HIV-1 subtype B- and C-predominant populations but not fully obtained in West Africa where HIV-1 subtype CRF02_AG is predominant. In the present study, to obtain accurate HLA typing data for analysis of HLA association with disease progression in HIV-1 infection in West African populations, HLA class I (HLA-A, -B, and -C) four-digit allele typing was performed in treatment-naïve HIV-1 infected individuals in Ghana (n = 324) by a super high-resolution single-molecule sequence-based typing (SS-SBT) using next-generation sequencing. Comparison of the SS-SBT-based data with those obtained by a conventional sequencing-based typing (SBT) revealed incorrect assignment of several alleles by SBT. Indeed, HLA-A*23:17, HLA-B*07:06, HLA-C*07:18, and HLA-C*18:02 whose allele frequencies were 2.5%, 0.9%, 4.3%, and 3.7%, respectively, were not determined by SBT. Several HLA alleles were associated with clinical markers, viral load and CD4+ T-cell count. Of note, the impact of HLA-B*57:03 and HLA-B*58:01, known as protective alleles against HIV-1 subtype B and C infection, on clinical markers was not observed in our cohort. This study for the first time presents SS-SBT-based four-digit typing data on HLA-A, -B, and -C alleles in Ghana, describing impact of HLA on viral load and CD4 count in HIV-1 infection. Accumulation of these data would facilitate high-resolution HLA genotyping, contributing to our understanding of the HIV-1 and host HLA interaction in Ghana, West Africa.

PurposeSince December 2019, coronavirus disease 2019 (COVID-19) has spread rapidly across the world. During the pandemic, physicians in our hospital have had to respond both to the issue of treating the patients and the increasing domestic burden associated with social disruption. The purpose of this study was to assess how much the burden on our doctors, especially female doctors, was increasing.Material and methodsThe Physicians' Career Support Committee in Sapporo Medical University conducted a questionnaire survey. The questionnaire inquired about a wide range of subjects with regard to working style and family life during the first and second waves of the COVID-19 pandemic, and was sent to all medical/dental physicians working in Sapporo Medical University.ResultsA total of 266 (42.7%) physicians in our hospital responded to our questionnaire and the data for 264 data were analyzed. The total numbers of males, females, and others, including those who did not want to specify, were 178 (67.4%), 82 (31.0%), and 4 (1.5%), respectively. Among them, 62 (23.5%) and 23 (8.7%) answered that their domestic burden was slightly or markedly increased. The increase in the domestic burden showed a significant difference between genders (p = 0.04). Even after correction for background differences using multivariate analysis, being female (pConclusionPhysician-mothers are caught in a dilemma between an increased home burden and clinical duties in the hospital, with a significantly higher ratio than physician-fathers during the pandemic. As we showed, female doctors could have not continued their careers and take responsible positions in the same way as male doctors. This is a social risk in the timing of a crisis, such as a pandemic.

BackgroundThis study aimed to clarify how SARS-CoV-2 RNAemia is related to COVID-19 critical condition development and mortality in comparison with other predictive markers and scoring systems.MethodsThis is a retrospective cohort study conducted at Yokohama Municipal Citizen's Hospital and National Institute of Infectious Diseases. We recruited adult patients with COVID-19 admitted between March 2020 and January 2021. We compared RNAemia with clinical status on admission including scoring systems such as the 4C Mortality, CURB-65, and A-DROP, as well as the Ct value of the nasopharyngeal PCR, in predicting COVID-19 mortality and critical condition development.ResultsOf the 92 recruited patients (median age, 58; interquartile range, 45-71 years), 14 (14.9%) had RNAemia. These patients had an older age (median, 68 years vs. 55.5 years; p = 0.011), higher values of lactated dehydrogenase (median, 381 U/L vs. 256.5 U/L, p < 0.001), C-reactive protein (median, 10.9 mg/dL vs. 3.8 mg/dL; p < 0.001), D-dimer (median, 2.07 μg/mL vs. 1.28 μg/mL; p = 0.015), lower values of lymphocyte (median, 802/μL vs. 1007/μL, p = 0.025) and Ct of the nasopharyngeal PCR assay (median, 20.59 vs. 25.54; p = 0.021) than those without RNAemia. Univariate analysis showed RNAemia was associated with mortality (odds ratio [OR], 18.75; 95% confidence interval [CI], 3.92-89.76; area under the receiver operating characteristic curve [AUC], 0.7851; p = 0.002) and critical condition (OR, 72.00; 95% CI, 12.98-399.29; AUC, 0.8198; p < 0.001). Plus, multivariate analysis also revealed the association of RNAemia with critical condition (adjusted OR, 125.71; 95% CI, 11.47-1377.32; p < 0.001).ConclusionOn-admission SARS-CoV-2 RNAemia is a potent predictive marker of COVID-19 critical condition and mortality. The adjusted OR for critical condition was as high as 125.71.

Because of the continuous rise of foodborne illnesses caused by the consumption of raw fruits and vegetables, effective post-harvest anti-microbial strategies are necessary. The aim of this study was to evaluate the anti-microbial efficacy of ozone (O3) against two common causes of fresh produce contamination, the Gram-negative Escherichia coli O157:H7 and Gram-positive Listeria monocytogenes, and to relate its effects to potential mechanisms of xenobiosis by transcriptional network modeling. The study on non-host tomato environment correlated the dose × time aspects of xenobiosis by examining the correlation between bacterial survival in terms of log-reduction and defense responses at the level of gene expression. In E. coli, low (1 μg O3/g of fruit) and moderate (2 μg O3/g of fruit) doses caused insignificant reduction in survival, while high dose (3 μg/g of fruit) caused significant reduction in survival in a time-dependent manner. In L. monocytogenes, moderate dose caused significant reduction even with short-duration exposure. Distinct responses to O3 xenobiosis between E. coli and L. monocytogenes are likely related to differences in membrane and cytoplasmic structure and components. Transcriptome profiling by RNA-Seq showed that primary defenses in E. coli were attenuated after exposure to a low dose, while the responses at moderate dose were characterized by massive upregulation of pathogenesis and stress-related genes, which implied the activation of defense responses. More genes were downregulated during the first hour at high dose, with a large number of such genes getting significantly upregulated after 2 hr and 3 hr. This trend suggests that prolonged exposure led to potential adaptation. In contrast, massive downregulation of genes was observed in L. monocytogenes regardless of dose and exposure duration, implying a mechanism of defense distinct from that of E. coli. The nature of bacterial responses revealed by this study should guide the selection of xenobiotic agents for eliminating bacterial contamination on fresh produce without overlooking the potential risks of adaptation.

Gene abnormalities, including mutations and fusions, are important determinants in the molecular diagnosis of myeloid neoplasms. The use of bone marrow (BM) smears as a source of DNA and RNA for next-generation sequencing (NGS) enables molecular diagnosis to be done with small amounts of bone marrow and is especially useful for patients without stocked cells, DNA or RNA. The present study aimed to analyze the quality of DNA and RNA derived from smear samples and the utility of NGS for diagnosing myeloid neoplasms. Targeted DNA sequencing using paired BM cells and smears yielded sequencing data of adequate quality for variant calling. The detected variants were analyzed using the bioinformatics approach to detect mutations reliably and increase sensitivity. Noise deriving from variants with extremely low variant allele frequency (VAF) was detected in smear sample data and removed by filtering. Consequently, various driver gene mutations were detected across a wide range of allele frequencies in patients with myeloid neoplasms. Moreover, targeted RNA sequencing successfully detected fusion genes using smear-derived, very low-quality RNA, even in a patient with a normal karyotype. These findings demonstrated that smear samples can be used for clinical molecular diagnosis with adequate noise-reduction methods even if the DNA and RNA quality is inferior.

Because of the continuous rise of foodborne illnesses caused by the consumption of raw fruits and vegetables, effective post-harvest anti-microbial strategies are necessary. The aim of this study was to evaluate the anti-microbial efficacy of ozone (O3) against two common causes of fresh produce contamination, the Gram-negative Escherichia coli O157:H7 and Gram-positive Listeria monocytogenes, and to relate its effects to potential mechanisms of xenobiosis by transcriptional network modeling. The study on non-host tomato environment correlated the dose × time aspects of xenobiosis by examining the correlation between bacterial survival in terms of log-reduction and defense responses at the level of gene expression. In E. coli, low (1 μg O3/g of fruit) and moderate (2 μg O3/g of fruit) doses caused insignificant reduction in survival, while high dose (3 μg/g of fruit) caused significant reduction in survival in a time-dependent manner. In L. monocytogenes, moderate dose caused significant reduction even with short-duration exposure. Distinct responses to O3 xenobiosis between E. coli and L. monocytogenes are likely related to differences in membrane and cytoplasmic structure and components. Transcriptome profiling by RNA-Seq showed that primary defenses in E. coli were attenuated after exposure to a low dose, while the responses at moderate dose were characterized by massive upregulation of pathogenesis and stress-related genes, which implied the activation of defense responses. More genes were downregulated during the first hour at high dose, with a large number of such genes getting significantly upregulated after 2 hr and 3 hr. This trend suggests that prolonged exposure led to potential adaptation. In contrast, massive downregulation of genes was observed in L. monocytogenes regardless of dose and exposure duration, implying a mechanism of defense distinct from that of E. coli. The nature of bacterial responses revealed by this study should guide the selection of xenobiotic agents for eliminating bacterial contamination on fresh produce without overlooking the potential risks of adaptation.

Objectives: To determine whether C-X-C chemokine ligand 1 (CXCL1), which is a potent neutrophil chemoattractant and activator that plays important role in inflammation, is elevated in patients with systemic sclerosis (SSc) and whether it is associated with the clinical features and disease activity of patients with SSc. In addition, to determine whether the changes in serum CXCL1 levels before and after treatment correlate with changes in disease activity in SSc patients who received an anti-CD20 monoclonal antibody drug. Patients and method: We examined patient serum collected in the DesiReS trial, which was a double-blind, parallel-group, randomized, placebo-controlled, multicenter, phase II clinical trial. In the trial, patients were randomly allocated to the drug or placebo group and received 375 mg/m2 of an anti-CD20 antibody, rituximab, or placebo once a week for four weeks. We obtained serum samples from 47 patients administered at our hospital, including 3 males and 44 females, the median age of 48 years, range 27–71 years, with 42 diffuse cutaneous SSc and 5 with limited cutaneous SSc. Serum CXCL1 levels were measured using multiplex immunoassay in patient serum before and 24 weeks after administration and also in serum from 33 healthy controls. Results: Serum CXCL1 levels were significantly higher in SSc patients (mean 25.70 ng/mL; 95% confidence interval (CI) 18.35–33.05 ng/mL) than in the healthy controls (15.61 ng/mL; 95% CI 9.73–21.51 ng/mL). In addition, SSc patients with elevated CXCL1 levels had a significantly higher percentage of area occupied with interstitial shadows (p < 0.05), increased serum levels of surfactant protein (SP)-A (p < 0.05), SP-D (p < 0.05), Krebs von den Lungen-6 (p < 0.01), and C-reactive protein (p < 0.05) compared to those with normal levels. Furthermore, defining Δ as the value after rituximab administration minus the value before rituximab administration, baseline serum CXCL1 levels correlated with Δ percent predicted diffusing capacity for carbon monoxide (p < 0.01). In addition, ΔCXCL1 correlated with ΔSP-A (p < 0.05). Similarly, serum CXCL1 levels after rituximab administration correlated with percent predicted forced vital capacity (p < 0.05) and serum SP-D levels (p < 0.05) after rituximab. Conclusions: Our results suggest that serum CXCL1 is associated with the disease activity of SSc-ILD, and high serum CXCL1 levels are one of the predictors of improvement in SSc-ILD with rituximab.