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Abstract Background Extracorporeal membrane oxygenation (ECMO) can provide temporary circulatory support and vital organ oxygenation and is potentially useful as a bridge therapy in some trauma cases. We aimed to demonstrate the characteristics and outcomes of patients with trauma treated with veno-arterial ECMO (V-A ECMO) using data from a Japanese nationwide trauma registry. Methods This retrospective descriptive study analyzed data from the Japan Trauma Data Bank between January 2019 and December 2021. Patients with severe trauma (injury severity score [ISS] ≥ 9) and treated using V-A ECMO were assessed. Results Among the 72,439 patients with severe trauma, 51 received V-A ECMO. Sixteen patients (31.3%) survived until hospital discharge. On hospital arrival, six (37.5%) survivors and 15 (42.9%) non-survivors experienced cardiac arrest. The median ISS for the survivor and non-survivor group was 25 (range, 25–39) and 25 (range, 17–33), respectively. Thoracic trauma was the most common type of trauma in both groups. In the non-survivor group, open-chest cardiopulmonary resuscitation, aortic cross-clamping, and resuscitative endovascular balloon occlusion of the aorta were performed in 10 (28.6%), 5 (14.3%), and 4 (11.4%) patients, respectively. However, these procedures were not performed in the survivor group. Peripheral oxygen saturation tended to be lower in the survivor group both before and upon arrival at the hospital. Conclusions The results of this study suggest the potential benefit of V-A ECMO in some challenging trauma cases. Further studies are warranted to assess the indications for V-A ECMO in patients with trauma.

Abstract Background Stenosis resulting in dysfunctional dialysis access may occur simultaneously on the anastomotic and central venous side. The purpose of this study was to retrospectively evaluate the feasibility of a single sheath inverse technique using the vertical puncture approach to perform bidirectional transvenous percutaneous transluminal angioplasty (PTA) from a single sheath for such dialysis access stenoses. Materials and Methods Twenty patients (26 cases; 13 males; median age, 74 [range: 50–89] years) who underwent PTA using the sheath inverse technique for dysfunctional arteriovenous fistula stenoses between April 2019 and June 2023 were included. All procedures were performed in an outpatient setting. A 4-cm sheath (4Fr, four cases; 5Fr, 19 cases; 6Fr, three cases) was inserted by vertical puncture through a cutaneous vein in the forearm (20 cases) or upper arm (six cases). After treating one side of the lesion, the sheath was reversed to treat the lesion on the opposite side. The vessel diameter at the sheath insertion site, the success rate of sheath inversion, the number of PTA balloon catheters used, the PTA success rate, adverse events, and primary and secondary patency rates up to one year after PTA were evaluated. Results The median diameter at the sheath indwelling site was 5.2 (range: 3.6–9.5) mm, and sheath inversion was successful in all cases, eliminating the need to place an additional sheath at another site for contralateral stricture treatment. The number of balloon catheters used was one and two in 17 (65%) and eight cases (31%), respectively, and three in one case wherein a drug-coated balloon was used. PTA was successful in all cases and major complications were not observed. However, in one case wherein a sheath had to be placed at the arterial needle puncture site, the skin was hard, leading to difficulty in inversion, and transient venous spasm occurred post-inversion. The primary patency rates at 3, 6 and 12 months after the PTA were 87.5%, 41.7%, and 20.8%, respectively. The secondary patency rates at 6 and 12 months were 100% and 75%, respectively. Conclusion The single-sheath inverse technique for arteriovenous fistulas was feasible without sheath withdrawal. Graphical Abstract

Background: Pediatric trauma patients often have disability after successful resuscitation for hemorrhage. Clinical characteristics related to dependency on living following injury were elucidated among pediatric patients without traumatic brain injury. Methods: This retrospective cohort study used the 2019–2021 Japan Trauma Data Bank and included pediatric patients aged ≤16 years without head injury (Abbreviated Injury Scale [AIS] ≥ 2). The unfavorable function was defined as dependency in daily life at discharge (Glasgow Outcome Scale ≤ 3), and predictors for unfavorable functional outcomes were examined using a generalized estimating equations (GEE) model, including age, sex, physical disability before injury, injury mechanism, transportation time, prehospital procedures, vital signs on arrival, surgery in each body region, transfusion, AIS in each region, and institutions. Furthermore, these factors were analyzed separately in toddler/preschool (≤5 years), school age (6–11 years), and adolescence (12–16 years). Results: Among 1,412 patients eligible for the study, 137 had an unfavorable physical function at discharge. The GEE model revealed that female sex, physical disability before injury, prehospital transfusion, lower Glasgow Coma Score (GCS) score on arrival, neck surgery, and higher AIS in the neck and extremity/pelvis were independently associated with unfavorable function at discharge. In age-specific analyses, physical disability before injury strongly predicted worse functional outcomes in toddlers/preschoolers, whereas higher AIS in the chest and lower systolic blood pressure on arrival were additional predictors of dependent living among adolescents. Conclusions: Severe neck/extremity/pelvis injury and lower GCS on arrival are associated with unfavorable functional outcomes in patients with pediatric trauma.

A 59-year-old man with pancytopenia underwent 18F-fluorodeoxyglucose positron emission tomography/computed tomography for suspected carcinomatosis. The scan revealed diffuse bone marrow uptake, prompting further investigation. Bone marrow analysis revealed no malignant cells; however, erythroblasts with cytoplasmic vacuolization were observed. Subsequent testing showed low serum copper and ceruloplasmin levels, indicating copper deficiency. Copper supplementation resulted in significant improvement in cytopenia. Notably, the bone marrow uptake on subsequent scans decreased significantly. This case highlights the importance of considering copper deficiency as a potential cause of diffuse bone marrow uptake of 18F-fluorodeoxyglucose on positron emission tomography/computed tomography.

Abstract Background and objective A prospective, postmarketing observational study was conducted to evaluate the safety and efficacy of lemborexant (LEM) tablets in daily clinical practice in Japan. No other studies of a similar size have been conducted since the marketing approval of LEM, making this the first report of its kind. Methods Insomnia patients (n = 550) administered LEM (5–10 mg daily) for the first time were enrolled. Adverse events were collected for target events (somnolence, parasomnia, narcolepsy and associated conditions, suicidal ideation and suicidal behavior). Overall improvement of insomnia symptoms was assessed by the investigator based on the patient’s complaint. Subjective sleep onset latency (sSOL) and subjective total sleep time (sTST) were investigated as sleep parameters. Results A case report form was obtained from 539 patients. The incidence of adverse drug reactions (ADRs) was 7.65% for somnolence, 1.76% for nightmares, 0.59% for abnormal dreams, and 0.20% for sleep paralysis. No serious ADRs or ADRs related to suicidal ideation or suicidal behavior were observed. The efficacy rate at the final evaluation was 80.83%. Decreased sSOL and increased sTST were observed as assessed starting from Week 8 of treatment. Conclusion Based on the results of this study, the safety result was consistent with the safety profile described in the current package insert. Efficacy results also indicated that LEM is clinically useful.

Abstract Background Resuscitative endovascular balloon occlusion of the aorta (REBOA) has been used to control massive hemorrhages. Although there is no consensus on the efficacy of REBOA, it remains an option as a bridging therapy in non-trauma centers where trauma surgeons are not available. To better understand the current landscape of REBOA application, we examined changes in its usage, target population, and treatment outcomes in Japan, where immediate hemostasis procedures sometimes cannot be performed. Methods This retrospective observational study used the Japan Trauma Data Bank data. All cases in which REBOA was performed between January 2004 and December 2021 were included. The primary outcome was the in-hospital mortality rate. We analyzed mortality trends over time according to the number of cases, number of centers, severity of injury, and overall and subgroup mortality associated with REBOA usage. We performed a logistic analysis of mortality trends over time, adjusting for probability of survival based on the trauma and injury severity score. Results Overall, 2557 patients were treated with REBOA and were deemed eligible for inclusion. The median age of the participants was 55 years, and male patients constituted 65.3% of the study population. Blunt trauma accounted for approximately 93.0% of the cases. The number of cases and facilities that used REBOA increased until 2019. While the injury severity score and revised trauma score did not change throughout the observation period, the hospital mortality rate decreased from 91.3 to 50.9%. The REBOA group without severe head or spine injuries showed greater improvement in mortality than the all-patient group using REBOA and all-trauma patient group. The greatest improvement in mortality was observed in patients with systolic blood pressure ≥ 80 mmHg. The adjusted odds ratios for hospital mortality steadily declined, even after adjusting for the probability of survival. Conclusions While there was no significant change in patient severity, mortality of patients treated with REBOA decreased over time. Further research is required to determine the reasons for these improvements in trauma care.

In a paper recently published in Nature Medicine, Fukumoto et al. tried to assess the government-led school closure policy during the early phase of the COVID-19 pandemic in Japan. They compared the reported incidence rates between municipalities that had and had not implemented school closure in selected periods from March–May 2020, where they matched for various potential confounders, and claimed that there was no causal effect on the incidence rates of COVID-19. However, the effective sample size (ESS) of their dataset had been substantially reduced in the process of matching due to imbalanced covariates between the treatment (i.e. with closure) and control (without closure) municipalities, which led to the wide uncertainty in the estimates. Despite the study title starting with “No causal effect of school closures”, their results are insufficient to exclude the possibility of a strong mitigating effect of school closure on incidence of COVID-19. In this replication/reanalysis study, we showed that the confidence intervals of the effect estimates from Fukumoto et al. included a 100% relative reduction in COVID-19 incidence. Simulations of a hypothetical 50% or 80% mitigating effect hardly yielded statistical significance with the same study design and sample size. We also showed that matching of variables that had large influence on propensity scores (e.g. prefecture dummy variables) may have been incomplete.

Abstract Background The organ dysfunction that is associated with death in COVID-19 patients has not been determined in multicenter epidemiologic studies. In this study, we evaluated the major association with death, concomitant organ dysfunction, and proportion of multiple organ failure in deaths in patients with COVID-19, along with information on organ support. Methods We performed an observational cohort study using the Japanese multicenter research of COVID-19 by assembling a real-world data (J-RECOVER) study database. This database consists of data on patients discharged between January 1 and September 31, 2020, with positive SARS-CoV-2 test results, regardless of intensive care unit admission status. These data were collected from the Diagnosis Procedure Combination and electronic medical records of 66 hospitals in Japan. The clinician identified and recorded the organ responsible for the death of COVID-19. Results During the research period, 4,700 patients with COVID-19 were discharged from 66 hospitals participating in the J-RECOVER study; of which, 272 patients (5.8%) from 47 institutions who died were included in this study. Respiratory system dysfunction (87.1%) was the leading association with death, followed by cardiovascular (4.8%), central nervous (2.9%), gastrointestinal (2.6%), and renal (1.1%) dysfunction. Most patients (96.7%) who died of COVID-19 had respiratory system damage, and about half (48.9%) had multi-organ damage. Of the patients whose main association with death was respiratory dysfunction, 120 (50.6%) received mechanical ventilation. Conclusion This study showed that although respiratory dysfunction was the most common association with death in many cases, multi-organ dysfunction was associated with death due to COVID-19.

Objectives: Invasive group A Streptococcus infection (iGAS) is a rare but fatal condition. We aimed to evaluate the effectiveness of intravenous immunoglobulin (IVIG) in the treatment of iGAS. Methods: Patients’ data were extracted from a Japanese nationwide database between April 2018 and March 2021. The primary outcome was in-hospital mortality rate, whereas the secondary outcomes were 30-day and 7-day mortality rates. Results: Overall, 481 patients (median age, 65 years; female, 49.7%) were included in the analysis. The overall mortality rate was 31.0%. After adjusting for background factors, we found that IVIG treatment had no effect on in-hospital mortality (adjusted odds ratio [OR]: 0.99, 95% confidence interval [CI]: 0.93-1.04, P = 0.92). Similar results were obtained after propensity score matching (OR: 1.00, 95% CI: 0.62-1.61, P >0.99). The 7-day and 30-day mortality rates were not associated with IVIG treatment. Conclusion: IVIG administration had no survival benefit in iGAS patients. However, these overall findings should not be extrapolated to streptococcal toxic shock syndrome as the effect of IVIG therapy in this condition remains uncertain. Considering the rarity of iGAS, conducting a randomized controlled trial may be impractical. Therefore, an equivalent or more extensive observational study is warranted to validate these findings.

Abstract Background Previous studies have reported conflicting results regarding fresh frozen plasma (FFP)-to-red blood cell (RBC) ratio and platelet-to-RBC ratio on outcomes for massive transfusion for trauma. Moreover, nationwide data on massive transfusion practices for trauma in the real-world clinical setting are scarce. This study aimed to examine the nationwide practice patterns and trends in massive transfusion for trauma in Japan using a national administrative, inpatient database. Method We identified patients who underwent emergency hospitalization for trauma and received massive transfusion, defined as administration of at least 20 units of RBC within the first 2 days of admission, using the nationwide inpatient database, which covers approximately 90% of all tertiary emergency hospitals in Japan, between 2011 and 2020. Trends in the incidence and practice patterns of massive transfusion were described by calendar year. The association of practice patterns with mortality or adverse events was tested. Results A total of 3,530,846 trauma hospitalizations were identified, of which 5247 (0.15%) received massive transfusion. A significant declining trend was observed in the incidence of massive transfusion in trauma hospitalizations from 0.24% in 2011 to 0.10% in 2020 (P for trend

Chinese yam production is thriving in Aomori Prefecture, a cold and snowy region in Japan. Recently, there has been an increasing risk of nitrogen leaching in Chinese-yam fields, which consist of sandy soil, due to localized torrential rain. The relationships between the type of fertilizer used for Chinese-yam cultivation, the amount of nitrogen (N) leaching, and the timing of leaching remain unknown. Therefore, this study aimed to fill this knowledge gap by investigating the effects of different fertilizers (fast-acting and/or slow-release fertilizer) and irrigation practices (conventional and/or excessive irrigation) in order to mitigate the detrimental impact of nitrogen leaching on groundwater quality. An enhanced mathematical model and the spatiotemporal dynamics of inorganic nitrogen concentration in soil pore water were evaluated the negative impact of nitrogen leaching on the groundwater environment was evaluated. The results showed that the combined use of slow-release fertilizers could significantly reduce nitrate-nitrogen concentration in soil-water, especially during the harvest season. This study demonstrated that cultivating Chinese yam with a fertilizer application system that includes the use of slow-release fertilizer can diminish the negative impact of nitrogen leaching on the groundwater environment, contributing to our understanding of sustainable agricultural practices in regions facing similar environmental challenges. Therefore, our findings represent an important advancement providing new approaches to maintaining productivity while mitigating the adverse impacts on groundwater environments, as well as offering guidelines for agricultural practices in regions facing similar environmental challenges.

In a paper recently published in Nature Medicine, Fukumoto et al. tried to assess the government-led school closure policy during the early phase of the COVID-19 pandemic in Japan. They compared the reported incidence rates between municipalities that had and had not implemented school closure in selected periods from March–May 2020, where they matched for various potential confounders, and claimed that there was no causal effect on the incidence rates of COVID-19. However, the effective sample size (ESS) of their dataset had been substantially reduced in the process of matching due to imbalanced covariates between the treatment (i.e. with closure) and control (without closure) municipalities, which led to the wide uncertainty in the estimates. Despite the study title starting with “No causal effect of school closures”, their results are insufficient to exclude the possibility of a strong mitigating effect of school closure on incidence of COVID-19. In this replication/reanalysis study, we showed that the confidence intervals of the effect estimates from Fukumoto et al. included a 100% relative reduction in COVID-19 incidence. Simulations of a hypothetical 50% or 80% mitigating effect hardly yielded statistical significance with the same study design and sample size. We also showed that matching of variables that had large influence on propensity scores (e.g. prefecture dummy variables) may have been incomplete.

Abstract Background The efficacies of fresh frozen plasma and coagulation factor transfusion have been widely evaluated in trauma-induced coagulopathy management during the acute post-injury phase. However, the efficacy of red blood cell transfusion has not been adequately investigated in patients with severe trauma, and the optimal hemoglobin target level during the acute post-injury and resuscitation phases remains unclear. Therefore, this study aimed to examine whether a restrictive transfusion strategy was clinically non-inferior to a liberal transfusion strategy during the acute post-injury phase. Methods This cluster-randomized, crossover, non-inferiority multicenter trial was conducted at 22 tertiary emergency medical institutions in Japan and included adult patients with severe trauma at risk of major bleeding. The institutions were allocated a restrictive or liberal transfusion strategy (target hemoglobin levels: 7–9 or 10–12 g/dL, respectively). The strategies were applied to patients immediately after arrival at the emergency department. The primary outcome was 28-day survival after arrival at the emergency department. Secondary outcomes included transfusion volume, complication rates, and event-free days. The non-inferiority margin was set at 3%. Results The 28-day survival rates of patients in the restrictive (n = 216) and liberal (n = 195) strategy groups were 92.1% and 91.3%, respectively. The adjusted odds ratio for 28-day survival in the restrictive versus liberal strategy group was 1.02 (95% confidence interval: 0.49–2.13). Significant non-inferiority was not observed. Transfusion volumes and hemoglobin levels were lower in the restrictive strategy group than in the liberal strategy group. No between-group differences were noted in complication rates or event-free days. Conclusions Although non-inferiority of the restrictive versus liberal transfusion strategy for 28-day survival was not statistically significant, the mortality and complication rates were similar between the groups. The restrictive transfusion strategy results in a lower transfusion volume. Trial registration number: umin.ac.jp/ctr: UMIN000034405, registration date: 8 October 2018.

Abstract This study aimed to determine whether obesity and disease outcomes are associated in patients with critically-ill coronavirus disease 2019 (COVID-19) requiring invasive mechanical ventilation (IMV). This retrospective observational study using Japanese multicenter registry data included COVID-19 patients who required IMV and were discharged between January and September 2020. The patients were divided into the obese (body mass index [BMI] ≥ 25 kg/m2) and nonobese (BMI

Abstract Cell proliferation processes play pivotal roles in timely adaptation to many biological situations. Herein, we establish a highly sensitive and simple strategy by which time-series showing the proliferation of a targeted cell type can be quantitatively monitored in vivo in the same individuals. We generate mice expressing a secreted type of luciferase only in cells producing Cre under the control of the Ki67 promoter. Crossing these with tissue-specific Cre-expressing mice allows us to monitor the proliferation time course of pancreatic β-cells, which are few in number and weakly proliferative, by measuring plasma luciferase activity. Physiological time courses, during obesity development, pregnancy and juvenile growth, as well as diurnal variation, of β-cell proliferation, are clearly detected. Moreover, this strategy can be utilized for highly sensitive ex vivo screening for proliferative factors for targeted cells. Thus, these technologies may contribute to advancements in broad areas of biological and medical research.

Abstract Background Anorectal injury caused by personal watercraft (PWC)‐related trauma is rare. However, PWC accidents have increased recently, and since patients tend to be younger, treatment strategies should consider anal function preservation in addition to saving lives. Case Presentation A 30‐year‐old female patient who fell into the water when a PWC suddenly accelerated and injured her perineum with a forceful water jet was transported to our hospital. On examination, she was diagnosed with a traumatic rectal perforation with intraperitoneal findings and an anorectal injury. Emergency surgery, which involved direct suturing, temporary colostomy with intraoperative endoscopy for the rectal perforation, and anorectal reconstruction, was performed. The patient was discharged on postoperative day 19 without complications, and the colostomy was closed 5 months postoperatively. Conclusion We encountered a case of multiple noncontinuous anorectal injuries due to a PWC accident that was successfully treated using a combination of surgery and intraoperative endoscopy.

Monitoring time-varying vaccine effectiveness (e.g., due to waning of immunity and the emergence of novel variants) provides crucial information for outbreak control. Existing studies of time-varying vaccine effectiveness have used individual-level data, most importantly dates of vaccination and variant classification, which are often not available in a timely manner or from a wide range of population groups. We present a novel Bayesian framework for estimating the waning of variant-specific vaccine effectiveness in the presence of multi-variant circulation from population-level surveillance data. Applications to simulated outbreaks and the COVID-19 epidemic in Japan are also presented. Our results show that variant-specific waning vaccine effectiveness estimated from population-level surveillance data could approximately reproduce the estimates from previous test-negative design studies, allowing for rapid, if crude, assessment of the epidemic situation before fine-scale studies are made available.

Abstract Aim The prophylactic effect of negative‐pressure wound therapy against incisional surgical site infection after highly contaminated laparotomies has not been sufficiently explored. This study aimed to evaluate the prophylactic effect of negative‐pressure wound therapy against incisional surgical site infection after emergency surgery for colorectal perforation. Methods This nationwide, multicenter, retrospective cohort study analyzed data from the 48 emergency hospitals certificated by the Japanese Society for Abdominal Emergency Medicine. Patients who underwent an emergency laparotomy for colorectal perforation between April 2015 and March 2020 were included in this study. Outcomes, including the incidence of incisional surgical site infection, were compared between patients who were treated with prophylactic negative‐pressure wound therapy and delayed sutures (i.e., negative‐pressure wound therapy group) and patients who were treated with regular wound management (i.e., control group) using 1:4 propensity score matching analysis. Results The negative‐pressure wound therapy group comprised 88 patients, whereas the control group consisted of 1535 patients. Of them, 82 propensity score‐matched pairs (negative‐pressure wound therapy group: 82; control group: 328) were evaluated. The negative‐pressure wound therapy group showed a lower incidence of incisional surgical site infection [18 (22.0%) in the negative‐pressure wound therapy group and 115 (35.0%) in the control group, odds ratio, 0.52; 95% confidence interval, 0.30 to 0.92; p = 0.026]. Conclusions The prophylactic use of negative‐pressure wound therapy with delayed sutures was associated with a lower incidence of incisional surgical site infection after emergency surgery for colorectal perforation.

Abstract Background A recurrent feature of infectious diseases is the observation that different individuals show different levels of secondary transmission. This inter-individual variation in transmission potential is often quantified by the dispersion parameter k. Low values of k indicate a high degree of variability and a greater probability of superspreading events. Understanding k for COVID-19 across contexts can assist policy makers prepare for future pandemics. Methods A literature search following a systematic approach was carried out in PubMed, Embase, Web of Science, Cochrane Library, medRxiv, bioRxiv and arXiv to identify publications containing epidemiological findings on superspreading in COVID-19. Study characteristics, epidemiological data, including estimates for k and R0, and public health recommendations were extracted from relevant records. Results The literature search yielded 28 peer-reviewed studies. The mean k estimates ranged from 0.04 to 2.97. Among the 28 studies, 93% reported mean k estimates lower than one, which is considered as marked heterogeneity in inter-individual transmission potential. Recommended control measures were specifically aimed at preventing superspreading events. The combination of forward and backward contact tracing, timely confirmation of cases, rapid case isolation, vaccination and preventive measures were suggested as important components to suppress superspreading. Conclusions Superspreading events were a major feature in the pandemic of SARS-CoV-2. On the one hand, this made outbreaks potentially more explosive but on the other hand also more responsive to public health interventions. Going forward, understanding k is critical for tailoring public health measures to high-risk groups and settings where superspreading events occur.

Abstract Objective A centrifugation-assisted peptide-mediated gene transfer (CAPT) method was recently developed as an efficient system for gene delivery into plant cells. However, the gene transfer efficiency of CAPT into plant cells was not entirely satisfactory for detecting transient expression of a transgene driven into mitochondria. Here, we report a new gene delivery system using a method called particle bombardment-assisted peptide-mediated gene transfer (PBPT). Results We investigated various parameters of the PBPT method to increase transient gene expression efficiency in Brassica campestris. The optimal conditions for PBPT were a single bombardment with gold particles coated with a DNA‒peptide complex (6 µg of DNA and 2 µg of peptide) at an acceleration pressure of 5 kg/cm2 and a target distance of 12.5 cm. Moreover, bombardment under the optimal conditions successfully transferred the transgene into the cells of other plant species, namely B. juncea and tomato. Thus, we developed a PBPT method for highly efficient delivery of a DNA‒peptide complex into plant mitochondria.

Abstract Seasonal influenza outbreaks remain an important public health concern, causing large numbers of hospitalizations and deaths among high-risk groups. Understanding the dynamics of individual transmission is crucial to design effective control measures and ultimately reduce the burden caused by influenza outbreaks. In this study, we analyzed surveillance data from Kamigoto Island, Japan, a semi-isolated island population, to identify the drivers of influenza transmission during outbreaks. We used rapid influenza diagnostic test (RDT)-confirmed surveillance data from Kamigoto island, Japan and estimated age-specific influenza relative illness ratios (RIRs) over eight epidemic seasons (2010/11 to 2017/18). We reconstructed the probabilistic transmission trees (i.e., a network of who-infected-whom) using Bayesian inference with Markov-chain Monte Carlo method and then performed a negative binomial regression on the inferred transmission trees to identify the factors associated with onwards transmission risk. Pre-school and school-aged children were most at risk of getting infected with influenza, with RIRs values consistently above one. The maximal RIR values were 5.99 (95% CI 5.23, 6.78) in the 7–12 aged-group and 5.68 (95%CI 4.59, 6.99) in the 4–6 aged-group in 2011/12. The transmission tree reconstruction suggested that the number of imported cases were consistently higher in the most populated and busy districts (Tainoura-go and Arikawa-go) ranged from 10–20 to 30–36 imported cases per season. The number of secondary cases generated by each case were also higher in these districts, which had the highest individual reproduction number (Reff: 1.2–1.7) across the seasons. Across all inferred transmission trees, the regression analysis showed that cases reported in districts with lower local vaccination coverage (incidence rate ratio IRR = 1.45 (95% CI 1.02, 2.05)) or higher number of inhabitants (IRR = 2.00 (95% CI 1.89, 2.12)) caused more secondary transmissions. Being younger than 18 years old (IRR = 1.38 (95%CI 1.21, 1.57) among 4–6 years old and 1.45 (95% CI 1.33, 1.59) 7–12 years old) and infection with influenza type A (type B IRR = 0.83 (95% CI 0.77, 0.90)) were also associated with higher numbers of onwards transmissions. However, conditional on being infected, we did not find any association between individual vaccination status and onwards transmissibility. Our study showed the importance of focusing public health efforts on achieving high vaccine coverage throughout the island, especially in more populated districts. The strong association between local vaccine coverage (including neighboring regions), and the risk of transmission indicate the importance of achieving homogeneously high vaccine coverage. The individual vaccine status may not prevent onwards transmission, though it may reduce the severity of infection.

Abstract We aimed to evaluate the association between ICU patient volume before the COVID-19 pandemic and the outcomes of ventilated COVID-19 patients. We analyzed ventilated patients with COVID-19 aged > 17 years and enrolled in the J-RECOVER study, a retrospective multicenter observational study conducted in Japan between January and September 2020. Based on the number of patients admitted to the ICU between January and December 2019, the top third institutions were defined as high-volume centers, the middle third ones as middle-volume centers, and the bottom third ones as low-volume centers. The primary outcome measure was in-hospital mortality. Multivariate logistic regression analysis for in-hospital mortality and ICU patient volume was performed after adjusting for multiple propensity scores. Among 461 patients, 158, 158, and 145 patients were admitted to low-volume (20 institutions), middle-volume (14 institutions), and high-volume (13 institutions) centers, respectively. Admission to middle- and high-volume centers was not significantly associated with in-hospital death compared with admission to low-volume centers (adjusted odds ratio, 1.11 [95% confidence interval (CI): 0.55–2.25] and adjusted odds ratio, 0.81 [95% CI: 0.31–1.94], respectively). In conclusion, institutional intensive care patient volume prior to the COVID-19 pandemic was not significantly associated with in-hospital death in ventilated COVID-19 patients.

Introduction Cardiac arrest is a critical condition, and patients often experience postcardiac arrest syndrome (PCAS) even after the return of spontaneous circulation (ROSC). Administering a restricted amount of oxygen in the early phase after ROSC has been suggested as a potential therapy for PCAS; however, the optimal target for arterial partial pressure of oxygen or peripheral oxygen saturation (SpO2) to safely and effectively reduce oxygen remains unclear. Therefore, we aimed to validate the efficacy of restricted oxygen treatment with 94%–95% of the target SpO2 during the initial 12 hours after ROSC for patients with PCAS.Methods and analysis ER-OXYTRAC (early restricted oxygen therapy after resuscitation from cardiac arrest) is a nationwide, multicentre, pragmatic, single-blind, stepped-wedge cluster randomised controlled trial targeting cases of non-traumatic cardiac arrest. This study includes adult patients with out-of-hospital or in-hospital cardiac arrest who achieved ROSC in 39 tertiary centres across Japan, with a target sample size of 1000. Patients whose circulation has returned before hospital arrival and those with cardiac arrest due to intracranial disease or intoxication are excluded. Study participants are assigned to either the restricted oxygen (titration of a fraction of inspired oxygen with 94%–95% of the target SpO2) or the control (98%–100% of the target SpO2) group based on cluster randomisation per institution. The trial intervention continues until 12 hours after ROSC. Other treatments for PCAS, including oxygen administration later than 12 hours, can be determined by the treating physicians. The primary outcome is favourable neurological function, defined as cerebral performance category 1–2 at 90 days after ROSC, to be compared using an intention-to-treat analysis.Ethics and dissemination This study has been approved by the Institutional Review Board at Keio University School of Medicine (approval number: 20211106). Written informed consent will be obtained from all participants or their legal representatives. Results will be disseminated via publications and presentations.Trial registration number UMIN Clinical Trials Registry (UMIN000046914).

ABSTRACT Aims/Introduction Whether basal β‐cell proliferation during adulthood is involved in maintaining sufficient β‐cell mass, and if so, the molecular mechanism(s) underlying basal β‐cell proliferation remain unclear. FoxM1 is a critical transcription factor which is known to play roles in ‘adaptive’ β‐cell proliferation, which facilitates rapid increases in β‐cell mass in response to increased insulin demands. Therefore, herein we focused on the roles of β‐cell FoxM1 in ‘basal’ β‐cell proliferation under normal conditions and in the maintenance of sufficient β‐cell mass as well as glucose homeostasis during adulthood. Materials and Methods FoxM1 deficiency was induced specifically in β‐cells of 8‐week‐old mice, followed by analyzing its short‐ (2 weeks) and long‐ (10 months) term effects on β‐cell proliferation, β‐cell mass, and glucose tolerance. Results FoxM1 deficiency suppressed β‐cell proliferation at both ages, indicating critical roles of FoxM1 in basal β‐cell proliferation throughout adulthood. While short‐term FoxM1 deficiency affected neither β‐cell mass nor glucose tolerance, long‐term FoxM1 deficiency suppressed β‐cell mass increases with impaired insulin secretion, thereby worsening glucose tolerance. In contrast, the insulin secretory function was not impaired in islets isolated from mice subjected to long‐term β‐cell FoxM1 deficiency. Therefore, β‐cell mass reduction is the primary cause of impaired insulin secretion and deterioration of glucose tolerance due to long‐term β‐cell FoxM1 deficiency. Conclusions Basal low‐level proliferation of β‐cells during adulthood is important for maintaining sufficient β‐cell mass and good glucose tolerance and β‐cell FoxM1 underlies this mechanism. Preserving β‐cell FoxM1 activity may prevent the impairment of glucose tolerance with advancing age.

Abstract Background Hemodynamic stabilization is a core component in the resuscitation of septic shock. However, the optimal target blood pressure remains debatable. Previous randomized controlled trials suggested that uniformly adopting a target mean arterial pressure (MAP) higher than 65 mmHg for all adult septic shock patients would not be beneficial; however, it has also been proposed that higher target MAP may be beneficial for elderly patients, especially those with arteriosclerosis. Methods A multicenter, pragmatic single-blind randomized controlled trial will be conducted to compare target MAP of 80–85 mmHg (high-target) and 65–70 mmHg (control) in the resuscitation of septic shock patients admitted to 28 hospitals in Japan. Patients with septic shock aged ≥65 years are randomly assigned to the high-target or control groups. The target MAP shall be maintained for 72 h after randomization or until vasopressors are no longer needed to improve patients’ condition. To minimize the adverse effects related to catecholamines, if norepinephrine dose of ≥ 0.1 μg/kg/min is needed to maintain the target MAP, vasopressin will be initiated. Other therapeutic approaches, including fluid administration, hydrocortisone use, and antibiotic choice, will be determined by the physician in charge based on the latest clinical guidelines. The primary outcome is all-cause mortality at 90 days after randomization. Discussion The result of this trial will provide great insight on the resuscitation strategy for septic shock in the era of global aged society. Also, it will provide the better understanding on the importance of individualized treatment strategy in hemodynamic management in critically ill patients. Trial registration UMIN Clinical Trials Registry; UMIN000041775. Registered 13 September 2020.

Key Clinical Message Even if cardiac rhythm deteriorated to asystole in the clinical course of fulminant myocarditis, cardiac function may recover, and the patient may be discharged without brain damage, if circulation could be maintained by appropriate mechanical cardiac supports. Abstract A 69‐year‐old man was diagnosed with fulminant myocarditis with circulatory collapse. His cardiac rhythm deteriorated to asystole on the second day; however, circulatory status was maintained through extracorporeal membrane oxygenation and intra‐aortic balloon pumping. After 38 h‐lasting asystole, his heart resumed beating. He was discharged without neurological deficits on Day 25.

Retention in healthcare and health behavior remains a critical issue, contributing to inequitable distribution of intervention benefits. In diseases such as HIV, where half of the new infections occur among racial and sexual minorities, it is important that interventions do not enlarge pre-existing health disparities. To effectively combat this public health issue, it is crucial that we quantify the magnitude of racial/ethnic disparity in retention. Further, there is a need to identify mediating factors to this relationship to inform equitable intervention design. In the present study, we assess the racial/ethnic disparity in retention in a peer-led online behavioral intervention to increase HIV self-testing behavior and identify explanatory factors. The research used data collected from the Harnessing Online Peer Education (HOPE) HIV Study that included 899 primarily African American and Latinx men who have sex with men (MSM) in the United States. Results show that African American participants had higher lost-to-follow-up rates at 12-week follow-up compared to Latinx participants (11.1% and 5.8% respectively, Odds Ratio = 2.18, 95% confidence interval: 1.12 – 4.11, p = 0.02), which is substantially mediated by participants’ self-rated health score (14.1% of the variation in the African American v.s. Latinx difference in lost-follow-up, p = 0.006). Thus, how MSM perceive their health may play an important role in their retention in HIV-related behavioral intervention programs and its racial/ethnic disparity.

Abstract Background Hospital- and community-onset sepsis are significant sepsis subgroups. Japanese data comparing these subgroups are limited. This study aimed to describe the epidemiology of hospital- and community-onset sepsis in critical care units in Japan. Methods We performed a retrospective cohort study using the Japanese Diagnosis and Procedure Combination database. Adult patients admitted to critical care units with sepsis from April 2010 to March 2020 were included. Sepsis cases were identified based on ICD-10 codes for infectious diseases, procedure codes for blood culture tests, and medication codes for antimicrobials. Patients’ characteristics, in-hospital mortality, and resource utilization were assessed. The in-hospital mortality between groups was compared using the Poisson regression generalized linear mixed-effect model. Results Of 516,124 patients, 52,183 (10.1%) had hospital-onset sepsis and 463,940 (89.9%) had community-onset sepsis. Hospital-onset sepsis was characterized by younger age, infrequent emergency hospitalization, frequent surgery under general anesthesia, and frequent organ support upon critical care unit admission compared to community-onset sepsis. In-hospital mortality was higher for hospital-onset than for community-onset sepsis (35.5% versus 19.2%; unadjusted mean difference, 16.3% [95% confidence interval (CI) 15.9–16.7]; adjusted mean difference, 15.6% [95% CI 14.9–16.2]). Mean hospital length of stay was longer for hospital-onset than for community-onset sepsis (47 days versus 30 days; unadjusted mean difference, 17 days [95% CI 16–17]; adjusted mean difference, 13 days [95% CI 12–14]). Conclusion Patients with hospital-onset sepsis admitted to critical care units in Japan had a poorer prognosis and more resource utilization including organ support rate, number of days with critical care unit surcharge codes, and hospital length of stay than those with community-onset sepsis.

Abstract Background Some academic organizations recommended that physicians intubate patients with COVID-19 with a relatively lower threshold of oxygen usage particularly in the early phase of pandemic. We aimed to elucidate whether early intubation is associated with decreased in-hospital mortality among patients with novel coronavirus disease 2019 (COVID-19) who required intubation. Methods A multicenter, retrospective, observational study was conducted at 66 hospitals in Japan where patients with moderate-to-severe COVID-19 were treated between January and September 2020. Patients who were diagnosed as COVID-19 with a positive reverse-transcription polymerase chain reaction test and intubated during admission were included. Early intubation was defined as intubation conducted in the setting of ≤ 6 L/min of oxygen usage. In-hospital mortality was compared between patients with early and non-early intubation. Inverse probability weighting analyses with propensity scores were performed to adjust patient demographics, comorbidities, hemodynamic status on admission and time at intubation, medications before intubation, severity of COVID-19, and institution characteristics. Subgroup analyses were conducted on the basis of age, severity of hypoxemia at intubation, and days from admission to intubation. Results Among 412 patients eligible for the study, 110 underwent early intubation. In-hospital mortality was lower in patients with early intubation than those with non-early intubation (18 [16.4%] vs. 88 [29.1%]; odds ratio, 0.48 [95% confidence interval 0.27–0.84]; p = 0.009, and adjusted odds ratio, 0.28 [95% confidence interval 0.19–0.42]; p

Abstract We report the case of a 33‐year‐old man with a self‐inflicted neck wound with severe hypopharynx injury, and hemorrhagic shock, which was well managed by a trauma surgeon trained in esophageal surgery. Training in cervical lymph node dissection for esophageal cancer could be useful in the management of penetrating neck injuries.

Abstract Background As the prognosis of esophageal cancer surgery has improved, reports on postoperative complications of gastric tubes have increased. Among them, gastric tube ulcer perforation is infrequent but often severe and difficult to treat. Case Presentation A 73‐year‐old man had undergone thoracoscopic subtotal esophagectomy and laparoscopic‐assisted gastric tube reconstruction via the retrosternal route for thoracic esophageal cancer 8 years previously. He was transferred to our hospital with a diagnosis of gastric tube ulcer perforation, penetrating the pericardium. Emergency surgery was performed to remove the gastric tube, followed by immediate reconstruction by right colon interposition. The patient was discharged on postoperative day 142. Conclusion We report a rare complication of gastric tube ulcer perforation, penetrating the pericardium, after esophagectomy for esophageal cancer. It was successfully treated with appropriate surgical management.

Aim To compare in‐hospital mortality of severely injured trauma patients who underwent resuscitative endovascular balloon occlusion of the aorta (REBOA) or aortic cross‐clamping (ACC). Methods In this multicenter, retrospective cohort study using data from a nationwide trauma registry of tertiary emergency medical centers in Japan (n = 280), trauma patients who underwent aortic occlusion at the emergency department from 2004 to 2019 were divided into two groups according to the treatment they received: patients treated with ACC and patients who underwent placement of a REBOA catheter. Multiple imputations were used to handle the missing data. In‐hospital mortality of the patients who underwent REBOA or ACC was compared using a mixed‐effect logistic regression analysis and a propensity score‐matching analysis, in which the confounders, including baseline patient demographics and severity, were adjusted. Results Of 1,670 patients (1,137 with REBOA and 533 with ACC), 66% were male. The median age was 56 years, and the mortality rate was 55.2% in the REBOA group and 81.6% in the ACC group. The mixed‐effect model regression analysis showed a significantly lower odds ratio for in‐hospital mortality rate in the REBOA group (odds ratio 0.17; 95% confidence interval, 0.12–0.26). A similar odds ratio was observed in the propensity score matching analysis (odds ratio 0.27; 95% confidence interval, 0.18–0.40). Conclusion Compared with ACC, REBOA use was associated with decreased mortality in severely injured trauma patients.

BackgroundThe volume-outcome relationship in patients with severe Coronavirus disease 2019 (COVID-19) is unclear and is important for establishing a system for the medical care of severe COVID-19. This study aimed to evaluate the association between institutional case volume and outcomes in patients with ventilated COVID-19.MethodsWe analyzed patients with severe COVID-19 on ventilatory control aged > 17 years who were enrolled in the J-RECOVER study, which is a retrospective multicenter observational study conducted between January 2020 and September 2020 in Japan. Based on the ventilated COVID-19 case volume, the higher one-third of institutions were defined as high-volume centers, the middle one-third as middle-volume centers, and the lower one-third as low-volume centers. The primary outcome measure was in-hospital mortality during hospitalization due to COVID-19. Multivariate logistic regression analysis for in-hospital mortality and ventilated COVID-19 case volume was performed after adjusting for multiple propensity scores and in-hospital variables. To estimate the multiple propensity score, we fitted a multinomial logistic regression model, which fell into one of the three groups based on patient demographics and prehospital factors.ResultsWe analyzed 561 patients who required ventilator management. In total, 159, 210, and 192 patients were admitted to low-volume (36 institutions, < 11 severe COVID-19 cases per institution during the study period), middle-volume (14 institutions, 11-25 severe cases per institution), and high-volume (5 institutions, > 25 severe cases per institution) centers, respectively. After adjustment for multiple propensity scores and in-hospital variables, admission to middle- and high-volume centers was not significantly associated with in-hospital death compared with admission to low-volume centers (adjusted odds ratio, 0.77 [95% confidence interval (CI): 0.46-1.29] and adjusted odds ratio, 0.76 [95% CI: 0.44-1.33], respectively).ConclusionsThere may be no significant relationship between institutional case volume and in-hospital mortality in patients with ventilated COVID-19.

A recent modelling paper on the coronavirus disease 2019 (COVID-19) epidemic in the US (Bartsch et al.) suggested that maintaining face mask use until a high vaccine coverage (70–90%) is achieved is generally cost-effective or even cost-saving in many of the scenarios considered. Their conclusion was based on the assumed effectiveness of continued face mask use, cited from a study that reported an 18% reduction in the effective reproduction number associated with the introduction of state-level mask mandate policies in the US in the summer of 2020. However, using this value implicitly assumes that the effect of face mask use in 2021 through 2022 is the same as that of summer 2020, when stringent nonpharmaceutical interventions were in place. The effectiveness of universal mask wearing in 2021–2022 is probably more uncertain than considered in Bartsch et al. and rigorous sensitivity analysis on this parameter is warranted.

In a paper recently published in Nature Medicine, Fukumoto et al. tried to assess the government-led school closure policy during the early phase of the COVID-19 pandemic in Japan. They compared the reported incidence rates between municipalities that had and had not implemented school closure in selected periods from March–May 2020, where they matched for various potential confounders, and claimed that there was no causal effect on the incidence rates of COVID-19. However, the effective sample size (ESS) of their dataset had been substantially reduced in the process of matching due to imbalanced covariates between the treatment (i.e. with closure) and control (without closure) municipalities, which led to the wide uncertainty in the estimates. Despite the study title starting with 'No causal effect of school closures', their results are insufficient to exclude the possibility of a strong mitigating effect of school closure on incidence of COVID-19. In this replication/reanalysis study, we showed that the confidence intervals of the effect estimates from Fukumoto et al. included a 100% relative reduction in COVID-19 incidence. Simulations of a hypothetical 50% or 80% mitigating effect hardly yielded statistical significance with the same study design and sample size. We also showed that matching of variables that had large influence on propensity scores (e.g. prefecture dummy variables) may have been incomplete.

While the Surviving Sepsis Campaign guidelines recommend an initial target value of 65 mmHg as the mean arterial pressure (MAP) in patients with septic shock, the optimal MAP target for improving outcomes remains controversial. We performed a meta-analysis to evaluate the optimal MAP for patients with vasodilatory shock, which included three randomized controlled trials that recruited 3,357 patients. Between the lower (60–70 mmHg) and higher (>70 mmHg) MAP target groups, there was no significant difference in all-cause mortality (risk ratio [RR], 1.06; 95% confidence intervals [CI], 0.98–1.16) which was similar in patients with chronic hypertension (RR, 1.10; 95% CI, 0.98–1.24) and patients aged ≥65 years (RR, 1.10; 95% CI, 0.99–1.21). No significant difference in adverse events was observed between the different MAP groups (RR, 1.04; 95% CI, 0.87–1.24); however, supraventricular arrhythmia was significantly higher in the higher MAP group (RR, 1.73; 95% CI, 1.15–2.60). Renal replacement therapy was reduced in the higher MAP group of patients with chronic hypertension (RR, 0.83; 95% CI, 0.71–0.98). Though the higher MAP control did not improve the mortality rate, it may be beneficial in reducing renal replacement therapy in patients with chronic hypertension.Systematic review registration: UMIN Clinical Trials Registry, identifier UMIN000042624

The distribution of the generation time (the interval between individuals becoming infected and transmitting the virus) characterises changes in the transmission risk during SARS-CoV-2 infections. Inferring the generation time distribution is essential to plan and assess public health measures. We previously developed a mechanistic approach for estimating the generation time, which provided an improved fit to data from the early months of the COVID-19 pandemic (December 2019-March 2020) compared to existing models (Hart et al., 2021). However, few estimates of the generation time exist based on data from later in the pandemic. Here, using data from a household study conducted from March to November 2020 in the UK, we provide updated estimates of the generation time. We considered both a commonly used approach in which the transmission risk is assumed to be independent of when symptoms develop, and our mechanistic model in which transmission and symptoms are linked explicitly. Assuming independent transmission and symptoms, we estimated a mean generation time (4.2 days, 95% credible interval 3.3–5.3 days) similar to previous estimates from other countries, but with a higher standard deviation (4.9 days, 3.0–8.3 days). Using our mechanistic approach, we estimated a longer mean generation time (5.9 days, 5.2–7.0 days) and a similar standard deviation (4.8 days, 4.0–6.3 days). As well as estimating the generation time using data from the entire study period, we also considered whether the generation time varied temporally. Both models suggest a shorter mean generation time in September-November 2020 compared to earlier months. Since the SARS-CoV-2 generation time appears to be changing, further data collection and analysis is necessary to continue to monitor ongoing transmission and inform future public health policy decisions.