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Background The joint committee of the Japanese Society of Intensive Care Medicine/Japanese Respiratory Society/Japanese Society of Respiratory Care Medicine on ARDS Clinical Practice Guideline has created and released the ARDS Clinical Practice Guideline 2021. Methods The 2016 edition of the Clinical Practice Guideline covered clinical questions (CQs) that targeted only adults, but the present guideline includes 15 CQs for children in addition to 46 CQs for adults. As with the previous edition, we used a systematic review method with the Grading of Recommendations Assessment Development and Evaluation (GRADE) system as well as a degree of recommendation determination method. We also conducted systematic reviews that used meta-analyses of diagnostic accuracy and network meta-analyses as a new method. Results Recommendations for adult patients with ARDS are described: we suggest against using serum C-reactive protein and procalcitonin levels to identify bacterial pneumonia as the underlying disease (GRADE 2D); we recommend limiting tidal volume to 4–8 mL/kg for mechanical ventilation (GRADE 1D); we recommend against managements targeting an excessively low SpO2 (PaO2) (GRADE 2D); we suggest against using transpulmonary pressure as a routine basis in positive end-expiratory pressure settings (GRADE 2B); we suggest implementing extracorporeal membrane oxygenation for those with severe ARDS (GRADE 2B); we suggest against using high-dose steroids (GRADE 2C); and we recommend using low-dose steroids (GRADE 1B). The recommendations for pediatric patients with ARDS are as follows: we suggest against using non-invasive respiratory support (non-invasive positive pressure ventilation/high-flow nasal cannula oxygen therapy) (GRADE 2D), we suggest placing pediatric patients with moderate ARDS in the prone position (GRADE 2D), we suggest against routinely implementing NO inhalation therapy (GRADE 2C), and we suggest against implementing daily sedation interruption for pediatric patients with respiratory failure (GRADE 2D). Conclusions This article is a translated summary of the full version of the ARDS Clinical Practice Guideline 2021 published in Japanese (URL: https://www.jsicm.org/publication/guideline.html). The original text, which was written for Japanese healthcare professionals, may include different perspectives from healthcare professionals of other countries.

We report a method for the synthesis of azafluoranthenes under neutral reaction conditions in a highly atom-economical manner by the iridium-catalyzed [2 + 2 + 2] cycloaddition of 1,8-dialkynylnaphthalenes with nitriles. A variety of nitriles react with methyl- or phenyl-substituted 1,8-dialkynylnaphthalenes to give a wide range of azafluoranthenes. Azafluoranthenes bearing an amino group show intense fluorescence at around 500 nm. Comparison of the fluorescence properties of amine-substituted azafluoranthenes with related compounds revealed the importance of the amine moiety for obtaining a high fluorescence quantum yield. The choice of the solvent affected the emission maxima and the fluorescence quantum yield. Azafluoranthenes bearing pyrrolidine exhibited blue-shifted emission bands in a non-polar solvent and gave a fluorescence quantum yield of 0.76 in toluene. A Lippert-Mataga plot and computational studies provide insight into the origin of the fluorescence of azafluoranthenes. Furthermore, cellular experiments using human breast adenocarcinoma cells SK-BR-3 demonstrated the feasibility of using azafluoranthenes as fluorescent probes.

This study is an international multi-institutional retrospective study comparing the clinical outcomes between intracavitary brachytherapy (ICBT) and the hybrid of intracavitary and interstitial brachytherapy (HBT) for locally advanced cervical cancer patients treated with definitive radiation therapy. Locally advanced cervical cancer, the initial size of which is larger than 4 cm and treated by concurrent chemoradiotherapy and image-guided adaptive brachytherapy, were eligible for this retrospective study. Patients who received HBT at least once were included in the HBT group, and patients who received only ICBT were included in the ICBT group. Anonymized data from 469 patients from 13 institutions in Japan, one from Korea and one from Thailand, were analyzed. Two hundred eighty and 189 patients were included in the ICBT group and the HBT group, respectively. Patients in the HBT group had more advanced stage, non-Scc histopathology, a higher rate of uterine body involvement, larger tumor at diagnosis, larger tumor before brachytherapy and a lower tumor reduction ratio. With a median follow-up of 51.3 months (2.1–139.9 months), 4-y local control (LC), progression-free survival (PFS) and overall survival (OS) for the entire patient population were 88.2%, 64.2% and 83%, respectively. The HBT group received a higher HR-CTV D90 than that of the ICBT group (68.8 Gy vs 65.6 Gy, P = 0.001). In multivariate analysis, the non-Scc histological subtype, HR-CTV D95 ≤ 60 Gy, reduction ratio ≤ 29% and total treatment time (TTT) ≥ 9 weeks were identified as the independent adverse prognostic factors for LC. Regarding LC, no difference was found between ICBT and HBT (4-y LC 89.3% vs 86.8%, P = 0.314). After adjustment for confounding factors by propensity score matching, no advantage of applying HBT was demonstrated regarding LC, PFS, or OS. Despite the fact that HBT patients had more adverse clinical factors than ICBT patients, HBT delivered a higher dose to HR-CTV and resulted in comparable LC.

This study aimed to investigate the effects of maternal exposure to external radiation on perinatal outcomes among women who experienced the Fukushima Daiichi Nuclear Disaster (FDND) using the Fukushima Health Management Survey (FHMS).Data from the Pregnancy and Birth Survey and Basic Survey in the FHMS were combined to analyze external maternal radiation exposure following the FDND, and the relationship between radiation dose and perinatal outcomes was analyzed using binomial logistic regression analysis. Missing dose data were supplemented using multiple imputation.A total of 6,875 individuals responded to the survey. Congenital anomalies occurred in 2.9% of patients, low birth weight (LBW) in 7.6%, small for gestation age (SGA;10th percentile) in 8.9%, and preterm birth in 4.1%. The median maternal external radiation dose was 0.5 mSv (maximum, 5.2 mSv). Doses were classified as follows:1 mSv (reference), 1 to2 mSv, and ≥2 mSv. For congenital anomalies, the crude odds ratio for 1 to2 mSv was 0.81 (95% confidence interval [CI], 0.56-1.17) (no participants with congenital anomaly were exposed to ≥2 mSv). At 1 to2 mSv and ≥2 mSv, the respective adjusted odds ratios were 0.91 (95% CI, 0.71-1.18) and 1.21 (95% CI, 0.53-2.79) for LBW, 1.14 (95% CI, 0.92-1.42) and 0.84 (95% CI, 0.30-2.37) for SGA, and 0.91 (95% CI, 0.65-1.29) and 1.05 (95% CI, 0.22-4.87) for preterm birth.External radiation dose due to the FDND was not associated with congenital anomalies, LBW, SGA, or preterm birth.

OBJECTIVE A recent comparative analysis between neurosurgical and endovascular treatments for craniocervical junction (CCJ) arteriovenous fistulas (AVFs) revealed better treatment outcomes in the neurosurgery group than in the endovascular group. This finding was attributed to the higher than expected rate of ischemic complications in the endovascular group than in the neurosurgery group (26% vs 7.7%, p = 0.037). The aim of the present study was to describe ischemic complications associated with treatments for CCJ AVFs. METHODS This descriptive study was authorized by the Neurospinal Society of Japan. Data from 97 consecutive patients with CCJ AVFs who underwent neurosurgical (n = 78) or endovascular (n = 19) treatment between 2009 and 2019 were collected from 29 centers. The primary endpoints were details on ischemic complications and their risk factors. Secondary endpoints were details on other complications. RESULTS Among all major complications, ischemic complications were the most common (11% of 97 patients), followed by hemorrhagic complications (7.2%), hydrocephalus (2.1%), and CSF leakage (2.1%). Ischemic complications included 8 spinal, 2 brainstem, and 1 cerebellar infarctions. Iatrogenic occlusion of the anterior or posterior spinal artery from the radiculomedullary or radiculopial arteries caused these complications. Ischemic complications resulted in neurological deficits, including motor paresis, sensory disturbances, and brainstem dysfunction. The modified Rankin Scale score was 3 or higher in 36% of patients with ischemic complications at the final follow-up of 23 months. Risk factors associated with ischemic complications were endovascular treatment (OR 4.3, 95% CI 1.1–16) and spinal feeding arteries (OR 3.8, 95% CI 1.03–14). Most of the other complications were addressed by additional treatment without permanent neurological deficits. CONCLUSIONS Among ischemic complications associated with treatments for CCJ AVFs, spinal infarctions were the most common and were mostly attributed to endovascular procedures for CCJ AVFs fed by spinal arteries. These results support the use of neurosurgery as the first-line treatment for CCJ AVFs.

Objectives: Differences in virulence genes, including psm-mec , which is a phenol-soluble modulin-mec (PSM-mec) encoding gene, of predominant staphylococcal cassette chromosome mec (SCCmec) types II and IV Methicillin-resistant Staphylococcus aureus (MRSA) may contribute to the virulence and clinical features of MRSA in Japan. We aimed to clarify the clinical characteristics and risk factors of infection among SCCmec types II and IV MRSA isolates from a Japanese secondary acute care hospital. / Methods: We analysed 58 SCCmec type II and 83 SCCmec type IV MRSA isolates collected from blood, central venous catheter tips, deep or superficial tissues, and sputum. / Results: SCCmec type II MRSA risk factors for progression to infection were seb , enterotoxin gene cluster, psm-me c mutation, and vancomycin minimum inhibitory concentrations (MIC) of 1 or 2 mg/L as viru- lence factors (adjusted odds ratio [aOR] = 11.8; 95% confidence interval [CI]: 2.49–77.7; P = 0.004); solid tumour was a host factor (aOR = 25.9; 95% CI: 3.66–300; P = 0.003). SCCmec type IV MRSA risk fac- tors were sea, cna , and vancomycin MIC of 1 or 2 mg/L as virulence factors (aOR = 3.14; 95% CI: 1.06–10.6; P = 0.049) and intravascular indwelling catheter as host factors (aOR = 3.78; 95% CI: 1.03–14.5; P = 0.045). Compared with SCCmec type II, SCCmec type IV MRSA resulted in more frequent bloodstream infections and higher Sequential Organ Failure Assessment scores. / Conclusion: We found that factors related to virulence genes and bacteriological and host characteristics are associated with SCCmec types II and IV MRSA infection and severity. These risk factors may be useful criteria for designing infection control programs.

Although the immunological memory produced by BNT162b2 vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been well studied and established, further information using different racial cohorts is necessary to understand the overall immunological response to vaccination. We evaluated memory B and T cell responses to the severe acute respiratory syndrome coronavirus 2 spike protein before and after the third booster using a Japanese cohort. Although the Ab titer against the spike receptor-binding domain (RBD) decreased significantly 8 mo after the second vaccination, the number of memory B cells continued to increase, whereas the number of memory T cells decreased slowly. Memory B and T cells from unvaccinated infected patients showed similar kinetics. After the third vaccination, the Ab titer increased to the level of the second vaccination, and memory B cells increased at significantly higher levels before the booster, whereas memory T cells recovered close to the second vaccination levels. In memory T cells, the frequency of CXCR5+CXCR3+CCR6− circulating follicular Th1 was positively correlated with RBD-specific Ab-secreting B cells. For the response to variant RBDs, although 60–80% of memory B cells could bind to the omicron RBD, their avidity was low, whereas memory T cells show an equal response to the omicron spike. Thus, the persistent presence of memory B and T cells will quickly upregulate Ab production and T cell responses after omicron strain infection, which prevents severe illness and death due to coronavirus disease 2019.

OBJECTIVE Residual anterior spinal cord compression (RASCC) after cervical laminoplasty, which has been confirmed on postoperative MRI, is reportedly associated with poor clinical outcomes. To date, only a few studies have described the risk factors associated with RASCC. The aim of this study was to identify the factors that can predict the occurrence of RASCC after laminoplasty for cervical spondylotic myelopathy (CSM), focusing on the location of the most stenotic segment. METHODS In this retrospective, single-center study, 120 patients who underwent C3–7 laminoplasty for multilevel CSM were included. Different techniques were used for C3 decompression, i.e., partial (dome-laminotomy) or complete (laminoplasty/laminectomy) decompression. RASCC was diagnosed using MRI conducted 3 weeks postoperatively. The patients were divided into two groups according to the segment with the most severe stenosis (Seg-MSS; C3–4 vs C4–7). Demographics, radiological data, and C3 decompression technique were compared between the two groups. Furthermore, intergroup comparisons were performed based on Seg-MSS. A logistic regression model was constructed to identify the factors predicting RASCC after patient stratification according to Seg-MSS. RESULTS Forty patients (33.3%) had RASCC. The patients with Seg-MSS at C3–4 (51.3%) had a significantly higher incidence of RASCC (p = 0.003) than those with Seg-MSS at C4–7 (24.7%). Logistic regression analysis showed that in patients with Seg-MSS at C3–4, C3 partial decompression demonstrated a greater association with RASCC as opposed to complete decompression. Conversely, in patients with Seg-MSS at C4–7, kyphotic segmental lordotic angle was associated with an increased risk of RASCC. CONCLUSIONS The risk factors for RASCC differed depending on the location of the most stenotic segment (C3–4 vs C4–7). If there is segmental kyphosis at the most stenotic segment at C4–7, anterior decompression and fusion should be considered. If C3–4 is the most stenotic segment, anterior surgery is also recommended, but alternatively, one can choose laminoplasty with complete C3 laminectomy and resection of the C2–3 ligamentum flavum.

Background: Fulminant myocarditis presentation (FMP) is a rare and severe presentation of myocarditis. The natural history of FMP and its clinical features associated with poor outcomes are incompletely understood because there is a lack of generalizable evidence. Methods: This multicenter retrospective cohort study included patients hospitalized with histologically proven myocarditis who underwent catecholamine or mechanical support from 235 cardiovascular training hospitals across Japan between April 2012 and March 2017. Clinical features and the prognostic predictors of death or heart transplantation within 90 days on the basis of clinical and pathologic findings were determined using the Kaplan-Meier method, log-rank test, and Cox regression analysis. Results: This study included 344 patients with histologically proven FMP (median age, 54 years; 40% female). The median follow-up was 600 days (interquartile range, 36 to 1599 days) and the cumulative risk of death or heart transplantation at 90 days was 29% (n=98). Results from multivariable Cox regression analysis showed that older age, nonsinus rhythm, low left ventricular wall motion ( Conclusions: The results from analyses of data from this multicenter registry demonstrated that patients with FMP are at a higher risk of death or heart transplantation in real-world settings. These observations inform which clinical and pathologic findings may be useful for prognostication in FMP. Registration: URL: https://www.umin.ac.jp/ctr ; Unique identifier: UMIN000039763.

Background: Inflammation is thought to be a risk factor for kidney disease. However, whether inflammatory status is either a cause or an outcome of chronic kidney disease remains controversial. We aimed to investigate the causal relationship between high-sensitivity C-reactive protein (hs-CRP) and estimated glomerular filtration rate (eGFR) using Mendelian randomization (MR) approaches. Methods: A total of 10,521 participants of the Japan Multi-institutional Collaborative Cohort Study was analyzed in this study. We used two-sample MR approaches (the inverse-variance weighted (IVW), the weighted median (WM), and the MR-Egger method) to estimate the effect of genetically determined hs-CRP on kidney function. We selected four and three hs-CRP associated single nucleotide polymorphisms (SNPs) as two instrumental variables (IV): IVCRP and IVAsian, based on SNPs previously identified in European and Asian populations. IVCRP and IVAsian explained 3.4% and 3.9% of the variation in hs-CRP, respectively. Results: Using the IVCRP, genetically determined hs-CRP was not significantly associated with eGFR in the IVW and the WM methods (estimate per 1 unit increase in ln(hs-CRP), 0.000; 95% confidence interval [CI], −0.019 to 0.020 and −0.003; 95% CI, −0.019 to 0.014, respectively). For IVAsian, we found similar results using the IVW and the WM methods (estimate, 0.005; 95% CI, −0.020 to 0.010 and −0.004; 95% CI, −0.020 to 0.012, respectively). The MR-Egger method also showed no causal relationships between hs-CRP and eGFR (IVCRP: −0.008; 95% CI, −0.058 to 0.042; IVAsian: 0.001; 95% CI, −0.036 to 0.036). Conclusion: Our two-sample MR analyses with different IVs did not support a causal effect of hs-CRP on eGFR.

Boron neutron capture therapy (BNCT) is a non-invasive type of radiation therapy developed for humans and translated to veterinary medicine. However, clinical trials on BNCT for patients with brain tumors are on-going. To improve the therapeutic efficacy of BNCT for brain tumors, we developed a boron delivery system that involves the cerebrospinal fluid (CSF), in contrast to the conventional method that involves intravenous (IV) administration. This study aimed to investigate the time-concentration profile of boron in the CSF as well as the uptake rate of boron by the brain cells after administering L-p‑boronophenylalanine (BPA) into the lateral ventricle of normal rats. Brain cell uptake rates were compared between the CSF-based and IV administration methods. The CSF-based and IV administration methods achieved comparable brain cell uptake levels; however, the former method involved lower BPA doses than the latter method. These findings suggest that the CSF method may reduce the economic and physical burdens associated with this treatment in brain tumor patients. Future studies should validate these findings in rat models of brain tumors.

There is still a scarcity of data on causes of long-term mortality in patients with venous thromboembolism (VTE).The COMMAND VTE Registry is a physician-initiated, retrospective, multicenter cohort study in which consecutive 3027 patients with acute symptomatic VTE among 29 centers in Japan were included between January 2010 and August 2014. We investigated detailed causes and risk factors for long-term mortality.During a median observation period of 1218 days, a total of 764 patients died, and the prevalence of active cancer was higher in patients who died than in patients alive (61 % versus 10 %, P 0.001). The cumulative incidences of cardiac death, pulmonary embolism (PE)-related death, bleeding death, cancer death, and non-cardiovascular non-cancer death were 2.2 %, 2.9 %, 2.0 %, 16.1 %, and 6.7 % at 5 years, respectively. The incidence of cancer death increased gradually, which was the most common cause of long-term death. Among patients without active cancer, the incidence of PE-related death increased rapidly and became a plateau beyond the acute phase, whereas the incidence of non-cardiovascular non-cancer death kept increasing, which became most common in the long term. The separate multivariable analysis among patient with and without active cancer identified independent risk factors of all-cause death including a few patient characteristics among patients with active cancer and several patient characteristics among patients without active cancer.Cancer was the most common cause of long-term mortality, while non-cardiovascular non-cancer death became most common among patients without active cancer.

Exposure of humans to aflatoxin B1 (AFB1) via ingestion of contaminated agricultural products is a major concern for human health throughout the world because epoxidized AFB1, biotransformed from AFB1 by hepatic CYP3A4, is strongly hepatotoxic and hepatocarcinogenic. Intestinal epithelial cells serve as a physical and physiological barrier against xenobiotics via their intercellular tight junction (TJ) seals and the metabolizing enzyme CYP3A4. However, the effect of AFB1 on the intestinal barrier remains unclear. Here, we investigated the influence of AFB1 on these physical and physiological intestinal barriers by means of an in vitro human intestinal model utilizing doxycycline-inducible CYP3A4-expressing Caco-2 cells, in which CYP3A4 activity is comparable to that in the adult human intestine. Cellular toxicity of AFB1 in induced Caco-2 cells (i.e., cells in which expression of CYP3A4 is induced by doxycycline) was approximately 5 times that of uninduced Caco-2 cells. Exposure to 16 µM AFB1 did not decrease the transepithelial electric resistance (TEER; a measure of TJ barrier integrity) in monolayers of uninduced Caco-2 cells to 95.8 % of that in vehicle-treated cells; in contrast, in induced Caco-2 cells, TEER was reduced to 28.8 %. Exposure to 16 µM AFB1 increased paracellular permeation of 4- and 20-kDa dextrans (paracellular permeation markers) through monolayers of induced Caco-2 cells to 5.4 and 5.2 times that through uninduced Caco-2 cells. These results together show that ingested AFB1 can modulate the intestinal barrier, and that inducible CYP3A4-expressing Caco-2 cells are a promising tool for evaluating the safety of food contaminants in the human intestine.

Tracking SARS-CoV-2 variants of concern (VOC) by genomic sequencing is time-consuming. The rapid screening of VOCs is necessary for clinical laboratories. In this study, we developed a rapid screening method based on multiplex RT-PCR by extended S-gene target failure (eSGTF), a false negative result caused by S-gene mutations.Three S-gene target (SGT) regions (SGT1, codons 65-72; SGT2, codons 152-159; and SGT3, codons 370-377) and an N-gene region (for internal control) were detected in single-tube. Four types of VOC (Alpha, Delta, Omicron BA.1, and Omicron BA.2) are classified by positive/negative patterns of 3 S-gene regions (eSGTF pattern).The eSGTF patterns of VOCs were as follows (SGT1, SGT2, SGT3; P, positive; N, negative): Alpha, NPP; Delta, PNP; Omicron BA.1, NPN pattern; and Omicron BA.2, PPN. As compared with the S-gene sequencing, eSGTF patterns were identical to the specific VOCs (concordance rate = 96.7%, N = 206/213). Seven samples with discordant results had a minor mutation in the probe binding region. The epidemics of VOCs estimated by eSGTF patterns were similar to those in Japan.Multiplex RT-PCR and eSGTF patterns enable high-throughput screening of VOCs. It will be useful for the rapid determination of VOCs in clinical laboratories.

Almost all preference-based measures (PBMs) have been developed in Western countries, with none having been formulated in Asian countries. In this study, we construct a new generic PBM based on concept elicitation using interview surveys in East and Southeast Asian countries and qualitative analysis.This cross-sectional study included 225 adults recruited from 9 East and Southeast Asian countries or regions (Indonesia, Japan, Korea, mainland China, Malaysia, the Philippines, Singapore, Taiwan, and Thailand). Trained interviewers conducted semistructured interviews with 25 participants from the general population of each country/region. Qualitative data were analyzed using a content analysis approach. The selection of items was determined based on interview surveys and team member discussions. The description of items was considered based on a detailed qualitative analysis of the interview survey.A new region-specific PBM-the Asia PBM 7 dimensions instrument-was designed. It reflects East and Southeast Asian values and comprises 7 items: pain, mental health, energy, mobility, work/school, interpersonal interactions, and burden to others.The new region-specific instrument is one of the first PBMs developed in the context of non-Western countries. The Asia PBM 7 dimensions contains 7 items that address the core concepts of health-related quality of life that are deemed important based on East and Southeast Asian health concepts.

Vaccine effectiveness against SARS-CoV-2 infections decreases due to waning immunity, and booster vaccination was therefore introduced. We estimated the anti-spike antibody (AS-ab) recovery by booster vaccination and analyzed the risk factors for SARS-CoV-2 infections.The subjects were health care workers (HCWs) in a Chiba University Hospital vaccination cohort. They had received two doses of vaccine (BNT162b2) and a booster vaccine (BNT162b2). We retrospectively analyzed AS-ab titers and watched out for SARS-CoV-2 infection for 90 days following booster vaccination.AS-ab titer eight months after two-dose vaccinations had decreased to as low as 587 U/mL (median, IQR (interquartile range) 360-896). AS-ab titer had then increased to 22471 U/mL (15761-32622) three weeks after booster vaccination. There were no significant differences among age groups. A total of 1708 HCWs were analyzed for SARS-CoV-2 infection, and 48 of them proved positive. SARS-CoV-2 infections in the booster-vaccinated and non-booster groups were 1.8% and 4.0%, respectively, and were not significant. However, when restricted to those 20-29 years old, SARS-CoV-2 infections in the booster-vaccinated and non-booster groups were 2.9% and 13.6%, respectively (p = 0.04). After multivariate logistic regression, COVID-19 wards (adjusted odds ratio (aOR):2.9, 95% confidence interval (CI) 1.5-5.6) and those aged 20-49 years (aOR:9.7, 95%CI 1.3-71.2) were risk factors for SARS-CoV-2 infection.Booster vaccination induced the recovery of AS-ab titers. Risk factors for SARS-CoV-2 infection were HCWs of COVID-19 wards and those aged 20-49 years. Increased vaccination coverage, together with implementing infection control, remains the primary means of preventing HCWs from SARS-CoV-2 infection.

The mesentery of the jejunum (MJ) of the Roux limb is conventionally divided when Roux-en-Y reconstruction is performed after total gastrectomy for gastric cancer (GC). However, the impact of dividing or preserving the MJ on anastomotic leakage (AL) at the esophagojejunostomy (EJS) site after minimally invasive total gastrectomy for GC is unclear.This retrospective cohort study enrolled 226 patients with GC who underwent EJS after laparoscopic or robotic total gastrectomy, including preservation of the MJ (n = 87) and division of the MJ (n = 137). The prevalence of anastomotic complications at the EJS and short-term outcomes were compared between groups using propensity score (PS) matching.After PS matching, 69 patients were selected for the preserving and dividing MJ groups. There were no significant intergroup differences in patient backgrounds, including oncological stage, body mass index, and gender ratio. After PS matching, overall and severe complications after surgery were compared between the preserving and dividing MJ groups (21.7% vs. 27.5%, p = 0.554 and 8.7% vs. 13.8%, p = 0.137, respectively). However, the rate of AL at the EJS was significantly lower in the preserving than that in the dividing MJ group (1.4% vs. 13.0%, p = 0.017). In addition, the median postoperative hospital stay was significantly shorter in the preserving than that in the dividing MJ group (13.0 days vs. 16.0 days, p = 0.005).Preserving the MJ significantly reduced AL at the EJS after minimally invasive total gastrectomy for GC.

The stable R-loop formed during transcription induces enzyme-mediated deamination of cytosine, and the uracil in the DNA produced activates the base excision repair (BER) pathway. DNA cleavage involved in the BER pathway is thought to be one of the possible causes of trinucleotide repeat instability. Here, we performed an in vitro assay to investigate the effect of a DNA-binding small molecule, naphthyridine carbamate dimer (NCD), on BER enzyme reactions. The gel electrophoretic mobility shift assay (EMSA) and thermal melting analysis revealed the binding of NCD to a 5'-XGG-3'/5'-XGG-3' triad (X = C or U or apurinic/apyrimidinic site), which is a mimic of a BER enzyme substrate. Polyacrylamide gel electrophoresis (PAGE) of the reaction products of these substrates with hSMUG1 and APE1 enzymes in the presence of NCD showed that NCD interfered with the repair reaction in the 5'-XGG-3'/5'-XGG-3' triad. These findings would broaden the potential of small molecules in modulating trinucleotide repeat instability.

An 80-year-old man presented to our hospital with general fatigue on exertion that had gradually worsened over 6 months. His blood test revealed severe anemia, and gastroscopy revealed findings consistent with gastric antral vascular ectasia (GAVE) and autoimmune gastritis. We diagnosed the patient with severe anemia caused by GAVE and autoimmune gastritis. The present case suggested that GAVE is triggered by autoimmune gastritis, and the mechanism is likely related to hypergastrinemia. The reporting of this rare case may help elucidate the cause of GAVE, which is currently unknown.

Japan currently lacks a data platform that can support quantitative assessments of the causal relationships between vaccines and adverse events. This study describes the development and application of the Vaccine Effectiveness, Networking, and Universal Safety (VENUS) Study to facilitate such assessments.A database was created by linking public insurance enrollees' claims data with vaccination records acquired from participating municipalities. To provide an overview of the study data, we produced descriptive statistics of sex, age, and vaccinations. We also conducted a pilot study using the database to assess influenza vaccine safety during the 2018/2019 season among older persons (≥65 years) residing in a single municipality.Our database was created using data from approximately 1.12 million individuals in 7 municipalities between 2013 and 2020. The data during fiscal year 2018 included 853,016 individuals (male: 363,079, female: 489,937) with a median age of 70 years (interquartile range: 52-79). We obtained information on 17 vaccine types, including the pneumococcal vaccine and influenza vaccine. In the pilot study, we analyzed 48,723 vaccinated persons matched with 48,723 unvaccinated persons. The only adverse event that occurred in both groups was Bell's palsy, which had an adjusted incidence rate ratio of 1.21 (95 % confidence interval: 0.48-3.07).The VENUS Study is Japan's first healthcare data platform that enables comparative assessments of vaccinated and unvaccinated persons in large samples covering all age groups. Efforts are underway to increase the number of participating municipalities and to generate evidence on vaccine effectiveness and safety.

To identify predictors of severe adverse events (≥grade 3) in patients with advanced hepatocellular carcinoma treated with lenvatinib.Of 41 patients, 25 and 16 were stratified into the severe and non-severe adverse events groups, respectively. Of these, 19 formed a lactulose-mannitol test subgroup, which was divided into severe adverse events (n=11) and non-severe adverse events (n=8) groups. Severe adverse events were assessed by liver disease etiology and modified albumin-bilirubin grade. Intestinal permeability by lactulose-mannitol test and serum soluble CD163, soluble mannose receptor, and zonulin levels.Severe adverse event incidence rates were higher in patients with advanced hepatocellular carcinoma related to alcoholic liver disease and nonalcoholic fatty-liver disease than in those with advanced hepatocellular carcinoma of other etiologies (p=0.014). The rates were higher for modified albumin-bilirubin grades 2a and 2b compared to modified albumin-bilirubin grade 1 (p=0.0104). Zonulin levels were higher in the severe adverse event group (p=0.0331) and were independently associated with severe adverse events (odds ratio=140, 95% confidence interval=1.66-11800; p=0.029). Patients with high zonulin levels (≥0.518 ng/ml) experienced more severe adverse events than those with low levels (0.518 ng/ml) (p=0.0137). In the lactulose-mannitol test subgroup, the urine lactulose:mannitol ratio was higher in the severe vs. non-severe adverse event group (p=0.0164). Moreover, it was higher in patients with alcoholic liver disease and nonalcoholic fatty-liver disease-related advanced hepatocellular carcinoma compared to those with other advanced hepatocellular carcinoma etiologies (p=0.0108).Serum zonulin levels predict severe adverse events in patients with advanced hepatocellular carcinoma treated with lenvatinib.

Although gut-derived lipopolysaccharide (LPS) affects the progression of non-alcoholic steatohepatitis (NASH) pathogenesis, few studies have focused on this relationship to develop treatments for NASH.To explore the effects of combination with rifaximin and lubiprostone on NASH liver fibrosis through the modulation of gut barrier function.To induce steatohepatitis, F344 rats were fed a choline-deficient l-amino acid-defined (CDAA) diet for 12 weeks and received oral administration of rifaximin and/or lubiprostone. Histological, molecular, and fecal microbial analyses were performed. Barrier function in Caco-2 cells were assessed by in vitro assays.Combination rifaximin/lubiprostone treatment significantly suppressed macrophage expansion, proinflammatory responses, and liver fibrosis in CDAA-fed rats by blocking hepatic translocation of LPS and activation of toll-like receptor 4 signaling. Rifaximin and lubiprostone improved intestinal permeability via restoring tight junction proteins (TJPs) with the intestinal activation of pregnane X receptor and chloride channel-2, respectively. Moreover, this combination increased the abundance of Bacteroides, Lactobacillus, and Faecalibacterium as well as decreased that of Veillonella resulting in an increase of fecal short-chain fatty acids and a decrease of intestinal sialidase activity. Both agents also directly suppressed the LPS-induced barrier dysfunction and depletion of TJPs in Caco-2 cells.The combination of rifaximin and lubiprostone may provide a novel strategy for treating NASH-related fibrosis.

There are limited studies on the risk of secondary cancers after carbon-ion radiotherapy (CIRT). We assessed the incidence of secondary cancers in patients treated with CIRT for cervical cancer. We also evaluated the incidence of secondary cancers in patients who received standard photon radiotherapy (RT) throughout the same period.This retrospective study included patients with cervical cancer who underwent curative RT at our hospital. All cancers discovered for the first time after RT were classified as secondary cancers. To compare the risk of secondary cancers among cervical cancer survivors to the general population, standardized incidence ratios (SIRs) were calculated.The analysis included a total of 197 and 417 patients in the CIRT and photon RT groups, respectively. The total person-years during the observation period were 1052.4 in the CIRT group and 2481.5 in the photon RT group. The SIR for all secondary cancers was 1.1 (95% confidence interval [CI], 0.6-2.1) in the CIRT group and 1.4 (95% CI, 1.0-2.1) in the photon RT group. The 10-year cumulative incidence of all secondary cancers was 9.5% (95% CI, 4.0-21.5) in the CIRT group and 9.4% (95% CI, 6.2-14.1) in the photon RT group. The CIRT and photon RT groups were not significantly different in incidence (p = 0.268).The incidence of secondary cancers after CIRT for cervical cancer was similar to that after photon RT. Validation of our findings after long-term observation is warranted.

The emergence of unusual G9P[8]-E2 human rotaviruses in the Tokyo metropolitan area, Japan, in 2018 has been reported. During rotavirus strain surveillance in different regions of Japan (Mie, Okayama, and Chiba prefectures), G9P[8]-E2 strains were detected in children with diarrhea from all three prefectures. Here, we characterized the whole genome of seven representative G9P[8]-E2 strains. In the full-genome-based analysis, the seven study strains exhibited a unique genotype configuration with the NSP4 gene of genogroup 2 in a genogroup 1 genomic backbone: G9-P[8]-I1-R1-C1-M1-A1-N1-T1-E2-H1. This genotype constellation was shared by the Tokyo G9P[8]-E2 strains. Phylogenetic analysis showed that all 11 genes, except NSP4, of the seven study strains appeared to have originated from co-circulating Wa-like G9P[8]-E1 strains. In contrast, NSP4 appeared to have originated from the co-circulating DS-1-like G2P[4]-E2 strains. Thus, G9P[8]-E2 strains appear to be derived through reassortment between G9P[8]-E1 and G2P[4]-E2 strains in Japan. Notably, the seven study G9P[8]-E2 strains and Tokyo G9P[8]-E2 strains were revealed to have 11-segment genomes almost indistinguishable from one another in their sequences (99.3-100%), indicating all these G9P[8]-E2 strains had a common origin. To our knowledge, this is the first description of the rapid spread of G9P[8]-E2 strains across a country.

This study aimed to assess the association between changes in metabolic phenotypes and incident type 2 diabetes.This retrospective cohort study included participants from a medical health checkup program conducted by the Panasonic Corporation, Japan, between 2008 and 2018. The metabolic phenotypes of the participants in 2008 and 2013 were assessed. The association between changes in metabolic phenotypes from 2008 to 2013 and incident type 2 diabetes (n = 58,638) were evaluated for a 5-year follow-up using Cox regression analyses.The stable, metabolically healthy obesity group was associated with a higher risk of incident type 2 diabetes than the stable, metabolically healthy nonobesity (MHNO) group (hazard ratio [HR] 3.22, 95% CI: 2.71-3.83). When participants with metabolically healthy obesity experienced a change to MHNO, their risk of incident type 2 diabetes was similar to that of participants in the stable MHNO group (HR 1.28, 95% CI: 0.78-1.90). Once the participants had metabolic abnormalities, the risk of incident type 2 diabetes was higher than that in the stable MHNO group, even after undergoing a change to MHNO.This study demonstrates that it is important to pay attention to the changes in metabolic phenotypes to prevent incident type 2 diabetes in Japanese populations.

Physiologically, people age at different rates, which leads to a discrepancy between physiological and chronological age. Physiological age should be a priority when considering the indications for adult spinal deformity (ASD) surgery. The primary objective of this study was to determine the characteristics of the postoperative course, surgical outcomes, and complication rates to extend the healthy life expectancy of older ASD patients (≥ 75 years). The secondary objective was to clarify the importance of physiological age in the surgical treatment of older ASD patients, considering frailty.A retrospective review of 109 consecutive patients aged ≥ 65 years with symptomatic ASD who underwent a corrective long fusion with lateral interbody fusion from the lower thoracic spine to the pelvis from 2015 to 2019 was conducted. Patients were classified into two groups according to age (group Y [65-74 years], group O [≥ 75 years]) and further divided into four groups according to the ASD-frailty index score (Y-F, Y-NF, O-F, and O-NF groups). To account for potential risk factors for perioperative course characteristics, complication rates, and surgical outcomes, patients from the database were subjected to propensity score matching based on sex, BMI, and preoperative sagittal spinal alignment (C7 sagittal vertical axis, pelvic incidence-lumbar lordosis, and pelvic tilt). Clinical outcomes were evaluated 2 years postoperatively, using three patient-reported outcome measures of health-related quality of life: the Oswestry Disability Index, Scoliosis Research Society questionnaire (SRS-22), and Short Form 36 (SF-36). Additionally, the postoperative time-to-first ambulation, as well as minor, major, and mechanical complications, were evaluated.In the comparison between Y and O groups, patients in group O were at a higher risk of minor complications (delirium and urinary tract infection). In contrast, other surgical outcomes of group O were comparable to those of group Y, except for SRS-22 (satisfaction) and time to ambulation after surgery, with better outcomes in Group O. Patients in the O-NF group had better postoperative outcomes (time to ambulation after surgery, SRS-22 (function, self-image, satisfaction), SF-36 [PCS]) than those in the Y-F group.Older age warrants monitoring of minor complications in the postoperative management of patients. However, the outcomes of ASD surgery depended more on frailty than on chronological age. Older ASD patients without frailty might tolerate corrective surgery and have satisfactory outcomes when minimally invasive techniques are used. Physiological age is more important than chronological age when determining the indications for surgery in older patients with ASD.

Background Increasing the coverage of vaccinations recommended by the World Health Organization in the older adult population is an urgent issue, especially in the context of avoiding co-epidemics during the current coronavirus disease 2019 crisis. The aim of this study was to examine factors associated with the quality of perceived patient-physician communication and whether this variable was associated with increased odds of vaccination. Methods We used cross-sectional data from the Japan Gerontological Evaluation Study conducted from October 2016 to January 2017. The participants were 22,253 physically and cognitively independent individuals aged 65 or older living in 39 municipalities in Japan. Multilevel logit models were used to estimate the odds of vaccination. Results Among the participants, 40.0% and 58.8% had received pneumococcal and influenza vaccinations as per the recommended schedule, respectively. People with low educational levels were more likely to have a family physician but rate their experience in asking questions lower than those with higher educational levels. Having a family physician and high rating for physicians' listening attitude were positively associated with increased odds of pneumococcal and influenza vaccinations. High rating for patients' questioning attitude and shared decision-making, compared to an ambiguous attitude toward medical decision-making, were positively associated with increased odds of pneumococcal vaccination. Conclusion The results suggest that promotion of having a family physician, better patient-physician communication, and shared decision-making may encourage older adults to undergo recommended vaccinations.

Diseases caused by Mycobacterium avium complex (MAC) infection in the lungs are increasing worldwide. The recurrence rate of MAC-pulmonary disease (PD) has been reported to be as high as 25-45%. A significant percentage of recurrences occurs because of reinfection with a new genotype from the environment. A focus on reducing exposure to MAC organisms from the environment is therefore an essential component of the management of this disease as well as standard MAC-PD treatment. A macrolide-containing three-drug regimen is recommended over a two-drug regimen as a standard treatment, and azithromycin is recommended rather than clarithromycin. Both the 2007 and 2020 guidelines recommend a treatment duration of MAC-PD of at least one year after the culture conversion. Previous clinical studies have reported that ethambutol could prevent macrolide resistance. Furthermore, the concomitant use of aminoglycoside, amikacin liposomal inhalation, clofazimine, linezolid, bedaquiline, and fluoroquinolone with modification of guideline-based therapy has been studied. Long-term management of MAC-PD remains challenging because of the discontinuation of multi-drug regimens and the acquisition of macrolide resistance. Moreover, the poor compliance of guideline-based therapy for MAC-PD treatment worldwide is concerning since it causes macrolide resistance. Therefore, in this review, we focus on MAC-PD treatment and summarize various treatment options when standard treatment cannot be maintained, with reference to the latest ATS/ERS/ESCMID/IDSA clinical practice guidelines revised in 2020.

Around 20% of all inborn errors of immunity (IEI) are autosomal dominant or monoallelic, either by haploinsufficiency, negative dominance, or gain of function (GOF). GOF phenotypes usually include autoinflammation, autoimmunity, lymphoproliferation, allergies, and some infections.We describe the cases of two unrelated patients born of HIV-seroconcordant parents. Both patients are HIV-negative but carry de novo GOF missense variants that resulted in inflammatory lymphoproliferative IEI diseases: signal transducer and activator of transcription 3 (STAT3)-GOF and phosphatidylinositol 3-kinase, catalytic delta (PIK3CD)-GOF. Both variants were found through whole-exome sequencing and confirmed by Sanger.An 11-year-old male with recurrent sinopulmonary infections, dysmorphism, growth delay, bronchiectasis, and mild mental retardation, as well as lymphopenia, thrombocytopenia, and high immunoglobulin M. Both his parents were known to be HIV-positive under anti-retroviral treatment. HIV infection was repeatedly ruled out in the patient, whom through whole-exome sequencing was found to have a heterozygous missense variant in exon 24 of PIK3CD, a hotspot transition, and the most reported variant in PIK3CD-GOF patients.A 6-year-old male with autoimmune hemolytic anemia, lymphoproliferation, short stature, and intractable diarrhea. Both his parents were found to be HIV-positive. HIV was repeatedly ruled out in the patient by ELISA and viral load. He was found to have a heterozygous missense/splice variant in exon 22 of STAT3, a hotspot transition, and the most reported variant in STAT3-GOF patients.The AID/APOBEC3 A-H family of proteins are cytidine deaminases that induce GA hypermutation in both the invading viral DNA and the host genome, which results in stop codons inside the endogenized retroviral sequence. Both variants found in our patients are G to A transitions. Retroviral infection might thus have resulted in host genome instability, and our patients' rare congenital diseases are the unfortunate consequence of somatic hypermutation in one of their parents' gametes.

Biologics are structurally heterogeneous and can undergo biotransformation in the body. Etanercept (ETN) is a fusion protein composed of a soluble tumor necrosis factor (TNF) receptor and the Fc portion of human immunoglobulin G1. The N-terminus of ETN has a putative sequence cleaved by dipeptidyl peptidase-4 (DPP-4). The purpose of this study was to investigate the biotransformation of ETN in humans and mice and evaluate its effects on functional properties.An analytical method using liquid chromatography-mass spectrometry (LC-MS/MS) was established. The N-terminal heterogeneity of ETN was assessed in the serum of patients with rheumatoid arthritis or mice receiving ETN. The in vitro N-terminal truncation was explored using recombinant DPP-4. The binding affinity to TNF-α or TNF-β was investigated using an in-house enzyme-linked immunosorbent assay.In the formulations, about 90% of ETN had an intact N-terminus, while the N-terminal truncated form was most abundant in the serum of the patients with rheumatoid arthritis and mice. Recombinant human DPP-4 cleaved two amino acids from the N-terminus of ETN in vitro. Sitagliptin, a DPP-4 inhibitor, inhibited N-terminal truncation both in vivo and in vitro. However, N-terminal truncation did not affect the binding ability to TNF-α or TNF-β and the pharmacokinetics of ETN. ETN biosimilars exhibited similar characteristics to the reference product in vivo and in vitro.ETN undergoes N-terminal truncation in the body, and DPP-4 cleaves exogenous ETN via N-terminal proteolysis. The application of an MS-based assay will detect novel biotransformation of therapeutic proteins.

Cancer immunotherapy using immune checkpoint inhibitors can cause immune reactions at various sites as a side effect called immune-related adverse events (irAEs). The gastrointestinal tract is susceptible to irAEs, however, the degree and presentation vary considerably from case to case. A 76-year-old woman was diagnosed with anal mucosal melanoma. She underwent radical surgery and received postoperative adjuvant therapy. However, because new metastases were also found in bilateral inguinal lymph nodes, immunotherapy with nivolumab was performed. Approximately 10 months after the initiation of nivolumab administration, she presented with epigastric discomfort and nausea, and her laboratory data showed severe eosinophilia (1938/mm