Search

Objectives: To identify clinical characteristics of patients with non-refractory Kawasaki disease (KD), which were defined as those who successfully responded to the standard initial intravenous immunoglobulin (IVIG) treatment (2 g/kg/day, single infusion) without any secondary or later additional specific treatments, and to investigate the factors associated with the development of coronary artery (CA) complications in patients with non-refractory KD., Design: Retrospective cohort study., Setting: Hospitals specialising in paediatrics and hospitals with ≥100 beds and a paediatric department throughout Japan., Patients: A total of 122 489 patients who developed KD across Japan during 2011-2018., Main Outcome Measures: CA abnormalities identified after acute illness of KD (defined as CA sequelae)., Results: A total of 69 735 patients with non-refractory KD were identified, of which 672 (0.96%) experienced CA sequelae. Among patients with non-refractory KD, the presence of CA abnormalities identified at initial echocardiographic assessment was strongly associated with CA sequelae (adjusted OR (95% CI): 37.8 (31.9 to 44.7)). CA sequelae was also associated with male patients, infants (<12 months old), older patients (≥60 months old) and patients who received delayed initial IVIG treatment (>7 days from KD onset). Subgroup analyses demonstrated that delayed initial IVIG treatment was significantly associated with the development of CA sequelae in both patients with and without CA abnormalities identified at initial echocardiographic assessment., Conclusions: Approximately 1% of patients with non-refractory KD may develop CA sequelae. Our findings highlight the importance of initial echocardiographic assessment and early initiation of IVIG treatments for patients with KD., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Medication adherence is important for the appropriate drug-based treatment in patients with chronic diseases, especially those with cardiovascular diseases (CVDs). The purpose of the present study was to evaluate medication adherence among patients with CVDs using subjective and objective measurements. We enrolled outpatients who visited Fukuoka University Chikushi Hospital from June to December 2022. As a subjective measurement, we used a self-reported questionnaire developed by Ueno et al., which consists of 12 questionnaire items grouped into the following four domains: medication compliance (subjective compliance), collaboration with health care providers (collaboration), willingness to access and use information about medication (willingness), and acceptance to take medication and how taking medication fits a patient's lifestyle (acceptance). The pill counting method was used as an objective measurement to calculate the medication adherence rate; Poor Adherence was defined as a medication adherence rate of <100%. Ninety-four patients were analyzed. No statistically significant differences were observed between the patients in the Good and Poor Adherence groups classified by pill counting, an objective indicator; in the subjective evaluation index Ueno scale scores of subjective compliance, collaboration, willingness, and acceptance domains; and in the total score. A multivariate analysis revealed that obesity (odds ratio, 3.527; 95% confidence interval, 1.387-9.423; p = 0.008) was an independent factor associated with Poor Adherence. In conclusion, we found a discrepancy between subjective and objective measurements for the evaluation of medication adherence. Furthermore, obesity was an independent factor associated with poor medication adherence assessed by the pill counting method; thus, patients with CVD and obesity require a careful follow-up.

Although immune checkpoint inhibitors (ICI) are used for unresectable hepatocellular carcinoma (HCC), it is unclear whether sequential ICI treatment-durvalumab plus tremelimumab (DT) after progression on atezolizumab plus bevacizumab (AB)-is effective for HCC. In this nationwide multicenter study, we aimed to investigate the effect of DT treatment based on the timing of treatment. A total of 85 patients receiving DT treatment were enrolled. The primary endpoint is treatment response at week 8 among patients receiving first-line DT treatment, those receiving second-line or later treatment without prior AB therapy, and those receiving second-line or later treatment with prior AB therapy. Objective response rates (ORRs) in patients with first-line treatment, second-line treatment without AB, and second-line treatment with prior AB were 44%, 54%, and 5%, respectively (p < 0.001). Similarly, disease control rates (DCRs) were 69%, 91%, and 26%, respectively (p < 0.001). ORR and DCR were significantly lower in patients with prior AB treatment. Progression free survival (PFS) was significantly shortened in patients receiving second-line therapy following prior AB treatment and an adjusted hazard ratio (95% confidence interval) in those patients for PFS, using first-line therapy as a reference, was 2.35 (1.1-5.1, p = 0.03). In conclusion, the impact of DT sequencing following AB treatment was limited. However, even after second-line treatment, the treatment effect can be equivalent to that of first-line treatment in cases with no history of AB treatment. Thus, prior treatment history should be taken into account when initiating DT treatment., Competing Interests: Declarations. Competing interests: Masayuki Kurosaki and Kaoru Tsuchiya received lecture fee from AstraZeneca and Chugai. Other authors have no conflicts of interest to declare related to the study., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background/aim: Maintaining liver function throughout the treatment of hepatocellular carcinoma (HCC) is crucial, yet the impact of durvalumab plus tremelimumab (DT) treatment on liver function is not well understood. This multicenter study aimed to examine the changes in liver function during DT treatment., Patients and Methods: This nationwide multicenter study included 80 patients who received DT treatment for unresectable HCC. The primary outcome was changes in albumin-bilirubin (ALBI) scores at baseline, week 8, week 12, and at the time of progressive disease (PD)., Results: The median (interquartile range) ALBI scores at baseline, week 8, week 12, and the time of PD were -2.24 (-2.49 to -1.94), -2.13 (-2.51 to -1.86), -2.23 (-2.51 to - 1.77), and -2.06 (-2.53 to -1.72), respectively. No significant differences were observed at 8 weeks (p=0.06), at 12 weeks (p=0.4), and at PD (p=0.8) compared to baseline. Subgroup analyses were conducted for patients with an ALBI grade of 2 at baseline and for those who received DT treatment as a second-line or later treatment. No deterioration in liver function was observed at any time point in both analyses., Conclusion: DT treatment can maintain liver function throughout the treatment period. Maintaining liver function is crucial in managing HCC, and this is an advantage of using DT treatment as a first-line treatment for unresectable HCC., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Aim: This study observed changes in respiratory rate measurement (RRM) and identified barriers and challenges in clinical practice that influence healthcare worker behaviour, aiming to improve RRM in a hospital setting., Design: An observational study was conducted., Methods: We observed and analysed changes in the behaviour of healthcare workers at a hospital where multi-nudges were introduced to improve RRM., Results: We checked respiration rate using electronic data and discovered that the original measurement rates were low. Measurement rates rapidly increased after posters were added. Barriers such as time constraints and measurement equipment were also noted., Conclusion: RRM was found to be effective in promoting behavioural economics in medical settings. The results show that incorporating behavioural science principles into medical interventions has the potential to positively change behaviour., Implications for the Profession And/or Patient Care: By increasing nurses' awareness of respiratory rate measurement and addressing barriers to it, the measurement rate of respiratory rate can also increase, leading to more accurate patient evaluations and triage., Impact: WHAT PROBLEM DID THE STUDY ADDRESS?: The proportion of respiratory rate measurements leading to rapid response system (RRS) calls was low. WHAT WERE THE MAIN FINDINGS?: The study observed that a multi-nudge approach effectively changes the behaviour of ward nurses, resulting in enhanced quality of medical care. WHERE AND ON WHOM WILL THE RESEARCH HAVE AN IMPACT?: This research can serve as a valuable reference for leaders promoting healthcare quality projects, by offering a method to encourage behavioural change., Reporting Method: This study complied with the EQUATOR guidelines and its reporting adheres to the STROBE checklist., Patient or Public Contribution: No patient or public contribution., (© 2024 John Wiley & Sons Ltd.)

The germinal centers (GCs) are structure found within secondary lymphoid organs and are important for the antibody-producing response against foreign antigens. In GCs, antigen-specific B cells proliferate intensely, inducing immunoglobulin class switching. Recent studies have shown that GCs are also an important site for class switching to IgE, which is implicated in allergy. However, the mechanisms by which IgE production is regulated in GCs remain unclear. Here, we found impairment in IgE-specific production and a reduction of GC B cells after immunization in mice deficient in the Aps/Sh2b2 gene encoding the Lnk/Sh2b family adaptor protein Aps. GC B cells express higher levels of the Aps gene than non-GC B cells, and cell death of Aps -/- GC B cells is enhanced compared to wild-type GC B cells. An in vitro culture system with purified Aps -/- B cells induced the same level of IgE production and frequencies of IgE + B cells as wild-type B cells. We found that Aps deficiency in B cells resulted in augmented depletion of IgE + blasts by B cell receptor crosslinking with anti-CD79b antibodies compared to wild-type IgE + cells. These results suggest that Aps regulates IgE production by controlling the survival of GC B cells and IgE + plasma cells and may serve as a potential therapeutic target to control IgE production., (© 2024. The Author(s).)

Introduction: The Cancer and Aging Research Group (CARG) prediction tool was designed in the United States to predict grade ≥ 3 chemotherapy-related adverse events (CRAE) in older patients. However, its usefulness among Japanese people, who have different sensitivities to anticancer drugs and life expectancy, remains unknown. We aimed to prospectively evaluate the utility of the CARG tool for predicting severe CRAE in older Japanese patients with cancer., Material and Methods: Patients with solid tumors aged 65 years and older who commenced anticancer drug regimens from April 2018 to October 2020 were divided into three groups (low, medium, and high-risk) based on their CARG risk scores. Toxicity was prospectively observed by a pharmacist. The primary objective was to evaluate the correlation between the incidence of grade ≥ 3 CRAE and the CARG risk score. The secondary objective was to evaluate hematological and non-hematological toxicities. CRAE incidence was compared among the three groups using a closed testing procedure: (1) Cochran-Armitage test for trend and (2) chi-square test for paired comparison., Results: The patients (N = 165) had a median age of 71 years (range: 65-89 years). CRAE in patients divided into low-, medium-, and high-risk groups, based on CARG risk scores, were 39%, 55%, and 82%, respectively (low vs high; p < 0.001, medium vs high; p < 0.01). The incidence of severe hematologic toxicity was 37%, 35%, and 50% in the low-, medium-, and high-risk groups, respectively; the incidence of severe non-hematologic toxicity was 15%, 36%, and 65%, respectively (low vs medium; p < 0.01, low vs high; p < 0.001, and medium vs high; p < 0.01)., Discussion: To our knowledge, this is the first prospective observational study to validate the CARG prediction tool in older Japanese patients with cancer. The CARG risk score may be effective in predicting the development of non-hematologic toxicities. These results should be considered when administering chemotherapy to older Japanese patients with advanced solid tumors., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest directly relevant to the content of this article., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background and Aim: In patients with chronic hepatitis C, 8 weeks of glecaprevir and pibrentasvir (GLE/PIB) treatment for chronic hepatitis (non-cirrhosis) and 12 weeks for cirrhosis have been approved in Japan. However, whether 8 weeks of treatment for cirrhosis may reduce treatment efficacy has not been adequately investigated., Methods: This prospective, nationwide, multicenter cohort study enrolled 1275 patients with chronic hepatitis C who received GLE/PIB therapy. The effect of liver fibrosis and treatment periods on the efficiency of GLE/PIB therapy was investigated. The primary endpoint was the sustained virological response (SVR) rate in patients with chronic hepatitis (non-cirrhosis) and cirrhosis. The association between treatment periods and liver fibrosis on the SVR after 12 weeks of treatment rate was investigated., Results: The SVR rates in patients with chronic hepatitis with 8 weeks of treatment, chronic hepatitis with 12 weeks of treatment, cirrhosis with 8 weeks of treatment, and cirrhosis with 12 weeks of treatment were 98.9% (800/809), 100% (87/87), 100% (166/166), and 99.1% (211/213), respectively, and were was not different among these groups ( P  = 0.4)., Conclusion: GLE/PIB therapy for chronic hepatitis C had high efficacy regardless of liver fibrosis status and treatment periods. Periods of GLE/PIB therapy could be chosen with available modalities, and high SVR rates could be achieved regardless of the decision., (© 2024 The Authors. JGH Open published by Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Obesity-induced adipose tissue inflammation plays a critical role in the development of metabolic diseases. For example, NK1.1 + group 1 innate lymphoid cells (G1-ILCs) in adipose tissues are activated in the early stages of inflammation in response to a high-fat diet (HFD). In this study, we examined whether the composition of fatty acids affected adipose inflammatory responses induced by an HFD. Mice were fed a stearic acid (C18:0)-rich HFD (HFD-S) or a linoleic acid (C18:2)-rich HFD (HFD-L). HFD-L-fed mice showed significant obesity compared with HFD-S-fed mice. Visceral and subcutaneous fat pads were enlarged and contained more NK1.1 + KLRG1 + cells, indicating that G1-ILCs were activated in HFD-L-fed mice. We examined early changes in adipose tissues during the first week of HFD intake, and found that mice fed HFD-L showed increased levels of NK1.1 + CD11b + KLRG1 + cells in adipose tissues. In adipose tissue culture, addition of 4-hydroxynonenal, the most frequent product of lipid peroxidation derived from unsaturated fatty acids, induced NK1.1 + CD11b + CD27 - cells. We found that calreticulin, a ligand for the NK activating receptor, was induced on the surface of adipocytes after exposure to 4-hydroxynonenal or a 1-week feeding with HFD-L. Thus, excess fatty acid intake and the activation of G1-ILCs initiate and/or modify adipose inflammation., (© 2024 The Authors. European Journal of Immunology published by Wiley‐VCH GmbH.)

Inert naive CD4 + T (T N ) cells differentiate into functional T helper (Th) or regulatory T (Treg) cell subsets upon encountering antigens, mediating properly directed immune responses. Although all T N cells can differentiate into any of the Th and Treg cell subsets, heterogeneity exists among T N cells. By constructing reporter mice to detect ongoing T cell receptor (TCR) signaling, we identify that interleukin (IL)-1β signaling affects T N cell characteristics, independent of tonic TCR signaling, which also alters T N cell phenotypes. IL-1β reversibly attenuates the differentiation potential of T N cells toward Treg cells. IL-1β signaling is elevated in the splenic T N cells, consequently attenuating their differentiation potential toward Treg cells. Aberrant elevation of IL-1β signaling augments colitogenic activities of T N cells. T N cells in patients with colitis exhibited elevated IL-1β signaling. We demonstrate that phenotypic alteration in T N cells by IL-1β is an important mechanism in the regulation of immune responses., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Post-intensive care syndrome comprises physical, cognitive, and mental impairments in patients treated in an intensive care unit (ICU). It occurs either during the ICU stay or following ICU discharge and is related to the patients' long-term prognosis. The same concept also applies to pediatric patients, and it can greatly affect the mental status of family members. In the 10 years since post-intensive care syndrome was first proposed, research has greatly expanded. Here, we summarize the recent evidence on post-intensive care syndrome regarding its pathophysiology, epidemiology, assessment, risk factors, prevention, and treatments. We highlight new topics, future directions, and strategies to overcome post-intensive care syndrome among people treated in an ICU. Clinical and basic research are still needed to elucidate the mechanistic insights and to discover therapeutic targets and new interventions for post-intensive care syndrome., Competing Interests: Dr. Yutaka Kondo is an Editorial Board member of AMS Journal and a co‐author of this article. To minimize bias, they were excluded from all editorial decision‐making related to the acceptance of this article for publication. The other authors declare no conflicts of interest in relation to this review article., (© 2024 The Authors. Acute Medicine & Surgery published by John Wiley & Sons Australia, Ltd on behalf of Japanese Association for Acute Medicine.)

Purpose: Non-contact continuous respiratory rate monitoring is preferred for early detection of patient deterioration. However, this technique is under development; a gold standard respiratory monitor has not been established. Therefore, this prospective observational method comparison study aimed to compare the measurement accuracy of a non-contact continuous respiratory rate monitor, a microwave Doppler sensor positioned beneath the mattress, with that of other monitors., Methods: The respiratory rate of intensive care unit patients was simultaneously measured using a microwave Doppler sensor, capnography, thoracic impedance pneumography, and a piezoelectric sensor beneath the mattress. Bias and 95% limits of agreement between the respiratory rate measured using capnography (standard reference) and that measured using the other three methods were calculated using Bland-Altman analysis for repeated measures. Clarke error grid (CEG) analysis evaluated the sensor's ability to assist in correct clinical decision-making., Results: Eighteen participants were included, and 2,307 data points were analyzed. The bias values (95% limits of agreement) of the microwave Doppler sensor, thoracic impedance pneumography, and piezoelectric sensor were 0.2 (- 4.8 to 5.2), 1.5 (- 4.4 to 7.4), and 0.4 (- 4.0 to 4.8) breaths per minute, respectively. Clinical decisions evaluated using CEG analyses were correct 98.1% of the time for the microwave Doppler sensor, which was similar to the performance of the other devices., Conclusion: The microwave Doppler sensor had a small bias but relatively low precision, similar to other devices. In CEG analyses, the risk of each monitor leading to inadequate clinical decision-making was low., Trial Registration Number: UMIN000038900, February 1, 2020., (© 2023. The Author(s), under exclusive licence to Springer Nature B.V.)

To effectively use data from intensive care unit patient information systems at multiple hospitals, it is necessary to standardize the data into a well-ordered form. However, terms often vary between devices. We designed a mechanical ventilation concept model and applied data to that model using existing tools and expert opinions. The JSICM glossary was revised based on this study.

Introduction: Systemic therapy is recommended for patients with Child-Pugh A in hepatocellular carcinoma (HCC). We analyzed the outcomes of a cohort of patients with HCC who received either sorafenib (Sor), lenvatinib (Len) or atezolizumab plus bevacizumab (Atezo + Bev) as first-line systemic therapy for HCC, with the aim of identifying prognostic factors for survival., Methods: A total of 825 patients with advanced HCC and Child-Pugh A or B received either Sor, Len or Atezo + Bev as first-line systemic therapy. Liver function was assessed according to the Child-Pugh score and the modified albumin-bilirubin (mALBI) grade., Results: Prognosis was analyzed according to liver function such as Child-Pugh classifications, scores, and mALBI grades that worsened with a decline in liver function (p &lt;0.001 for all). A Child-Pugh score of 7 was a factor significantly associated with OS. In patients with a Child-Pugh score of 7, an mALBI grade of 3 was an independent predictor of OS. In Child-Pugh B patients with HCC, receiving Atezo + Bev was identified as a factor associated with PFS., Conclusion: Determining the hepatic reserve of patients with unresectable HCC might be useful for identifying patents suitable for systemic treatment for HCC. Atezo + Bev might prolong the PFS of patients with a Child-Pugh score of 7., (© 2023 S. Karger AG, Basel.)

Acute kidney injury (AKI) after cardiac surgery is a common complication that can lead to death. We previously reported that the creatinine reduction ratio (CRR) serves as a useful prognostic factor for AKI. The primary objective of this study was to determine the predictors of AKI after surgery. The secondary objective was to determine the reliability of the CRR for short- and long-term outcomes. We retrospectively collected information about cardiac surgery patients who underwent cardiopulmonary bypass. Patients were divided into AKI and non-AKI groups based on the AKIN and RIFLE criteria. We analyzed the two groups regarding the preoperative patient data and operative information. The CRR was calculated as follows: (preoperative creatinine-postoperative creatinine)/preoperative creatinine. The prognostic factors of AKI-CS were surgery time, CPB time, aorta clamp time, platelet transfusion, and CRR < 20%. In the multivariate logistical analysis, CRR was an independent predictor of AKI (adjusted odds ratio: 0.90 [0.87-0.93], p < 0.001). However, there were no significant differences in CRR in terms of the rate of new onset chronic kidney disease (CKD). After cardiac surgery with cardiopulmonary bypass, CRR has good diagnostic power for predicting perioperative AKI. However, we cannot use it as a prognostic factor over a long-term period.

A total of 137 HCC patients treated with atezolizumab plus bevacizumab from October 2020 to September 2022 were enrolled. The median overall survival (OS) and progression-free survival (PFS) from the beginning of atezolizumab plus bevacizumab were 21.1 months (range, 18.8 months-not reached) and 10.5 months (range, 8.2-12.1 months), respectively. Fifty patients were diagnosed with progressive disease after atezolizumab plus bevacizumab. Of this group, 24 patients were administered lenvatinib, and the median OS and PFS from the beginning of lenvatinib were 15.3 months (range, 10.5 months-not reached) and 4.0 months (range, 2.5-6.4 months), respectively. The objective response rates based on the response evaluation criteria in solid tumors (RECISTs) criteria version 1.1 and modified RECISTs were 33.3% and 54.2%, respectively. There was no significant difference in the median serum alpha-fetoprotein level between before and after lenvatinib. In the multivariate analysis, Child-Pugh class A (hazard ratio 0.02, 95% confidence interval (CI) 0.02-0.76, p = 0.02) and intrahepatic tumor occupancy rate < 50% (hazard ratio < 0.01, 95% CI 0.003-0.35, p < 0.01) were the significant factors for OS. There were some frequent adverse events (AEs) in patients treated with lenvatinib such as hypertension, fatigue, anorexia, proteinuria, and so on, but none directly caused death. In conclusion, lenvatinib after atezolizumab plus bevacizumab for unresectable HCC should be considered an effective treatment option.

Background: The assessment of post-intensive care syndrome (PICS) is challenging due to the numerous types of instruments. We herein attempted to identify and propose recommendations for instruments to assess PICS in intensive care unit (ICU) survivors., Methods: We conducted a scoping review to identify PICS follow-up studies at and after hospital discharge between 2014 and 2022. Assessment instruments used more than two times were included in the modified Delphi consensus process. A modified Delphi meeting was conducted three times by the PICS committee of the Japanese Society of Intensive Care Medicine, and each score was rated as not important (score: 1-3), important, but not critical (4-6), and critical (7-9). We included instruments with ≥ 70% of respondents rating critical and ≤ 15% of respondents rating not important., Results: In total, 6972 records were identified in this scoping review, and 754 studies were included in the analysis. After data extraction, 107 PICS assessment instruments were identified. The modified Delphi meeting reached 20 PICS assessment instrument recommendations: (1) in the physical domain: the 6-min walk test, MRC score, and grip strength, (2) in cognition: MoCA, MMSE, and SMQ, (3) in mental health: HADS, IES-R, and PHQ-9, (4) in the activities of daily living: the Barthel Index, IADL, and FIM, (5) in quality of life: SF-36, SF-12, EQ-5D-5L, 3L, and VAS (6), in sleep and pain: PSQI and Brief Pain Inventory, respectively, and (7) in the PICS-family domain: SF-36, HADS, and IES-R., Conclusion: Based on a scoping review and the modified Delphi method, 20 PICS assessment instruments are recommended to assess physical, cognitive, mental health, activities of daily living, quality of life, sleep, and pain in ICU survivors and their families., (© 2023. The Author(s).)

Reactive lymphoid hyperplasia (RLH) of the liver is extremely rare. Despite advancements in diagnostic imaging technology, it is still difficult to distinguish from hepatocellular carcinoma (HCC). Herein, we present a case of hepatic RLH mimicking HCC that was postoperatively diagnosed using several imaging modalities. A 78-year-old female was referred to our hospital with a positive hepatitis C virus antibody (HCV Ab) test. Ultrasonography revealed a 13 mm isoechoic lesion in segment 8 of the liver. Contrast-enhanced computed tomography (CE-CT) demonstrated arterial hyperintensity and washout during the later phase. On ethoxybenzyl magnetic resonance imaging (EOB-MRI), the lesion was hyperenhanced in the arterial phase and of low intensity in the hepatocyte phase. Although the tumor markers were all within normal limits, the pattern of contrast enhancement of the tumor on CT and MRI was consistent with that of HCC. We performed S8 segmentectomy of the liver. Histological examination of the resected specimen revealed dense lymphoid tissue of variable sizes and shapes with expanded germinal centers. Immunohistochemical examination was positive for CD3, CD10 (germinal center), and CD20, and negative for B-cell lymphoma 2 (bcl-2) (germinal center) and Epstein-Barr virus (EBV). A polymerase chain reaction (PCR) analysis of IgH-gene rearrangements revealed polyclonality. Based on these findings, hepatic RLH was diagnosed. The postoperative course was uneventful, and the patient was discharged on the 10 th postoperative day. She had a good quality of life after surgery and no liver nodule recurrence was detected at the 4-month medical follow-up. Hepatic RLH is an extremely rare disease and preoperative diagnosis is difficult. This should be considered in the differential diagnosis of single small hepatic tumors. An echo-guided biopsy and careful observation of imaging may help diagnose hepatic RLH, and a PCR analysis of IgH-gene rearrangements would be necessary for the definitive diagnosis of hepatic RLH., Competing Interests: Conflict of interestThe authors declare that they have no competing interests., (© The Author(s) under exclusive licence to The Japan Society of Clinical Oncology 2023. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Background: Persistent inflammation, immunosuppression, and catabolism syndrome (PIICS) is known as a prolonged immunodeficiency that occurs after severe infection. Few studies have demonstrated a direct relationship between PIICS and physical dysfunction in post-intensive care syndrome (PICS). We herein investigated how each component of PICS was affected by the diagnosis of PIICS during hospitalization and examined the relationship between PIICS and PICS using PICS assessments performed at the Hitachi General Hospital PICS Clinic., Methods: The 273 patients who visited the PICS clinic at one month after discharge from the ICU at Hitachi General Hospital were included in the study. We used the diagnostic criteria for PIICS described in previous studies. At least two of the following blood test values on day 14 of hospitalization had to be met for a diagnosis of PIICS: C-reactive protein (CRP) > 2.0 mg/dL, albumin (Alb) < 3.0 g/dL, and lymphocytes (Lym) < 800/μL. Blood test values closest to day 14 out of 11-17 days of hospitalization were used. The primary outcome was a Barthel Index (BI) < 90, while secondary outcomes were the results of various PICS assessments, including mental and cognitive impairments, performed at the PICS clinic. We supplemented missing data with multiple imputations by chained equations. We performed a nominal logistic regression analysis with age, sex, BMI, SOFA, and the presence of PIICS as variables for BI < 90., Results: Forty-three out of two hundred seventy-three PICS outpatients met the diagnostic criteria for PIICS during hospitalization. In comparisons with non-PIICS patients, significantly higher severity scores for APACHE II and SOFA and a longer hospital stay were observed in PIICS patients, suggesting a higher clinical severity. The primary outcome, BI, was lower in the PIICS group (97.5 (58.5, 100) vs. 100 (95, 100), p = 0.008), as were the secondary outcomes (FSS-ICU: 35 (31, 35) vs. 35 (35, 35), MRC score: 55 (50.25, 58) vs. 58 (53, 60), grip strength: 16.45 (9.2, 25.47) vs. 20.4 (15.3, 27.7)). No significant differences were noted in mental or cognitive function assessments, such as HADS, IES-R, and SMQ. A multivariable analysis supplemented with missing data revealed that PIICS (odds ratio: 1.23 (1.08-1.40 p = 0.001) and age (odds ratio: 1.007 (1.004-1.01), p < 0.001) correlated with BI < 90, independent of clinical severity such as sequential organ failure assessment (SOFA). Similar results were obtained in the sensitivity analysis excluding missing data., Conclusions: The present study revealed a strong relationship between PIICS and post-discharge PICS physical dysfunction in patients requiring intensive care.

Background: Post-pyloric enteral feeding reduces respiratory complications and shortens the duration of mechanical ventilation. Blind placement of post-pyloric enteral feeding tubes (EFT) in patients with critical illnesses is often the first-line method because endoscopy or fluoroscopy cannot be easily performed at bedside; however, difficult placements regularly occur. We reported an association between the stomach position caudal to spinal level L1-L2, evaluated by abdominal radiographs after placement, and difficult placement; however, this method could not indicate difficulty before EFT placement. The aim of our study was to evaluate the association between stomach position, estimated using computed tomography (CT) images taken before the blind placement of the post-pyloric EFT, and the difficulty of EFT placement., Methods: Data from patients aged ≥ 20 years who underwent post-pyloric EFT in our intensive care unit were obtained retrospectively. Logistic regression analysis was used to evaluate the association between successful initial EFT placement and explanatory variables, including stomach position estimated by CT. Two cut-off values were used: caudal to L1-L2 based on a previous study and the best cut-off value calculated by the receiver operating characteristic curve. Variable selection was performed backward stepwise using Akaike's Information Criterion., Results: Of the total of 453 patients who were enrolled, the success rate of the initial EFT placement was 43.5%. The adjusted odds ratio for successful initial EFT placement of the stomach position caudal to L1-L2 was 0.61 (95% confidence interval: 0.41-1.07). Logistic regression analysis, including the stomach position caudal to L2-L3, calculated as the best cut-off value, indicated that stomach position was an independent factor for failure of initial EFT placement (adjusted odds ratio, 0.55; 95% confidence interval: 0.33-0.91)., Conclusions: Stomach position evaluated using CT images was associated with successful initial post-pyloric EFT placement. The best cut-off value of the greater curvature of the stomach to predict the success or failure of the first attempt was spinal level L2-L3. Trial registration University Hospital Medical Information Network Clinical Trials Registry (UMIN000046986; February 28, 2022). https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr&#95;view.cgi?recptno=R000052151., (© 2023. The Author(s).)

This study aimed to describe the real-world efficacy and safety of the combination therapy of atezolizumab and bevacizumab (Atezo/Bev) for unresectable hepatocellular carcinoma (HCC). This retrospective analysis of a multicenter registry cohort included 268 patients treated with Atezo/Bev. The incidence of adverse events (AE) and its impact on overall survival (OS) and progression-free survival (PFS) were analyzed. Of the 268 patients, 230 (85.8%) experienced AE. The median OS and PFS in the whole cohort were 462 and 239 days, respectively. The OS and PFS were not different in terms of AE, but they were significantly shorter in patients with increased bilirubin level and those with increased aspartate aminotransferase (AST) or alanine aminotransferase (ALT). Regarding increased bilirubin level, the hazard ratios (HRs) were 2.61 (95% confidence interval [CI]: 1.04-6.58, P = 0.042) and 2.85 (95% CI: 1.37-5.93, P = 0.005) for OS and PFS, respectively. Regarding increased AST or ALT, the HRs were 6.68 (95% CI: 3.22-13.84, P < 0.001) and 3.54 (95% CI: 1.83-6.86, P < 0.001) for OS and PFS, respectively. Contrarily, the OS was significantly longer in patients with proteinuria (HR: 0.46 [95% CI: 0.23-0.92], P = 0.027). Multivariate analysis confirmed that proteinuria (HR: 0.53 [95% CI: 0.25-0.98], P = 0.044) and increased AST or ALT (HR: 6.679 [95% CI: 3.223-13.84], P = 0.003) were independent risk factors for a shorter OS. Furthermore, analysis limited to cases who completed at least 4 cycles confirmed that increased AST or ALT and proteinuria were negative and positive factors for OS, respectively. In the real-world setting, increased AST or ALT and bilirubin level during Atezo/Bev treatment were found to have a negative impact on PFS and OS, whereas proteinuria had a positive impact on OS., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

PE&#95;PGRS30 belongs to the PE&#95;PGRS protein family and is characterized by a conserved Pro-Glu (PE) domain and a typically polymorphic GC-rich sequence (PGRS) domain. PE&#95;PGRS30 is a virulence factor of Mycobacterium tuberculosis that induces macrophage cell death. We found that RAW264.7 cells and murine alveolar macrophages underwent apoptosis in response to PE&#95;PGRS30. The host protein prohibitin 2 (PHB2) was identified as a target molecule. PE&#95;PGRS30 and PHB2 interact via the PGRS domain and mitochondrial targeting sequence, respectively. PHB2 overexpression reduced macrophage apoptosis in response to PE&#95;PGRS30. PE&#95;PGRS30 co-localized with PHB2, not in mitochondria, but in lysosomes. The maintenance of mitochondrial structure by PHB2 was impaired in response to the PGRS domain. These results indicated that PE&#95;PGRS30 reduces PHB2 in mitochondria, resulting in mitochondrial dysfunction and cellular apoptosis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Matsumura, Takaki and Kirikae.)

Aim: We investigated pretreatment neutrophil-to-lymphocyte ratio (NLR) for predicting survival outcomes of atezolizumab plus bevacizumab therapy for hepatocellular carcinoma (HCC) and determined the predictive ability of combined liver reserve-NLR., Methods: This retrospective, multicenter study enrolled 242 patients receiving atezolizumab plus bevacizumab for unresectable HCC. Pretreatment NLR <2.56 was designated as the "low group" and NLR ≥2.56 as the "high group" (120 and 122 patients, respectively). Propensity score-matched analysis was undertaken between the low and high groups., Results: In this cohort, the objective response and disease control rates were 20% and 72.5%, respectively, in the low group and 19.6% and 72.9%, respectively, in the high group. After matching, median progression-free survival (PFS) time was 283 and 167 days in the low and high groups, respectively (p = 0.022). Neutrophil-to-lymphocyte ratio ≥2.56 (hazard ratio [HR], 1.54; 95% confidence interval [CI], 1.05-2.28; p = 0.028), modified albumin-bilirubin index (mALBI) grade 2b or 3 (HR 1.55; 95% CI, 1.05-2.29; p = 0.025), and protein induced by vitamin K absence or antagonist-II ≥ 400 (HR 2.03; 95% CI, 1.36-3.02; p = 0.001) were significantly associated with PFS in univariate analysis using the Cox proportional hazards model. In cases involving mALBI grade 1 or 2a (n = 131), the median PFS time was not reached in the low group, whereas it was 210 days in the high group (p = 0.037)., Conclusions: Pretreatment NLR is a simple tool for routine measurement in clinical practice. It can predict PFS in patients with unresectable HCC treated with atezolizumab plus bevacizumab, especially mALBI grade 1 or 2a., (© 2022 The Authors. Hepatology Research published by John Wiley & Sons Australia, Ltd on behalf of Japan Society of Hepatology.)

Aims: This study aimed to analyze the cost-effectiveness of intradiscal condoliase injection compared to surgical or conservative treatment for patients with lumbar disc herniation (LDH) who are refractory to conservative treatment., Methods: We performed the following cost-effectiveness analyses: (I) condoliase followed by open surgery (for non-responders to condoliase) vs. open surgery from the beginning, (II) condoliase followed by endoscopic surgery (for non-responders to condoliase) vs. endoscopic surgery from the beginning, and (III) condoliase + conservative treatment vs. conservative treatment. In the first two comparisons with surgical treatments, we assumed that utilities were equal in both groups and estimated the tangible (treatment, adverse events, postoperative follow-up) and intangible (mental and physical burden, and productivity loss) costs based on the existing literature, the medical expense scoring table, and online questionnaire. In the last comparison without surgical treatment, we estimated the incremental cost-effectiveness., Results: The average cost per patient of condoliase followed by open surgery (for non-responders to condoliase) was 701,643 yen, with a reduction of 663,369 in comparison to that of open surgery from the beginning (1,365,012 yen). The average cost per patient of condoliase followed by endoscopic surgery (for non-responders to condoliase) was 643,909 yen, with a reduction of 514,909 in comparison to that of endoscopic surgery from the beginning (1,158,817 yen). ICER was 1.58 million yen/QALY (ΔQALY = 0.119, 95% confidence interval: 0.059-0.180; Δcost = 188,809 yen at 2 years post-treatment)., Conclusions: Condoliase as a first line treatment option ahead of surgical treatment for LDH is superior, from a cost perspective, to surgical treatment from the beginning. Condoliase is also a cost-effective alternative to non-surgery conservative treatment.

The current study investigated pregnant women's use of pregnancy applications (apps) and how these apps affect their mental health. A questionnaire was administered in the outpatient obstetrics and gynecology department at a university hospital. Of 110 pregnant women included in the analysis, 97 had downloaded and used pregnancy apps and believed that these were either helpful or a little helpful . Among the 110 respondents, 20 (18.2%) women were identified as having psychological distress. Thus, the percentage of women with psychological distress who downloaded pregnancy apps was significantly lower than women in the mentally healthy group. Non-use of pregnancy apps was strongly associated with psychological distress, indicating that pregnancy apps improve pregnant women's mental health. Alternatively, non-use of apps could arise from deteriorated mental health, causing reduced energy or inclination to use these apps. Screening for good mental health among pregnant women is important; non-use of pregnancy apps may indicate risk of mental health deterioration among pregnant women. [ Journal of Psychosocial Nursing and Mental Health Services, 61 (1), 32-38.].

A 78-year-old female patient presented to our hospital with abdominal pain and melena. Abdominal ultrasonography detected a multiple concentric ring sign and retrograde invagination mass near the hepatic flexure. Colonoscopy revealed a 40-mm diameter type 1 tumor in the transverse colon near the splenic flexure, and the biopsy specimen demonstrated a well-differentiated adenocarcinoma. Retrograde intussusception due to transverse colon cancer was diagnosed, and laparoscopic transverse colon resection with lymph node dissection was performed. The resected specimen revealed a 48×40mm diameter type 1 tumor in the transverse colon and was diagnosed as pT2N0M0 pStage I. Contrast-enhanced computed tomography was unavailable, but real-time assessment of the invaginated mass and bowel blood flow was possible by abdominal ultrasonography, which was useful in determining the diagnosis and treatment strategy.

Alpha-fetoprotein (AFP) response (relative decline in AFP) is associated with imaging response evaluated by response evaluation criteria in solid tumors ver1.1 (RECIST) and survival in treatment for hepatocellular carcinoma (HCC). However, the optimal threshold of AFP response is still unknown, especially in atezolizumab and bevacizumab (Atez/Bev) treatment. In this prospective multicenter study, we aimed to investigate an optimal threshold of AFP response in Atez/Bev treatment. Out of 284 patients with unresectable HCC who were treated with Atez/Bev, 91 patients with AFP ≥ 10 ng/ml were enrolled in the multicenter study. We investigated the relationship between various AFP response thresholds (relative decline ≥ 20%, ≥ 50%, and ≥ 75%) and treatment response and progression-free survival (PFS). An AFP relative decrease of ≥ 50% was associated with an overall response rate (ORR) with an odds ratio (95% confidence interval [CI]) of 5.7 (1.9-17). Disease control rate (DCR) was associated with an AFP relative decrease of ≥ 20%, with a 100% positive predictive value and a 52.0% sensitivity. AFP relative decreases of ≥ 50% and ≥ 20% were significantly associated with PFS with a hazard ratio (HR) of 5.60 (95% CI: 1.6-19, p = 0.006) and a HR of 4.44 (95% CI: 1.9-10, p < 0.001), respectively. AFP response of ≥ 50% and ≥ 20% were related to ORR and DCR, respectively, and both of these responses were also associated with PFS. AFP can be used as a real-time monitor during Atez/Bev treatment and is helpful for treatment optimization., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The awareness of healthcare practitioners concerning heated tobacco product (HTP) use risks has been evaluated; however, few studies have investigated general dental practitioners’ awareness regarding HTP-use risks. In this cross-sectional study, we investigated dentists’ awareness of the risks of smoking, particularly HTP use. A self-administered questionnaire, including eight questions on conventional cigarette and HTP smoking/using status and both knowledge and awareness of HTP-use risks, was posted to 3883 dentists belonging to the Aichi Dental Association, Japan, in August 2019. Statistical analysis was performed using the Statistical Package for Social Sciences; statistical significance was set at p < 0.05. We analyzed the data of 1317 dentists (participation rate, 41.6%). The study group included cigarette smokers (11.5%) and HTP users (8.5%), among whom 41.1% were dual users. HTP users were more likely than never smokers/users to correctly perceive HTP-use risks (p < 0.05). This study indicates that in Japan, the proportion of HTP users is higher than that of the general population. It is important to educate not only smokers/users but also never smokers/users on the risks of smoking and using HTPs. Smoking cessation, including ceasing HTP use, and aiming to quit smoking and HTP use among dentists would contribute to appropriate smoking cessation among patients., Competing Interests: The authors declare no conflicts of interest.

Transarterial chemoembolization (TACE) has been the standard treatment for intermediate-stage, unresectable hepatocellular carcinoma (u-HCC). However, with recent advances in systemic therapy and the emergence of the concept of TACE-refractory or -unsuitable, the effectiveness of systemic therapy, as well as TACE, has been demonstrated for patients judged to be TACE-refractory or -unsuitable. In this study, the efficacy of lenvatinib and its combination with TACE after lenvatinib was investigated in 140 patients with intermediate-stage u-HCC treated with lenvatinib mainly because of being judged to be TACE-refractory or -unsuitable. Median overall survival (OS) and progression-free survival (PFS) were 24.4 and 9.0 months, respectively, indicating a good response rate. In multivariate analysis, modified albumin-bilirubin (mALBI) grade and up to seven criteria were identified as independent factors for OS, and mALBI grade and tumor morphology were identified as independent factors for PFS. While 95% of all patients were TACE-refractory or -unsuitable, the further prognosis was prolonged by the combination with TACE after lenvatinib initiation. These findings suggest that systemic therapy should be considered for intermediate-stage u-HCC, even in patients judged to be TACE-refractory or -unsuitable. The use of TACE after the start of systemic therapy may further improve prognosis.

Assessing learners' individual differences helps identify students who need teacher support in classrooms. Previous studies have examined second language (L2) achievement based on reading anxiety because reading is an input-based activity essential for successful L2 learning. This study applied a latent rank model to identify L2 learners who are likely to be struggling or successful in classrooms according to their L2 reading anxiety symptoms. Moreover, a psychometric function was developed to determine the cutoff anxiety scores that discriminate against their substantial differences. The model was applied to responses from the Foreign Language Reading Anxiety Scale (FLRAS) provided by 335 Japanese learners of English. The results showed that the FLRAS classified students into three ranked groups with ordinal information regarding L2 reading anxiety. Rank 1 exhibited good conditions in L2 reading anxiety. Rank 2 reported high anxiety toward unfamiliar grammar during L2 reading. Rank 3 had even higher anxiety levels, especially for vocabulary and grammatical knowledge deficits and reading difficulty. The cutoff anxiety scores estimated by the model detected students who failed their L2 class with 79% accuracy. Theoretical, methodological, and pedagogical issues in language anxiety were discussed in terms of diagnosis and different approaches to teaching L2 reading., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Hamada and Takaki.)

Recessive dystrophic epidermolysis bullosa (RDEB) is an intractable genetic disease of the skin caused by mutations in the COL7A1 gene. The majority of patients with RDEB harbor compound heterozygous mutations-two distinct mutations on each chromosome-without any apparent hotspots in the COL7A1 mutation pattern. This situation has made it challenging to establish a reliable RDEB mouse model with mutations that accurately mimic the genomic background of patients. Here, we established an RDEB mouse model harboring patient-type mutations in a compound heterozygous manner, using the CRISPR-based genome-editing technology i-GONAD. We selected two mutations, c.5818delC and E2857X, that have frequently been identified in cohorts of Japanese patients with RDEB. These mutations were introduced into the mouse genome at locations corresponding to those identified in patients. Mice homozygous for the 5818delC mutation developed severe RDEB-like phenotypes and died immediately after birth, whereas E2857X homozygous mice did not have a shortened lifespan compared to wild-type mice. Adult E2857X homozygous mice showed hair abnormalities, syndactyly, and nail dystrophy; these findings indicate that E2857X is indeed pathogenic in mice. Mice with the c.5818delC/E2857X compound heterozygous mutation presented an intermediate phenotype between the c.5818delC and E2857X homozygous mice. Single-cell RNA sequencing further clarified that the intrafollicular keratinocytes in c.5818delC/E2857X compound heterozygous mice exhibited abnormalities in cell cycle regulation. The proposed strategy to produce compound heterozygous mice, in addition to the established mouse line, will facilitate research on RDEB pathogenesis to develop a cure for this devastating disease., (© 2022. The Author(s), under exclusive licence to United States and Canadian Academy of Pathology.)

Calcineurin inhibitors (CNIs), used as immunosuppressants, have revolutionized transplantation medicine with their strong suppressive activity on alloreactive T lymphocytes; however, they may also cause various adverse effects, including an increased risk for infection and nephrotoxicity. Regulatory T (Treg) cells can complement the deleterious side effects of CNIs with their effective Ag-specific suppressive activities. However, several studies have shown that CNIs suppress Treg cell differentiation. Therefore, an understanding of the mechanisms by which CNIs suppress Treg cell differentiation, as well as an approach for promoting the differentiation of Treg cells in the presence of CNIs, has significant clinical value. In this article, we report that the nuclear orphan receptor Nr4a1 plays a pivotal role in Treg cell differentiation in the presence of CNIs. Unlike that of its family members, Nr4a2 and Nr4a3, the expression of Nr4a1 was not suppressed by CNI treatment, thereby mediating Treg cell differentiation in the presence of CNIs. In a mouse allogeneic graft-versus-host disease model, Nr4a1 mediated tolerance by promoting Treg cell differentiation in mice administered cyclosporine A, prolonging the survival of recipients. Furthermore, activation of Nr4a1 via its agonist partially restored Treg cell differentiation, which was suppressed by cyclosporine A treatment. Finally, we found that the rs2701129 single-nucleotide polymorphism, which was shown to downregulate NR4A1 expression, showed a trend toward a higher incidence of chronic graft-versus-host disease in patients undergoing hematopoietic stem cell transplantation. Therefore, our study will be of clinical significance because we demonstrated the role of Nr4a1 in Treg cell differentiation in the presence of CNIs., (Copyright © 2022 by The American Association of Immunologists, Inc.)

Continuous monitoring of the respiratory rate is crucial in an acute care setting. Contact respiratory monitoring modalities such as capnography and thoracic impedance pneumography are prone to artifacts, causing false alarms. Moreover, their cables can restrict patient behavior or interrupt patient care. A microwave Doppler sensor is a novel non-contact continuous respiratory rate monitor. We compared respiratory rate measurements performed with a microwave Doppler sensor mounted on the ceiling of an intensive care unit with those obtained by conventional methods in conscious and spontaneously breathing patients. Participants' respiratory rate was simultaneously measured by visual counting of chest wall movements for 60 s; a microwave Doppler sensor; capnography, using an oxygen mask; and thoracic impedance pneumography, using electrocardiogram electrodes. Bland-Altman analysis for repeated measures was performed to calculate bias and 95% limits of agreement between the respiratory rate measured by visual counting (reference) and that measured by each of the other methods. Among 52 participants, there were 336 (microwave Doppler sensor), 275 (capnography), and 336 (thoracic impedance pneumography) paired respiratory rate data points. Bias (95% limits of agreement) estimates were as follows: microwave Doppler sensor, 0.3 (- 6.1 to 6.8) breaths per minute (bpm); capnography, - 1.3 (- 8.6 to 6.0) bpm; and thoracic impedance pneumography, 0.1 (- 4.4 to 4.7) bpm. Compared to visual counting, the microwave Doppler sensor showed small bias; however, the limits of agreement were similar to those observed in other conventional methods. Our monitor and the conventional ones are not interchangeable with visual counting.Trial registration number: UMIN000032021, March/30/2018., (© 2021. The Author(s), under exclusive licence to Springer Nature B.V.)

The association between radiological response and overall survival (OS) was retrospectively evaluated in patients treated with lenvatinib as a first-line systemic treatment for unresectable hepatocellular carcinoma. A total of 182 patients with Child-Pugh class A liver function and an Eastern Cooperative Oncology Group performance status of zero or one were enrolled. Radiological evaluation was performed using Response Evaluation Criteria in Solid Tumors (RECIST) and modified Response Evaluation Criteria in Solid Tumors (mRECIST). Initial radiological evaluation confirmed significant stratification of OS by efficacy judgment with both RECIST and mRECIST, and that initial radiological response was an independent prognostic factor for OS on multivariate analysis. Furthermore, in patients with stable disease (SD) at initial evaluation, macrovascular invasion at the initial evaluation on RECIST and modified albumin-bilirubin grade at initial evaluation on mRECIST were independent predictors of OS on multivariate analysis. In conclusion, if objective response is obtained at the initial evaluation, continuation of treatment appears desirable because prolonged OS can be expected; but, if SD is obtained at the initial evaluation, one should determine whether to continue or switch to the next treatment, with careful consideration of factors related to the tumor and hepatic reserve at the initial evaluation.

This study aims to clarify the impact of COVID-19 on the mental health of users with mental illness of home visit nursing services. We sent a questionnaire to 1,740 home visit nursing station managers, 374 (21.5%) of whom responded. The total number of valid responses was 328, which amounted to 87.7% of the returned surveys. In total, 103 (31.4%) stations reported that their users' mental health deteriorated owing to the spread of COVID-19. Eighty-nine (86.4%) stations reported that their users' anxiety increased. More than 80% of the stations explained infection control measures to their users, but 194 (59.1%) stations answered that their users found it challenging to practice cleanliness. A total of 207 (63.1%) stations answered that the promotion of strategies for coping with stress is necessary for their users. Users with mental illness are vulnerable to stress and have a higher risk of death due to COVID-19. Thus, they should be carefully observed and referred to facilities if required. Home visit nursing staff have an important role to play in the preservation of the well-being of their users with mental illness during the COVID-19 pandemic.

Background: Trans-jejunal nutrition via a post-pyloric enteral feeding tube has a low risk of aspiration or reflux; however, placement of the tube using the blind method can be difficult. Assistive devices, such as fluoroscopy or endoscopy, are useful but may not be suitable for patients with hemodynamic instability or severe respiratory failure. The aim of this study was to explore factors associated with first-pass success in the blind placement of post-pyloric enteral feeding tubes in critically ill patients., Methods: Data were obtained retrospectively from the medical records of adult patients who had a post-pyloric enteral feeding tube placed in the intensive care unit between January 1, 2012, and December 31, 2018. Logistic regression analysis was performed to assess the association between first-pass success and the independent variables. For logistic regression analysis, the following 13 variables were defined as independent variables: age, sex, height, fluid balance from baseline, use of sedatives, body position during the procedure, use of cardiac assist devices, use of prokinetic agents, presence or absence of intestinal peristalsis, postoperative cardiovascular surgery, use of renal replacement therapy, serum albumin levels, and position of the greater curvature of the stomach in relation to spinal levels L1 - L2., Results: Data obtained from 442 patients were analyzed. The first-pass success rate was 42.8% (n = 189). Logistic regression analysis demonstrated that the position of the greater curvature of the stomach cephalad to L1 - L2 was only associated with successful placement (odds ratio for first-pass success, 0.62; 95% confidence interval: 0.40 - 0.95)., Conclusions: In critically ill patients, the position of the greater curvature of the stomach caudal to L1 - L2 may be associated with a lower first-pass success rate of the blind method for post-pyloric enteral feeding tube placement. Further studies are needed to verify our results because the position of the stomach was estimated by radiographs after enteral feeding tube placement., Trial Registration: University Hospital Medical Information Network Clinical Trials Registry (UMIN000036549; April 20, 2019)., (© 2021. The Author(s).)

Background: The study aimed to investigate the efficacy of vonoprazan 10 mg compared with 20 mg in patients with erosive esophagitis., Method: Seventy-three patients with erosive esophagitis were randomly divided into two groups either vonoprazan 20 mg (n = 37) or 10 mg (n = 36). They were administered each dose for 4 weeks as the initial treatment followed by maintenance treatment with 10 mg for 8 weeks. The primary endpoints were mucosal healing rate and symptom relief at 4 weeks. The secondary endpoint was symptom relief at 12 weeks after the maintenance treatment. Mucosal healing was assessed endoscopically, and symptom relief was assessed using the FSSG score., Results: At 4 weeks, the endoscopic healing rates of the 20 mg and 10 mg groups were 94.6% and 94.4%, respectively. The FSSG scores of the 20 mg and 10 mg groups were significantly decreased in both treatment groups from 13 (4-39) to 4 (0-25) and 14 (4-40) to 3 (0-29), respectively. At 12 weeks, the scores further decreased to 2 (0-13) and 2 (0-26), respectively. The vonoprazan 10 mg group showed a similar therapeutic effect to the 20 mg group in mucosal healing at 4 weeks and in symptom relief throughout the study period. When stratified by esophagitis grading, these findings were still demonstrated in grade A/B patients but not in grade C/D patients., Conclusion: Our findings suggest that initial treatment with vonoprazan 10 mg might be useful especially in patients with mild erosive esophagitis. Large controlled studies are warranted to confirm our investigation.

Background: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare but life-threatening disorders characterized by widespread epidermal necrosis of the skin and mucosa. The severity-of-illness scoring system for TEN (SCORTEN) was widely used since 2000 as a standard prognostic tool consisting of seven clinical values., Methods: To evaluate the prognosis using current treatments and risk factors for mortality, we retrospectively analyzed 59 cases of TEN, including SJS/TEN overlap treated in two university hospitals from January 2000 to March 2020., Results: The mortality rate of TEN was 13.6% (8/59). All patients treated with high-dose steroid administration in combination with plasma exchange and/or immunoglobulin therapy recovered. Logistic regression analysis showed nine clinical composite scores, namely: heart rate (≧120 bpm), malignancy present, percentage of body surface area with epidermal detachment (>10%), blood urea nitrogen (>28 mg/dL), serum bicarbonate level (<20 mEq/L), serum glucose level (>252 mg/dL), age (≧71 years), the interval between disease onset and treatment initiation at the specialty hospital (≧8 days), and respiratory disorder within 48 h after admission. The receiver operating characteristic curves confirmed a high potential for predicting the prognosis of TEN., Conclusions: Recent developments in treatment strategies have contributed to the improved prognosis of TEN patients. A modified severity scoring model composed of nine scores may be helpful in the prediction of TEN prognosis in recent patients. Further large-scale studies are needed to confirm mortality findings to improve prognostication in patients with TEN., (Copyright © 2020 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.)

Background: The Acute Physiology and Chronic Health Evaluation (APACHE) III-j model is widely used to predict mortality in Japanese intensive care units (ICUs). Although the model's discrimination is excellent, its calibration is poor. APACHE III-j overestimates the risk of death, making its evaluation of healthcare quality inaccurate. This study aimed to improve the calibration of the model and develop a Japan Risk of Death (JROD) model for benchmarking purposes., Methods: A retrospective analysis was conducted using a national clinical registry of ICU patients in Japan. Adult patients admitted to an ICU between April 1, 2018, and March 31, 2019, were included. The APACHE III-j model was recalibrated with the following models: Model 1, predicting mortality with an offset variable for the linear predictor of the APACHE III-j model using a generalized linear model; model 2, predicting mortality with the linear predictor of the APACHE III-j model using a generalized linear model; and model 3, predicting mortality with the linear predictor of the APACHE III-j model using a hierarchical generalized additive model. Model performance was assessed with the area under the receiver operating characteristic curve (AUROC), the Brier score, and the modified Hosmer-Lemeshow test. To confirm model applicability to evaluating quality of care, funnel plots of the standardized mortality ratio and exponentially weighted moving average (EWMA) charts for mortality were drawn., Results: In total, 33,557 patients from 44 ICUs were included in the study population. ICU mortality was 3.8%, and hospital mortality was 8.1%. The AUROC, Brier score, and modified Hosmer-Lemeshow p value of the original model and models 1, 2, and 3 were 0.915, 0.062, and < .001; 0.915, 0.047, and < .001; 0.915, 0.047, and .002; and 0.917, 0.047, and .84, respectively. Except for model 3, the funnel plots showed overdispersion. The validity of the EWMA charts for the recalibrated models was determined by visual inspection., Conclusions: Model 3 showed good performance and can be adopted as the JROD model for monitoring quality of care in an ICU, although further investigation of the clinical validity of outlier detection is required. This update method may also be useful in other settings.

Helper T (Th) and regulatory T (Treg) cell differentiation programs promote the eradication of pathogens, while minimizing adverse immune reactions. Here, we found that Nr4a family of nuclear receptors supports Treg cell induction and represses Th1 and Th2 cell differentiation from naive CD4 + T cells. Nr4a factors are transiently induced in CD4 + T cells immediately after antigen stimulation, thereby mediating epigenetic changes. In differentiating Treg cells, Nr4a factors mainly upregulated the early responsive genes in the Treg cell-specifying gene set, either directly or in cooperation with Ets family transcription factors. In contrast, Nr4a factors repressed AP-1 activity by interrupting a positive feedback loop for Batf factor expression, thus suppressing Th2 cell-associated genes. In an allergic airway inflammation model, Nr4a factors suppressed the pathogenesis, mediating oral tolerance. Lastly, pharmacological activation of an engineered Nr4a molecule prevented allergic airway inflammation, indicating that Nr4a factors may be novel therapeutic targets for inflammatory diseases., Competing Interests: K.F. received lecture fees from Astrazeneca and Boelinger-Ingelheim., (© 2021 The Author(s).)

Background & Aims: Proper resolution of inflammation is essential to maintaining homeostasis, which is important as a dysregulated inflammatory response has adverse consequences, even being regarded as a hallmark of cancer. However, our picture of dynamic changes during inflammation remains far from comprehensive., Methods: Here we used single-cell transcriptomics to elucidate changes in distinct cell types and their interactions in a mouse model of chemically induced colitis., Results: Our analysis highlights the stromal cell population of the colon functions as a hub with dynamically changing roles over time. Importantly, we found that Serpina3n, a serine protease inhibitor, is specifically expressed in stromal cell clusters as inflammation resolves, interacting with a potential target, elastase. Indeed, genetic ablation of the Serpina3n gene delays resolution of induced inflammation. Furthermore, systemic Serpina3n administration promoted the resolution of inflammation, ameliorating colitis symptoms., Conclusions: This study provides a comprehensive, single-cell understanding of cell-cell interactions during colorectal inflammation and reveals a potential therapeutic target that leverages inflammation resolution., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: This study compared clinical outcomes of 2nd- and 3rd-line regorafenib in patients with unresectable hepatocellular carcinoma., Methods: In this retrospective cohort study, 48 patients were treated with regorafenib for unresectable hepatocellular carcinoma. Thirty-five and 13 patients were initiated on 2nd- and 3rd-line therapy, respectively. We assessed the responses to and safety of the therapy., Results: There were no statistically significant differences in clinical characteristics at the start of 2nd- or 3rd-line regorafenib therapy. The overall response rate of 2nd- and 3rd-line regorafenib was 20 and 8%, respectively. The disease control rate was 57 and 54%, respectively. Median overall survival (mOS) from the start of 2nd-line regorafenib was 17.5 months. mOS from the start of 3rd-line regorafenib was not obtained. Median progression-free survival of 2nd- and 3rd-line regorafenib was 4.9 and 2.3 months, respectively. mOS from 1st-line therapy with tyrosine kinase inhibitor plus sorafenib-regorafenib-lenvatinib was 29.5 months; that with lenvatinib-sorafenib-regorafenib was not obtained. Patients on 3rd-line therapy tended to have better Child-Pugh scores and tumor factors at the start of 1st-line therapy than other patients., Conclusion: Patients on 2nd- and 3rd-line regorafenib showed favorable responses. Good Child-Pugh scores and tumor factors may be associated with a better response rate and OS., (© 2021 S. Karger AG, Basel.)

Atezolizumab is an immune checkpoint inhibitor that is a key drug in non-small-cell lung cancer treatment. However, it can cause immune-related adverse events, including liver injury. Several patterns of liver injury associated with immune checkpoint inhibitor therapy have been reported; however, not much is known about sclerosing cholangitis. We present here a case of lung adenocarcinoma with atezolizumab-induced secondary sclerosing cholangitis diagnosed using needle biopsy of the liver. A 77-year-old woman with lung adenocarcinoma, cT3N2M0, stage IIIA, was treated with concurrent chemoradiotherapy involving carboplatin and paclitaxel, which markedly reduced the tumor diameter. However, 5 months later, the lesion regrew, and she underwent 39 cycles of pemetrexed monotherapy. As pulmonary metastasis progressed, she was treated with atezolizumab. After 13 cycles of atezolizumab therapy, she complained of nausea. Laboratory tests showed elevated levels of the biliary tract and hepatic enzymes. Nevertheless, abdominal computed tomography and ultrasonography revealed no underlying related cause. Ultrasound-guided needle biopsy of the liver was performed, and histopathological analysis of biopsy samples showed features of sclerosing cholangitis. Further examinations were performed, and a diagnosis of atezolizumab-induced secondary sclerosing cholangitis without strictures and dilatations of the large bile ducts was established. Prednisolone was administered orally, after which the biliary tract and hepatic enzyme levels improved immediately. In patients presenting with a hepatic injury during immune checkpoint inhibitor therapy, clinicians should be aware of the possibility of immune checkpoint inhibitor-induced sclerosing cholangitis, even if the large bile ducts have no strictures and dilatations., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Introduction: The clinical outcome of ramucirumab in multi-molecular targeted agent (MTA) sequential therapy for unresectable hepatocellular carcinoma (u-HCC) was assessed in comparison with that of prior tyrosine kinase inhibitor (TKI) therapy., Methods: Sixteen patients who received ramucirumab as part of multi-MTA sequential therapy for u-HCC were enrolled in a retrospective, cohort study. Ramucirumab was started as 2nd line in 7 patients, 3rd line in 5 patients, and 4th line in 4 patients., Results: The overall response rate was 6.3%, the disease control rate (DCR) was 50.0%, median progression-free survival was 2.0 months (evaluated by mRECIST), median overall survival (OS) with ramucirumab was 7.9 months, and the median OS from 1st-line therapy was 28.1 months. One month after the start of ramucirumab, α-fetoprotein (AFP) decreased in 6 of 12 cases (50.0%), and the DCR in AFP-decreased cases was 83.3%. The DCR of ramucirumab was 66.7% in cases in which disease control was obtained by prior TKI therapy, whereas it was 0.0% in the cases in which disease control was not obtained by prior TKI therapy. Examining the adverse events, no new safety concerns were confirmed., Conclusion: The AFP response to ramucirumab and the treatment response to prior TKI therapy are associated with treatment response to ramucirumab., (© 2021 S. Karger AG, Basel.)

Introduction: We evaluated the efficacy and safety of lenvatinib-transcatheter arterial chemoembolization (LEN-TACE) sequential therapy for patients (n = 88) with intermediate-stage hepatocellular carcinoma (HCC)., Methods: Eighty-eight patients who obtained tumor control by LEN treatment were analyzed; 30 received LEN followed by TACE (LEN-TACE sequential therapy), and 58 received LEN monotherapy. Propensity score matching was performed, and the outcomes of 19 patients in the LEN-TACE group and 19 patients in the LEN-alone group were compared. Objective response rate (ORR), progression-free survival (PFS), overall survival (OS), incidence of adverse events (AEs), and change in albumin-bilirubin (ALBI) score were evaluated., Results: After matching, baseline characteristics were similar between the groups. The ORR was 63.2% with LEN-TACE group and 63.2% with the LEN-alone group. Multivariate analysis showed that addition of TACE during LEN treatment (hazard ratio [HR] 0.264, 95% confidence interval [CI] 0.087-0.802, p =  0.019) and Child-Pugh score 5 (HR 0.223, 95% CI 0.070-0.704, p = 0.011) were the significant factors for PFS. Median PFS was 11.6 months with LEN-TACE and 10.1 months with LEN-alone. The survival rate of the LEN-TACE group was significantly higher than that of the LEN-alone group (median survival time; not reached vs. 16.9 months, p = 0.007). The incidence of common LEN-associated AEs was similar between groups. Although elevated aspartate aminotransferase/alanine aminotransferase and fever were more frequent with LEN-TACE group, these events were manageable., Conclusion: For patients with intermediate-stage HCC, LEN-TACE sequential therapy may provide a deep response and favorable prognosis., (© 2021 S. Karger AG, Basel.)

The hepatitis C virus (HCV) NS5A-P32 deletion (P32del) confers potent resistance to NS5A inhibitors. Chronic hepatitis C patients in whom NS5A-P32del variants had emerged during prior direct-acting antiviral (DAA) therapy with an NS5A inhibitor show poor response to DAA retreatment. Here, we report three patients with HCV NS5A-P32del infection who were treated with sofosbuvir, velpatasvir plus ribavirin (SOF/VEL + RBV) in a real-world setting. The patients developed HCV NS5A-P32del, L31F + P32del, or L31V + P32del variants following failure of daclatasvir plus asunaprevir (DCV/ASV) therapy. One of the patients failed to respond to subsequent DCV/ASV and beclabuvir therapy, and the remaining two patients failed to respond to subsequent glecaprevir and pibrentasvir therapy. All three patients completed 24-week SOF/VEL + RBV therapy. Serum HCV RNA became negative at the end of the therapy in all three patients. Two patients with NS5A-P32del and NS5A-L31F + P32del achieved sustained virological response 12 weeks after completion of treatment (SVR12), but HCV relapsed in the remaining NS5A-L13V + P32del patient. Direct sequence analysis detected no additional variants within either the NS5A or NS5B regions at the time of relapse. In conclusion, three patients with prior NS5A-P32del-associated DAA treatment failure received 24 weeks of SOF/VEL + RBV therapy, and two of the patients achieved SVR12.

Aim: Combination therapy with sofosbuvir (SOF) plus velpatasvir (VEL) is approved for patients with hepatitis C virus (HCV)-related decompensated cirrhosis. We analyzed the real-world efficacy of SOF/VEL therapy., Methods: Thirty-three patients with HCV-related decompensated cirrhosis (25 and eight patients with Child B and C, respectively) were treated with SOF/VEL for 12 weeks. The HCV non-structural protein (NS)5A and NS5B drug resistance-associated substitutions (RASs) were determined by direct sequencing., Result: Thirty-two of 33 patients completed the treatment, but the remaining patient discontinued the therapy during third week of the treatment due to aggravation of hepatic encephalopathy. Serum HCV-RNA became negative during the treatment in all patients but relapsed after the end of therapy in five patients. In total, 28 out of 33 patients (85%) achieved sustained virological response 12 weeks following completion of treatment (SVR12). The SVR12 rate was 96% in patients with Child B, but significantly lower, at 50%, in patients with Child C (P < 0.05). In genotype 1b HCV-infected patients, all eight patients without baseline NS5A RASs, but only three of seven patients with RASs, achieved SVR12. Multivariate analysis identified Child B (odds ratio, 35.8 for Child C; P = 0.045) as an independent predictor of SVR12. Median serum albumin levels significantly increased only in patients who achieved SVR12. Child-Pugh scores improved in 16 of 28 patients (57%) following achievement of SVR12., Conclusion: The effect of SOF/VEL therapy is lower for patients with Child C. Improvement of hepatic function is expected after viral eradication with SOF/VEL therapy in patients with decompensated cirrhosis., (© 2020 The Japan Society of Hepatology.)

Background: Precise control of tidal volume is one of the keys in limiting ventilator-induced lung injury and ensuring adequate ventilation in mechanically ventilated neonates. The aim of the study was to compare the tidal volume (mVT) measured from the expiratory limb of the ventilator with the actual tidal volume (aVT) that would be delivered to the patient using a lung model to simulate a neonate., Methods: This study was conducted using the ASL5000 lung simulator. Three combinations of parameters were set: resistance (cmH 2 O/L/sec) and compliance (mL/cmH 2 O) of 50 and 2 (Group 1), 100 and 1 (Group 2), and 150 and 0.5 (Group 3), respectively. The ASL5000 was connected to each of the ventilators including one anesthesia machine ventilator (Drager Fabius GS) and two ICU ventilators (Servo-i Universal and Evita Infinity V500). Each ventilator was evaluated with a set tidal volume of 30 mL (sVT) and a respiratory rate of 25 breathes/minute in both the volume-controlled ventilation (VCV) and dual-controlled ventilation (DCV) modes., Results: The discrepancies between sVT, mVT and aVT were highest with the Fabius anesthesia machine ventilator and increased in the simulated lung injury groups. When comparing the ICU ventilators, the difference was greater the Servo-i and increased when using the DCV mode and with simulated lung injury., Conclusion: Accurate tidal volumes were achieved only with the Infinity ICU ventilator. This was true regardless of mode of ventilation and even during simulated lung injury., Competing Interests: The authors declare no conflict of interest., (© 2020 Yamaguchi et al.)