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The isotopic production cross sections for the reactions of 136Xe induced by proton, deuteron and carbon at 168 MeV/u were obtained by using the inverse kinematics technique at RIKEN Radioactive Isotope Beam Factory. The target dependence of the cross sections was investigated systematically. It was found that for the light-mass products, the cross sections on carbon are larger than those on deuteron and proton. The measured cross sections on proton were compared with the previous data at higher reaction energies to study the energy dependence. The experimental results were compared with the theoretical calculations including both the intranuclear cascade and evaporation processes using PHITS and with the EPAX and SPACS empirical parameterizations.

Background: We previously reported that the fecal microflora of infants with cow's milk hypersensitivity who were fed casein-hydrolyzed formula supplemented with raffinose (New-MA-1) way normalized. The purpose of this study was to elucidate whether oral administration of bifidobacteria influenced the intestinal microflora of infants with cow's milk hypersensitivity with atopic dermatitis who were fed New-MA-1 an( whether their allergic symptoms were thereby improved.Methods: Seventeen infants with cow milk hypersensitivity with atopic dermatitis who had less than 30% Bifidobacterium in their intestinal microflora were selected for this study, and were randomly divided into two groups. Ten subjects were orally given lyophilized bifidobacteria (Bifidobacterium breve M-16V strain), and the remaining 7 infants were not.Results: The changes in fecal microflora and clinical symptoms were compared between the 2 groups. In the bifidobacteria-administered group, the proportion of Bifidobacterium in the fecal microflora increased while the proportion of aerobic bacteria decreased after 3 months of the administration, and was associated with a significant improvement of allergic symptoms compared to the beginning of the study. In the control group, there were no significant changes to the overall fecal microflora and total allergic score during the entire study period.Conclusion: Administration of bifidobacteria to infants with cow's milk hypersensitivity with atopic dermatitis significantly increased the proportion of bifidobacteria in the fecal microflora and also might improve their allergic symptoms. [ABSTRACT FROM AUTHOR]

Background: We tried to clarify the safety and usefulness of a hypoallergenic cupcake in 9 patients with atopic dermatitis, who had wheat allergy. All patients had a history of severe urticaria, when cereal-based products were ingested.Method: We determined CAP-RAST for wheat as well as ELISA for wheat, the hypoallergenic wheat, and the salt-soluble and salt-insoluble fractions of wheat.Result: Positive correlations were observed between CAP-RAST and ELISA of wheat (P<0.015), between ELISA of wheat and the hypoallergenic wheat (P<0.043). There was a positive correlation between ELISA of the salt-soluble and salt-insoluble fractions (P<0.005). The provocation with the hypoallergenic cupcake showed a positive immediate reaction (severe urticaria) in only 2 patients. ELISA of hypoallergenic wheat of these 2 patients showed a high titer of more than 0.1.Conclusion: The hypoallergenic cupcake is safe in most patients with wheat allergy, if ELISA of the hypoallergenic wheat is examined before ingestion. [ABSTRACT FROM AUTHOR]

The subjects studied were 22 pediatric patients newly diagnosed with atopic dermatitis (AD); 11 were treated with acid electrolytic water (AEW), which has a strong bactericidal activity (AEW group), and the other 11 with tap water (placebo group). AEW or tap water 1 ml/cm² (body surface area), was sprayed on their skin lesions with a spray gun each twice a day for a week. There were no significant differences between the two groups in regard to sex, age, serum IgE, peripheral eosinophil counts, grading scores of AD, and duration of AD. The study was designed as a randomized, placebo-controlled, double-blind clinical trial. Colony counts of Staphylococcus aureus on skin lesions in the AEW group, both 3 min after spraying (P<0.05) and after 1 week of skin treatment (P<0.01), were significantly decreased as compared with colony counts before treatment, while there was no significant difference in the placebo group before and after treatment. Grading scores of AD also decreased in the AEW group (P<0.01), but not in the placebo group. Both the subjects' guardians' evaluation and a referee physician's evaluation of treatment effect were significantly higher in the AEW group than in the placebo group (P<0.01 ). AEW may be potentially effective in preventing a staphylococcal chronic inflammation in AD because of its strong bactericidal activity. [ABSTRACT FROM AUTHOR]

Unlabelled: Plasma thrombomodulin (TM) levels were measured in 68 patients with atopic dermatitis (AD) and 35 controls. Plasma TM levels in patients with AD were significantly higher than those of controls (p < 0.01). A significant correlation was observed between plasma TM levels and skin scores of AD or peripheral eosinophil counts (p < 0.01). There was also a positive correlation between plasma TM and vascular cell adhesion molecule-1 levels (p < 0.05).Conclusion: These results suggest that plasma TM levels may reflect a severity of AD and/or endothelial cell activation induced by an allergic inflammation. [ABSTRACT FROM AUTHOR]

We reported a 15-year-old Japanese girl with possible eosinophilic pneumonia (EP) from inhaled Alternaria. She presented with a fever, cough and general fatigue and with a moderate infiltrate in the right lower to middle lung fields on a chest roentgenogram one week previously. On admission, the above infiltrate had disappeared, while a left upper infiltrate had appeared. Eosinophilic pneumonia (EP) was diagnosed by a cytological study of bronchoalveolar lavage fluid and histology of a transbronchial lung biopsy. Skin test to and specific serum IgE antibody against Alternaria were both positive. An inhaled Alternaria challenge test showed both immediate and late phase allergic reactions as evidenced by %FEV1. In addition, Alternaria was significantly detected in all places of the patient's house. Alternaria could be a causative organism of EP and should always be considered one of its etiologic agents.

Abstract Background The aim of this study was to investigate the role of specific IgG4 antibodies to hen’s egg white and determine their utility as a marker for the outcome of oral challenge test in children sensitized to hen’s egg Methods The hen’s egg oral food challenge test was performed in 105 sensitized children without atopic dermatitis, and the titers of egg white-specific immunoglobulin G4 (IgG4) and immunoglobulin E (IgE) antibodies were measured. To set the cut-off values of IgG4, IgE, and the IgE/IgG4 ratio for predicting positive results in oral challenges, receiver operating characteristic curves were plotted and the area under the curves (AUC) were calculated. Results Sixty-four of 105 oral challenges with whole eggs were assessed as positive. The AUC for IgE, IgG4, and IgE/IgG4 for the prediction of positive results were 0.609, 0.724, and 0.847, respectively. Thus, the IgE/IgG4 ratio generated significantly higher specificity, sensitivity, positive predictive value (%), and negative predictive value (%) than the individual IgE and IgG4. The negative predictive value of the IgE/IgG4 ratio was 90% at a value of 1. Conclusions We have demonstrated that the egg white-specific serum IgE/IgG4 ratio is important for predicting reactivity to egg during food challenges.

Background: Few studies have investigated fracture risk and mortality in a Japanese chronic kidney disease (CKD) stages G3-5 population using a large-scale clinical database., Methods: This retrospective cohort study extracted data from 1 April 2008 to 30 April 2023. A single age-sex-matched control without CKD was matched with each non-dialysis CKD (estimated glomerular filtration rate < 60 mL/min/1.73 m 2 ) patient. The incidences of all and hip fractures and all-cause mortality after the index date were calculated., Results: Among 76,598 (38,299 per group) individuals matched, the incidence of all fractures did not differ between the CKD and control groups (5.7% vs 5.8%; hazard ratio [HR] 1.022 [95% confidence interval CI 0.952-1.098], P = 0.542). The CKD group had higher risk of hip fracture than the control group (incidence of hip fracture, 1.7% vs 1.3%; HR 1.415 [95% CI 1.234-1.622], P < 0.001). Multivariable regression analysis showed an increased risk for hip fracture in the CKD vs control groups, and a greater difference in this risk was observed with younger age. Osteoporosis treatment and bone mineral density (BMD) measurements were 10.0% and 5.3% in the CKD group and 4.4% and 4.4% in the control group, respectively. Mortality was also higher in the CKD group (HR 1.413 [95% CI 1.330-1.501], P < 0.001)., Conclusions: Japanese patients with CKD had higher risk of hip fracture than those without. Treatment and BMD measurement for fracture are insufficient in Japanese patients with CKD, and more adequate management of fracture risk is needed., (© 2024. The Author(s).)

Background Patients with chronic kidney disease (CKD) were excluded in most trials that investigated the effects of urate-lowering agents, such as febuxostat and allopurinol, in hyperuricemic patients. This exclusion leads to uncertainty regarding the efficacy of febuxostat in patients with CKD. Due to the high prevalence of hyperuricemia in patients with CKD, we aimed to assess the effect of febuxostat on improving patient outcomes concerning cardiovascular events and survival compared with those treated with allopurinol among patients with CKD. Methods We conducted a retrospective cohort study using Japanese nationwide administrative data from Jan 1, 2013, to Sep 30, 2020. Patients aged over 60 years diagnosed with CKD were included in this study if they were prescribed either febuxostat or allopurinol. The primary outcome was the occurrence of cardiovascular events including myocardial infarction, stroke, unstable angina requiring urgent revascularization, and all-cause deaths. We estimated hazard ratios (HR) and 95% CI using a Cox proportional hazard regression model adjusted for comorbidities, medications, and laboratory data. We also assessed defined starting kidney replacement therapy as a secondary endpoint treating death as a competing risk using the Fine & Gray regression model. Results A total of 21,015 patients included those with febuxostat (n=17,796) and those with allopurinol (n=3,219). The association between the type of drug and the occurrence of cardiovascular events did not show a significant difference (0.107 vs. 0.116 events per patient-year; adjusted HR 0.953, 95% CI: 0.854 to 1.062, P=0.381). Similar results were seen for all-cause deaths (0.060 vs. 0.068 events per patient-year; adjusted HR 0.877, 95% CI: 0.760 to 1.012, P=0.073). Regarding the secondary endpoint, the association between the type of drug and the timing of starting kidney replacement therapy did not show a significant difference (0.118 vs. 0.097 events per patient-year; adjusted HR 0.953, 95% CI: 0.854 to 1.062, P=0.425). Conclusion The use of febuxostat was neither associated with a decreased risk of cardiovascular events or deaths nor with the timing of starting kidney replacement therapy compared to the use of allopurinol in patients with CKD., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: Ayumi Shintani is compensated by Kyowa Kirin, and the payment is made to the institution. Financial relationships: Ayumi Shintani declare(s) personal fees from Daiichi Sankyo. Payment was made to her. Ayumi Shintani declare(s) personal fees from Eisai. Payment was made to her. Ayumi Shintani declare(s) personal fees from Maruho. Payment was made to her. Ayumi Shintani declare(s) personal fees from Novo Nordisk Pharma. Payment was made to her. Ayumi Shintani declare(s) personal fees from Pfizer. Payment was made to her. Ayumi Shintani declare(s) personal fees from Taisho Pharmaceutical. Payment was made to her. Ayumi Shintani declare(s) personal fees from Torii Pharmaceutical. Payment was made to her. Ayumi Shintani declare(s) personal fees from Janssen Pharmaceutical. Payment was made to her. Ayumi Shintani declare(s) personal fees from Kisei Pharmaceutical. Payment was made to her. Ayumi Shintani declare(s) personal fees from Mallinckrodt Pharmaceuticals. Payment was made to her. Ayumi Shintani declare(s) personal fees from Mitsubishi Tanabe Pharma Corporation. Payment was made to her. Ayumi Shintani declare(s) personal fees from Nippon Shinyaku. Payment was made to her. Ayumi Shintani declare(s) personal fees from Ono Pharmaceutical Company Limited. Payment was made to her. Ayumi Shintani declare(s) personal fees from Takeda Pharmaceutical Company Limited. Payment was made to her. Ayumi Shintani declare(s) personal fees from Taisho Pharmaceutical. Payment was made to her. Ayumi Shintani declare(s) personal fees from Kyowa Kirin. Payment was made to her. Ayumi Shintani declare(s) personal fees from Merck Biopharma. Payment was made to her. Ayumi Shintani declare(s) personal fees from Nipro Corporation. Payment was made to her. Yuta Nonomiya declare(s) a grant from Osaka Metropolitan University. An annual fellowship of 3.9 million yen is paid to the author. Yasutaka Ihara declare(s) employment from Daiichi Sankyo. Yasutaka Ihara is an employee of Daiichi Sankyo. Kazuhiko Tsuruya declare(s) a grant from Teijin. Kazuhiko Tsuruya declare(s) a grant from Mochida. Kazuhiko Tsuruya declare(s) personal fees from Teijin. Kazuhiko Tsuruya declare(s) personal fees from Mochida. Kazuhiko Tsuruya declare(s) personal fees from Sanwa Chemical. Kazuhiko Tsuruya declare(s) personal fees from Fuji. Ayumi Shintani declare(s) personal fees from Chugai Pharmaceutical. Payment was made to the institution. Ayumi Shintani declare(s) personal fees from Daiichi Sankyo. Payment was made to the institution. Ayumi Shintani declare(s) personal fees from Kyowa Kirin. Payment was made to the institution and to her. Ayumi Shintani declare(s) personal fees from Takeda Pharmaceutical Company Limited. Payment was made to the institution. Ayumi Shintani declare(s) personal fees from Shionogi Pharma. Payment was made to her. Ayumi Shintani declare(s) personal fees from Abbvie. Payment was made to her. Ayumi Shintani declare(s) personal fees from Asahi Kasei Corporation. Payment was made to her. Ayumi Shintani declare(s) personal fees from AstraZeneca plc. Payment was made to her. Ayumi Shintani declare(s) personal fees from Astellas Pharma. Payment was made to her. Ayumi Shintani declare(s) personal fees from Bayer Yakuhin. Payment was made to her. Ayumi Shintani declare(s) personal fees from Bristol Myers Squibb. Payment was made to her. Ayumi Shintani declare(s) personal fees from Chugai Pharmaceutical. Payment was made to her. Ayumi Shintani declare(s) personal fees from Sanofi K.K. Payment was made to her. Ayumi Shintani declare(s) personal fees from Nippon Kayaku. Payment was made to her. Ayumi Shintani declare(s) personal fees from JCR Pharmaceuticals Co. Payment was made to her. Ayumi Shintani declare(s) personal fees from MSD. Payment was made to her. Hisako Yoshida declare(s) personal fees from Organization for Clinical Medicine Promotion. Other relationships: Febuxostat is sold by the following companies, which I declared in the COI: Teijin, DAIICHI SANKYO ESPHA CO., LTD., and NIPRO CORPORATION. Allopurinol is sold by the following companies, which I declared in the COI: NIPRO ES PHARMA and Shionogi Pharma Co. ., (Copyright © 2024, Otani et al.)

Introduction: Pelvic arteriovenous malformation is often a source of intraoperative bleeding. Here, we report our experience with a case of ureteral cancer with pelvic arteriovenous malformation treated using laparoscopic nephroureterectomy with temporary intraoperative occlusion of the internal iliac artery., Case Presentation: A 75-year-old man presented to our hospital with asymptomatic macro-hematuria. Contrast-enhanced computed tomography revealed right ureteral tumor with no apparent metastases, and right pelvic arteriovenous malformation. Three months later, multiple bladder cancers were identified and the patient underwent trans-urethral resection of bladder tumor. The pathological diagnosis was urothelial carcinoma, pTa. We performed right laparoscopic nephroureterectomy with temporary intraoperative occlusion of the internal iliac artery. There was little intraoperative bleeding, and the surgery was safely completed. The pathological diagnosis was urothelial carcinoma, pT2 + Tis., Conclusion: A patient showing ureteral cancer with pelvic arteriovenous malformation was safely treated using laparoscopic nephroureterectomy with temporary occlusion of the internal iliac artery., Competing Interests: The authors declare no conflict of interest., (© 2024 The Author(s). IJU Case Reports published by John Wiley & Sons Australia, Ltd on behalf of Japanese Urological Association.)

Background: Recent clinical studies suggest protective effects of SGLT2 inhibitors on kidney disease outcome. Chronic hypoxia has a critical role in kidney disease development, thus we speculated that canagliflozin, an SGLT2 inhibitor, can improve kidney oxygenation., Methods: A single-arm study was conducted to investigate the effects of canagliflozin on T2* value, which reflects oxygenation level, in patients with type 2 diabetes (T2D) using repeated blood oxygenation level-dependent MRI (BOLD MRI) examinations. Changes in cortical T2* from before (Day 0) to after single-dose treatment (Day 1) and after five consecutive treatments (Day 5) were evaluated using 12-layer concentric objects (TLCO) and region of interest (ROI) methods., Results: In the full analysis set (n=14 patients), the TLCO method showed no change of T2* with canagliflozin treatment, whereas the ROI method found that cortical T2* was significantly increased on Day 1 but not on Day 5. Sensitivity analysis using TLCO in 13 well-measured patients showed that canagliflozin significantly increased T2* on Day 1 with no change on Day 5, whereas a significant improvement in cortical T2* following canagliflozin treatment was found on both Day 1 and 5 using ROI., Conclusions: Short-term canagliflozin treatment may improve cortical oxygenation and lead to better kidney outcomes in patients with T2D., Competing Interests: KM has received speaker fees from Mitsubishi Tanabe Pharma Corporation, Daiichi Sankyo Co., Nippon Boehringer Ingelheim Co., Eli Lilly Japan K.K., AstraZeneca K.K., Ono Pharmaceutical Co. Ltd., Novo Nordisk Pharma Ltd., Kyowa Kirin Co. Ltd., and Mochida Pharmaceutical Co. Ltd., and unrestricted research grants from Chugai Pharmaceutical Co. Ltd, Kyowa Kirin Co. Ltd., Torii Pharmaceutical Co. Ltd., and Sumitomo Pharma Co. Ltd., and research funding from Kyowa Kirin Co. Ltd. TI has received speaker fees from Mitsubishi Tanabe Pharma Corporation, Daiichi Sankyo Co., Nippon Boehringer Ingelheim Co., Eli Lilly Japan K.K., AstraZeneca K.K., Ono Pharmaceutical Co. Ltd., Novo Nordisk Pharma Ltd., Kyowa Kirin Co. Ltd., Mochida Pharmaceutical Co. Ltd., Torii Pharmaceutical Co. Ltd., Otsuka Pharmaceutical Co., Ltd., Sanwa Kagaku Kenkyusho CO., LTD., and Bayer Yakuhin, Ltd., and unrestricted research grant from Eli Lilly Japan K.K. HU has received speaker fees from Mitsubishi Tanabe Pharma Corporation, Daiichi Sankyo Co., Kyowa Kirin, and Mochida Pharmaceutical Co., Ltd. SN has received speaker fees from AstraZeneca K.K., Ono Pharmaceutical Co. Ltd., Otsuka Pharmaceutical Co., Ltd., Novartis Pharmaceutical Co. Ltd., and Chugai Pharmaceutical Co. Ltd. ST has received speaker fees from Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Kyowa Kirin Co., Ltd., and Takeda Pharmaceutical Co., Ltd. HO has received speaker fees from Mitsubishi Tanabe Pharma Corporation, Daiichi Sankyo Co., Nippon Boehringer Ingelheim Co., Eli Lilly Japan K.K., AstraZeneca K.K., Ono Pharmaceutical Co. Ltd., Kyowa Kirin Co. Ltd., Novartis Pharmaceutical Co. Ltd., Torii Pharmaceutical Co. Ltd., Otsuka Pharmaceutical Co. Ltd., and Bayer Pharmaceutical Co. Ltd., and unrestricted research grants from Ono Pharmaceutical Co. Ltd., Kyowa Kirin Co. Ltd., Torii Pharmaceutical Co. Ltd., Chugai Pharmaceutical Co. Ltd., and Bayer Pharmaceutical Co. Ltd., and research funding from Kyowa Kirin Co. Ltd., Torii Pharmaceutical Co. Ltd., Kissei Pharmaceutical Co. Ltd., Chugai Pharmaceutical Co. Ltd., and Bayer Pharmaceutical Co. Ltd. ME has received speaker fees from Novo Nordisk Pharma Ltd., Nippon Boehringer Ingelheim Co., Sumitomo Pharma Co. Ltd., Sanofi K.K., Kyowa Kirin Co. Ltd., AstraZeneca K.K., and Ono Pharmaceutical Co. Ltd., and unrestricted research grants from Sumitomo Pharma Co. Ltd., Nippon Boehringer Ingelheim Co., Eisai Co. Ltd., Kyowa Kirin Co. Ltd., Mitsubishi Tanabe Pharma Corporation, Chugai Pharmaceutical Co. Ltd, and Bayer Pharmaceutical Co. Ltd. and research funding from Mitsubishi Tanabe Pharma Corporation and Kyowa Kirin Co. Ltd. The remaining 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 © 2024 Mori, Inoue, Machiba, Uedono, Nakatani, Ishikawa, Taniuchi, Katayama, Yamamoto, Kobayashi, Kozawa, Shimono, Miki, Okada and Emoto.)

Background: Previous studies have attempted to establish predictive models for post-hepatectomy liver failure (PHLF) in patients with hepatocellular carcinoma (HCC) undergoing liver resection. However, a versatile and useful predictive model for PHLF remains to be developed. Therefore, we aimed to develop predictive models for PHLF based on type IV collagen 7s domain (7s collagen) in patients with HCC. Methods: We retrospectively collected data from 972 patients with HCC who had undergone initial curative liver resection between February 2000 and December 2020 at our hospital. Multivariate logistic regression analysis using a restricted cubic spline was performed to evaluate the effect of 7s collagen on the incidence of PHLF. A nomogram was developed based on 7s collagen. Results: PHLF grades B or C were identified in 104 patients (11%): 98 (10%) and 6 (1%) PHLF grades B and C, respectively. Multivariate logistic regression analysis revealed that the preoperative serum level of 7s collagen was significantly associated with a proportional increase in the risk of PHLF, which was confirmed in both laparoscopic and open liver resections. A nomogram was developed based on 7s collagen, with a concordance index of 0.768. The inclusion of 7s collagen values in the predictive model increased the predictive accuracy. Conclusion: The findings highlight the efficacy of the serum level of 7s collagen as a predictive factor for PHLF. Our novel nomogram using 7s collagen may be useful for predicting the risk of PHLF.

Background and Objective: The relative effectiveness of initial non-invasive respiratory strategies for acute respiratory failure using continuous positive airway pressure (CPAP) or high-flow nasal cannula (HFNC) is unclear., Methods: We conducted a multicenter, open-label, parallel-group randomized controlled trial to compare the efficacy of CPAP and HFNC on reducing the risk of meeting the prespecified criteria for intubation and improving clinical outcomes of acute hypoxemic respiratory failure. The primary endpoint was the time taken to meet the prespecified criteria for intubation within 28 days., Results: Eighty-five patients were randomly assigned to the CPAP or HFNC group. Eleven (28.9%) in the CPAP group and twenty (42.6%) in the HFNC group met the criteria for intubation within 28 days. Compared with HFNC, CPAP reduced the risk of meeting the intubation criteria (hazard ratio [HR], 0.327; 95% CI, 0.148-0.724; p = 0.006). There were no significant between-group differences in the intubation rates, in-hospital and 28-day mortality rates, ventilator-free days, duration of the need for respiratory support, or duration of hospitalization for respiratory illness. Pulmonary oxygenation was significantly better in the CPAP group, with significantly lower pH and higher partial pressure of carbon dioxide, but there were no differences in the respiratory rate between groups. CPAP and HFNC were associated with few possibly causal adverse events., Conclusion: CPAP is more effective than HFNC at reducing the risk of meeting the intubation criteria in patients with acute hypoxemic respiratory failure., (© 2023 Asian Pacific Society of Respirology.)

Background: Immune-related adverse events (irAEs) in patients treated with immune check inhibitors are associated with favourable response rate and survivals in multiple cancers, including renal cell carcinoma (RCC). The aim of this study was to investigate how irAEs were associated with improved survivals in advanced RCC patients treated with nivolumab plus ipilimumab., Materials and Methods: This retrospective study included patients who received nivolumab plus ipilimumab at six centres, institutions, or hospitals between September 2018 and February 2022. We assessed associations of the development and the number of irAEs with overall survival (OS) and progression-free survival (PFS). To eliminate immortal time bias, landmark analysis and a Cox model with time-dependent variables were used., Results: This study included 129 patients with a median follow-up of 12.3 months. The 2-year OS and PFS rates were 55% and 42%, respectively. Ninety six patients experienced irAEs. The development of irAEs was positively associated with OS and PFS rates (hazard ratio [HR] 0.328, 95% confidence interval [CI] 0.165-0.648, p = 0.001; HR 0.334, 95% CI 0.151-0.737, p = 0.007). Patients who experienced multiple irAEs had longer OS (HR 0.507, 95% CI 0.235-1.097, p = 0.085 or HR 0.245, 95% CI 0.110-0.544, p < 0.001) and PFS (HR 0.572, 95% CI 0.316-1.036, p = 0.085 or HR 0.267, 95% CI 0.113-0.628, p = 0.002) compared with those who experienced single or zero irAE., Conclusions: Developing irAEs, particularly multiple irAEs, is associated with favourable survivals in advanced RCC patients treated with nivolumab plus ipilimumab., (© 2023. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.)

Aim: Serum levels of cholesterol absorption and synthesis markers have been associated with cardiovascular risk in the United States and European countries. In this study, we examined the relevance of these biomarkers and the presence of cardiovascular disease (CVD) in Japanese individuals., Methods: The CACHE consortium, comprising of 13 research groups in Japan possessing data on campesterol, an absorption marker, and lathosterol, a synthesis marker measured by gas chromatography, compiled the clinical data using the REDCap system., Results: Among the 2,944 individuals in the CACHE population, those with missing campesterol or lathosterol data were excluded. This cross-sectional study was able to analyze data from 2,895 individuals, including 339 coronary artery disease (CAD) patients, 108 cerebrovascular disease (CeVD) patients, and 88 peripheral artery disease (PAD) patients. The median age was 57 years, 43% were female, and the median low-density lipoprotein cholesterol and triglyceride levels were 118 mg/dL and 98 mg/dL, respectively. We assessed the associations of campesterol, lathosterol, and the ratio of campesterol to lathosterol (Campe/Latho ratio) with the odds of CVD using multivariable-adjusted nonlinear regression models. The prevalence of CVD, especially CAD, showed positive, inverse, and positive associations with campesterol, lathosterol, and the Campe/Latho ratio, respectively. These associations remained significant even after excluding individuals using statins and/or ezetimibe. The associations of the cholesterol biomarkers with PAD were determined weaker than those with CAD. Contrarily, no significant association was noted between cholesterol metabolism biomarkers and CeVD., Conclusion: This study showed that both high cholesterol absorption and low cholesterol synthesis biomarker levels were associated with high odds of CVD, especially CAD.

Background: In transfemoral transcatheter aortic valve implantation (TF-TAVI), which approach has lower vascular access site complications between the open puncture (OP) and percutaneous puncture (PP) approaches is still controversial. Moreover, few studies have analyzed risk factors for vascular access site complications in TF-TAVI. This study aimed to compare vascular access site complications between the OP and PP approaches in patients undergoing TF-TAVI and access risk factors for vascular access site complications., Methods: Three hundred fifty-one patients who underwent TF-TAVI via the PP (n=251) and OP (n=100) were retrospectively examined., Results: Incidence of vascular access site complications was 7.0% in the OP group and 8.4% in the PP group (P=0.828). Two deaths from vascular access site complications occurred in the PP group. After performing inverse probability weighting (IPW), regression analysis showed that PP was associated with a significantly higher odds of vascular access site complications [odds ratio =2.033; 95% confidence interval (CI): 1.397-2.958; P<0.001]. Common femoral artery (CFA) depth (hazard ratio =1.04; 95% CI: 1.000-1.070; P=0.045) and sheath/CFA diameter ratio (hazard ratio =971; 95% CI: 22.6-41,700; P<0.001) were independent complication risk factors. In patients with CFA depth ≥35 mm, the incidence of vascular access site complications was higher with PP than OP. Sheath/CFA diameter ratio ≥0.9 was associated with increased risk of vascular injury with both approaches., Conclusions: The incidence of vascular access site complications in patients undergoing TF-TAVI was significantly lower with OP than PP after IPW. OP may be preferable when CFA depth is ≥35 mm. When the sheath/CFA diameter ratio is ≥0.9, approaches other than the TF approach should be considered., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-23-999/coif). The authors have no conflicts of interest to declare., (2023 Journal of Thoracic Disease. All rights reserved.)

mRNA vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have played a key role in reducing morbidity and mortality from coronavirus disease 2019 (COVID-19). We conducted a double-blind, placebo-controlled phase I/II trial to evaluate the safety, tolerability, and immunogenicity of EXG-5003, a two-dose, controllable self-replicating RNA vaccine against SARS-CoV-2. EXG-5003 encodes the receptor binding domain (RBD) of SARS-CoV-2 and was administered intradermally without lipid nanoparticles (LNPs). The participants were followed for 12 months. Forty healthy participants were enrolled in Cohort 1 (5 µg per dose, n = 16; placebo, n = 4) and Cohort 2 (25 µg per dose, n = 16; placebo, n = 4). No safety concerns were observed with EXG-5003 administration. SARS-CoV-2 RBD antibody titers and neutralizing antibody titers were not elevated in either cohort. Elicitation of antigen-specific cellular immunity was observed in the EXG-5003 recipients in Cohort 2. At the 12-month follow-up, participants who had received an approved mRNA vaccine (BNT162b2 or mRNA-1273) >1 month after receiving the second dose of EXG-5003 showed higher cellular responses compared with equivalently vaccinated participants in the placebo group. The findings suggest a priming effect of EXG-5003 on the long-term cellular immunity of approved SARS-CoV-2 mRNA vaccines.

This prospective observational single-center cohort study aimed to determine an association between cerebrovascular autoregulation (CVAR) and outcomes in hypoxic-ischemic brain injury post-cardiac arrest (CA), and assessed 100 consecutive post-CA patients in Japan between June 2017 and May 2020 who experienced a return of spontaneous circulation. Continuous monitoring was performed for 96 h to determine CVAR presence. A moving Pearson correlation coefficient was calculated from the mean arterial pressure and cerebral regional oxygen saturation. The association between CVAR and outcomes was evaluated using the Cox proportional hazard model; non-CVAR time percent was the time-dependent, age-adjusted covariate. The non-linear effect of target temperature management (TTM) was assessed using a restricted cubic spline. Of the 100 participants, CVAR was detected using the cerebral performance category (CPC) in all patients with a good neurological outcome (CPC 1-2) and in 65 patients (88%) with a poor outcome (CPC 3-5). Survival probability decreased significantly with increasing non-CVAR time percent. The TTM versus the non-TTM group had a significantly lower probability of a poor neurological outcome at 6 months with a non-CVAR time of 18%-37% (p < 0.05). Longer non-CVAR time may be associated with significantly increased mortality in hypoxic-ischemic brain injury post-CA., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Aim: Blood cholesterol absorption and synthesis biomarkers predict cardiovascular risk. This study aimed to determine the values of serum non-cholesterol sterol markers [lathosterol (Latho), campesterol (Campe), and sitosterol (Sito)] in healthy individuals and factors affecting these markers., Methods: The CACHE Consortium compiled clinical data, including serum Latho (cholesterol synthesis marker), and Campe and Sito (cholesterol absorption markers), by a gas chromatography method in 2944 individuals. Healthy subjects were selected by excluding those with prior cardiovascular disease, diabetes mellitus, hypertension, chronic kidney disease, familial hypercholesterolemia, sitosterolemia, current smokers, those with low (＜17 kg/m 2 ) or high (≥ 30 kg/m 2 ) body mass index (BMI), and those with treatment for dyslipidemia or hyperuricemia. Nonlinear regression stratified by sex was used to examine the associations of cholesterol metabolism markers with age, BMI, and serum lipid levels., Results: Of 479 individuals selected, 59.4% were female; the median age was 48 years in females and 50 years in males. The three markers showed positively skewed distributions, and sex differences were present. Age was associated positively with Latho, inversely with Campe, but not significantly with Sito. BMI was associated positively with Latho, but not significantly with Campe or Sito. High-density lipoprotein cholesterol (HDL-C) was positively associated with Campe and Sito, but not significantly with Latho. Non-HDL-C was positively associated with the three markers., Conclusion: Our study results in the healthy subjects help to interpret the non-cholesterol sterol markers for cardiovascular risk assessment in patients with cardiovascular risk factors.

Aim: Serum levels of cholesterol absorption and synthesis markers are known to be associated with cardiovascular risk. Familial hypercholesterolemia (FH) is a well-known inherited disorder presenting elevated low-density lipoprotein cholesterol (LDL-C) and total cholesterol (TC) levels and premature coronary disease. In this study, we aim to examine the differences in terms of serum markers of cholesterol metabolism between FH and non-FH individuals and to examine their associations with serum lipid levels., Methods: In this study, we utilized data on serum markers of cholesterol metabolism, namely, lathosterol (Latho, synthesis marker), campesterol (Campe, absorption marker), and sitosterol (Sito, absorption marker) measured by gas chromatography of the CACHE consortium, which comprised of 13 research groups in Japan. Clinical data were compiled using REDCap system. Among the 2944 individuals in the CACHE population, we selected individuals without lipid-lowering medications and hemodialysis patients for this CACHE study FH analysis. Multivariable adjustment was performed to assess the associations., Results: In this study, we analyzed data from 51 FH patients and 1924 non-FH individuals. After adjustment for possible confounders, the FH group was shown to have significantly higher Campe and Sito concentrations and insignificantly higher Latho concentrations than the non-FH group. These marker concentrations showed nonlinear associations with TC in the FH group. Campe/Latho and Sito/Latho ratios were significantly higher in the FH group than in the non-FH group., Conclusion: FH group had significantly elevated serum Campe and Sito concentrations and insignificantly elevated Latho concentrations; thus, intestinal cholesterol absorption relative to hepatic cholesterol synthesis was suggested to be elevated in patients with FH. Serum Latho, Campe, and Sito concentrations showed nonlinear associations with TC in the FH group.

Aim: Risk of cardiovascular disease is increased in patients with diabetes mellitus (DM). Cholesterol metabolism (hepatic synthesis and intestinal absorption) is known to be associated with cardiovascular risk. Next, we examined the association of DM with cholesterol absorption/synthesis., Methods: The CACHE Consortium, which is comprised of 13 research groups in Japan possessing data of lathosterol (Latho, synthesis marker) and campesterol (Campe, absorption marker) measured by gas chromatography, compiled the clinical data using the REDCap system. Among the 3597 records, data from 2944 individuals were used for several analyses including this study., Results: This study analyzed data from eligible 2182 individuals including 830 patients with DM; 42.2% were female, median age was 59 years, and median HbA1c of patients with DM was 7.0%. There was no difference in Latho between DM and non-DM individuals. Campe and Campe/Latho ratio were significantly lower in DM individuals than in non-DM individuals. When the associations of glycemic control markers with these markers were analyzed with multivariable-adjusted regression model using restricted cubic splines, Campe and Campe/Latho ratio showed inverse associations with glucose levels and HbA1c. However, Latho showed an inverted U-shaped association with plasma glucose, whereas Latho showed a U-shaped association with HbA1c. These associations remained even after excluding statin and/or ezetimibe users., Conclusion: We demonstrated that DM and hyperglycemia were independent factors for lower cholesterol absorption marker levels regardless of statin/ezetimibe use.

To increase the prediction accuracy of positive oral food challenge (OFC) outcomes during stepwise slow oral immunotherapy (SS-OIT) in children with a hen's egg (HE) allergy, we evaluated the predictive value of the combination of antigen-specific IgE (sIgE) with antigen binding avidity and sIgG4 values. Sixty-three children with HE allergy undergoing SS-OIT were subjected to repeated OFCs with HE. We measured the ovomucoid (OVM)-sIgE by ImmunoCAP or densely carboxylated protein (DCP) microarray, sIgG4 by DCP microarray, and the binding avidity of OVM-sIgE defined as the level of 1/IC 50 (nM) measured by competitive binding inhibition assays. The OFC was positive in 37 (59%) patients undergoing SS-OIT. Significant differences in DCP-OVM-sIgE, CAP-OVM-sIgE, I/IC 50 , DCP-OVM-sIgG4, the multiplication products of DCP-OVM-sIgE, and the binding avidity of DCP-OVM-sIgE (DCP-OVM-sIgE/IC 50 ) and DCP-OVM-sIgE/sIgG4 were compared between the negative and positive groups ( p < 0.01). Among them, the variable with the greatest area under the receiver operating characteristic curve was DCP-OVM-sIgE/IC 50 (0.84), followed by DCP-OVM-sIgE/sIgG4 (0.81). DCP-OVM-sIgE/IC 50 and DCP-OVM-sIgE/sIgG4 are potentially useful markers for the prediction of positive OFCs during HE-SS-OIT and may allow proper evaluation of the current allergic status in the healing process during HE-SS-OIT.

Aim: Serum levels of cholesterol absorption and synthesis markers are known to be associated with cardiovascular risk. Individuals with reduced kidney function or chronic kidney disease (CKD) are at an increased risk for cardiovascular disease. Hence, we examined the relationship between estimated glomerular filtration rate (eGFR) and serum markers of cholesterol absorption and synthesis., Methods: The CACHE (Cholesterol Absorption and Cholesterol synthesis in High-risk patiEnts) Consortium, comprised of 13 research groups in Japan possessing data of lathosterol (Latho, synthesis marker) and campesterol (Campe, absorption marker) measured via gas chromatography, compiled the clinical data using the REDCap system. Among the 3597 records, data from 2944 individuals were utilized for five analyses including this CKD analysis., Results: This study analyzed data from 2200 individuals including 522 hemodialysis patients; 42.3% were female, the median age was 58 years, and the median eGFR was 68.9 mL/min/1.73 m 2 . Latho, Campe, and Campe/Latho ratio were significantly different when compared across CKD stages. When the associations of eGFR with these markers were assessed with multivariable nonlinear regression models, Latho, Campe, and Campe/Latho ratio showed positive, inverse, and inverse associations with eGFR. These associations were significantly modified by sex, the presence/absence of diabetes mellitus, and the presence/absence of statin use., Conclusion: We showed that individuals with lower eGFR have lower cholesterol synthesis marker levels and higher cholesterol absorption marker levels in this large sample.

Aim: We carried out a randomized controlled trial using ipragliflozin. We analyzed changes in diastolic function using echocardiography in patients with type 2 diabetes and heart failure with preserved ejection fraction., Methods: We carried out an open-label, multicenter, randomized, two-arm interventional trial. A total of eligible 68 participants were randomly assigned into two groups (ipragliflozin group n = 36; conventional treatment group n = 32). Primary end-points were the change in E/e' and e'. Secondary end-points were other parameters of echocardiography, plasma NT-proBNP level, New York Heart Association class, hemoglobin A1c and blood pressure., Results: After 24 weeks of follow up, E/e' decreased in both groups (ipragliflozin: 11.0 vs 10.4; conventional treatment 10.5 vs 10.1; multivariate-adjusted P = 0.95). There were no significant differences in the amount of change in E/e', e', echocardiography parameters, plasma NT-proBNP level, New York Heart Association class, hemoglobin A1c and blood pressure between the two groups. In the subgroup analysis, ipragliflozin treatment decreased in left ventricular mass index in patients aged ≥70 years and also decreased in NT-proBNP levels in patients with baseline NT-proBNP ≥400 pg/mL., Conclusions: In this randomized controlled study carried out in patients with type 2 diabetes and heart failure with preserved ejection fraction, 24-week ipragliflozin treatment did not improve left ventricular diastolic function compared with conventional treatment. As the subgroup, ipragliflozin treatment decreased in left ventricular mass index in participants aged ≥70 years. Geriatr Gerontol Int 2022; 22: 298-304., (© 2022 The Authors. Geriatrics & Gerontology International published by John Wiley & Sons Australia, Ltd on behalf of Japan Geriatrics Society.)

Myelofibrosis is characterized by stem cell-derived clonal proliferation potentially resulting in bone marrow fibrosis. As the disease progresses, extramedullary hematopoiesis is frequently detected in the spleen and the liver but rarely in other organs. We report a case of a 68-year-old woman with myelofibrosis with a JAK2 mutation, showing extramedullary hematopoiesis (EMH) in various organs with a marked increase in reticulin fibers, and myeloproliferative neoplasm (MPN)-related necrotizing crescent glomerulonephritis. She was admitted to our hospital owing to respiratory discomfort. Computed tomography revealed a mass in the anterior mediastinum. Ten days later, the patient died owing to respiratory distress. At autopsy, EMH were detected in the anterior mediastinum, heart, lung, spleen, and the kidney with a marked increase in reticulin fibers. We considered that respiratory distress was partially caused by EMH. In the kidney, necrotizing crescent glomerulonephritis was observed. Immunohistochemically, the glomerular basement and mesangial area were IgA- and C3d-positive. Ultrastructural examination revealed the presence of dense deposits in the subendothelial space and the mesangial and paramesangial areas. Thus, we suspected that MPN-related necrotizing crescentic glomerulonephritis harbored a pathogenesis similar to that of IgA-dominant post-infectious glomerulonephritis or IgA nephropathy. This case report could widen the spectrum of MPN- or EMH-related lesions., (© 2021. The Japanese Society for Clinical Molecular Morphology.)

Background: The proportion of adult patients with return of spontaneous circulation (ROSC) following out-of-hospital cardiac arrest (OHCA) remains unchanged since 2012. A better resuscitation strategy is needed. This study evaluated the effectiveness of a regional cerebral oxygen saturation (rSO 2 )-guided resuscitation protocol without rhythm check based on our previous study., Methods: Because defibrillation is the definitive therapy that should be performed without delay for shockable rhythm, the study subjects were OHCA patients with non-shockable rhythm on hospital arrival at three emergency departments. They were divided into three groups based on their baseline rSO 2 value (%): ≥50, ≥40 to <50, or <40. Continuous chest compression without rhythm checks was performed for 16 minutes or until a maximum increase in rSO 2 of 10%, 20%, or 35% was achieved in each group, respectively. This intervention cohort was compared with a historical control cohort regarding the probability of ROSC using inverse probability of treatment weighting (IPTW) with propensity score., Results: The control and intervention cohorts respectively included 86 and 225 patients. The rate of ROSC was not significantly different between the groups (adjusted OR 0.91 [95% CI, 0.64-1.29], P = 0.60), but no serious adverse events occurred. Sensitivity analyses 1 and 2 showed a significant difference or positive tendency for higher probability of ROSC (adjusted OR 1.63 [95% CI, 1.22-2.17], P < 0.001) (adjusted OR 1.25 [95% CI, 0.95-1.63], P = 0.11)., Conclusions: This trial suggested that a new cardiopulmonary resuscitation protocol with different rhythm check timing could be created using the rSO 2 value. Clinical trial number: UMIN000025684., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

While ATF6α plays a central role in the endoplasmic reticulum (ER) stress response, the function of its paralogue ATF6β remains elusive, especially in the central nervous system (CNS). Here, we demonstrate that ATF6β is highly expressed in the hippocampus of the brain, and specifically regulates the expression of calreticulin (CRT), a molecular chaperone in the ER with a high Ca 2+ -binding capacity. CRT expression was reduced to ~ 50% in the CNS of Atf6b -/- mice under both normal and ER stress conditions. Analysis using cultured hippocampal neurons revealed that ATF6β deficiency reduced Ca 2+ stores in the ER and enhanced ER stress-induced death. The higher levels of death in Atf6b -/- neurons were recovered by ATF6β and CRT overexpressions, or by treatment with Ca 2+ -modulating reagents such as BAPTA-AM and 2-APB, and with an ER stress inhibitor salubrinal. In vivo, kainate-induced neuronal death was enhanced in the hippocampi of Atf6b -/- and Calr +/- mice, and restored by administration of 2-APB and salubrinal. These results suggest that the ATF6β-CRT axis promotes neuronal survival under ER stress and excitotoxity by improving intracellular Ca 2+ homeostasis.

Background: Empagliflozin reduces the risk of hospitalization for heart failure in patients with type 2 diabetes and cardiovascular disease. We sought to elucidate the effect of empagliflozin as an add-on therapy on decongestion and renal function in patients with type 2 diabetes admitted for acute decompensated heart failure., Methods: The study was terminated early due to COVID-19 pandemic. We enrolled 59 consecutive patients with type 2 diabetes admitted for acute decompensated heart failure. Patients were randomly assigned to receive either empagliflozin add-on (n=30) or conventional glucose-lowering therapy (n=29). We performed laboratory tests at baseline and 1, 2, 3, and 7 days after randomization. Percent change in plasma volume between admission and subsequent time points was calculated using the Strauss formula., Results: There were no significant baseline differences in left ventricular ejection fraction and serum NT-proBNP (N-terminal pro-B-type natriuretic peptide), hematocrit, or serum creatinine levels between the 2 groups. Seven days after randomization, NT-proBNP level was significantly lower in the empagliflozin group than in the conventional group ( P =0.040), and hemoconcentration (≥3% absolute increase in hematocrit) was more frequently observed in the empagliflozin group than in the conventional group ( P =0.020). The decrease in percent change in plasma volume between baseline and subsequent time points was significantly larger in the empagliflozin group than in the conventional group 7 days after randomization ( P =0.017). The incidence of worsening renal function (an increase in serum creatinine ≥0.3 mg/dL) did not significantly differ between the 2 groups., Conclusions: In this exploratory analysis, empagliflozin achieved effective decongestion without an increased risk of worsening renal function as an add-on therapy in patients with type 2 diabetes with acute decompensated heart failure. Registration: URL: https://www.umin.ac.jp/ctr/index.htm; Unique identifier: UMIN000026315.

We report a case of polycythaemia vera (PV) associated with IgA vasculitis. A 45-year-old man was admitted for evaluation of abdominal pain and palpable purpura. IgA vasculitis was diagnosed, and oral prednisolone therapy (30 mg/day) was initiated. On day 6, the patient developed left hemiparesis, and magnetic resonance imaging revealed acute cerebral infarction. Bone marrow biopsy results and the identification of a Janus kinase 2 ( JAK2 ) mutation led to the diagnosis of PV. Despite steroid therapy, urine protein levels increased to 15 g/g・Cre. Renal biopsy demonstrated mild mesangial proliferation with IgA deposits, but immunosuppressive therapy was partially effective. This case suggests that PV can be a complication of IgA vasculitis and that preventive measures for thrombosis should be taken in such cases.

Posttransplant donor-specific anti-HLA antibodies (DSA) cause chronic antibody-mediated rejection. Anti-DR and anti-DQ DSAs have especially been shown to be associated with negative graft function. In contrast, the prevalence and significance of anti-DP DSA have not been well established and remain unclear. We report a case of living donor kidney transplantation. The level of serum creatinine gradually became elevated because of chronic active antibody-mediated rejection, which was considered to be caused by anti-DP DSA. In this report, we indicate the significance of pretransplant screening for HLA-DP in donors to evaluate more comprehensively the donor specificity of posttransplant HLA antibodies., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The integrated stress response (ISR) is one of the most important cytoprotective mechanisms and is integrated by phosphorylation of the α subunit of eukaryotic translation initiation factor 2 (eIF2α). Four eIF2α kinases, heme-regulated inhibitor (HRI), double-stranded RNA-dependent protein kinase (PKR), PKR-like endoplasmic reticulum kinase (PERK), and general control nonderepressible 2 (GCN2), are activated in response to several stress conditions. We previously reported that nanosecond pulsed electric fields (nsPEFs) are a potential therapeutic tool for ISR activation. In this study, we examined which eIF2α kinase is activated by nsPEF treatment. To assess the responsible eIF2α kinase, we used previously established eIF2α kinase quadruple knockout (4KO) and single eIF2α kinase-rescued 4KO mouse embryonic fibroblast (MEF) cells. nsPEFs 70 ns in duration with 30 kV/cm electric fields caused eIF2α phosphorylation in wild-type (WT) MEF cells. On the other hand, nsPEF-induced eIF2α phosphorylation was completely abolished in 4KO MEF cells and was recovered by HRI overexpression. CM-H2DCFDA staining showed that nsPEFs generated reactive oxygen species (ROS), which activated HRI. nsPEF-induced eIF2α phosphorylation was blocked by treatment with the ROS scavenger N-acetyl-L-cysteine (NAC). Our results indicate that the eIF2α kinase HRI is responsible for nsPEF-induced ISR activation and is activated by nsPEF-generated ROS., Competing Interests: The authors have declared that no competing interests exist.

Competing Interests: Competing interests: None declared.