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Abstract: Influence of impurity Si on microstructure in a plutonium and uranium mixed oxide (MOX), which is used for fast breeder reactor fuel, was investigated, and phase state in 25% SiO2 – (U0.7Pu0.3)O2 was observed as a function of oxygen chemical potential. Compounds composed of Pu and Si with other elements were observed at grain boundaries of the MOX parent phase in the specimens after annealing. These compounds were not observed in the grain interior and the MOX phase was not affected significantly by impurity Si. It was found that the compounds tended to form more observably with decreasing O/M ratio and with increasing annealing temperatures. [Copyright &y& Elsevier]

Abstract: Scattering of 300K effusive D2 beam from H/Si(100) surfaces has been investigated in the dynamics experiments on angular and velocity distributions of scattered molecules. The results are compared with that of the He scattering which is governed mostly by the direct inelastic scattering (DIS). Although the angular distribution of D2 molecules is nearly cosine but it includes considerable contribution of DIS. This may be explained in terms of the geometrical corrugation of D2–Si surface interaction potential. [Copyright &y& Elsevier]

Pompe disease is an autosomal recessive disease due to a deficiency in lysosomal acid alpha glucosidase (GAA). Cardiomyopathy is usually observed in infant-onset Pompe disease, and, rare in late onset Pompe disease (LOPD) cases. We report atypical LOPD patient who died at 39-year-old due to dilated cardiomyopathy. She had a muscle pain and elevated creatine kinase from childhood. She worked as a care worker from the age of 22. At age of 34, she had a fever and cough, and diagnosed as dilated cardiomyopathy. At age of 37, her aortic valve was replaced, but her cardiac function was not improved. At age 39, she was admitted to be examined for heart transplantation. She could not walk due to dilated cardiomyopathy, but had mild muscle weakness. She died due to aspiration pneumonia caused by dilated cardiomyopathy. On autopsy, the myocardium was thin, and showed many rimmed vacuoles and PAS-positive glycogen depositions. Rimmed vacuoles and accumulated glycogen were scattered in the skeletal muscle. In tongue tissue, PAS-positive glycogen deposits was also observed. GAA activity of DBS was decreased (19.5%, 4.18pmol/punch/h), but genetic studies could not reveal any mutation of GAA gene. [Copyright &y& Elsevier]

It has not yet been established whether angiotensin II receptor blockers (ARB), statins, and multiple drugs affect the severity of COVID-19. Therefore, we herein performed an observational study on the effects of 1st- and 2nd-generation ARB, statins, and multiple drugs, on COVID-19 in patients admitted to 15 Japanese medical facilities. The results obtained showed that ARB, statins, and multiple drugs were not associated with the primary outcome (odds ratio: 1.040, 95% confidence interval: 0.688-0.571; 0.696, 0.439-1.103; 1.056, 0.941-1.185, respectively), each component of the primary outcome (in-hospital death, ventilator support, extracorporeal membrane oxygenation support, and admission to the intensive care unit), or the secondary outcomes (oxygen administration, disturbed consciousness, and hypotension, defined as systolic blood pressure ≤90 mmHg). ARB were divided into 1st- and 2nd-generations based on their approval for use (before 2000 and after 2001), with the former consisting of losartan, candesartan, and valsartan, and the latter of telmisartan, olmesartan, irbesartan, and azilsartan. The difference of ARB generation was not associated with the primary outcome (odds ratio with 2nd-generation ARB relative to 1st-generation ARB: 1.257, 95% confidence interval: 0.613-2.574). The odd ratio for a hypotension as one of the secondary outcomes with 2nd-generation ARB was 1.754 (95% confidence interval: 1.745-1.763) relative to 1st-generation ARB. These results suggest that patients taking 2nd-generation ARB may be at a higher risk of hypotension than those taking 1st-generation ARB and also that careful observations are needed. Further studies are continuously needed to support decisions to adjust medications for co-morbidities., (© 2024. The Author(s), under exclusive licence to The Japanese Society of Hypertension.)

Introduction: Previous studies have not evaluated the surgical difficulty of minimally invasive distal pancreatectomy for pancreatic cancer in elderly patients. Therefore, we aimed to investigate the effect of elderly age on the perioperative outcomes of minimally invasive distal pancreatectomy, focusing on surgical difficulty., Methods: This single-center retrospective study included patients who underwent minimally invasive distal pancreatectomy for pancreatic cancer at Kansai Rosai Hospital between September 2012 and December 2023. Perioperative outcomes were investigated between the elderly (>75 years) and non-elderly (≤75 years) groups., Results: Fifty-six patients were included: 26 and 30 in the elderly and non-elderly groups, respectively. The median operative time was significantly shorter in the elderly group than in the non-elderly group (324 vs. 414 min, p = .022), but other surgical outcomes were not significantly different including oncological factors. The median difficulty score was similar between the elderly and non-elderly groups (6 vs. 7, respectively; p = .699). The incidences of postoperative complications and pancreatic fistulas were not significantly different in the elderly and non-elderly groups (23% vs. 43%, p = .159, and 19% vs. 36%, p = .236, respectively), even though analyzed in subgroups with low-to-intermediate or high difficulty score., Conclusions: The safety and feasibility of minimally invasive distal pancreatectomy for pancreatic cancer were not significantly different between elderly and non-elderly patients, even when surgical difficulty was considered. This surgical procedure can be safe and feasible for elderly patients., (© 2024 Asia Endosurgery Task Force and Japan Society of Endoscopic Surgery and John Wiley & Sons Australia, Ltd.)

Manufacturing semiconductor devices requires advanced patterning technologies, including reactive ion etching (RIE) based on the synergistic interactions between ions and etch gas. However, these interactions weaken as devices continuously scale down to sub-nanoscale, primarily attributed to the diminished transport of radicals and ions into the small features. This leads to a significant decrease in etch rate (ER). Here, a novel synergistic interaction involving ions, surface-adsorbed chemistries, and materials at cryogenic temperatures is found to exhibit a significant increase in the ER of SiO 2 using CF 4 /H 2 plasmas. The ER increases twofold when plasma with H 2 /(CF 4 + H 2 ) = 33% is used and the substrate temperature is lowered from 20 to -60 °C. The adsorption of HF and H 2 O on the SiO 2 surface at cryogenic temperatures is confirmed using in situ Fourier transform infrared spectroscopy. The synergistic interactions of the surface-adsorbed HF/H 2 O as etching catalysts and plasma species result in the ER enhancement. Therefore, a mechanism called "pseudo-wet plasma etching" is proposed to explain the cryogenic etching process. This synergy demonstrates that the enhanced etch process is determined by the surface interactions between ions, surface-adsorbed chemistry, and the material being etched, rather than interactions between ion and gas phase, as observed in the conventional RIE., (© 2024 The Author(s). Small Methods published by Wiley‐VCH GmbH.)

Self-disclosure is the attitude of communicating one's experiences and condition to others and is an indicator of mental health and an open personality. Frailty, characterized by reduced physical and psychological resistance, predicts the incidence of dependency and mortality. Although low self-disclosure may be associated with frailty, there is no scale to measure older adults' self-disclosure. This cross-sectional study assessed the validity of a self-assessment self-disclosure questionnaire and examined the association between the content of self-disclosures to friends and acquaintances and frailty among community-dwelling older adults. A total of 237 adults aged ≥65 in Japan were surveyed using a mailed self-administered questionnaire in 2021. The self-disclosure scale consisted of 10 items and showed adequate validity. Participants were classified into a robust group ( n = 117, women 57.3%) and a frailty group ( n = 120, women 73.3%) using the Kihon Checklist. After adjusting for covariates, multivariate-adjusted logistic regression models revealed frailty was associated with lower self-disclosure of recent positive events, motivation and strengths (indicating strong points) in life, relationships with family and relatives, experiences of work and social activities, and financial status. The proposed questionnaire must still be further tested in other populations, but our initial results may contribute to preventing frailty and improving mental health among community-dwelling older adults.

Background: This study investigated whether the chronic use of adaptive servo-ventilation (ASV) reduces all-cause mortality and the rate of urgent rehospitalization in patients with heart failure (HF)., Methods and results: This multicenter prospective observational study enrolled patients hospitalized for HF in Japan between 2019 and 2020 who were treated either with or without ASV therapy. Of 845 patients, 110 (13%) received chronic ASV at hospital discharge. The primary outcome was a composite of all-cause death and urgent rehospitalization for HF, and was observed in 272 patients over a 1-year follow-up. Following 1:3 sequential propensity score matching, 384 patients were included in the subsequent analysis. The median time to the primary outcome was significantly shorter in the ASV than in non-ASV group (19.7 vs. 34.4 weeks; P=0.013). In contrast, there was no significant difference in the all-cause mortality event-free rate between the 2 groups., Conclusions: Chronic use of ASV did not impact all-cause mortality in patients experiencing recurrent admissions for HF.

Objective: There is a need for a robust tool to stratify the patient's risk with COVID-19. We assessed the prognostic values of cardiac biomarkers for COVID-19 patients., Methods: This is a single-centre retrospective cohort study. Consecutive laboratory-confirmed COVID-19 patients admitted to the Kobe City Medical Center General Hospital from July 2020 to September 2021 were included. We obtained cardiac biomarker values from electronic health records and institutional blood banks. We stratified patients with cardiac biomarkers as high-sensitive troponin I (hsTnI), N-terminal pro-B-type natriuretic peptide (NT-proBNP), creatine kinase (CK) and CK myocardial band (CK-MB), using the clinically relevant thresholds. Prespecified primary outcome measure was all-cause death., Results: A total of 917 patients were included. hsTnI, NT-proBNP, CK and CK-MB were associated with the significantly higher cumulative 30-day incidence of all-cause death (hsTnI: <5.0 ng/L group; 4.3%, 5.0 ng/L-99%ile upper reference limit (URL) group; 8.8% and ≥99% ile URL group; 25.2%, p<0.001. NT-proBNP: <125 pg/mL group; 5.3%, 125-900 pg/mL group; 10.5% and ≥900 pg/mL group; 31.9%, p<0.001. CK:

A 91-year-old man had a history of cholecystectomy and choledochostomy for cholecystolithiasis and choledocholithiasis. Eleven years earlier, intrahepatic stones were found in the posterior bile duct, and he did not wish to undergo treatment. Over time, worsening of the intrahepatic stones and dilation of the intrahepatic bile duct were observed. At 91 years old, enhanced abdominal CT revealed wall thickening of the hilar bile duct, and MRCP showed stenosis of the hilar bile duct. Endoscopic retrograde cholangiography showed no contrast in the right intrahepatic bile duct and marked dilation of the left intrahepatic bile duct. Brush cytology confirmed adenocarcinoma, leading to a diagnosis of hilar cholangiocarcinoma. He underwent open right and caudal lobectomy with biliary reconstruction. Histopathological examination revealed a hilar cholangiocarcinoma, T3N1M0, Stage Ⅲc, mainly located at the confluence of the right and left hepatic ducts. This case suggests a potential association between hepatolithiasis and hilar cholangiocarcinoma, emphasizing the importance of regular imaging examinations for timely surgical resection. Early intervention, including liver resection, is recommended for the management of hepatolithiasis.

Laparoscopic pancreaticoduodenectomy has been covered by insurance since 2016 in Japan, and advance laparoscopic and robotic pancreaticoduodenectomy has been also covered by insurance since 2020 in Japan. It has been reported that laparoscopic pancreatectomy causes few postoperative adhesions in the abdominal cavity and that repeat laparoscopic surgery could be performed. However, in robotic pancreatectomy, there have been no such reports yet. We reported that even after robotic pancreaticoduodenectomy, there were few adhesions in the abdominal cavity, and we were able to perform the robotic distal pancreatectomy with preservation of the splenic artery and vein. This suggested that robotic surgery was an effective treatment method for repeat pancreatectomy, given its low invasiveness and minimal adhesion.

Enzymatic reactions that involve a luminescent substrate (luciferin) and enzyme (luciferase) from luminous organisms enable a luminescence detection of target proteins and cells with high specificity, albeit that conventional assay design requires a prelabeling of target molecules with luciferase. Here, we report a luciferase-independent luminescence assay in which the target protein directly catalyzes the oxidative luminescence reaction of luciferin. The SARS-CoV-2 antigen (spike) protein catalyzes the light emission of Cypridina luciferin, whereas no such catalytic function was observed for salivary proteins. This selective luminescence reaction is due to the enzymatic recognition of the 3-(1-guanidino)propyl group in luciferin at the interfaces between the units of the spike protein, allowing a specific detection of the spike protein in human saliva without sample pretreatment. This method offers a novel platform to detect virus antigens simply and rapidly without genetic manipulation or antibodies., Competing Interests: The authors declare the following competing financial interest(s): R.N. and R.K. are co-inventors on the international patent application (PCT/JP2023/026063) that contains materials and methods outlined in this manuscript., (© 2024 The Authors. Published by American Chemical Society.)

Introduction: Cholangiolocellular carcinoma (CoCC) resembles cholangiocellular carcinoma (CCC) and presents a variety of imaging findings; thus, preoperative diagnosis is often difficult., Methods: We retrospectively studied patients who were diagnosed with CoCC at the Kansai Rosai Hospital from 2006 to 2021 and treated by laparoscopic liver resection (LLR) or open liver resection (OLR)., Result: Among 918 liver resections, 15 patients were diagnosed with CoCC: 11 underwent LLR and 4 OLR. For LLR and OLR, respectively, patient age was 69.9 ± 6.8 and 72.8 ± 10.6, sex was M/F: 10/1 and 2/2, Child-Pugh was A/B/C: 10/1/0 and 4/0/0, liver damage was A/B/C: 8/3/0 and 4/0/0, preoperative diagnosis was CoCC/CCC/HCC: 1/2/8 and 2/2/0, pathological stage of Union for International Cancer Control (UICC) was IA/IB/II/IIIA/IIIB/IV: 8/0/2/1/0/0 and 0/0/3/0/1/0 (p = .0312), and extent of liver resection was Hr0/HrS/Hr1/Hr2/: 3/0/5/3 and 1/1/0/2. In LLR and OLR, respectively, operation time was 417.5 ± 191.0 and 407.5 ± 187.9 min, blood loss was 123.3 ± 217.4 and 1385.0 ± 1038.7 mL, and postoperative hospital stay was 12.2 ± 13.7 and 15.0 ± 6.6 days. For stages I and II/III, respectively, the 5-year disease-free survival rates were 100.0% and 34.3%, and the 5-year overall survival rates were 100.0% and 55.6%. For stage II/III LLR and OLR, respectively, the 3-year disease-free survival rates were 33.3% and 37.5% (p = .8418), and the 5-year overall survival rates were 66.7% and 50.0% (p = .8084)., Conclusion: Although further studies are still needed to confirm, minimally invasive liver resection without lymph node dissection is one of a safe and effective approach to the management of CoCC., (© 2023 Asia Endosurgery Task Force and Japan Society of Endoscopic Surgery and John Wiley & Sons Australia, Ltd.)

Vitamin B 12 (B 12 ) deficiency causes neurological manifestations resembling multiple sclerosis (MS); however, a molecular explanation for the similarity is unknown. FTY720 (fingolimod) is a sphingosine 1-phosphate (S1P) receptor modulator and sphingosine analog approved for MS therapy that can functionally antagonize S1P 1 . Here, we report that FTY720 suppresses neuroinflammation by functionally and physically regulating the B 12 pathways. Genetic and pharmacological S1P 1 inhibition upregulates a transcobalamin 2 (TCN2)-B 12 receptor, CD320, in immediate-early astrocytes (ieAstrocytes; a c-Fos-activated astrocyte subset that tracks with experimental autoimmune encephalomyelitis [EAE] severity). CD320 is also reduced in MS plaques. Deficiency of CD320 or dietary B 12 restriction worsens EAE and eliminates FTY720's efficacy while concomitantly downregulating type I interferon signaling. TCN2 functions as a chaperone for FTY720 and sphingosine, whose complex induces astrocytic CD320 internalization, suggesting a delivery mechanism of FTY720/sphingosine via the TCN2-CD320 pathway. Taken together, the B 12 -TCN2-CD320 pathway is essential for the mechanism of action of FTY720., Competing Interests: Declaration of interests J.C. has received honoraria, consulting fees, and funding support from Novartis, Bristol-Myers Squibb (Celgene), Biogen, and Janssen Pharmaceuticals. J.C. has an employment relationship with Neurocrine Biosciences, Inc., a company that may potentially benefit from the research results. Dr. Chun’s relationship with Neurocrine Biosciences, Inc. has been reviewed and approved by Sanford Burnham Prebys Medical Discovery Institute in accordance with its conflict of interest policies. D.J. is currently employed by Radionetics Oncology. A.G. is currently affiliated with University of California, Los Angeles. R.M. is currently affiliated with Loyola University Chicago. A.S. is currently affiliated with University of Wisconsin-Milwaukee. R.R. is currently employed by 8five8 Therapeutics., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: Laparoscopic pancreaticoduodenectomy(LPD)has been covered by insurance since 2016 in Japan. Advance LPD and robotic pancreaticoduodenectomy(RPD)has been also covered by insurance since 2020 in Japan. The aim of this study was to analyze the perioperative results and outcomes of RPD and LPD for the elderly patients and to compare to the non-elderly patients., Patients and Method: Between July 2020 and April 2023, 67 patients underwent RPD and between May 2012 and February 2021, 63 patients underwent LPD at Kansai Rosai Hospital. Sixty-seven RPD and 62 LPD patients without extended resection were divided into 2 groups those who were over 75 years old(R/LPD E)(n=55)and under 74 years old(R/LPD non-E)(n=74). Control patients who received open pancreaticoduodenectomy(OPD)without extended resection between April 2010 and April 2023 were also divided into 2 groups those who were over 75 years old(OPD E)(n =60)and under 74 years old(OPD non-E)(n=78). The patient age was 79.0 and 60.5 years, the male to female ratio was 35/20 and 45/29, disease ratio(invasive ductal carcinoma or not)was 7/48 and 9/65 in R/LPD E and R/LPD non-E groups, respectively. The patient age was 79.0 and 79.5 years, the male to female ratio was 35/20 and 31/29, disease ratio (invasive ductal carcinoma or not)was 7/48 and 30/30(p<0.0001)in R/LPD E and OPD E groups, respectively. This study was approved by the Human Ethics Review Committee of Kansai Rosai Hospital(Certificate Number: 2001019)., Results: The average operation time was 644.6 and 675.2 minutes, an estimated blood loss was 220.8 and 134.4 g, postoperative pancreatic fistula(ISGPS 2016, [-]/BL/Grade B/C)was 24/18/13/0 and 28/25/21/0, delayed gastric emptying(ISGPS 2007, [-]/Grade A/B/C)was 48/0/4/3 and 61/2/6/5 and postoperative hospital stay was 27.9 and 25.9 and in R/LPD E and R/LPD non-E groups, respectively. No significant differences were noted between the groups, However, postoperative complication over Ⅲa Clavien-Dindo classification was 8(15.7%)and 3(4.4%)cases(p=0.0319)in R/LPD E and R/ LPD non-E groups. The average operation time was 644.6 and 492.1 minutes(p<0.0001), an estimated blood loss was 220.8 and 534.8 g(p=0.0004), postoperative pancreatic fistula(ISGPS 2016, [-]/BL/Grade B/C)was 24/18/13/0 and 27/8/24/1(p=0.0442), postoperative hospital stay was 27.9 and 42.0(p=0.0490)in R/LPD E and OPD E groups, respectively., Conclusion: The R/LPD was undergone in safety, even for the over 75 years old patients.

Tumor mutation burden(TMB)-High is known to potentially elicit a favorable response to immune checkpoint inhibitors. In this report, we present a case of recurrent hilar cholangiocarcinoma with TMB-High, in which we performed comprehensive treatment including immune checkpoint inhibitor pembrolizumab. The patient was a 58-year-old male diagnosed with hilar cholangiocarcinoma who underwent extended right hepatectomy, caudate lobe resection, bile duct excision, and bile duct reconstruction. Postoperatively, peritoneal seeding recurrence and liver metastasis were observed, indicating TMB-High. Therefore, pembrolizumab therapy was administered. The tumor marker CA19-9 significantly decreased, and the peritoneal seeding and liver metastatic lesions disappeared on imaging. In this case, we experienced the use of pembrolizumab monotherapy for TMB-High recurrent bile duct cancer with early postoperative peritoneal seeding recurrence. Further accumulation of cases is needed, but pembrolizumab monotherapy holds promise as a treatment option for TMB-High bile duct cancer at the hepatic hilum.

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: Glomerular lipidosis is a rare histological feature presenting the extensive glomerular accumulation of lipids with or without histiocytic infiltration, which develops under various conditions. Among its various etiologies, macrophage activation syndrome (MAS) is a condition reported to be associated with histiocytic glomerular lipidosis. Here we describe the first case of glomerular lipidosis observed in a renal allograft that histologically mimicked histiocytic glomerulopathy owing to MAS., Case Presentation: A 42-year-old man underwent successful living-donor kidney transplantation. However, middle-grade proteinuria and increased serum triglyceride levels indicative of type V hyperlipidemia developed rapidly thereafter. An allograft biopsy performed 6 months after the transplantation showed extensive glomerular infiltration of CD68 + foam cells (histiocytes) intermingled with many CD3 + T-cells (predominantly CD8 + cells). Furthermore, frequent contact between glomerular T-cells and histiocytes, and the existence of activated CD8 + cells (CD8 + , HLA-DR + cells) were observed by double immunostaining. There was no clinicopathological data suggesting lipoprotein glomerulopathy or lecithin cholesterol acyltransferase deficiency, both of which are well-known causes of glomerular lipidosis. The histological findings were relatively similar to those of histiocytic glomerulopathy caused by MAS. As systemic manifestations of MAS, such as fever, pancytopenia, coagulation abnormalities, hyperferritinemia, increased liver enzyme levels, hepatosplenomegaly, and lymphadenopathy were minimal, this patient was clinicopathologically diagnosed as having renal-limited MAS. Although optimal treatment strategies for MAS in kidney transplant patients remains unclear, we strengthened lipid-lowering therapy using pemafibrate, without modifying the amount of immunosuppressants. Serum triglyceride levels were normalized with this treatment; however, the patient's extensive proteinuria and renal dysfunction did not improve. Biopsy analysis at 1 year after the transplantation demonstrated the disappearance of glomerular foamy changes, but the number of glomerular infiltrating cells remained similar., Conclusion: To our knowledge, this is the first reported case of glomerular lipidosis in a transplanted kidney. Increased interaction-activation of histiocytes (macrophages) and CD8 + T-cells, the key pathogenic feature of MAS, was observed in the glomeruli of this patient, who did not demonstrate overt systemic manifestations, suggesting a pathological condition of renal-limited MAS. The clinical effects of triglyceride-lowering therapy were limited, suggesting that hypertriglyceridemia was not the cause of but rather may be a consequence of renal-limited MAS., (© 2023. The Author(s).)

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.

The Concise Guide to PHARMACOLOGY 2023/24 is the sixth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of approximately 1800 drug targets, and about 6000 interactions with about 3900 ligands. There is an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (https://www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes almost 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/bph.16177. G protein-coupled receptors are one of the six major pharmacological targets into which the Guide is divided, with the others being: ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2023, and supersedes data presented in the 2021/22, 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate., (© 2023 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of The British Pharmacological Society.)

Medical artificial intelligence (AI) offers great potential for recognizing signs of health conditions in retinal images and expediting the diagnosis of eye diseases and systemic disorders 1 . However, the development of AI models requires substantial annotation and models are usually task-specific with limited generalizability to different clinical applications 2 . Here, we present RETFound, a foundation model for retinal images that learns generalizable representations from unlabelled retinal images and provides a basis for label-efficient model adaptation in several applications. Specifically, RETFound is trained on 1.6 million unlabelled retinal images by means of self-supervised learning and then adapted to disease detection tasks with explicit labels. We show that adapted RETFound consistently outperforms several comparison models in the diagnosis and prognosis of sight-threatening eye diseases, as well as incident prediction of complex systemic disorders such as heart failure and myocardial infarction with fewer labelled data. RETFound provides a generalizable solution to improve model performance and alleviate the annotation workload of experts to enable broad clinical AI applications from retinal imaging., (© 2023. The Author(s).)

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.

Multiple sclerosis (MS) is a neurological, immune-mediated demyelinating disease that affects people in the prime of life. Environmental, infectious, and genetic factors have been implicated in its etiology, although a definitive cause has yet to be determined. Nevertheless, multiple disease-modifying therapies (DMTs: including interferons, glatiramer acetate, fumarates, cladribine, teriflunomide, fingolimod, siponimod, ozanimod, ponesimod, and monoclonal antibodies targeting ITGA4, CD20, and CD52) have been developed and approved for the treatment of MS. All the DMTs approved to date target immunomodulation as their mechanism of action (MOA); however, the direct effects of some DMTs on the central nervous system (CNS), particularly sphingosine 1-phosphate (S1P) receptor (S1PR) modulators, implicate a parallel MOA that may also reduce neurodegenerative sequelae. This review summarizes the currently approved DMTs for the treatment of MS and provides details and recent advances in the molecular pharmacology, immunopharmacology, and neuropharmacology of S1PR modulators, with a special focus on the CNS-oriented, astrocyte-centric MOA of fingolimod., Competing Interests: Declaration of Competing Interest Y.K. declares no competing financial interests. JC has received grant support from Janssen, Novartis, and Bristol Meyers Squibb., (Copyright © 2023. Published by Elsevier Inc.)

Background: Nocturnal hypertension assessed by a home blood pressure monitoring (HBPM) device is associated with an increased risk of cardiovascular events. However, it is still difficult to assess nighttime blood pressure (BP) frequently. The purpose of this cross-sectional study was to identify significant correlates of nocturnal hypertension assessed by an HBPM device in patients with hypertension who are treated with antihypertensive drugs., Methods: We measured nighttime BP, morning BP, and evening BP by an HBPM device for 7 consecutive days in 365 medicated patients with hypertension., Results: Of the 365 subjects, 138 (37.8%) had nocturnal hypertension defined as a mean nighttime systolic BP of ≥ 120 mm Hg. Receiver operating characteristic curve analyses showed that the diagnostic accuracy of morning systolic BP for subjects with nocturnal hypertension was significantly superior to that of evening systolic BP (P = 0.04) and that of office systolic BP (P < 0.001). Multivariate analysis revealed that morning systolic BP of 125-<135 mm Hg (odds ratio [OR], 2.26; 95% confidence interval [CI], 1.13-4.58; P = 0.02), morning systolic BP of ≥ 135 mm Hg (OR, 16.4; 95% CI, 8.20-32.7; P < 0.001), and a history of cerebrovascular disease (OR, 3.99; 95% CI, 1.75-9.13; P = 0.001) were significantly associated with a higher risk of nocturnal hypertension and that bedtime dosing of antihypertensive drugs was significantly associated with a lower risk of nocturnal hypertension (OR, 0.56; 95% CI, 0.32-0.97; P = 0.04)., Conclusions: Morning systolic BP of ≥ 125 mm Hg, a history of cerebrovascular disease, and bedtime dosing were significant correlates of nocturnal hypertension in medicated patients with hypertension, and may help detect this risky BP condition., Clinical Trials Registration: University Hospital Medical Information Network Clinical Trials Registry (UMIN000019173)., (© The Author(s) 2023. Published by Oxford University Press on behalf of American Journal of Hypertension, Ltd. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Soluble epoxide hydrolase (EC 3.3.2.10) is a key enzyme in the regulation of inflammation and metabolism, whereas, the role of its N-terminal phosphatase activity (N-phos) has been poorly understood because of a lack of selective inhibitors. Here we report 4-aminobenzoic (Ki 15.3 µm) and 3-amino-4-hydroxy benzoic acid (Ki 11.7 µm) as selective competitive inhibitors of N-phos., (© The Author(s) 2023. Published by Oxford University Press on behalf of Japan Society for Bioscience, Biotechnology, and Agrochemistry.)

Competing Interests: None.

Background: Cholecystitis can represent a comorbidity during gallbladder cancer surgery; nonetheless, the prognostic impact of acute cholecystitis comorbidity remains unclear. This study aimed to evaluate the impact of acute cholecystitis comorbidity on prognosis after gallbladder cancer surgery, with adjustment for background factors using propensity score analysis., Methods: A total of 218 patients who underwent gallbladder cancer surgery at our institute between 1986 and 2022 were retrospectively included in the analysis. Patients were divided into two groups according to the presence or absence of acute cholecystitis at the time of surgery. Background factors were adjusted by including intraoperative bile leakage as a covariate in propensity score calculation. Overall survival and recurrence-free survival were compared between the two groups using one-to-one propensity score matching and inverse probability weighting., Results: Of the 218 patients, 37 had coexisting acute cholecystitis. In one-to-one propensity score matching, the overall survival time in the acute cholecystitis group tended to be shorter than that in the non-acute cholecystitis group, although not significantly (hazard ratio, 2.41; 95% confidence interval, 0.96-6.06). Other analyses using inverse probability weighting showed significantly poor overall survival in the acute cholecystitis group. Regarding recurrence-free survival in propensity score matching, the acute cholecystitis group showed a significantly shorter duration than the non-acute cholecystitis group (hazard ratio, 6.69; 95% confidence interval, 1.46-30.6). The inverse probability weighting-adjusted analysis also indicated a significantly higher risk of recurrence in the acute cholecystitis group., Conclusions: Acute cholecystitis comorbidity at the time of gallbladder cancer surgery may have a negative impact on gallbladder cancer prognosis., (© 2023. The Author(s).)

Objectives: The emergence of the Alpha variant of novel coronavirus 2019 (SARS-CoV-2) is a concerning issue but their clinical implications have not been investigated fully., Methods: We conducted a nested case-control study to compare severity and mortality caused by the Alpha variant (B.1.1.7) with the one caused by the wild type as a control from December 2020 to March 2021, using whole-genome sequencing. 28-day mortality and other clinically important outcomes were evaluated., Results: Infections caused by the Alpha variant were associated with an increase in the use of oxygen (43.4% vs 26.3%. p = 0.017), high flow nasal cannula (21.2% vs 4.0%, p = 0.0007), mechanical ventilation (16.2% vs 6.1%, p = 0.049), ICU care (30.3% vs 14.1%, p = 0.01) and the length of hospital stay (17 vs 10 days, p = 0.031). More patients with the Alpha variant received medications such as dexamethasone. However, the duration of each modality did not differ between the 2 groups. Likewise, there was no difference in 28-day mortality between the 2 groups (12% vs 8%, p = 0.48), even after multiple sensitivity analyses, including propensity score analysis., Conclusion: The Alpha variant was associated with a severe form of COVID-19, compared with the non-Alpha wild type, but might not be associated with higher mortality., Competing Interests: Declaration of competing interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be considered a potential conflict of interest., (Copyright © 2022 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Background: Early recovery from shock improves prognosis in septic shock patients. We determined whether cytokine modulation by Continuous Renal Replacement Therapy (CRRT) following acute care surgery resulted in stable hemodynamics in them. To investigate our hypothesis, we measured proinflammatory cytokines IL-6, IL-1ra and the coagulation cascade activator plasminogen activator inhibitor-1 (PAI-1) following CRRT with polymyxin B immobilized fiber (PMX-DHP) which has been utilized as an adjuvant treatment option for patients with severe septic shock., Methods: 66 septic shock patients requiring 2 h direct hemoperfusion therapy PMX-DHP were included. 36 patients of them also received continuous hemodiafiltration (CHDF) after performing PMX-DHP. Circulatory dynamics and levels of inflammatory mediators, namely IL-6, IL-1ra, and PAI-1 were assessed before, immediately after, and 24 h initiation of PMX-DHP., Results: Mean Arterial Pressure (MAP) rose intentionally by PMX-DHP just after enforcement 24 h later ( p  < 0.01). Levels of IL-6, IL-1ra, and PAI-1 significantly decreased after PMX-DHP ( p  < 0.05) and this trend was observed up to 24 h post initiation of PMX-DHP ( p  < 0.05). IL-6 modulation by PMX-DHP was enhanced with using CHDF and there was a significant correlation between IL-6 and MAP ( p  < 0.0001). In addition, levels of Il-6 and PAI-1 showed a significant correlation., Conclusion: Our data showed employing CRRT as cytokine modulators could be an additional therapeutic strategy to improve septic shock outcomes via the crucial role of IL-6 signaling in endothelial dysfunction., 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 Ueno, Ikeda, Okihara, Akashi, Yokoyama, Kihara, Konno, Nakamura, Iwamoto, Ueno and Chandraker.)

Mutant calreticulin (CALR) proteins resulting from a -1/+2 frameshifting mutation of the CALR exon 9 carry a novel C-terminal amino acid sequence and drive the development of myeloproliferative neoplasms (MPNs). Mutant CALRs were shown to interact with and activate the thrombopoietin receptor (TpoR/MPL) in the same cell. We report that mutant CALR proteins are secreted and can be found in patient plasma at levels up to 160 ng/mL, with a mean of 25.64 ng/mL. Plasma mutant CALR is found in complex with soluble transferrin receptor 1 (sTFR1) that acts as a carrier protein and increases mutant CALR half-life. Recombinant mutant CALR proteins bound and activated the TpoR in cell lines and primary megakaryocytic progenitors from patients with mutated CALR in which they drive thrombopoietin-independent colony formation. Importantly, the CALR-sTFR1 complex remains functional for TpoR activation. By bioluminescence resonance energy transfer assay, we show that mutant CALR proteins produced in 1 cell can specifically interact in trans with the TpoR on a target cell. In comparison with cells that only carry TpoR, cells that carry both TpoR and mutant CALR are hypersensitive to exogenous mutant CALR proteins and respond to levels of mutant CALR proteins similar to those in patient plasma. This is consistent with CALR-mutated cells that expose TpoR carrying immature N-linked sugars at the cell surface. Thus, secreted mutant CALR proteins will act more specifically on the MPN clone. In conclusion, a chaperone, CALR, can turn into a rogue cytokine through somatic mutation of its encoding gene., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background: Since a randomized phase Ⅲ trial conducted in the UK in 2009 showed the superiority of gemcitabine (GEM)plus cisplatin(CDDP)combination therapy over GEM monotherapy, GEM plus CDDP combination therapy has been first-line chemotherapy for unresectable biliary tract cancer., Methods: GEM plus CDDP combination therapy was administered to 29 patients with unresectable biliary tract cancer from 2016 to 2021., Results: The mean age was 71.9 years, male/ female 19/10. The target of chemotherapy was below, local progression was 3 cases, first distant metastasis 7 cases, metastatic recurrence 19 cases. The type of cancer was below, intrahepatic bile duct carcinoma was 8 cases, hepatic hilar bile duct carcinoma 6 cases, gallbladder carcinoma 5 cases, cystic duct carcinoma 1 case, distal bile duct carcinoma 6 cases, and papilla Vater's cancer 3 cases. The dosing period was 23.1 weeks(range 2-52 weeks). The relative dose intensities of GEM and CDDP were 73.7% and 75.1%. The adverse events were below, the hematological toxicities of Grade 3 or higher were neutropenia(65.5%), leukopenia(3.4%), and thrombocytopenia(10.3%). Non-hematological toxicities of Grade 2 or higher were fatigue(13.7%)and skin rash(6.9%). There was no interstitial pneumonia. The disease control rate was 66.7 %(complete response, n=0; partial response, n=6; stable disease, n=10; progressive disease, n=8)., Conclusion: GEM plus CDDP combination therapy was safe to perform and was an effective treatment for unresectable biliary tract cancer.

Introduction: There are few reports of surgery which preserve the function of pancreas for benign or low malignant tumors. While we have introduced laparoscopic pancreaticoduodenectomy (LPD), we have also performed laparoscopic pancreas-sparing duodenectomy (LPSD). In the present study, we investigated surgical techniques and results of LPSD., Materials and Methods: Between October 2019 and January 2022, 3 patients were underwent LPSD. The procedure was performed after obtaining approval from the Ethics Review Committee of our hospital., Results: Three patients conducted LPSD were all males with a median age of 74 years, and diagnoses were adenomas of duodenum in 2 cases and gastrointestinal stromal tumor of duodenum in 1 case. The median blood loss was small amount. The median operative time was 430 minutes, and the median postoperative hospital stay was 13 days. One of the cases was performed with conversion to HALS. In LPSD, an intraoperative ultrasonography and an intraoperative radiographic contrast study were performed to confirm that the ampulla of Vater was preserved. There were no postoperative complications., Conclusion: We experienced cases performed LPSD in our hospital. We need further research for feasibility and safety of the procedure.

We report a case of postoperative multiple recurrence of hepatocellular carcinoma(HCC)treated with atezolizumab plus bevacizumab. A 73-year-old man with a chief complaint of abdominal distention was indicated a 90-mm-sized tumor extending from the lateral hepatic segment to the extrahepatic region by a contrast-enhanced CT scan of the abdomen. He underwent a laparoscopic liver resection of the lateral segment for suspected HCC, and was diagnosed as pStage Ⅱ HCC. Six months after surgery, multiple recurrent at intrahepatic lesions and suspected lymph node recurrence or peritoneal dissemination were observed, and tumor markers were markedly elevated. The patient was diagnosed with multiple intrahepatic and extrahepatic recurrences of postoperative HCC and started combination chemotherapy with atezolizumab (1,200 mg/body)plus bevacizumab(15 mg/kg). After the initiation of the therapy, tumor size reduction and normalization of tumor markers were observed, and at 17 months postoperatively, tumor size reduction has been maintained and tumor markers were in the normal range. We report a case of postoperative intrahepatic and extrahepatic multiple recurrences of he patocellular carcinoma treated with atezolizumab plus bevacizumab.

Long QT syndrome (LQTS) is one of the most common inherited arrhythmias and multiple genes have been reported as causative. Presently, genetic diagnosis for LQTS patients is becoming widespread and contributing to implementation of therapies. However, causative genetic mutations cannot be detected in about 20% of patients. To elucidate additional genetic mutations in LQTS, we performed deep-sequencing of previously reported 15 causative and 85 candidate genes for this disorder in 556 Japanese LQTS patients. We performed in-silico filtering of the sequencing data and found 48 novel variants in 33 genes of 53 cases. These variants were predicted to be damaging to coding proteins or to alter the binding affinity of several transcription factors. Notably, we found that most of the LQTS-related variants in the RYR2 gene were in the large cytoplasmic domain of the N-terminus side. They might be useful for screening of LQTS patients who had no known genetic factors. In addition, when the mechanisms of these variants in the development of LQTS are revealed, it will be useful for early diagnosis, risk stratification, and selection of treatment., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2022 Nagata et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

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.

Background: Falls and fear of falling (FoF) inhibit healthy longevity and have been suggested to be associated with cognitive function. However, the domains of cognitive function that are associated with them remain controversial. It is speculated that clarifying this will help in the assessment of health status and interventions in the community., Aim: To analyse the associations between fall history and FoF and multidimensional cognitive function in independent community-dwelling older adults., Methods: The data from 9759 (73.3 ± 5.4 years, 59.9% women) older individuals enrolled in the cross-sectional ORANGE study were analysed. Simple questions were used to assess fall history in the past year and current FoF. Assessments of multidimensional cognitive function were performed using the National Center for Geriatrics and Gerontology-Functional Assessment Tool (NCGG-FAT) to evaluate memory, attention, executive function, and processing speed. The independent associations of fall history and FoF with multidimensional cognitive function were assessed using multivariate linear regressions adjusted for potential confounding variables., Results: A total of 18.3% and 35.4% of participants presented with fall history and FoF, respectively. Fall history (p = 0.008) and FoF (p = 0.002) were significantly associated with memory. FoF, but not fall history was associated with attention (p = 0.004), executive function (p < 0.01), and processing speed (p < 0.01)., Conclusion: In independent community-dwelling older adults, fall history was associated only with the memory domain; in contrast, fear of falling was associated with multidimensional cognitive function. This study provides weak evidence suggesting the need to assess falls and FoF in all situations involving independent community-dwelling older adults., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Introduction: Laparoscopic pancreaticoduodenectomy(LPD)has been covered by insurance since 2016 in Japan. Advance LPD and robotic pancreaticoduodenectomy(RPD)has been also covered by insurance since 2020 in Japan. We report our technique and the short-term outcome of RPD performed in our institution., Surgical Procedures: As a first step, the resection phase was performed laparoscopically. Pancreato-jejunostomy and choledocho-jejunostomy were performed robotically (hybrid-RPD). As a second step, Kocher maneuver and jejunal transection were performed laparoscopically. Other procedures were performed robotically(modified-RPD). As a final step, all procedures were performed robotically(pure-RPD)., Surgical Techniques: RPD is performed in reverse Trendelenburg supine position. An extended Kocher maneuver is performed. The common bile duct is then identified and transected after proximal aspect is secured with a surgical bulldog clamp. IPDA is divided by using an energy device after clip placement. The pancreatic neck is then divided with the use of scissors. Pancreato-jejunostomy was performed by modified Blumgart and pancreatic duct to jejunal mucosa method. Choledocho- jejunostomy was performed with continuous and interrupted suturing., Patients and Method: Between 2020 and 2022, 45 patients underwent RPD at our institution. Cases were divided into hybrid-RPD(n=20), modified-RPD(n=9) and pure-RPD(n=16)., Results: No significant differences were noted between hybrid-RPD, modified-RPD and pure-RPD groups with respect to patient age(73.6, 68.7, 70.6 years old), gender(male/female 15/5, 6/3, 8/8), respectively. The operation time was longer(667, 770, 746 minutes)and the resection time was longer(286, 399, 380 minutes)in modified- RPD and pure-RPD than hybrid-RPD group. In the pure-RPD group, the resection time was decreasing(y=-12.0×+ 481.5)as a learning curve. No significant differences were noted between hybrid-RPD, modified-RPD and pure-RPD groups with respect to reconstruction time(388, 371, 367 minutes)and the estimated blood(261, 199, 293 mL), respectively. All postoperative pancreatic fistula was under Grade B., Conclusion: Although further studies are still needed to confirm the benefit of RPD, RPD is safe, minimally invasive, and effective approach to the management of pancreatic tumor.

Introduction: Laparoscopic liver resection(LLR)has been reported as a safe, minimally invasive, and effective approach to the management of liver tumor. The aim of this study was to analyze the perioperative results and outcomes of LLR for the elderly hepatocellular carcinoma(HCC)patients and to compare to the non-elderly HCC patients., Patients and Method: Between May 2010 and November 2021, 725 patients(HCC 407, CRC Mets 171, others 147)patients underwent LLR at Kansai Rosai Hospital. 407 patients who underwent LLR for HCC were divided into 2 groups those who were over 80 years old(n=67)and under 79 years old(n=340). The patient age was 82.7 and 68.8 years, while the male to female ratio was 41/26 and 238/102 in the elderly and non-elderly groups, respectively. According to the liver cancer study group of Japan, the pathological Stage 0/Ⅰ/Ⅱ/Ⅲ/Ⅳ was 23/34/8/2 and 117/146/57/20 patients(p=0.1086)in the elderly and non- elderly groups, respectively. This study was approved by the Human Ethics Review Committee of Kansai Rosai Hospital(Certificate Number: 2101006)., Results: The elderly group had an average operation time of 316.1 minutes, an estimated blood loss of 277.3 g, and a hospital stay of 14.3 days. The non-elderly group had an average operation time of 347.2 minutes, an estimated blood loss of 233.7 g, and a hospital stay of 12.9 days. No significant differences were noted between the elderly patients and the non-elderly patients with respect to the rate of procedure, operation time, intraoperative blood loss, hospital stay, morbidity, and postoperative laboratory data., Conclusion: The LLR was undergone in safety, even for the over 80 years old patients. The results of LLR for HCC over 80 years old were comparable both in short-term results with under 79 years old group. It was considered that the minimally invasiveness of LLR allows comparable surgical treatment for the elderly with non-eldery.

The enzymatic luminescence reactions of fireflies are accelerated in the presence of biomolecular condensates comprising a positively charged peptide and ATP. We revealed that this acceleration is caused by the enrichment of reaction elements, local pH changes, and promotion of inhibitory intermediate dissociation, improving the bioluminescence quantum yield by approximately 10%.

The laparoscopic surgery is less invasive and better cosmetic. The laparoscopic liver resection(LLR)has been accepted for the insurance in April 2010, and increasingly performed in many hospitals, and also expected in metastasis of colorectal cancer. We retrospectively examined the results of LLR for liver metastasis of colorectal cancer. From June 2010 to July 2021, 174 cases of LLR for liver metastasis of colorectal cancer were performed in our hospital. The operation time was 384.5 minutes, the blood loss was small amount, and the postoperative hospital stay was 8 days. The complications were post-bleeding in 1 case, bile leakage in 7 cases, SSI in 16 cases, and no surgery-related deaths were observed. The 3-year disease-free survival rate was 22.8%, and the 5-year overall survival rate was 53.3%. In the comparison between single LLR and multiple LLR, the operation time and the blood loss increased, but there was no significant difference in the length of postoperative hospital stay. In initial LLR and repeat LLR, there were no significant differences in the operation time, blood loss, and postoperative hospital stay. In the primary lesion and simultaneous LLR and heterochronous LLR, the operation time and blood loss were not significantly different, but postoperative intra-abdominal abscess and SSI were more happened, and the postoperative hospital stay was significantly extended. LLR for liver metastasis of colorectal cancer can be safely performed at multiple sites or multiple times, and good treatment results have been obtained, so it was considered to be an effective treatment method.

Background: Atrial fibrillation (AF) and recurrence of AF after pulmonary vein isolation (PVI) have been linked to sinus node dysfunction., Objective: The purpose of this study was to investigate the association between the heart rate-associated single nucleotide polymorphisms (SNPs) identified in genome-wide association studies and recurrence of AF after PVI., Methods: In this study, patients with paroxysmal AF who underwent initial PVI, including 522 patients for screening and 172 patients for replication, were recruited and 21 heart rate-associated SNPs identified in genome-wide association studies were genotyped. The association between these SNPs and the recurrence of AF was investigated., Results: Throughout the follow-up period of 21 ± 12 months, 119 patients with paroxysmal AF (22.8%) exhibited AF recurrences in the screening set. The rate of AF recurrence was significantly associated with the minor allele C of the gap junction alpha-1 protein (GJA1) rs1015451 (additive model: odds ratio 2.07; P = 9.32 × 10 -7 ), but not with other SNPs. This association was confirmed in the replication set (allelic model: odds ratio 1.81; P = 2.70 × 10 -2 ). Multivariate analysis revealed that the recurrence of AF after AF ablation was independently related to the GJA1 SNP rs1015451 additive model, duration of AF >1 year, AF from non-pulmonary vein foci, and thicker interventricular septum., Conclusion: The GJA1 SNP rs1015451, coding for a gap junction protein (connexin-43), may be considered a novel genetic marker for AF recurrence after PVI., (Copyright © 2022. Published by Elsevier Inc.)

Kidney biopsy is commonly used to diagnose kidney transplant dysfunction after transplantation. Therefore, the development of minimally invasive and quantitative methods to evaluate kidney function in transplant recipients is necessary. Here, we used capillary electrophoresis-mass spectrometry to analyze the biofluids collected from transplant recipients with impaired (Group I, n = 31) and stable (Group S, n = 19) kidney function and from donors (Group D, n = 9). Metabolomics analyses identified and quantified 97 metabolites in plasma, 133 metabolites in urine, and 108 metabolites in saliva. Multivariate analyses revealed apparent differences in the metabolomic profiles of the three groups. In plasma samples, arginine biosynthesis and purine metabolism between the I and S Groups differed. In addition, considerable differences in metabolomic profiles were observed between samples collected from participants with T cell-mediated rejection (TCR), antibody-mediated rejection, and other kidney disorders (KD). The metabolomic profiles in the three types of biofluids showed different patterns between TCR and KD, wherein 3-indoxyl sulfate showed a significant increase in TCR consistently in both plasma and urine samples. These results suggest that each biofluid has different metabolite features to evaluate kidney function after transplantation and that 3-indoxyl sulfate could predict acute rejection., Competing Interests: The authors declare no conflicts of interest.

Introduction: Duchenne muscular dystrophy (DMD) is a progressive disease that leads to damage of muscle and myocardium due to genetic abnormalities in the dystrophin gene. In utero cell transplantation that might facilitate allogenic transplantation is worth considering to treat this disease., Methods: We performed allogeneic in utero transplantation of GFP-positive myoblasts and adipose-derived mesenchymal stem cells into murine DMD model animals. The transplantation route in this study was fetal intraperitoneal transplantation and transplacental transplantation. Transplanted animals were examined at 4-weeks old by immunofluorescence staining and RT-qPCR., Results: No GFP-positive cells were found by immunofluorescence staining of skeletal muscle and no GFP mRNA was detected by RT-qPCR in any animal, transplantation method and cell type. Compared with previous reports, myoblast transplantation exhibited an equivalent mortality rate, but adipose-derived stem cell (ASC) transplantation produced a higher mortality rate., Conclusions: In utero transplantation of myoblasts or ASCs to murine models of DMD does not lead to engraftment and, in ASC transplantation primarily, frequently results in fetal death., Competing Interests: The authors declare no conflicts of interest associated with this manuscript., (© 2022 The Japanese Society for Regenerative Medicine. Production and hosting by Elsevier B.V.)

Objective: The number of older patients with heart failure (HF) is increasing in Japan and has become a social problem. There is an urgent need to develop a comprehensive assessment methodology based on the common language of healthcare; the International Classification of Functioning, Disability and Health (ICF). The purpose of this study was to develop and confirm the appropriateness of a scoring methodology for 43 ICF categories in older people with HF., Design: Cross-sectional survey. We applied the RAND/University of California at Los Angeles (UCLA) Appropriateness Method with a modified Delphi method., Setting and Participants: We included a panel of 26 multidisciplinary experts on HF care consisting of home physicians, cardiovascular physicians, care managers, nurses, physical therapists, a pharmacist, occupational therapist, nutritionist and a social worker., Measures: We conducted a literature review of ICF linking rules and developed a questionnaire on scoring methods linked to ICF categories in older people with HF. In the Delphi rounds, we sent the expert panel a questionnaire consisting of three questions for each of the 43 ICF categories. The expert panel responded to the questionnaire items on a 1 (very inappropriate) - 9 (very appropriate) Likert scale and repeated rounds until a consensus of 'Appropriate' and 'Agreement' was reached on all items., Results: A total of 21 panel members responded to all the Delphi rounds. In the first Delphi round, six question items in four ICF categories did not reach a consensus of 'Agreement', but the result of our modifications based on panel members' suggestions reached to a consensus of 'Appropriate' and 'Agreement' on all questions in the second Delphi round., Conclusion: The ICF-based scoring method for older people with HF developed in this study was found to be appropriate. Future work is needed to clarify whether comprehensive assessment and information sharing based on ICF contributes to preventing readmissions., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The employment rate of older people in Japan is expected to increase in the future owing to the increase in the retirement age. Preventing frailty is imperative to maintaining productive roles of older adults. Therefore, this study aimed to examine the association between productive roles and frailty factors among community-dwelling older adults. A total of 135 older adults, enrolled in 2017, participated in the study. Productive roles and domains related to frailty were measured. We measured usual gait speed and grip strength for the physical domain; Mini-Mental State Examination (MMSE) and Geriatric Depression Scale (GDS-15) scores for the cognitive and mental domains; and social role and group activity for the social domain. Multivariate-adjusted logistic regression models revealed that having productive roles was associated with faster usual gait speed (odds ratios [OR] = 1.05; 95% confidence interval [CI], 1.01-1.08; p = 0.005) and lower GDS-15 score (OR = 0.79; 95% CI, 0.64-0.97; p = 0.023). These results suggest that health promotion to maintain gait speed and prevent depressive symptoms may contribute to maintaining productivity in community-dwelling older adults.