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Background: Pro re nata (PRN) medication is used "as needed" for symptoms such as agitation and insomnia, in addition to regular daily pharmacotherapy of mental disorders. However, there is no high-quality evidence on the effectiveness of psychotropic PRN medications and concerns have been raised about their potential to contribute to polypharmacy. This study introduced a psychotropic PRN prescription-monitoring programme for psychiatric inpatients with the aim of examining the change before and after the implementation of the programme., Method: This study included 389 patients admitted to the psychiatric department between 1 July 2021 and 30 June 2023. The psychotropic PRN prescription-monitoring programme was implemented in July 2022, and the participants were classified into monitoring and non-monitoring groups. Demographic data (age, sex, and diagnosis), regular prescriptions before admission and at discharge, psychotropic PRN prescriptions before admission and at discharge, and the total number of psychotropic PRN prescriptions during hospitalisation were compared between the two groups. Data on psychotropic prescription were collected by psychotropic category. The significance level of 5% was set at 1.67 × 10 -3 using the Bonferroni correction for multiple testing., Results: The psychotropic PRN prescription ratio at discharge in the monitoring group was 9.3%, which was significantly lower than the 28.1% in the non-monitoring group. The percentage of patients with a PRN prescription during hospitalisation in the monitoring group was 29.8%, which was significantly lower than the 64.5% in the non-monitoring group. In the non-monitoring group, there was no statistically significant difference in the number of psychotropic drugs prescribed regularly before and after admission. However, in the monitoring group, the number of psychotropic drugs in the regular prescriptions at discharge was 1.87 ± 1.24, which was significantly lower than 2.47 ± 1.90 in the regular prescription before admission., Conclusions: Our findings suggest that a psychotropic PRN prescription-monitoring programme may contribute to the elimination of polypharmacy, including regular prescriptions. Further research is required to optimise psychotropic PRN prescriptions and reduce polypharmacy., Competing Interests: Declarations. Ethics approval and consent to participate: This study was approved by the Ethics Committee of Kitasato University Hospital (approval no. B23-074, date of approval: 27 September 2023) and conducted in accordance with the Declaration of Helsinki. As this was a retrospective observational study using existing medical information, the need for signed informed consent from the patients was waived by the Kitasato University Hospital Ethics Committee. Patients were informed about the purpose and procedures of the study and were given the option to opt-out. Consent for publication: Not applicable. Competing interest: Hiroyuki Muraoka received honoraria from Eisai, Merck, Otsuka, Meiji Seika, Yoshitomi Pharmaceuticals, Sumitomo Pharma, Viatris, Janssen, Takeda Pharmaceuticals, Lundbeck, Japan, and KYOWA Pharmaceutical Industry. Satoru Oishi has received honoraria from Otsuka, Meiji Seika Pharma, Astellas Pharma, Towa Pharmaceuticals, Yoshitomi Pharmaceutical Industries, Sumitomo Pharma, and Viatris. Taiyo Nishikawa has received an honorarium from Sumitomo Pharma. Ken Inada received personal fees from Daiichi Sankyo, Eisai, Eli Lilly, Janssen, Lundbeck Japan, Meiji Seika Pharma, Mitsubishi Tanabe Pharma, Mochida, MSD, Nipro, Novartis, Otsuka, Pfizer, Shionogi, Sumitomo Pharma, Yoshitomiyakuhin, and Viatris, and he received research grant support from Mochida and Sumitomo Pharma. Other authors declare no conflicts of interest., (© 2025. The Author(s).)

Background: Upward-directed exit-site has been believed to be the worst for frequent ESI by an old retrospective study using straight catheters. No comparison study of 3 exit-site directions using swan-neck catheter has been performed regarding which direction is the best for our endpoints, Easy-to-see the backside area of exit-site: ESBE, Easy-to-disinfect the backside area of exit-site: EDBE, reduction of both exit-site infection (ESI), symptomatic catheter dislocation and peritonitis., Methods: We assessed the relationship of exit-site direction with our endpoints in a quantitative cross-sectional, multicentered questionnaire survey. Patients who received either non-surgical catheter implantation or exit-site surgery were excluded., Results: The numbers (percentage) of exit-site directions in included 291 patients were upward 79 (26.0), lateralward 108 (37.5) and downward 105 (36.5). Cochran-Armitage analysis showed a significant step-ladder increase in the prevalence of ESI as the direction changed from upward to lateralward to downward (0.15 ± 0.41, 0.25 ± 0.54, 0.38 ± 0.69 episodes/patient-year, p = 0.03). Multivariable regression analysis revealed the upward exit-site independently associates with both higher frequency of ESBE (OR 5.55, 95% CI 2.23-16.45, p < 0.01) and reduction of prevalence of ESI (OR 0.55, 95%CI 0.27-0.98, p = 0.04). Positive association between the prevalence of symptomatic catheter dislocation and ESI (OR 2.84, 95% CI 1.27-7.82, p = 0.01), and inverse association between EDBE and either prevalence of symptomatic catheter dislocation (OR 0.27, 95% CI 0.11-0.72) or peritonitis (OR 0.48, 95% CI 0.23-0.99) observed., Conclusion: Upward-directed swan-neck catheter exit-site may be the best for both ESBE and prevention of ESI. EDBE may reduce catheter dislocation and peritonitis. Symptomatic catheter dislocation may predict ESI., (© 2024. The Author(s).)

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignancies, and the prognosis for its recurrence after surgery is very poor. Here, we report a case of metachronous oligo-hepatic and peritoneal metastases in a patient who survived without recurrence for 3 years after conversion surgery combined with perioperative sequential chemotherapy using gemcitabine plus nab-paclitaxel (GnP) and modified FOLFIRINOX (mFOLFIRINOX). The patient was a 70-year-old man with pancreatic ductal carcinoma, classified as cT3N0M0, cStage IIA, who underwent a distal pancreatosplenectomy. At 1 year and 4 months later, two liver metastases and one peritoneal metastasis were detected. A systemic 9-month course of chemotherapy was administered with GnP and mFOLFIRINOX as the first- and second-line chemotherapeutic agents, respectively. The two liver metastases were judged as showing a partial response, but one dissemination was considered stable disease. After receiving informed consent from the patient, we performed resection of the disseminated tumor and lateral segmentectomy of the liver. Adjuvant chemotherapy using mFOLFIRINOX and GnP was administered for 10 months. The patient has now been alive for 5 years and 6 months after the initial pancreatosplenectomy, and 3 years and 3 months after the conversion surgery, without subsequent tumor recurrence. Thus, a multidisciplinary treatment approach including surgery and perioperative sequential chemotherapy using GnP and mFOLFIRINOX may be beneficial for treating metachronous oligo-hepatic and peritoneal metastases, depending on the patient's condition., (© 2024. Japanese Society of Gastroenterology.)

Chromosomal region 9p21 containing tumor suppressors CDKN2A/B and methylthioadenosine phosphorylase (MTAP) is one of the most frequent genetic deletions in cancer. 9p21 loss is correlated with reduced tumor-infiltrating lymphocytes (TILs) and resistance to immune checkpoint inhibitor (ICI) therapy. Previously thought to be caused by CDKN2A/B loss, we now show that it is loss of MTAP that leads to poor outcomes on ICI therapy and reduced TIL density. MTAP loss causes accumulation of methylthioadenosine (MTA) both intracellularly and extracellularly and profoundly impairs T cell function via the inhibition of protein arginine methyltransferase 5 (PRMT5) and by adenosine receptor agonism. Administration of MTA-depleting enzymes reverses this immunosuppressive effect, increasing TILs and drastically impairing tumor growth and importantly, synergizes well with ICI therapy. As several studies have shown ICI resistance in 9p21/MTAP null/low patients, we propose that MTA degrading therapeutics may have substantial therapeutic benefit in these patients by enhancing ICI effectiveness., Competing Interests: Declaration of interests Drs. Stone and Gjuka are inventors of intellectual property related to this work. Dr. Georgiou serves as scientific advisory board member for Asher Bio and Amgen. Dr. Gao is an advisory committee member for CRISPR Therapeutics, Jounce Therapeutics, Polaris and Seagen, and a consultant for AstraZeneca, Aveo Pharmaceuticals, Infinity Pharmaceuticals, Janssen, Pfizer, and Symphogen. D. Gjuka and E. Stone are inventors of intellectual property related to this work owned by The University of Texas at Austin., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Cytomegalovirus viremia and infection have been reported to increase the risks for acute graft rejection and mortality in kidney transplant recipients. Previous studies demonstrated that a lower absolute lymphocyte count in peripheral blood is associated with cytomegalovirus infection. The aim of this study was to investigate whether absolute lymphocyte count could predict cytomegalovirus infection in kidney transplant recipients., Methods: From January 2010 to October 2021, 48 living kidney transplant recipients in whom both donor and recipient were positive for immunoglobulin G of cytomegalovirus were included in this retrospective study. The primary outcome was defined as cytomegalovirus infection occurring ≥28 days after kidney transplantation. All recipients were followed for 1 year after kidney transplantation. The diagnostic accuracy of absolute lymphocyte count on day 28 post-transplantation for cytomegalovirus infection was analyzed using receiver operating characteristic curves. A Cox proportional hazards model was used to calculate hazard ratios for the incidence of cytomegalovirus infection., Results: There were 13 patients (27%) with cytomegalovirus infection. The sensitivity and specificity for cytomegalovirus infection were 62% and 71%, respectively; the negative predictive value was 83% when an absolute lymphocyte count of 1100 cells/μL on day 28 post-transplantation was used as the cutoff. The incidence of cytomegalovirus infection was significantly higher when the absolute lymphocyte count was <1100 cells/μL on day 28 post-transplantation (hazard ratio, 3.32; 95% CI, 1.08-10.2)., Conclusion: Absolute lymphocyte count is an inexpensive and easy test that can effectively predict cytomegalovirus infection. Further validation is needed to confirm its utility., 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 © 2023 Elsevier Inc. All rights reserved.)

The humoral response of kidney transplant recipients (KTR) to the mRNA vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is generally poor. We evaluated the booster effect of the third dose (D3) of two SARS-CoV-2 mRNA vaccines 6 months after the second dose (D2) in Japanese KTR. The anti-spike (anti-S) antibody titer 1 and 3 months after the D3 was evaluated in 82 Japanese KTR. The primary endpoint was the seropositivity rate, and factors associated with the lack of a response were evaluated in a logistic regression model. Overall, the anti-S antibody seropositivity rate 1 and 3 months after the D3 was 74.7% and 76.0%. The anti-S antibody titers after the first and second doses were higher in patients vaccinated with the mRNA-1273 than with the BNT162b2 vaccine. Among the 38 KTR who were seronegative 5 months after the D2, 18 (47.4%) became seropositive following the D3. Factors associated with a non-response were mycophenolic acid dose, post-transplant duration, hemoglobin, and lymphocyte count. A humoral response 1 and 3 months after the D3 was obtained in ~ 75% of KTR, but 20% were non-responders. Additional studies are needed to clarify the factors hindering a vaccine response., (© 2023. The Author(s).)

Objective: Periictal water drinking (PIWD), which is a rare seizure-related autonomic behavior, has been reported in temporal lobe epilepsy (TLE) but only rarely in extra-TLE. Additionally, the lateralizing value of PIWD is controversial. We aimed to clarify the occurrence and lateralizing value of PIWD in patients with focal epilepsy., Methods: This retrospective study included 240 focal epilepsy patients aged >10 years with a favorable postoperative seizure outcome (Engel class I). PIWD was defined as water drinking behavior during a seizure or within 2 min in the postictal phase. The occurrence of PIWD documented on video-electroencephalogram monitoring was assessed. The lateralizing value of PIWD was analyzed among patients whose language dominant hemisphere was identified., Results: Twenty-three (9.5%) patients exhibited PIWD. PIWD occurred more frequently in frontal lobe epilepsy (FLE; eight of 41 patients, 19.5%) than in TLE (15 of 188 patients, 8%). The occurrence of PIWD was significantly different between FLE and extra-FLE (P = 0.035), with a low positive predictive value (34.8%). In FLE with PIWD, all but one patient underwent resective surgery involving the medial frontal lobe. In 194 patients whose language dominant hemisphere was determined, the lateralizing value of PIWD in FLE and TLE showed no statistical significance (P = 0.69 and P = 0.27, respectively)., Significance: Periictal water drinking occurred more often in FLE than TLE. Thus, PIWD might not be a specific periictal symptom in TLE. There was no evidence for the lateralizing value of PIWD in FLE and TLE. These findings can provide useful clinical clues for preoperative evaluations to estimate the epileptogenic zone based on seizure semiology and allow for a better understanding of pathophysiological insights into PIWD., (© 2023 The Authors. Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

We report the first case of proteinase 3-antineutrophil cytoplasmic antibody-positive granulomatosis with polyangiitis (GPA) with predominant ears, nose, and throat manifestations following coronavirus disease 2019 (COVID-19) vaccination. A 63-year-old woman presented with aural fullness 3 days after vaccination. She presented with progressive rhinosinusitis and otitis media leading to profound hearing loss within 3 weeks. Clinical imaging revealed soft-tissue shadows in the paranasal sinuses with multiple pulmonary nodules, and histopathology was consistent with a diagnosis of GPA. It is crucial to be wary of the possibility of GPA in patients who received COVID-19 vaccines due to its rapid disease progression., (© Japan College of Rheumatology 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

A 39-year-old woman with end-stage renal failure of unknown origin was on peritoneal dialysis for 10 years. One year ago, she underwent ABO-incompatible living-donor kidney transplantation from her husband. After the kidney transplantation, her serum creatinine level remained around 0.7 mg/dL, but her serum potassium level remained low at around 3.5 mEq/L despite potassium supplementation and spironolactone. The patient's plasma renin activity (PRA) and plasma aldosterone concentration (PAC) were markedly elevated (20 ng/mL/h and 868 pg/mL, respectively). A CT angiogram of the abdomen performed 1 year previously suggested stenosis of the left native renal artery, which was considered responsible for the hypokalemia. Renal venous sampling was done on both the native kidneys and the transplanted kidney. Since renin secretion from the left native kidney was significantly elevated, a laparoscopic left nephrectomy was performed. Postoperatively, the renin-angiotensin-aldosterone system was markedly improved (PRA: 6.4 ng/mL/h, PAC: 147.3 pg/mL), and the serum potassium levels also improved. Pathological examination of the removed kidney showed many atubular glomeruli and hyperplasia of the juxtaglomerular apparatus (JGA) in residual glomeruli. In addition, renin staining showed strong positivity in the JGA of these glomeruli. Here, we report a case of hypokalemia caused by left native renal artery stenosis in a kidney transplant recipient. This valuable case study provides histological confirmation of maintained renin secretion in an abandoned native kidney after kidney transplantation., (© 2023 S. Karger AG, Basel.)

Introduction: In kidney transplant recipients (KTRs) whose primary disease is IgA nephropathy (IgAN), IgAN recurrence occurs in approximately half of patients by 5 years postoperatively and is associated with graft survival. Although the alternative and lectin pathways are important in the primary pathogenesis of IgAN, the significance of mesangial C1q deposition, which triggers the classical pathway, is unknown. We investigated the clinicopathological significance of mesangial C1q deposition in both recurrent IgAN in KTRs and native IgAN., Methods: Between 2000 and 2021, we conducted a 1:2 matched case-control study of 18 KTRs diagnosed with recurrent IgAN, with a group of native IgAN patients as the control. We evaluated the rate and presence/absence of mesangial C1q deposition in terms of pathological findings and kidney outcomes in each group., Results: The rate of mesangial C1q deposition was significantly higher in the recurrent IgAN patients in KTRs than in native IgAN patients (11/18 [61.1%] vs. 5/36 [13.9%], p = 0.001). In the former group, the incidence of glomerular crescents was relatively higher in C1q-positive patients. There was no significant difference in the annual rate of estimated glomerular filtration rate decline between C1q-positive and C1q-negative patients in either group., Conclusion: Mesangial C1q deposition was more frequent in KTRs with recurrent IgAN than in patients with native IgAN, but we found no difference in kidney outcomes with respect to mesangial C1q deposition. Further large-scale investigations of the importance of mesangial C1q deposition are needed in both KTRs with recurrent IgAN and patients with native IgAN., (© 2023 S. Karger AG, Basel.)

Pharmacogenetics (PGx) enhances personalized care, often reducing medical costs, and improving patients' QOL. Unlike single variant analysis, multiplex PGx panel tests can result in applying comprehensive PGx-guided medication to maximize drug efficacy and minimize adverse reactions. Among PGx genes, drug-metabolizing enzymes and drug transporters have significant roles in the efficacy and safety of various pharmacotherapies. In this study, a genotyping panel has been developed for the Japanese population called PGx&#95;JPN panel comprising 36 variants in 14 genes for drug-metabolizing enzymes and drug transporters using a mass spectrometry-based genotyping method, in which all the variants could be analyzed in two wells for multiplex analysis. The verification test exhibited good concordance with the results analyzed using the other standard genotyping methods (microarray, TaqMan assay, or another mass spectrometry-based commercial kit). However, copy number variations such as CYP2D6*5 could not apply to this system. In this study, we demonstrated that the mass spectrometry-based multiplex method could be useful for in the simultaneous genotyping of more than 30 variants, which are essential among the Japanese population in two wells, except for copy number variations. Further study is needed to assess our panel to demonstrate the clinical use of pharmacogenomics for precision medicine in the Japanese population.

A 39-year-old male kidney transplant recipient with Down syndrome (DS) was admitted to our hospital for biopsy. He had proteinuria at age 9, was diagnosed with immunoglobulin A nephropathy (IgAN) at age 22, had a tonsillectomy at age 35, and underwent ABO-compatible kidney transplantation (from his mother) at age 36. His serum creatinine was stable at 2.21 mg/dL 3 months after the kidney transplant, and his urine protein was 0.11 g/day. A protocol biopsy was performed 7 months after the kidney transplant, and there was suspicion of early recurrence of IgAN. One year after the transplant, urine erythrocytes were elevated and proteinuria was 0.41 g/day; at 3 years and 5 months after the kidney transplant, hematuria was evident along with proteinuria (0.74 g/day). Therefore, an episode biopsy was performed. A total of 23 glomeruli were obtained, four of which exhibited global sclerosis; three others showed intra- and extracapillary proliferative glomerulonephritis compatible with IgAN recurrence. Here, we report a rare case of early recurrence of IgAN with disease progression despite tonsillectomy in a patient with DS., (© 2023 S. Karger AG, Basel.)

Cell cycle-dependent regulation of chromosome is a dynamic event. After replication in S phase, sister chromatids show dynamic behavior including condensation, alignment, and segregation in M phase. These beautiful behaviors of chromosomes observed through the microscope have fascinated people since more than 100 years ago, and now we can sketch the dynamics of regulatory proteins and their posttranscriptional modifications through the fluorescent microscope. The purpose of this chapter is describing the basic methods of immunofluorescence analysis of mitotic cells and chromosomes. Besides, the key ideas for improving the preparation of the specimen are also described. Because the characteristic of the proteins of your interest differs one by one, modifying the method might cause the crucial improvement in the observation., (© 2023. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: Residual renal function (RRF) is one of the most crucial factors in the management of peritoneal dialysis (PD). The aim of this study was to evaluate the association between lipid profile and preservation of RRF among incident PD patients., Methods: This retrospective cohort study investigated 113 patients (male, 72%; age, 59 ± 14 years) who initiated PD between 2006 and 2017. We investigated the relationships between high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) at PD initiation and change in renal Kt/V during the first year after PD initiation., Results: Alterations in renal Kt/V during the first year after PD initiation correlated negatively with HDL-C at PD initiation but not with LDL-C. On multivariate analysis, HDL-C at PD initiation was independently associated with a change in renal Kt/V during the first year after PD initiation., Conclusion: These results suggest the importance of lipid management among incident PD patients for the preservation of RRF., (© 2022 International Society for Apheresis and Japanese Society for Apheresis.)

The Trp metabolite kynurenine (KYN) accumulates in numerous solid tumours and mediates potent immunosuppression. Bacterial kynureninases (KYNases), which preferentially degrade kynurenine, can relieve immunosuppression in multiple cancer models, but immunogenicity concerns preclude their clinical use, while the human enzyme (HsKYNase) has very low activity for kynurenine and shows no therapeutic effect. Using fitness selections, we evolved a HsKYNase variant with 27-fold higher activity, beyond which exploration of >30 evolutionary trajectories involving the interrogation of >10 9 variants led to no further improvements. Introduction of two amino acid substitutions conserved in bacterial KYNases reduced enzyme fitness but potentiated rapid evolution of variants with ~500-fold improved activity and reversed substrate specificity, resulting in an enzyme capable of mediating strong anti-tumour effects in mice. Pre-steady-state kinetics revealed a switch in rate-determining step attributable to changes in both enzyme structure and conformational dynamics. Apart from its clinical significance, our work highlights how rationally designed substitutions can potentiate trajectories that overcome barriers in protein evolution., Competing Interests: Competing interests J.B., C.S.K., N.M., W.C.L., G.G., and E.S. are inventors on intellectual property related to this work, including the active patent US9975959B2 and the pending patents US20190350975A1 and US20210207110A1, which are assigned to the Board of Regents of the University of Texas System. G.G., E.S., X.M.Z., K.M., S.C., and M.M. have equity interest in Ikena Oncology, a company pursuing the commercial development of this technology. J.B., C.S.K., C.L., and E.S. have consulted for Ikena Oncology (previously Kyn Therapeutics). The remaining authors declare no competing interests.

Competing Interests: Conflict of interestThe authors declare that they have no conflict of interest.

Background: The mortality rate due to COVID-19 in kidney transplant recipients (KTRs) is 16.8 to 32%. Vaccination against COVID-19 is expected to contribute to the prevention of infection, severe disease, and mortality; however, it has been reported that the humoral response to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccine in KTRs is poor. Vaccination strategies against COVID-19 vary from country to country, and in Japan, the third dose is given 6 months after the second dose. Few studies have evaluated long-term humoral responses after the second dose of SARS-CoV-2 mRNA vaccine. In addition, the superiority of BNT162b2 vaccine and mRNA-1,273 vaccine in KTRs regarding humoral response is controversial., Methods: Ninety-four KTRs were administered a second dose of the BNT162b2 or mRNA-1,273 vaccines, and anti-spike (anti-S) and anti-nucleocapsid (anti-N) SARS-CoV-2 antibody levels were measured 5 months (149.2 ± 45.5 days) later. The cutoff value of anti-S antibodies was defined ≥50 AU/ml and 1.4 Index for anti-N antibodies. The primary outcome was the rate of seropositivity, and factors associated with an appropriate humoral response were assessed by univariate and multivariate analysis., Results: Of 94 KTRs, only 45 (47.9%) patients were positive for anti-S antibodies. The median anti-S SARS-CoV-2 IgG antibody titers was 35.3 (Interquartile range 3.8 to 159.7). Anti-N SARS-CoV-2 IgG antibodies in all patients were < 1.4 Index. Response to SARS-CoV-2 mRNA vaccines were 43.2 and 65% for BNT162b2 and mRNA-1,273, respectively ( p  = 0.152). In comparison with high-dose, low-dose of mycophenolic acid was a robust factor associated with an adequate humoral response., Conclusion: The long-term humoral response after a second dose of SARS-CoV-2 mRNA vaccine in Japanese KTRs was poor. In comparison with high-dose, low-dose mycophenolic acid was related to an appropriate humoral response. Five months is too long to wait for a 3rd dose after 2nd dose of SARS-CoV-2 vaccine in KTRs. In this cohort, there was no statistical difference in humoral response to the BNT162b2 and mRNA-1,273 vaccines. Additional large observational studies and meta-analyses are needed to clarify the factors related to an appropriate humoral immune response to COVID-19 vaccination., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Ohki, Kawabe, Yamamoto, Katsumata, Nakada, Kobayashi, Urabe, Miki, Yamada, Kimura, Matsuo, Tanno, Horino, Ohkido, Yamamoto and Yokoo.)

Background: Tubulointerstitial nephritis (TIN) is an important cause of acute kidney injury (AKI) and advanced CKD. Only a limited number of studies have reported etiology-based differences in the clinical and/or histopathological properties and kidney outcomes of the biopsy-proven TIN., Methods: Patients with biopsy-proven TIN identified from 2005 to 2016 in five hospitals were categorized based on the etiologies and were retrospectively analyzed in relation to the clinicopathological findings and kidney outcomes., Results: Among 4815 biopsy cases screened, 153 Japanese TIN patients were identified, of whom 139 patients with ≥ 6 months of follow-up data (median 58 years old, 45.3% female, median 31.5 months follow-up) were further analyzed. TIN was drug-induced in 32.4%, autoimmune-related in 24.5%, of unknown etiology in 27.3% and other disease-related in 15.8%. Non-steroidal anti-inflammatory drugs and antibiotics were major causative drugs in drug-induced TIN, and IgG4-related disease, Sjögren's syndrome and sarcoidosis were common in autoimmune-related TIN. Among etiology groups, drug-induced TIN showed advanced AKI with elevated serum creatinine (sCr) and increased C-reactive protein levels at the diagnosis. TIN patients with autoimmune diseases showed less-severe AKI, but were more frequently treated with corticosteroids than others. Tubulointerstitial injury expansion in biopsy specimens was comparable among the groups. Complete or partial kidney function recovery at 6 months was more frequent in drug-induced and autoimmune-related TIN than in others. sCr levels at 6 months were similar among the groups., Conclusions: This largest case series study of the biopsy-proven TIN in Japan provides detailed information regarding both etiology-based clinicopathological properties and kidney outcomes., (© 2022. Japanese Society of Nephrology.)

Background: Intracerebral hemorrhage (ICH) and acute ischemic stroke (AIS) have common vascular risk factors; however, ICH often occurs in adults aged < 70 years. Intracerebral hemorrhage and AIS in adults aged < 70 years should be preventable; however, it is unclear why different subtypes of ICH or AIS occur among adults aged < 70 years with vascular risk factors. This study aimed to identify independent variables for ICH or AIS onset in patients aged < 70 years., Methods: We included patients aged 40-69 years who experienced ICH or AIS between August 2016 and July 2019. Patients aged < 40 years were excluded because other diseases, rather than vascular risk factors, are often associated with stroke etiology in this age group. Data on age, systolic blood pressure (SBP), serum lipids, and serum fatty acid levels were compared between patients with ICH and those with AIS. In addition, we conducted multivariable logistic regression analyses to identify independent factors among the variables, such as blood pressure or biomarkers, with significant differences between the two groups., Results: Of the 1252 acute stroke patients screened, 74 patients with ICH and 149 patients with AIS met the inclusion criteria. After excluding variables with multicollinearity, SBP, glycated hemoglobin (HbA1c), and eicosapentaenoic acid (EPA) proportion (%) of total fatty acids were identified as independent factors affecting ICH and AIS. The SBP and EPA% threshold values for ICH compared to AIS were ≥ 158 mmHg and ≤ 2.3%, respectively. The HbA1c threshold value for AIS compared to ICH was ≥ 6.1%., Conclusions: Systolic blood pressure, HbA1c, and EPA%, were independent factors between ICH and AIS. Patients aged 40-69 years with high SBP and low EPA% were at a higher risk of ICH than AIS, and those with a high HbA1c were at a higher risk of AIS than ICH., (© 2022. The Author(s).)

Objectives: Angiographic "slow flow" in the middle cerebral artery (MCA), caused by carotid stenosis, may be associated with high oxygen extraction fraction (OEF). If the MCA slow flow is associated with a reduced relative signal intensity (rSI) of the MCA on MR angiography, the reduced rSI may be associated with a high OEF. We investigated whether the MCA slow flow ipsilateral to carotid stenosis was associated with a high OEF and aimed to create a practical index to estimate the high OEF., Methods: We included patients who underwent digital subtraction angiography (DSA) and MRA between 2015 and 2019 to evaluate carotid stenosis. MCA slow flow by image count using DSA, MCA rSI, minimal luminal diameter (MLD) of the carotid artery, carotid artery stenosis rate (CASr), and whole-brain OEF (wb-OEF) was evaluated. When MCA slow flow was associated with a high wb-OEF, the determinants of MCA slow flow were identified, and their association with high wb-OEF was evaluated., Results: One hundred and twenty-seven patients met our inclusion criteria. Angiographic MCA slow flow was associated with high wb-OEF. We identified MCA rSI and MLD as determinants of angiographic MCA slow flow. The upper limits of MCA rSI and MLD for angiographic MCA slow flow were 0.89 and 1.06 mm, respectively. The wb-OEF was higher in patients with an MCA rSI ≤ 0.89 and ipsilateral MLD ≤ 1.06 mm than patients without this combination., Conclusions: The combination of reduced MCA rSI and ipsilateral narrow MLD is a straightforward index of high wb-OEF., Key Points: • The whole-brain OEF in patients with angiographic slow flow in the MCA ipsilateral to high-grade carotid stenosis was higher than in patients without it. • Independent determinants of MCA slow flow were MCA relative signal intensity (rSI) on MRA or minimal luminal diameter (MLD) of the carotid stenosis. • The wb-OEF was higher in patients with an MCA rSI ≤ 0.89 and ipsilateral MLD ≤ 1.06 mm than patients without this combination., (© 2021. The Author(s).)

Background/purpose of the Study: If non-alcoholic fatty liver disease (NAFLD) frequency is very high in stroke patients, NAFLD may be a risk factor for stroke and identifying factors of NAFLD presence may lead to stroke prevention. This retrospective study aimed to investigate whether NAFLD frequency was very high and identify factors associated with NAFLD presence at acute stroke admission., Methods: We included stroke patients aged 40 - 79 years who (1) were admitted from 2016 to 2019, within 24 h of onset; (2) underwent abdominal ultrasonography; and (3) underwent blood examination of biomarkers. We evaluated the frequency and significant factors of NAFLD presence., Results: Among 1672 stroke patients, 676 patients met our inclusion criteria, and 267 patients (39.5%) had NAFLD. Compared to patients without NAFLD, patients with NAFLD were young; had high anthropometric values; high blood pressure; low aspartate aminotransferase/alanine aminotransferase ratio (AST/ALT) ratio; high levels of liver enzymes, serum albumin, HbA1c, and serum lipids; low-density lipoprotein; high serum level of some fatty acids; and high fatty acid% of palmitic acid (PA) and dihomo-gamma-linolenic acid (DGLA). After excluding variables with multicollinearity, independent NAFLD-presence factors were high body mass index (BMI), low AST/ALT ratio, high serum albumin level, high PA%, and high DGLA level., Conclusions: The frequency of NAFLD was high in our patient group. Significant NAFLD-presence factors were high BMI, low AST/ALT ratio, high serum albumin level, high PA%, and high DGLA level. A further study is warranted to determine the effects of the NAFLD-presence factors on stroke onset or prevention., (© 2021. The Author(s).)

Notch signaling is one of the most common drivers of carcinogenesis in many types of cancers, including hepatocellular carcinoma (HCC); however, it occasionally suppresses tumor progression. Moreover, it is virtually unknown how different sets of Notch ligands and receptors regulate the HCC development. In this study, we demonstrate that the expression of the Notch ligands, Delta-like 4 (Dll4) and Jagged-1 (Jag1), is upregulated during diethylnitrosamine-induced hepatocarcinogenesis. Dll4 is detected in the preneoplastic hepatocytes and HCC cells, but not in the normal hepatocytes, while Jag1 is expressed in the desmin-positive mesenchymal cells. Hepatocyte-specific Dll4 knockout abolishes the Notch1 signaling and suppresses the tumor progression. In contrast, Jag1 deletion induces the ectopic expression of Dll4 in hepatocytes along with the loss of Notch2 signaling, leading to the tumor progression. These results indicate that the two distinct Notch signals, Dll4/Notch1 and Jag1/Notch2, are antagonistic to each other, exerting opposite effects on HCC progression., (© 2022. The Author(s).)

Vulnerable lesions with intraplaque hemorrhages are associated with a high incidence of complications following carotid artery stenting (CAS). CAS for vulnerable lesions has not been established; therefore, we gradually expand stents in such patients. This study aimed to compare the incidences of complications between gradual-expansion CAS for vulnerable lesions and standard CAS for non-vulnerable lesions. For gradual-expansion CAS, we used 3.0 or 4.0 mm balloons for minimal luminal diameters (MLDs) <2.0 or ≥2.0 mm, respectively, for pre-stenting angioplasty (SA) and did not overinflate them. By contrast, for standard CAS, we used a 4.0 mm balloon and overinflated it to 4.23 mm. A closed-cell stent was deployed, and post-SA was not performed in both groups. We evaluated the MLD before and minimal stent diameter (MSD) immediately after CAS, as well as periprocedural complications of combined stroke, death, and myocardial infarction within 30 days after CAS. In the vulnerable and non-vulnerable groups, 30 and 38 patients were analyzed, the MLDs were 0.76 and 0.96 mm before CAS, the MSDs were 2.97 mm and 3.58 mm after CAS, and the numbers of complications were 0 and 1, respectively. Gradual-expansion CAS for vulnerable lesions was as safe as standard CAS for non-vulnerable lesions.

Hyperglycemia, a predictor of poor clinical outcomes in acute stroke, must be lowered safely and promptly. We investigated the safety and effectiveness of sodium-glucose cotransporter 2 inhibitors (SGLT2is) combined with medical nutrition therapy in lowering blood glucose levels. This retrospective study included stroke patients admitted between 2014 and 2019, who (1) had glycated hemoglobin ≥6.5%, blood glucose level ≥ 11.1 mmol/L at admission, (2) took their diet and drugs orally during hospitalization, (3) underwent SGLT2is pharmacotherapy after admission, and (4) underwent a fasting blood glucose (FBG) test on day 7. Patients were provided with a moderate-carbohydrate diet combined with total energy restriction. We assessed the achievement of FBG < 7 mmol/L on day 7 and the need for sulfonylurea or a long-acting insulin analog (LIA) treatment during hospitalization, which carries a risk of hypoglycemia. Fifty-one patients met our inclusion criteria. Of them, 33 (64.7%) achieved the target FBG on day 7. Only eight patients were treated with a small dose of LIA; however, no patients required sulfonylurea. No dehydration occurred. SGLT2is combined with a moderate carbohydrate- and energy-restricted diet achieved the target FBG level safely, effectively, and promptly in mild stroke patients with oral ingestion.

Space-valence metaphors (e.g., bad is down) are embedded within cognitive and emotional processing (e.g., negative stimuli at a lower space capture visual attention more than those at an upper space). Previous studies have revealed that motor action to vertical direction affects the emotional valence rating of stimuli in a metaphor-congruent manner only when the action was introduced after the stimuli presentation. In the present study, we hypothesized that motor action before the stimuli presentation does not affect valence rating while it may affect visual selective attention. In Experiment 1 (participants: 28 university students; mean age = 19.50 years), we partially replicated the previous result with repeated ANOVA and t -tests; manual action introduced before the stimuli presentation does not affect the valence rating. Then, in Experiment 2 (participants: 28 university students; mean age = 19.57 years), we employed a modified version of the dot-probe task as a measure of visual selective attention to emotional stimuli, where participants' vertical or horizontal manual action was introduced before the presentation of a pair of emotional words. The results of the t -tests revealed that an upward manual action promoting selective attention to negative words, which was incongruent with the space-valence metaphorical correspondence. These results suggest that even though manual action does not affect the evaluative process of emotional stimuli prospectively, upward manual action introduced before stimuli presentation can promote visual attention to the subsequent negative stimuli in a way that is incongruent with the space-valence metaphor., Competing Interests: The authors declare no conflict of interest., (© 2021 The Author(s).)

Epigenome research has employed various methods to identify the genomic location of proteins of interest, such as transcription factors and histone modifications. A recently established method called CUT&Tag uses a Protein-A Tn5 transposase fusion protein, which cuts the genome and inserts adapter sequences nearby the target protein. Throughout most of the CUT&Tag procedure, cells are held on concanavalin A (con A)-conjugated magnetic beads. Proper holding of cells would be decisive for the accessibility of Tn5 to the chromatin, and efficacy of the procedure of washing cells. However, BioMag®Plus ConA magnetic beads, used in the original CUT&Tag protocol, often exhibit poor suspendability and severe aggregation. Here, we compared the BioMag beads and Dynabeads® magnetic particles of which conjugation of con A was done by our hands, and examined the performance of these magnetic beads in CUT&Tag. Among tested, one of the Dynabeads, MyOne-T1, kept excessive suspendability in a buffer even after overnight incubation. Furthermore, the MyOne-T1 beads notably improved the sensitivity in CUT&Tag assay for H3K4me3. In conclusion, the arrangement and the selection of MyOne-T1 refine the suspendability of beads, which improves the association of chromatin with Tn5, which enhances the sensitivity in CUT&Tag assay., Competing Interests: The authors report that there were material support and technical advice from VERITAS corporation for this study that could have influenced its outcome and that one of the authors, Y.T. is its employee. This does not alter our adherence to PLOS ONE policies on sharing data and materials." We believe our revised manuscript would suffice the reviewer’s concerns. It would be greatly appreciated if the editorial office and reviewers could consider this revision. All the authors have read the manuscript and have approved this submission. All study participants provided informed consent, and the study design was approved by an ethics review board.

Background: Intermittent pneumatic compression (IPC) is commonly used to prevent deep vein thrombosis (DVT) during hospitalization in patients with acute stroke. However, if DVT exists at admission, IPC of the legs with DVT may cause migration of the thrombi, resulting in pulmonary emboli. Whole-leg ultrasonography (wl-US) is a practical tool to detect DVT; however, wl-US is not always performed at admission in all stroke patients. This retrospective cross-sectional study aimed to investigate DVT frequency and identify significant factors indicating the presence of DVT at admission for acute stroke., Methods: We included patients admitted within 24 h of stroke onset between 2017 and 2019. Patients who did not undergo blood tests for D-dimer or wl-US within 72 h of arrival were excluded. We collected patient data on age; sex; anthropometric variables; presence of DVT on wl-US; and biomarkers such as D-dimer, high-sensitivity C-reactive protein (hs-CRP), and lipids., Results: Of 1129 acute stroke patients, 917 met our inclusion criteria. DVT was detected in 161 patients (17.6 %). Patients with DVT were older; were more likely to be female; had lower body weight; had higher D-dimer and hs-CRP levels; had lower albumin, hemoglobin, and triglyceride levels; and had higher National Institutes of Health Stroke Scale and pre-stroke modified Rankin scale scores than patients without DVT (n = 756). In addition, multiple logistic regression analysis showed that sex (female) and D-dimer levels (≥ 1.52 µg/mL) were independent significant factors for the presence of DVT. Among 161 patients with DVT, 78 (48.4 %) had both these significant factors. Among 756 patients without DVT, 602 (79.6 %) had no or one significant factor. The odds ratio of the presence of DVT in patients with both significant factors was 6.29, using patients without any significant factors as the group for comparison., Conclusions: The frequency of DVT is high in acute stroke patients at admission. Female sex and a high D-dimer level were independent significant factors for the presence of DVT. Therefore, in patients with these two significant factors at admission, IPC should be avoided or wl-US should be performed before IPC., (© 2021. The Author(s).)

Creatine (Cr)/phosphocreatine has the ability to buffer the high-energy phosphate, thereby contributing to intracellular energy homeostasis. As Cr biosynthetic enzyme deficiency is reported to increase susceptibility to colitis under conditions of inflammatory stress, Cr is critical for maintaining intestinal homeostasis under inflammatory stress. Cr is mainly produced in the hepatocytes and then distributed to other organs of the body by the circulatory system. Since monocarboxylate transporter 9 (MCT9) and monocarboxylate transporter 12 (MCT12) have been reported to accept Cr as a substrate, these transporters are proposed as candidates for Cr efflux transporter in the liver. The aim of this study was to elucidate the transport mechanism on Cr supply from the hepatocytes. Immunohistochemical staining of the rat liver sections revealed that both MCT9 and MCT12 were localized on the sinusoidal membrane of the hepatocytes. In the transport studies using Xenopus laevis oocyte expression system, [ 14 C]Cr efflux from MCT9- or MCT12-expressing oocytes was significantly greater than that from water-injected oocytes. [ 14 C]Cr efflux from primary cultured hepatocytes was significantly decreased following MCT12 mRNA knockdown, whereas this efflux was not decreased after mRNA knockdown of MCT9. Based on the extent of MCT12 protein downregulation and Cr efflux after knockdown of MCT12 in primary cultured rat hepatocytes, the contribution ratio of MCT12 in Cr efflux was calculated as 76.4%. Our study suggests that MCT12 substantially contributes to the efflux of Cr at the sinusoidal membrane of the hepatocytes. NEW & NOTEWORTHY Our study is the first to identify the role of monocarboxylate transporter 12 (MCT12) as a transporter of creatine (Cr) in the liver. MCT12 was found to significantly contribute to the efflux of Cr on the sinusoidal membrane of the hepatocytes. Since hepatocytes are known to be involved in creatine biosynthesis, the present findings can be beneficial for the regulation of Cr biosynthesis and supply.

Seasonal influenza vaccination elicits a diminished adaptive immune response in the elderly, and the mechanisms of immunosenescence are not fully understood. Using Ig-Seq, we found a marked increase with age in the prevalence of cross-reactive (CR) serum antibodies that recognize both the H1N1 (vaccine-H1) and H3N2 (vaccine-H3) components of an egg-produced split influenza vaccine. CR antibodies accounted for 73% ± 18% of the serum vaccine responses in a cohort of elderly donors, 65% ± 15% in late middle-aged donors, and only 13% ± 5% in persons under 35 years of age. The antibody response to non-HA antigens was boosted by vaccination. Recombinant expression of 19 vaccine-H1+H3 CR serum monoclonal antibodies (s-mAbs) revealed that they predominantly bound to non-HA influenza proteins. A sizable fraction of vaccine-H1+H3 CR s-mAbs recognized with high affinity the sulfated glycans, in particular sulfated type 2 N-acetyllactosamine (Galβ1-4GalNAcβ), which is found on egg-produced proteins and thus unlikely to contribute to protection against influenza infection in humans. Antibodies against sulfated glycans in egg-produced vaccine had been identified in animals but were not previously characterized in humans. Collectively, our results provide a quantitative basis for how repeated exposure to split influenza vaccine correlates with unintended focusing of serum antibody responses to non-HA antigens that may result in suboptimal immunity against influenza.

Background: Dynamic axial computed tomographic angiography (dynax-CTA), covering a thin width, with a focus on the bilateral middle cerebral artery (MCA), can quickly visualize the internal carotid artery (ICA) or MCA occlusion. We aimed to investigate whether dynax-CTA appropriately evaluated the collateral status coupled with the upper limit of the onset-to-reperfusion (OtR) time to achieve a major neurological improvement (MNI) at a 24-h follow-up examination after mechanical thrombectomy (MT)., Methods: We included acute ischemic stroke patients admitted from 2018 to 2020 who underwent dynax-CTA on admission and emergent MT for ICA or MCA occlusion. We performed dynax-CTA using an 80-row CT scanner and acquired 25 volume scans, consisting of 40 images of 1-mm thickness and 4-cm width. We classified the collateral status as good, intermediate, and poor based on MCA branch opacification. We evaluated the collateral status and the upper OtR time limit to achieve MNI., Results: Forty-eight patients met our inclusion criteria. Dynax-CTA findings demonstrated MCA and ICA occlusion in 30 and 18 patients, respectively. The collateral status was good, intermediate, and poor in four, 25, and 19 patients, respectively. The upper limits of the OtR time for MNI were 3.63, 8.08, and 8.67 h in patients with poor, intermediate, and intermediate or good collateral status, respectively., Conclusions: Dynax-CTA appropriately evaluated the collateral status coupled with the upper limit of the OtR time before performing MT.

The molecular composition and binding epitopes of the immunoglobulin G (IgG) antibodies that circulate in blood plasma after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are unknown. Proteomic deconvolution of the IgG repertoire to the spike glycoprotein in convalescent subjects revealed that the response is directed predominantly (>80%) against epitopes residing outside the receptor binding domain (RBD). In one subject, just four IgG lineages accounted for 93.5% of the response, including an amino (N)-terminal domain (NTD)-directed antibody that was protective against lethal viral challenge. Genetic, structural, and functional characterization of a multidonor class of "public" antibodies revealed an NTD epitope that is recurrently mutated among emerging SARS-CoV-2 variants of concern. These data show that "public" NTD-directed and other non-RBD plasma antibodies are prevalent and have implications for SARS-CoV-2 protection and antibody escape., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

The aim of this study was to compare the changes in peritoneal function and residual renal function in the first year between diabetic and non-diabetic patients receiving peritoneal dialysis (PD). We extracted 73 incident PD patients (male, 73%; age, 59 ± 15 years) from a previous cohort, and investigated the changes in PD-related parameters, including the dialysate to plasma ratio of creatinine (D/P Cr) and Kt/V. D/P Cr increased in non-diabetics, whereas it did not change significantly in diabetic patients. These differences were more pronounced among icodextrin users. On multivariate analysis, the presence of diabetes was independently associated with the changes in D/P Cr. On the contrary, there was no significant difference in the changes of renal Kt/V between the two groups. A higher peritoneal solute transport rate at the start of PD in diabetics was attenuated within 1 year. Icodextrin is thought to have an important role through improving body fluid status., (© 2020 International Society for Apheresis, Japanese Society for Apheresis, and Japanese Society for Dialysis Therapy.)

The eligibility for kidney donation and long-term post-donation renal prognosis of patients with Gitelman syndrome (GS) are unknown. We herein report a 44-year-old woman with GS who donated her kidney for transplant. A gene sequence analysis revealed compound heterozygous mutations of T180K and L858H in the SLC12A3 gene. Since transplantation, the renal function and serum potassium and magnesium levels of the donor and recipient have remained stable for seven years with careful monitoring and supplementation. Patients with asymptomatic GS who have no complications can be considered eligible to donate their kidney for transplant with proper monitoring after transplantation.

Objective: We investigated whether thoraco-cervical CTA provided useful information to determine an access route (AR) for mechanical thrombectomy (MT)., Methods: We included acute stroke patients who (1) were admitted between January 2018 and December 2018 and (2) underwent MT for large artery occlusion in the anterior circulation and were able to be treated within 24 hours of the time last known to be well. We evaluated the AR, occlusion site, aortic arch (AA) type, take-off angles (TOA) between the arch and the left common carotid artery (CCA) or the brachiocephalic artery (BCA), successful insertion rate (SIR) of the guiding catheter, puncture-to-initial angiography time (PtIA), and puncture-to-reperfusion time (PtR)., Results: We analyzed 32 patients: femoral-artery access (group F) in 26 and brachial-artery access (group B) in 6 patients. There were no differences in arch types between the two groups, but there were differences in occlusion sites: proximal CCA occlusion in two patients in the B group. Moreover, the TOA of the CCA was less than 25° in two patients in the B group. In the F and B groups, the SIR was 100%, the median PtIA was 9.0 and 9.6 minutes, and the median PtR was 54 and 72 minutes, respectively., Conclusion: Thoraco-cervical CTA provided useful information to determine the appropriate AR for MT. SIR of 100% and short PtIA were achieved., Competing Interests: The authors declare no conflict of interest., (©2021 The Japanese Society for Neuroendovascular Therapy.)

Background and Purpose: Intracranial hemorrhage due to hyperperfusion syndrome is a severe carotid artery stent placement complication of extremely high-grade stenosis, causing hemodynamic insufficiency. To prevent hyperperfusion syndrome, we attempted intentional residual stent stenosis and implemented "gentle" carotid artery stent placement, defined as carotid artery stent placement using a closed-cell stent coupled with slight balloon predilation, without balloon postdilation. Gradual stent expansion was expected. We investigated the incidence of hyperperfusion syndrome and long-term outcomes after gentle carotid artery stent placement., Materials and Methods: We included patients who underwent carotid artery stent placement for extremely high-grade stenosis from January 2015 to March 2019. We defined extremely high-grade stenosis as carotid stenosis with conventional angiographic "slow flow" and a reduced MCA signal intensity on MRA. A reduced MCA signal intensity was defined as MCA with a relative signal intensity of <0.9 in the ipsilateral compared with the contralateral MCA. We evaluated the stent diameter, CBF on SPECT, hyperperfusion syndrome, and intracranial hemorrhage. We defined hyperperfusion syndrome as a triad of ipsilateral headache, seizure, and hemiparesis., Results: Twenty-eight of the 191 patients met our inclusion criteria. After carotid artery stent placement, their median minimal stent diameter was 2.9 mm, which expanded to 3.9 mm at 4 months. Neither cerebral hyperperfusion syndrome nor intracranial hemorrhage occurred., Conclusions: The gentle carotid artery stent placement strategy for intentional residual stent stenosis may prevent hyperperfusion syndrome in high-risk patients. Stents spontaneously dilated in 4 months., (© 2021 by American Journal of Neuroradiology.)

Although humoral immunity is essential for control of SARS-CoV-2, the molecular composition, binding epitopes and effector functions of the immunoglobulin G (IgG) antibodies that circulate in blood plasma following infection are unknown. Proteomic deconvolution of the circulating IgG repertoire (Ig-Seq 1 ) to the spike ectodomain (S-ECD 2 ) in four convalescent study subjects revealed that the plasma response is oligoclonal and directed predominantly (>80%) to S-ECD epitopes that lie outside the receptor binding domain (RBD). When comparing antibodies directed to either the RBD, the N-terminal domain (NTD) or the S2 subunit (S2) in one subject, just four IgG lineages (1 anti-S2, 2 anti-NTD and 1 anti-RBD) accounted for 93.5% of the repertoire. Although the anti-RBD and one of the anti-NTD antibodies were equally potently neutralizing in vitro , we nonetheless found that the anti-NTD antibody was sufficient for protection to lethal viral challenge, either alone or in combination as a cocktail where it dominated the effect of the other plasma antibodies. We identified in vivo protective plasma anti-NTD antibodies in 3/4 subjects analyzed and discovered a shared class of antibodies targeting the NTD that utilize unmutated or near-germline IGHV1-24, the most electronegative IGHV gene in the human genome. Structural analysis revealed that binding to NTD is dominated by interactions with the heavy chain, accounting for 89% of the entire interfacial area, with germline residues uniquely encoded by IGHV1-24 contributing 20% (149 Å 2 ). Together with recent reports of germline IGHV1-24 antibodies isolated by B-cell cloning 3,4 our data reveal a class of shared IgG antibodies that are readily observed in convalescent plasma and underscore the role of NTD-directed antibodies in protection against SARS-CoV-2 infection.

Guanidinoacetate (GAA), which is a precursor of creatine, is mainly biosynthesized in the renal proximal tubular epithelial cells (RPTECs). Plasma concentration of GAA has been reported to be reduced in patients with monocarboxylate transporter 12 (MCT12) mutation (p.Q215X). However, the mechanism underlying GAA release from the RPTECs remains unclear. Therefore, to elucidate the role of MCT12 in renal GAA release, MCT12-mediated GAA transport was evaluated using the human and rat MCT12-expressing Xenopus laevis oocytes and primary-cultured rat RPTECs. [ 14 C]GAA uptake by the human and rat MCT12-expressing oocytes was significantly higher than that by the water-injected oocytes. Rat MCT12-mediated uptake of [ 14 C]GAA by the oocytes was found to be sodium ion (Na + )-independent and exhibited saturable kinetics with a Michaelis-Menten constant of 3.38 mM. Transport activities of rat MCT12 tend to increase along with increasing of extracellular pH. In addition, the efflux transport of [ 14 C]GAA from the human and rat MCT12-expressing oocytes was significantly higher than that from the water-injected oocytes. These results suggest that both the influx and efflux transport of GAA is mediated by MCT12. In the primary-cultured rat RPTECs, [ 14 C]GAA efflux transport was significantly reduced by the transfection of MCT12-specific siRNAs, suggesting that MCT12 participates in GAA efflux transport in rat RPTECs. Therefore, it suggests that MCT12 is involved in GAA release from RPTECs to the circulating blood, since MCT12 is known to be localized on the basal membrane of RPTECs., 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. Disclosure The authors declare no competing interests., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The ability to visualize intraluminal surface of peritoneal dialysis (PD) catheter and peritoneal cavity could allow elucidation of the cases of outflow problems, and provide information on changes to the peritoneal membrane leading to encapsulating peritoneal sclerosis. A non-invasive examination that allows those monitoring in need is desirable. We have developed a disposable ultra-fine endoscope that can be inserted into the lumen of the existing PD catheter, allowing observation of the luminal side of the catheter and peritoneal cavity from the tip of the PD catheter, with minimum invasion in practice. In a pre-clinical study in pigs and a clinical study in 10 PD patients, the device provided detailed images, enabling safe, easy observation of the intraluminal side of the entire catheter, and of the morphology and status of the peritoneal surface in the abdominal cavity under dwelling PD solution. Since this device can be used repeatedly during PD therapy, clinical application of this device could contribute to improved management of clinical issues in current PD therapy, positioning PD as a safer, more reliable treatment modality for end-stage renal disease.

Dietary triglycerides influence the serum concentrations of fatty acids (FA) and their weight percentages (wt%), which might be associated with the age of onset of intracerebral hemorrhage (ICH). We investigated the correlation between serum FA levels and proportions at admission, and the age at onset of ICH. We included patients admitted between 2016 and 2019 within 24 h of the onset of ICH, and calculated the correlation coefficients between their age, serum FA concentration, and FA wt%. We performed multiple linear regression analysis to identify individual FAs related to the age at onset of ICH. Furthermore, we estimated the threshold values of FAs that were independently associated with the age at onset of ICH <65 years, using receiver operating characteristic curves by logistic regression. Our inclusion criteria were met by 141 patients (mean age, 67 years). The concentration of dihomo-gamma-linolenic acid (DGLA) and the wt% of eicosapentaenoic acid (EPA) were significant independent variables for the age at onset of ICH. The ROC curves for the age of onset <65 years were ≥108.6 µmol/L for DGLA and ≤1.7% for EPA. Increased DGLA concentration and decreased EPA wt% were significantly associated with young-onset ICH.

In addition to diet therapy, statins are used to prevent cardiovascular disease in patients with hypercholesterolemia (HC). However, acute ischemic stroke (AIS) still occurs in statin-treated patients. How strictly statin-treated patients follow diet therapy before they experience AIS and whether they increase seafood consumption remains unknown. We investigated the serum concentrations and proportions (weight percentages: wt %) of fatty acids (FAs) at AIS onset in statin-treated patients (statin group), compared to those in non-treated patients with HC (6.465 mmol/L or higher) as controls (non-treated group). We included patients with AIS admitted between 2016 and 2019 within 24 h of AIS onset who underwent analysis of serum FAs. During the study period, 188 patients met the inclusion criteria: 133 in the statin group and 55 in the non-treated group. Interestingly, serum FA concentrations in the statin group were lower than those in the non-treated group. However, serum FA wt % in the statin group was almost identical to that in the non-treated group. In conclusion, statin-treated AIS patients had low FA concentrations and identical FA wt %, compared to non-treated AIS patients with HC.

Background: Recurrence of IgA nephropathy (IgAN) in the transplanted kidney is associated with graft survival, but no specific treatment is available. Tonsillectomy (TE) reportedly arrests the progression of IgAN in the native kidney. Thus, we conducted a single-center retrospective cohort study to evaluate the effect of TE prior to IgAN recurrence. Methods: Of the 36 patients with biopsy-proven IgAN who underwent kidney transplantation, 27 were included in this study. Nine patients underwent TE at 1 year after kidney transplantation (group 1), and the remaining 18 did not undergo TE (group 2). Results: The rate of histological IgAN recurrence was significantly lower in group 1 than in group 2 (11.1 vs. 55.6%, log-rank p = 0.046). In addition, half of the recurrent patients in group 2 exhibited active lesions, compared to none in group 1. Serum Gd-IgA1 levels decreased after TE in group 1, whereas they remained stable or increased slightly in group 2. In the recurrent cases, IgA and Gd-IgA1 were found in the germinal center in addition to the mantle zone of tonsils. Finally, mesangial IgA and Gd-IgA1 immunoreactivity was reduced after TE in some cases. Conclusion: Our data suggest that TE at 1 year after kidney transplantation might be associated with the reduced rate of histological IgAN recurrence. TE arrested or reduced serum Gd-IgA1 and mesangial Gd-IgA1 immunoreactivity. Therefore, we generated a hypothesis that serum Gd-IgA1 derived from the tonsils may play a pivotal role in the pathogenesis of IgAN. Based on these findings, we need to conduct verification in a prospective randomized controlled trial., (Copyright © 2020 Kawabe, Yamamoto, Yamakawa, Katsumata, Isaka, Katsuma, Nakada, Kobayashi, Koike, Ueda, Tanno, Koike, Miki, Yamada, Kimura, Ohkido, Tsuboi, Yamamoto, Kojima and Yokoo.)

Euglena gracilis exhibits photomovements in response to various light stimuli, such as phototactic and photophobic responses. Our recent study revealed that carotenoids in the eyespot apparatus are required for triggering phototaxis in this alga. However, the role of chloroplasts in eyespot formation is not understood. Here, we isolated carotenoid-less (cl) strains of E. gracilis from cells silenced gene expression of phytoene synthase (EgcrtB). Unlike WT, the culture colors of cl1, cl3, and the non-photosynthetic mutant SM-ZK were orange, while that of cl4 was white. Electron microscope observations showed that SM-ZK, cl1, and cl3 had no developed chloroplast and formed a normal eyespot apparatus, similar to that of WT, but this was not the case for cl4. Carotenoids detected in WT were diadinoxanthin, neoxanthin, and β-carotene. However, the most abundant species of SM-ZK, cl1, and cl3 was zeaxanthin, and there was no diadinoxanthin or neoxanthin. Photomovement analysis showed that SM-ZK, cl1, and cl3 exhibited negative phototactic and photophobic responses, similar to those of WT, whereas cl4 lacked negative phototaxis. Taken together, the formation of the eyespot apparatus required for phototaxis is independent of chloroplast development in E. gracilis, suggesting that this property is different from other photosynthetic flagellates., Competing Interests: Declaration of Competing Interest Authors have no competing interest to declare., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Chronic kidney disease-mineral and bone disorder (CKD-MBD) management in patients with end-stage renal disease is important owing to the risk of cardiovascular diseases. In clinical practice, we manage patients not by monitoring the levels of biologically active ionized calcium (iCa) but by monitoring total serum calcium or corrected calcium (cCa). We previously reported that iCa/cCa ratio was different between patients with hemodialysis and those with peritoneal dialysis (PD). In PD patients, several factors are expected to affect iCa/cCa ratio. Therefore, modifying the strategy to achieve better CKD-MBD management might be necessary; however, no reports have studied this to date. Therefore, we investigated the factors influencing iCa/cCa ratio in PD patients., Methods: This retrospective cross-sectional study examined background and laboratory data, including iCa, collected at routine outpatient visits. The patients were divided into the first, second, and third tertile of iCa/cCa ratio groups to compare patient background and laboratory data. Multiple regression analysis was used to investigate the factors influencing iCa/cCa ratio. We used multiple imputation to deal with missing covariate data., Results: In total, 169 PD patients were enrolled. In PD patients with lower iCa/cCa ratio, PD duration was longer and pH was higher. Urine volume and weekly renal Kt/V were lower in the patients with lower iCa/cCa ratio than in those with higher iCa/cCa ratio. iCa/cCa ratio and weekly renal Kt/V were directly correlated (r = 0.41, p < 0.01), and weekly renal Kt/V and pH were independent factors affecting iCa/cCa ratio (t = 2.86, p < 0.01 and t = - 5.42, p < 0.01, respectively)., Conclusions: iCa levels were lower in PD patients with lower residual renal function (RRF) even though their cCa levels were equal to those with maintained RRF, warranting caution in the assessment and management of CKD-MBD in PD patients.

Dietary triglycerides influence fatty acid (FA) serum concentrations and weight percentages (wt %), which may be associated with the age of onset of acute ischemic stroke (AIS). We investigated the correlations between serum FA levels and proportions at admission and the age of onset of AIS. We evaluated patients with AIS admitted between 2016 and 2019 within 24 h of AIS onset and calculated the correlation coefficients between their ages, serum FA concentrations, and FA wt % values. Multiple linear regression analysis was performed to identify independent FAs indicating AIS age of onset. Furthermore, we estimated the threshold values of independent FAs for age of onset <60 years using receiver operating characteristic curves by logistic regression. A total of 525 patients (median age: 75 years) met the inclusion criteria. The concentration of dihomo-gamma-linolenic acid (DGLA) and wt % of docosahexaenoic acid (DHA) were significant independent variables for age of onset of AIS, and receiver operating characteristic curves for age of onset <60 years showed thresholds of ≥117.7 µmol/L for DGLA and ≤3.7% for DHA. An increased DGLA concentration and decreased DHA wt % were significantly associated with onset of AIS at a younger age.

Carotenoids are essential components of photosynthetic organisms including land plants, algae, cyanobacteria, and photosynthetic bacteria. Although the light-mediated regulation of carotenoid biosynthesis, including the light/dark cycle as well as the dependence of carotenoid biosynthesis-related gene translation on light wavelength, has been investigated in land plants, these aspects have not been studied in microalgae. Here, we investigated carotenoid biosynthesis in Euglena gracilis and found that zeaxanthin accumulates in the dark. The major carotenoid species in E. gracilis, namely β-carotene, neoxanthin, diadinoxanthin and diatoxanthin, accumulated corresponding to the duration of light irradiation under the light/dark cycle, although the translation of carotenoid biosynthesis genes hardly changed. Irradiation with either blue or red-light (3 μmol photons m -2  s -1 ) caused a 1.3-fold increase in β-carotene content compared with the dark control. Blue-light irradiation (300 μmol photons m -2  s -1 ) caused an increase in the cellular content of both zeaxanthin and all trans-diatoxanthin, and this increase was proportional to blue-light intensity. In addition, pre-irradiation with blue-light of 3 or 30 μmol photons m -2  s -1 enhanced the photosynthetic activity and tolerance to high-light stress. These findings suggest that the accumulation of β-carotene is regulated by the intensity of light, which may contribute to the acclimation of E. gracilis to the light environment in day night conditions., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to declare., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Natively paired sequencing (NPS) of B cell receptors [variable heavy (VH) and light (VL)] and T cell receptors (TCRb and TCRa) is essential for the understanding of adaptive immunity in health and disease. Despite many recent technical advances, determining the VH:VL or TCRb:a repertoire with high accuracy and throughput remains challenging. We discovered that the recently engineered xenopolymerase, RTX, is exceptionally resistant to cell lysate inhibition in single-cell emulsion droplets. We capitalized on the characteristics of this enzyme to develop a simple, rapid, and inexpensive in-droplet overlap extension reverse transcription polymerase chain reaction method for NPS not requiring microfluidics or other specialized equipment. Using this technique, we obtained high yields (5000 to >20,000 per sample) of paired VH:VL or TCRb:a clonotypes at low cost. As a demonstration, we performed NPS on peripheral blood plasmablasts and T follicular helper cells following seasonal influenza vaccination and discovered high-affinity influenza-specific antibodies and TCRb:a., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)

Carotenoids are the most universal and most widespread pigments in nature. They have played pivotal roles in the evolution of photosensing mechanisms in microbes and of vision in animals. Several groups of phytoflagellates developed a photoreceptive organelle called the eyespot apparatus (EA) consisting of two separable components: the eyespot, a cluster of carotenoid-rich globules that acts as a reflector device, and actual photoreceptors for photobehaviors. Unlike other algal eyespots, the eyespot of Euglenophyta lacks reflective properties and is generally considered to act as a shading device for the photoreceptor (paraflagellar body, PFB) for major photomovements. However, the function of the eyespot of Euglenophyta has not yet been fully proven. Here, we report that the blocking carotenoid biosynthesis in Euglena gracilis by suppressing the phytoene synthase gene (crtB) caused a defect in eyespot function resulting in a loss of phototaxis. Raman spectroscopy and transmission electron microscopy suggested that EgcrtB-suppressed cells formed eyespot globules but had a defect in the accumulation of carotenoids in those packets. Motion analysis revealed the loss of phototaxis in EgcrtB-suppressed cells: a defect in the initiation of turning movements immediately after a change in light direction, rather than a defect in the termination of cell turning at the appropriate position due to a loss of the shading effect on the PFB. This study revealed that carotenoids are essential for light perception by the EA for the initiation of phototactic movement by E. gracilis, suggesting one possible photosensory role of carotenoids in the EA for the phototaxis., (© 2019 The Authors. The Plant Journal published by Society for Experimental Biology and John Wiley & Sons Ltd.)

The T cell repertoire in each individual includes T cell receptors (TCRs) of enormous sequence diversity through the pairing of diverse TCR α- and β-chains, each generated by somatic recombination of paralogous gene segments. Whether the TCR repertoire contributes to susceptibility to infectious or autoimmune diseases in concert with disease-associated major histocompatibility complex (MHC) polymorphisms is unknown. Due to a lack in high-throughput technologies to sequence TCR α-β pairs, current studies on whether the TCR repertoire is shaped by host genetics have so far relied only on single-chain analysis. Using a high-throughput single T cell sequencing technology, we obtained the largest paired TCRαβ dataset so far, comprising 965,523 clonotypes from 15 healthy individuals including 6 monozygotic twin pairs. Public TCR α- and, to a lesser extent, TCR β-chain sequences were common in all individuals. In contrast, sharing of entirely identical TCRαβ amino acid sequences was very infrequent in unrelated individuals, but highly increased in twins, in particular in CD4 memory T cells. Based on nucleotide sequence identity, a subset of these shared clonotypes appeared to be the progeny of T cells that had been generated during fetal development and had persisted for more than 50 y. Additional shared TCRαβ in twins were encoded by different nucleotide sequences, implying that genetic determinants impose structural constraints on thymic selection that favor the selection of TCR α-β pairs with entire sequence identities., Competing Interests: The authors declare no competing interest.