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Background: The coronavirus disease 2019, caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), has become a global epidemic. There are concerns regarding the severity of SARS-CoV-2 infections in kidney transplant (KTx) recipients. However, there is limited data on how the epidemic has affected the treatment and prognosis of these patients. Therefore, we aimed to report the changes in the treatment and outcomes of KTx recipients infected with SARS-CoV-2 during each wave at our institution., Methods: A total of 282 KTx recipients who were infected with SARS-CoV-2 during the study period were followed up at Tokyo Women's Medical University between March 2020 and August 2022. We investigated the outcomes and treatments of infected KTx recipients., Results: Nineteen (6.7%) patients showed severe outcomes, including eight SARS-CoV-2 infection-related deaths. Risk factors associated with severe outcomes included underlying conditions, such as diabetes mellitus, heart disease, and liver disease (odds ratios, 2.09, 2.88, and 5.52, respectively). Treatment strategies changed throughout the epidemic in response to changes in the SARS-CoV-2 variants. Antiviral drugs were gradually administered as soon as they were approved for use., Conclusions: Treatment strategies for KTx recipients were gradually established over the course of the epidemic. Although the proportion of infected KTx recipients decreased compared to that of the general population throughout the epidemic, many patients still followed a severe course., (© 2024. The Author(s), under exclusive licence to Japanese Society of Nephrology.)

Poor post-vaccination production of antibody against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a concern among solid organ transplant (SOT) recipients. Furthermore, the timing and kinetics of antibody titers after the second vaccine dose are unknown. We conducted a multicenter prospective observational study that included 614 SOT recipients: 460 kidney, 53 heart, 50 liver, 20 lung, and 31 simultaneous pancreas-kidney (SPK). The participants received two doses of the mRNA vaccine (Pfizer BNT162b2 or Moderna mRNA-1273), as indicated. Serum samples were collected before the first and second vaccinations and at 1, 3, and 6 months after the second vaccine dose, which were then assessed for SARS-CoV-2 antibodies. The overall seropositivity rate was 43% at 1 month after administration of the second vaccine dose; it gradually increased to 68% at 3 months after second dose administration and to 70% at 6 months. In addition, recipient of kidney, lung or SPK transplants had lower antibody titers at the 3- and 6-month time points than did the other recipients. SOT recipients acquired SARS-CoV-2 S-IgG antibodies slowly, and the peak titer differed significantly from that of the general population., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Yoshio Hirota reports financial support was provided by Health Labor Administration. Yoshio Hirota reports a relationship with Japan Health Labor Administration that includes: funding grants. The authors of this manuscript have no conflicts of interest to disclose as described by the Vaccine. If there are other authors, they 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 © 2024 Elsevier Ltd. All rights reserved.)

Background: Kidney transplantation is a well-established alternative in renal replacement therapy. Compared with hemodialysis, low-immunological-risk kidney transplantation can reduce the medical treatment costs associated with end-stage renal disease. However, there are few reports on whether high-immunological-risk kidney transplantation reduces the financial burden on governments. We investigated the medical costs of high-immunological-risk kidney transplantation in comparison with the cost of hemodialysis in Japan., Methods: We compared the medical costs of high-immunological-risk kidney transplantation with those of hemodialysis. 15 patients who underwent crossmatch-positive and/or donor-specific antibody-positive kidney transplantations between 2020 and 2021 were enrolled in this study. The patients received intravenous immunoglobulin, plasmapheresis, and rituximab as desensitizing therapy., Results: Acute antibody-mediated rejection was detected in nine (60%) recipients, while there were no indications of graft function deterioration during the follow-up. For each patient, the transplant hospitalization cost was 38 428 ± 8789 USD. However, the cumulative costs were 59 758 ± 10 006 USD and 79 781 ± 16 366 USD, at 12 and 24 months, respectively. Compared with hemodialysis (34 286 USD per year), high-immunological-risk kidney transplantation tends to be expensive in the first year, but the cost is likely to be lower than that of hemodialysis after 3 years., Conclusions: Although kidney transplantation is initially expensive compared with hemodialysis, the medical cost becomes advantageous after 3 years even in kidney transplant recipients with high immunological risk., (© 2024 The Japanese Urological Association.)

Background: Brain natriuretic peptides (BNP) are an important diagnostic and prognostic marker in patients with heart failure. However, the relationship between BNP levels and stroke severity in patients with atrial fibrillation (AF) remains unelucidated. In this study, we aimed to investigate the association between stroke severity at admission and BNP levels., Methods: In this prospective observational study, we used data from 513 patients with AF and acute ischemic stroke treated with oral anticoagulants (OAC) registered in the Multicenter Prospective Analysis of Stroke Patients Taking Oral Anticoagulants study. The patients were divided into two groups: high-BNP (≥200 pg/mL) and low-BNP level (<200 pg/mL) groups. We compared the clinical characteristics between the two groups and determined the effect of BNP levels on stroke severity on admission., Results: Among the 513 enrolled patients, 248 (females, n = 30; median age, 82 years) and 265 (females, n = 76; median age, 71 years) were assigned to the high- and low-BNP level groups, respectively. The high-BNP level group had a higher proportion of patients with severe stroke (National Institutes of Health Stroke Scale score, ≥10) on admission (49.2% vs. 32.8%, p = 0.002) and major vessel occlusion (57.5% vs. 39.2%, p < 0.0001) than that had by the low-BNP level group. Multivariate analysis showed that high BNP level was independently associated with severe stroke on admission (odds ratio 1.07, 95% confidence interval 1.00-1.15; p = 0.0478)., Conclusions: High BNP level compared with low BNP level was associated with severe stroke and major vessel occlusion, even before OAC treatment., Competing Interests: Declaration of competing interest S.S. received research funding from the All Japan Coffee Association and lecture fees from Daiichi Sankyo Co. Ltd. and Eisai Co., Ltd. Y.I. received lecture fees from Bayer Healthcare Co. Ltd., Pfizer Japan Inc., Nippon Boehringer Ingelheim Co. Ltd., Takeda Pharmaceutical Co. Ltd., Otsuka Pharmaceutical Co., Ltd., and Daiichi Sankyo Co. Ltd. Research funding was obtained from Sanofi Co., Ltd. Y.Y. received lecture fees from Daiichi Sankyo Co. Ltd. T.K. received lecture fees from Bayer Healthcare Co. Ltd., Nippon Boehringer Ingelheim Co. Ltd., and Daiichi Sankyo Co. Ltd. S.F. received personal lecture fees (not related to the current work) from Takeda Pharmaceutical Co. Ltd., Nippon Boehringer Ingelheim, Co. Ltd., Otsuka Pharmaceutical, Co. Ltd., Bayer Yakuhin, Ltd., Pfizer Japan Inc., Daiichi Sankyo Co. Ltd., Eisai Co. Ltd., and Bristol-Myers Squibb Co. Ltd. K.K. received lecture fees from Bristol-Myers Squibb Co. Ltd., Nippon Boehringer Ingelheim Co. Ltd., Bayer Healthcare Co. Ltd., and Daiichi Sankyo Co. Ltd. Research funding from Nippon Boehringer Ingelheim Co. Ltd. And Daiichi Sankyo Co. Ltd., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Recent developments in intensive desensitization protocols have enabled kidney transplantation in human leukocyte antigen (HLA)-sensitized recipients. However, cases of active antibody-mediated rejection (AABMR), when they occur, are difficult to manage, graft failure being the worst-case scenario. We aimed to assess the impact of our desensitization and AABMR treatment regimen and identify risk factors for disease progression. Among 849 patients who underwent living-donor kidney transplantation between 2014 and 2021 at our institution, 59 were diagnosed with AABMR within 1 year after transplantation. All patients received combination therapy consisting of steroid pulse therapy, intravenous immunoglobulin, rituximab, and plasmapheresis. Multivariable analysis revealed unrelated donors and preformed donor-specific antibodies as independent risk factors for AABMR. Five-year death-censored graft survival rate was not significantly different between patients with and without AABMR although 27 of 59 patients with AABMR developed chronic AABMR (CABMR) during the study period. Multivariate Cox proportional hazard regression analysis revealed that a donor age greater than 59 years and microvascular inflammation (MVI) score (g + ptc) ≥4 at AABMR diagnosis were independent risk factors for CABMR. Our combination therapy ameliorated AABMR; however, further treatment options should be considered to prevent CABMR, especially in patients with old donors and severe MVI., 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 © 2024 Banno, Hirai, Oki, Yagisawa, Unagami, Kanzawa, Omoto, Shimizu, Ishida and Takagi.)

Background and Purpose: The impact of CHADS 2 score on outcome in patients with stroke taking an oral anticoagulant (OAC) has not yet been fully elucidated. We investigated the association between pre-stroke CHADS 2 score and outcome at discharge in patients with acute cardioembolic (CE) stroke due to atrial fibrillation (AF) who were prescribed OAC., Methods: The data of 548 OAC-treated patients with AF and CE stroke who were registered in the multicenter Prospective Analysis of Stroke patients Taking oral Anticoagulants (PASTA) study were analyzed. High CHADS 2 score was defined as a pre-stroke CHADS 2 score ≥2. Unfavorable outcome was defined as a modified Rankin scale (mRS) of 3-6. The impacts of pre-stroke CHADS 2 score on outcome at discharge were evaluated using multiple logistic regression analysis., Result: A high CHADS 2 score was found in 472/548 patients and unfavorable outcome was found in 330/548 patients. In patients with unfavorable outcome, age, male sex, pre-stroke CHADS2 score, initial National Institute Health Stroke Scale (NIHSS) score, and glucose level on admission were significantly higher, whereas creatinine clearance and body weight were significantly lower, than those with favorable outcome (each p < 0.001). Multivariate logistic regression analysis indicated that high CHADS 2 score (OR 2.18, 95 %CI 1.08-4.42, p = 0.031), pre-stroke mRS (OR 2.21, 95 %CI 1.69-2.67, p < 0.001), and initial NIHSS score (OR 1.19, 95 %CI 1.17-1.24, p < 0.001) were independently associated with unfavorable outcome., Conclusion: Pre-stroke CHADS 2 score was associated with poor outcome in patients with cardioembolic stroke due to AF, even in those taking OAC., Competing Interests: Declaration of Competing Interest S.S received research funding from Pfizer Co., Ltd and lecture fees from Daiichi Sankyo Co. Ltd, Eisai Co., Ltd, and Bristol-Myers Squibb Co. Ltd. Y.I. received lecture fees from Bayer Healthcare Co. Ltd.; Pfizer Japan Inc.; Nippon Boehringer Ingelheim Co. Ltd.; Takeda Pharmaceutical Co. Ltd.; Otsuka Pharmaceutical Co., Ltd.; and Daiichi Sankyo Co. Ltd. Research funding was obtained from Sanofi Co., Ltd. Y.Y. received lecture fees from Daiichi Sankyo Co. Ltd. T.K. received lecture fees from Bayer Healthcare Co. Ltd.; Nippon Boehringer Ingelheim Co. Ltd.; and Daiichi Sankyo Co. Ltd. S.F. received personal lecture fees (not related to the current work) from Takeda Pharmaceutical Co. Ltd.; Nippon Boehringer Ingelheim, Co. Ltd.; Otsuka Pharmaceutical, Co. Ltd.; Bayer Healthcare Co. Ltd.; Pfizer Japan Inc.; Daiichi Sankyo Co. Ltd.; Eisai Co. Ltd.; and Bristol-Myers Squibb Co. Ltd. K.K. received lecture fees from Bristol-Myers Squibb Co. Ltd.; Nippon Boehringer Ingelheim Co. Ltd.; Bayer Healthcare Co. Ltd.; and Daiichi Sankyo Co. Ltd. Research funding was received from Nippon Boehringer Ingelheim Co. Ltd. and Daiichi Sankyo Co. Ltd., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Purpose: To investigate the rate and timing of oral anticoagulant (OAC) resumption and its safety in patients after intracerebral hemorrhage (ICH) in current clinical practice in Japan., Methods: We conducted a sub-analysis of the PASTA registry, an observational, multicenter registry of 1043 patients with stroke receiving OACs in Japan, by including patients with ICH on OAC treatment for non-valvular atrial fibrillation (NVAF). The clinical characteristics of the patients in the resumption and non-resumption groups, rate and timing of OAC resumption, its safety, and switching of OACs after ICH were investigated., Results: Of the 160 patients (women, n = 52; median age, 77 years) included, OACs were resumed in 108 (68%) at a median of 7 days (interquartile range, 4-11) after acute ICH onset. The non-resumption group had higher rates of hematoma expansion (21.2% vs. 7.4%; P = 0.0118) and modified Rankin Scale (mRS) scores at discharge (4 (Suda et al., 2019; Steiner et al., 2014 [3, 4]) vs. 4 (Suda et al., 2019; Steiner et al., 2014; Pasquini et al., 2014 [3-5]); P = 0.0302}. The resumption rate in the mRS 0-4 group was higher than that in the mRS 5 group (75.2% vs. 46.5%; P = 0.00006). The number of days to resumption after ICH onset was longer in the mRS 5 than that in the mRS 0-4 group (median 12 days vs. 7 days, P = 0.0065). There were no significant differences in new-onset ICH, symptomatic hematoma expansion, or gastrointestinal bleeding between groups (P > 0.05)., Conclusions: Early resumption of OAC for NVAF in patients after ICH appeared to be safe. Expected functional outcomes at discharge were associated with OAC resumption and with the timing of resumption., Registration: https://upload.umin.ac.jp/cgi-open-bin/ctr&#95;e/ctr&#95;view.cgi?recptno=R000034958., Competing Interests: Declaration of Competing Interest S·S received research funding from the All Japan Coffee Association and Pfizer Co., Ltd. and lecture fees from Daiichi Sankyo Co. Ltd., Eisai Co., Ltd. and, and Bristol-Myers Squibb Co. Ltd. Y.I. received lecture fees from Bayer Healthcare Co. Ltd.; Pfizer Japan Inc.; Nippon Boehringer Ingelheim Co. Ltd.; Takeda Pharmaceutical Co. Ltd.; Otsuka Pharmaceutical Co., Ltd.; and Daiichi Sankyo Co. Ltd. Research funding was obtained from Sanofi Co., Ltd. T.K. received lecture fees from Bayer Healthcare Co. Ltd.; Nippon Boehringer Ingelheim Co. Ltd.; and Daiichi Sankyo Co. Ltd. S.F. received personal lecture fees (not related to the current work) from Takeda Pharmaceutical Co. Ltd.; Nippon Boehringer Ingelheim, Co. Ltd.; Otsuka Pharmaceutical, Co. Ltd.; Bayer Healthcare Co. Ltd.; Pfizer Japan Inc.; Daiichi Sankyo Co. Ltd.; Eisai Co. Ltd.; and Bristol-Myers Squibb Co. Ltd. Y.K. received research funding from Sanofi Co. Ltd. K.K. received lecture fees from Bristol-Myers Squibb Co. Ltd.; Nippon Boehringer Ingelheim Co. Ltd.; Bayer Healthcare Co. Ltd.; and Daiichi Sankyo Co. Ltd. Research funding from Nippon Boehringer Ingelheim Co. Ltd. and Daiichi Sankyo Co. Ltd., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Objective In recent decades, living conditions have changed drastically. However, there are few data regarding the interaction between living conditions and the risk of ischemic stroke (IS) in young adults. The present study explored the association between living conditions or marital status and the risk factors, etiology, and outcome of IS in young adults. Methods We prospectively enrolled patients with incident IS who were 20-49 years old from 37 clinical stroke centers. We collected the demographic data, living conditions, marital status, vascular risk factors, disease etiology, treatment, and outcomes at discharge. A comparison group was established using the official statistics of Japan. We categorized patients into the two groups based on living conditions: solitary group and cohabiting group. Clinical characteristics were then compared between living conditions. Results In total, 303 patients were enrolled (224 men; median age at the onset: 44 years old). Significant factors associated with the incidence of IS were as follows: solitary status, body mass index >30 kg/m 2 , current smoking, heavy alcohol consumption, hypertension, diabetes mellitus, and dyslipidemia. Furthermore, in the solitary group, the proportions of men, unmarried individuals, and current smokers were significantly higher than in the cohabiting group. In addition, poor outcomes (modified Rankin Scale ≥4) of IS were more common in the solitary group than in the cohabiting group. Conclusion Our study showed that not only conventional vascular risk factors but also living conditions, especially living alone while unmarried, were independent risk factors for IS in young adults.

Background: The safety of intravenous recombinant tissue plasminogen activator (rtPA) and mechanical thrombectomy (MT) in patients treated with direct oral anticoagulants (DOACs) before stroke has not been fully investigated. Therefore, we aimed to investigate the safety of recanalization therapy in patients receiving DOACs., Methods: We assessed data from a prospective multicenter registry of patients with stroke, including those with acute ischemic stroke (AIS) treated with rtPA and/or MT who were administered DOACs. We evaluated the safety of recanalization considering the DOACs dosage and interval between the last DOAC intake and recanalization., Results: The final analysis included 108 patients (women, n = 54; median age, 81 years; DOAC overdose, n = 7; appropriate dose, n = 74; and inappropriate low dose, n = 27). The rate of any ICH differed significantly among overdose-, appropriate dose-, and inappropriate-low dose DOACs groups (71.4, 23.0, and 33.3%, respectively; P = 0.0121), whereas no significant difference was observed in respect of symptomatic ICH (P = 0.6895). Multivariate analysis showed that the National Institutes of Health Stroke Scale score on admission (odds ratio [OR]: 1.06, 95% confidence interval [CI]: 1.01-1.11; P = 0.0267) and overdose-DOAC (OR: 8.40, 95% CI: 1.24-56.88; P = 0.0291) were independently associated with any ICH. No relationship was observed between the timing of the last DOAC intake and occurrence of ICH in patients treated with rtPA and/or MT (all P > 0.05)., Conclusion: Recanalization therapy during DOAC treatment may be safe in selected patients with AIS, if it is performed >4 h after the last DOAC intake and the patient is not overdosed with DOACs., Registration: https://upload.umin.ac.jp/cgi-open-bin/ctr&#95;e/ctr&#95;view.cgi?recptno=R000034958., Competing Interests: Declaration of Competing Interest S·S received research funding from the All Japan Coffee Association and Pfizer Co., Ltd. and lecture fees from Daiichi Sankyo Co. Ltd. and Eisai Co., Ltd. Y.I. received lecture fees from Bayer Healthcare Co. Ltd.; Pfizer Japan Inc.; Nippon Boehringer Ingelheim Co. Ltd.; Takeda Pharmaceutical Co. Ltd.; Otsuka Pharmaceutical Co., Ltd.; and Daiichi Sankyo Co. Ltd. Research funding was obtained from Sanofi Co., Ltd. T.K. received lecture fees from Bayer Healthcare Co. Ltd.; Nippon Boehringer Ingelheim Co. Ltd.; and Daiichi Sankyo Co. Ltd. S.F. received personal lecture fees (not related to the current work) from Takeda Pharmaceutical Co. Ltd.; Nippon Boehringer Ingelheim, Co. Ltd.; Otsuka Pharmaceutical, Co. Ltd.; Bayer Healthcare Co. Ltd.; Pfizer Japan Inc.; Daiichi Sankyo Co. Ltd.; Eisai Co. Ltd.; and Bristol-Myers Squibb Co. Ltd. Y.K. received research funding from Sanofi Co. Ltd. K.K. received lecture fees from Bristol-Myers Squibb Co. Ltd.; Nippon Boehringer Ingelheim Co. Ltd.; Bayer Healthcare Co. Ltd.; and Daiichi Sankyo Co. Ltd. Research funding from Nippon Boehringer Ingelheim Co. Ltd. and Daiichi Sankyo Co. Ltd., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background and Purpose: Prior concomitant use of vitamin K antagonists (VKAs) and antiplatelet (AP) therapy increase the hematoma volume and mortality compared with VKA monotherapy in patients with intracranial hemorrhage (ICH). However, the prior concomitant use of non-vitamin K oral antagonists (NOACs) and AP has not been clarified., Methods: We conducted a PASTA registry study, which was an observational, multicenter, registry of 1043 patients with stroke receiving oral anticoagulants (OACs) in Japan. In the present study, ICH from the PASTA registry was used to analyze the clinical characteristics including mortality among the four groups (NOAC, VKA, NOAC and AP, and VKA and AP) using univariate and multivariate analyses., Results: Among the 216 patients with ICH, 118 (54.6%), 27 (12.5%), 55 (25.5%), 16 (7.4%) were taking NOAC monotherapy, NOAC and AP, VKA, and VKA and AP, respectively. In-hospital mortality rates were the highest in VKA and AP (31.3%) than in NOACs (11.9%), NOACs and AP (7.4%), and VKA (7.3%). Multivariate logistic regression analysis demonstrated that the concomitant use of VKA and AP (odds ratio [OR], 20.57; 95% confidence interval [CI], 1.75-241.75, p = 0.0162), initial National Institutes of Health Stroke Scale score (OR, 1.21; 95%CI, 1.10-1.37, p < 0.0001), hematoma volume (OR, 1.41; 95%CI, 1.10-1.90, p = 0.066), and systolic blood pressure (OR, 1.31; 95%CI, 1.00-1.75, p = 0.0422) were independently associated with in-hospital mortality., Conclusions: Although VKA in addition to AP therapy could increase the in-hospital mortality, NOAC and AP did not increase the hematoma volume, stroke severity, or mortality compared to NOAC monotherapy., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Pregnancy in kidney transplantation (KT) recipients has been challenging because of the high risk of maternal, fetal, and renal complications. Although patients with immunoglobulin A nephropathy (IgAN)-chronic kidney disease (CKD) are at a high risk for hypertension in pregnancy (HIP), the maternal risk in KT recipients with IgAN as the etiology remains unclear. We retrospectively reviewed the medical records of pregnant KT recipients who delivered at our hospital. The incidence of maternal and fetal complications and the impact on kidney allografts between the group with IgAN as the primary kidney disease and the group with other primary diseases were compared. The analysis included 73 pregnancies in 64 KT recipients. The IgAN group had a higher incidence of HIP than the non-IgAN group (69% vs. 40%, p = 0.02). IgAN as primary kidney disease and interval from transplantation to conception were associated with HIP (OR 3.33 [1.11-9.92], p = 0.03, OR 0.83 [0.72-0.96], p < 0.01, respectively). The 20-year graft survival or prevention of CKD stage 5 in group with IgAN was lower than that in the group with other primary disease ( p < 0.01). KT recipients should be informed of the risk of HIP and possibility of long-term worsening of postpartum renal function., 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 Oki, Unagami, Kakogawa, Beppu, Banno, Yagisawa, Kanzawa, Hirai, Omoto, Kitajima, Shirakawa, Hoshino, Takagi and Ishida.)

Background: Kidney transplantation (KTx) after urinary tract conversion surgery is extremely difficult due to several complications. In our case, KTx was performed after multiple operative procedures, including diversion urethrostomy., Case Report: The patient was a 46-year-old woman with a right atrophic kidney, an ectopic opening of the left ureter, and urethral dysplasia since birth. The patient underwent a right nephrectomy, left ureteral sigmoidostomy, Stamey surgery, augmentation ileocystoplasty, and left ureteroileostomy. Thereafter, she underwent nephrostomy, ileal conduit diversion, open sigmoid colectomy, and total cystectomy because of persistent urinary incontinence, sigmoid colon cancer, and recurrent cystitis. Her renal function gradually deteriorated, and hemodialysis was initiated. Before the KTx, she underwent laparoscopic left nephrectomy, an intraperitoneal adhesion debridement, and left ileal conduit resection. We dissected the left ileal conduit in the abdominal cavity and penetrated the anorectal side of the free ileal conduit into the wall of the right side of the abdomen. Thereafter, a kidney from a living donor was transplanted into the right iliac fossa through the existing right ileal conduit when the patient was 46 years old. The allograft function was stable without rejection for 2 years., Conclusions: We report the case of a patient who underwent multiple urethral modifications followed by ileal conduit transfer and living donor KTx, which progressed without major postoperative complications., Competing Interests: Declaration of Competing Interest All the authors declare 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.)

Introduction: Transplant recipients (TRs) are at high risk for severe coronavirus disease 2019 (COVID-19). Neutralizing monoclonal antibodies (mAbs) are used for treating mild-to-moderate COVID-19. However, reports comparing the efficacy of COVID-19 treatment without/with mAbs in TRs are limited. We assessed the efficacy of casirivimab/imdevimab against mild-to-moderate COVID-19 in TRs., Methods: Forty-one patients were retrospectively evaluated. The duration until defervescence, oxygen (O 2 ) requirement ≥5 L, and neutralizing antibody levels were compared in TRs with COVID-19 without/with casirivimab/imdevimab., Results: Casirivimab/imdevimab was correlated with shorter duration until defervescence and non-requirement of O 2  ≥ 5 L in TRs with COVID-19 [mean: without/with: 6 vs. 2; P = 0.0002, hazard ratio (HR) = 0.3333, 95% confidence interval (CI) = 0.1763-0.6301; 15 vs. 8; P < 0.0001, HR = 0.5333, 95% CI = 0.2878-0.9883; P = 0.0377, HR = 0.1502, 95% CI = 0.02511-0.8980]. Casirivimab/imdevimab was associated with early defervescence after adjusting for sex and age (P = 0.013, HR = 0.412, 95% CI = 0.205-0.826). The antibody levels between patients without/with casirivimab/imdevimab on the day of hospitalization were not significantly different (P = 0.1055), including 13 TRs with vaccination. Antibody levels were higher in patients with casirivimab/imdevimab at 3-5 days after hospitalization than in those without, at 7-9 days after hospitalization (P < 0.0001, mean, without/with: 414.9/40000 AU/mL)., Conclusion: Casirivimab/imdevimab was effective and increased the neutralizing antibody in TRs with mild-to-moderate COVID-19, it may contribute toward preventing the progression., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Aim: This study aimed to assess the potential effect of prior antithrombotic medication for thrombolysis in an unknown onset stroke., Methods: This was a predefined sub-analysis of the THAWS trial. Stroke patients with a time last known well ＞4.5 h who had a DWI-fluid-attenuated inversion recovery mismatch were randomly assigned (1:1) to receive alteplase at 0.6 mg/kg (alteplase group) or standard medical treatment (control group). Patients were dichotomized by prior antithrombotic medication., Results: Of 126 patients (intention-to-treat population), 40 took antithrombotic medication (24 with antiplatelets alone, 13 with anticoagulants alone, and 3 with both), and the remaining 86 did not before stroke onset. Of these, 17 and 52 patients, respectively, received alteplase, and 23 and 34, respectively, had standard medical treatment. Antithrombotic therapy was initiated within 24 h after randomization less frequently in the alteplase group (12% vs. 86%, p＜0.01). Both any intracranial hemorrhage within 22-36 h (26% vs. 14%) and a modified Rankin Scale score of 0-1 at 90 days (good outcome) (47% vs. 48%) were comparable between the two groups. A good outcome was more common in the alteplase group than in the control group in patients with prior antithrombotic medication [relative risk (RR) 2.25, 95% confidence interval (CI) 1.02-4.99], but it tended to be less common in the alteplase group in those without (RR 0.69, 95% CI 0.46-1.03) (p＜0.01 for interaction). The frequency of any intracranial hemorrhage did not significantly differ between the two groups in any patients dichotomized by prior antithrombotic medication., Conclusion: Alteplase appears more beneficial in patients with prior antithrombotic medication.

Objectives: Many researchers have demonstrated that the seropositivity rate after SARS-CoV-2 coronavirus vaccination is lower in patients receiving oral immunosuppressants. In this article, we report on a comparative study on the seropositivity rate after 2 doses of coronavirus vaccine before or after kidney transplant., Materials and Methods: We studied 111 recipients vaccinated after transplant, 19 patients vaccinated before transplant, and 10 healthy patients. We retrospectively measured antibody titers using preserved serum samples. The antibody testing was performed 1 month and 3 months after vaccination. The measurement was via LABScreen COVID Plus, which enables simultaneous determination of 5 coronavirus protein antigens., Results: Seropositivity to coronavirus antibodies was observed in all 19 patients vaccinated before transplant (100%) and in all the 10 healthy patients (100%). Forty- six of the 111 recipients (42%) vaccinated after transplant developed seropositivity. Analyzed at each time point after vaccination, the mean fluorescence intensity of antibodies was unchanged between 1 month and 3 months after vaccination in transplant recipients who were vaccinated after transplant and developed seropositivity. On the other hand, the antibody mean fluorescence intensity in patients vaccinated before transplant was markedly lower at 3 months (posttransplant)., Conclusions: All patients with renal failure who were vaccinated before transplant showed a high seropositivity rate, similar to that in healthy patients. The seropositivity rate for each of the viral fragment antibodies in patients vaccinated before transplant was maintained, as seen in healthy patients. However, in patients vaccinated before transplant who tested positive for antibody production at 1 month after vaccination,the antibody mean fluorescence intensity at 3 months after vaccination (posttransplant) was remarkedly lower than the mean fluorescence intensity at 1 month, which was probably caused by the types of immunosuppressive regimens used atthe time of transplant.

Background and Purpose: Prescribing under-dose direct oral anticoagulants (DOACs) for non-valvular atrial fibrillation (NVAF) is alerted to increase cardiovascular events or death. However, the association between dose selection of DOACs and the clinical course remains unclear. This study aimed to propose a novel criterion for selecting the DOAC dose and investigate clinical characteristics of ischemic stroke (IS) under this criterion., Methods: We assessed the pooled prospective multicenter registry data of stroke patients taking anticoagulant agents, including IS patients with NVAF and prior DOAC usage. The recommended dose according to the reduction criteria of each DOAC and the selected dose were identified for each patient, and patients were categorized into four groups: no alternative low-dose, selecting low-dose appropriately with all DOACs applicable for reduction criteria; selected low-dose, selecting low-dose appropriately or inappropriately despite at least one DOAC inapplicable for reduction criteria; selected standard-dose, appropriate standard-dose use; and absolute over-dose, inappropriate standard-dose regardless of criteria. We investigated the effects of dose selection of DOACs on short-term poor functional outcomes., Results: 322 patients were included in the analysis. The prevalence of no alternative low-dose, selected low-dose, selected standard-dose, and absolute over-dose was 74 (23%), 144 (45%), 89 (27%), and 15 (5%), respectively. Multivariable analysis found that the selected low-dose group showed significantly poorer functional outcomes than the selected standard-dose group only in patients without renal dysfunction (OR, 2.60; 95% CI, 1.17-6.00; P = 0.0186)., Conclusions: Selecting a low dose DOAC might be associated with poor functional outcomes in patients without renal dysfunction., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Objective Limited data exist regarding the comparative detailed clinical characteristics of patients with ischemic stroke (IS)/transient ischemic attack (TIA) and intracerebral hemorrhage (ICH) receiving oral anticoagulants (OACs). Methods The prospective analysis of stroke patients taking oral anticoagulants (PASTA) registry, a multicenter registry of 1,043 stroke patients receiving OACs [vitamin K antagonists (VKAs) or non-vitamin K antagonist oral anticoagulant (NOACs)] across 25 medical institutions throughout Japan, was used. Univariate and multivariable analyses were used to analyze differences in clinical characteristics between IS/TIA and ICH patients with atrial fibrillation (AF) who were registered in the PASTA registry. Results There was no significant differences in cardiovascular risk factors, such as hypertension, diabetes mellitus, dyslipidemia, smoking, or alcohol consumption (all p>0.05), between IS/TIA and ICH among both NOAC and VKA users. Cerebral microbleeds (CMBs) [odds ratio (OR), 4.77; p<0.0001] were independently associated with ICH, and high brain natriuretic peptide/N-terminal pro B-type natriuretic peptide levels (OR, 1.89; p=0.0390) were independently associated with IS/TIA among NOAC users. A history of ICH (OR, 13.59; p=0.0279) and the high prothrombin time-international normalized ratio (PT-INR) (OR, 1.17; p<0.0001) were independently associated with ICH, and a history of IS/TIA (OR, 3.37; 95% CI, 1.34-8.49; p=0.0101) and high D-dimer levels (OR, 2.47; 95% CI, 1.05-5.82; p=0.0377) were independently associated with IS/TIA among VKA users. Conclusion The presence of CMBs, a history of stroke, natriuretic peptide and D-dimer levels, and PT-INR may be useful for risk stratification of either IS/TIA or ICH development in patients with AF receiving OACs.

Background: Atrial fibrillation (AF) includes paroxysmal and sustained (persistent or permanent) AF, and both forms are considered risk factors for ischemic stroke. This study aimed to investigate the differences in stroke severity at admission between patients with paroxysmal AF and sustained AF when treated with direct oral anticoagulants (DOACs)., Methods: Using data from DOAC-treated 300 nonvalvular patients with AF and acute anterior circulation stroke who were registered in the Multicenter Prospective Analysis of Stroke Patients Taking Oral Anticoagulants study, patients were divided into two groups, namely, paroxysmal AF and sustained AF. We compared the clinical characteristics between the two groups and determined the effect of these two types of AF on stroke severity on admission., Results: Of 300 patients, 246 (males, n = 149; median age, 80 years) and 54 (males, n = 32; median age, 78 years) were assigned to the sustained AF and paroxysmal AF groups, respectively. The sustained AF group had a higher proportion of severe stroke (National Institutes of Health Stroke Scale score, >20) on admission (22.0% vs. 5.7%, p = 0.006) and internal carotid artery occlusion (11.4% vs. 1.9%, p = 0.03) compared to the paroxysmal AF group. Multivariate analysis showed that sustained AF was independently associated with severe stroke on admission (odds ratio 4.31, 95% confidence interval 1.24-15.0, p = 0.02)., Conclusions: Sustained AF was associated with a higher severity of stroke accompanied with major vessel occlusion than paroxysmal AF, even prior to DOACs treatment. Registration https://upload.umin.ac.jp/cgi-open-bin/ctr&#95;e/ctr&#95;view.cgi?recptno=R000034958., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Pediatric renal transplantation is associated with various surgical complications due to the complexity of the technique and the often-fragile condition of patients with end-stage renal disease. We evaluated the surgical complications associated with renal transplantation via the extraperitoneal approach in pediatric recipients. This retrospective study enrolled 280 patients younger than 16 years old who underwent renal transplantation via the extraperitoneal approach: 216 patients underwent transplant placement in the iliac fossa like in adults, and 64 underwent transplant placement in the distal part of the original renal lower pole (the extraperitoneal cavity). On the basis of the Clavien-Dindo classification, 30 patients (10.7%) showed grade 2 complications and 12 patients (4.3%) showed grade 3 or higher complications. None of the patients showed gastrointestinal complications. In a Cox regression analysis, grade 2 or higher complications were significantly associated with weight less than 15 kg (P = .027) and operative times longer than 245 minutes (P = .029). Among the 49 patients weighing less than 15 kg with an allograft placed in a distal portion of the original renal lower pole, only 3 patients (6.1%) developed surgical complications. Thus, allograft placement in the extraperitoneal cavity can be performed safely in children weighing less than 15 kg., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Transplantation outcomes are affected by the increase in rejection associated with ischemia reperfusion injury (IRI). Fractalkine (FKN), a chemokine for recruitment of CX3CR1 + leukocytes, contributes to the pathogenesis of various inflammatory diseases. Herein, we evaluated the importance of the FKN-CX3CR1 axis during IRI-related rejections using a mouse heterotopic heart transplantation model. FKN expression and graft survival was compared between wild-type C57BL/6 recipients transplanted with BALB/c hearts preserved for 8 (WT-IRI) and 0.5 h (WT-control) at 4°C. Graft survival of WT-IRI was shorter than that of WT-control. FKN was expressed on the vascular endothelium in WT-IRI allografts, but minimally in WT-control. The role of the FKN-CX3CR1 axis in IRI-related rejection was directly investigated using the transplant model with CX3CR1-deficient recipients (CX3CR1 KO-IRI) or treatment with anti-mouse FKN monoclonal antibodies. Graft survival of CX3CR1 KO-IRI was longer than that of WT-IRI; antibody treatment prolonged graft survival. The contribution of CX3CR1 + monocytes to IRI-related rejection was evaluated by adoptive transfer to CX3CR1 KO-IRI. Adoptive transfer of CX3CR1 + monocytes attenuated the effect of prolonged graft survival in CX3CR1 KO-IRI. Overall, the FKN-CX3CR1 axis plays a major role during IRI-related rejection; its blockade has the potential to improve the outcomes of deceased donor transplantation., Competing Interests: Author TI is employed by the company KAN Research Institute, Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Kanzawa, Tokita, Saiga, Yamakawa, Ishigooka, Fukuda, Katsumata, Miyairi, Ishii, Hirai, Imai, Okumi and Tanabe.)

Objectives: Antibody-mediated rejection in patients with positive crossmatches can be severe and result in sudden onset of oliguria, leading to graft loss. In an attempt to prevent posttransplant oliguria, we adopted a preoperative desensitization protocol involving the use of high-dose intravenous immunoglobulin/plasmapheresis and the anti-CD20 antibody, rituximab, in 41 transplant recipients with positive crossmatch test results., Materials and Methods: We retrospectively examined the clinical courses of the 41 kidney transplant recipients, paying special attention to renal graft function, urine volume, and changes in the titers of donor-specific antibodies., Results: Four grafts were lost during an average of 4.5-year follow-up. Average graft function was excellent, with a serum creatinine level of 1.3 ± 0.4 mg/dL. Sufficient urine output, with no oliguria or anuria, was achieved postoperatively in 40 of the 41 patients. However, among the 34 patients who underwent graft biopsies, the biopsies revealed acute antibody-mediated rejection in 21 patients (62%), and chronic antibodymediated rejection in 10 patients (30%)., Conclusions: The high-dose intravenous immunoglobulin treatment included in our desensitization protocol was shown to be safe and effective for achieving successful transplant outcomes and allowed the avoidance of more aggressive B-cell-targeted treatments, such as C5 inhibitors and/or proteosome inhibitors, for preventing posttransplant oliguria and anuria.

Background: Nephron-sparing surgery is required for patients with kidney transplant with organ-confined renal cell carcinoma (RCC) in the allograft kidney to preserve renal function. Robot-assisted laparoscopic partial nephrectomy (RAPN) is expected to be the optimal surgical approach for these patients, as in the general population. However, RAPN for RCC arising in the allograft kidney is rarely reported. Here, we report 2 cases of patients who underwent RAPN for allograft RCC., Case Presentation: Two patients were diagnosed with RCC in the renal allograft based on enhanced computed tomography findings. Case 1 was a 69-year-old man with a 32-mm mass in the middle portion of the right iliac fossa renal allograft, and case 2 was a 55-year-old man with a 24-mm mass in the lower pole of the right iliac fossa renal allograft. In each patient, RAPN was performed for the renal mass through a transperitoneal approach, with clamping of the renal artery. No major perioperative complications occurred in either patient, negative surgical margins were achieved, and no significant changes in kidney function were observed during either surgery. Pathologic findings showed clear cell RCC in case 1 and papillary RCC in case 2., Conclusion: RAPN can be a feasible and effective treatment option for allograft RCC., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background and Purpose: We determined to identify patients with unknown onset stroke who could have favorable 90-day outcomes after low-dose thrombolysis from the THAWS (Thrombolysis for Acute Wake-Up and Unclear-Onset Strokes With Alteplase at 0.6 mg/kg) database., Methods: This was a subanalysis of an investigator-initiated, multicenter, randomized, open-label, blinded-end point trial. Patients with stroke with a time last-known-well >4.5 hours who showed a mismatch between diffusion-weighted imaging (DWI) and fluid-attenuated inversion recovery were randomly assigned (1:1) to receive alteplase at 0.6 mg/kg intravenously or standard medical treatment. The patients were dichotomized by ischemic core size or National Institutes of Health Stroke Scale score, and the effects of assigned treatments were compared in each group. The efficacy outcome was favorable outcome at 90 days, defined as a modified Rankin Scale score of 0 to 1., Results: The median DWI-Alberta Stroke Program Early CT Score (ASPECTS) was 9, and the median ischemic core volume was 2.5 mL. Both favorable outcome (47.1% versus 48.3%) and any intracranial hemorrhage (26% versus 14%) at 22 to 36 hours were comparable between the 68 thrombolyzed patients and the 58 control patients. There was a significant treatment-by-cohort interaction for favorable outcome between dichotomized patients by ASPECTS on DWI ( P =0.026) and core volume ( P =0.035). Favorable outcome was more common in the alteplase group than in the control group in patients with DWI-ASPECTS 5 to 8 (RR, 4.75 [95% CI, 1.33-30.2]), although not in patients with DWI-ASPECTS 9 to 10. Favorable outcome tended to be more common in the alteplase group than in the control group in patients with core volume >6.4 mL (RR, 6.15 [95% CI, 0.87-43.64]), although not in patients with volume ≤6.4 mL. The frequency of any intracranial hemorrhage did not differ significantly between the 2 treatment groups in any dichotomized patients., Conclusions: Patients developing unknown onset stroke with DWI-ASPECTS 5 to 8 showed favorable outcomes more commonly after low-dose thrombolysis than after standard treatment. Registration: URL: https://www.clinicaltrials.gov; Unique Identifier: NCT02002325. URL: https://www.umin.ac.jp/ctr; Unique Identifier: UMIN000011630.

Dementia is a progressive cognitive syndrome, with few effective pharmacological treatments that can slow its progress. Hence, non-pharmacological treatments (NPTs) play an important role in improving patient symptoms and quality of life. Designing the optimal personalised NPT strategy relies on objectively and quantitatively predicting the treatment outcome. Magnetoencephalography (MEG) findings can reflect the cognitive status of patients with dementia, and thus potentially predict NPT outcome. In the present study, 16 participants with cognitive impairment underwent NPT for several months. Their cognitive performance was evaluated based on the Mini-Mental State Examination and the Alzheimer's Disease Assessment Scale - Cognitive at the beginning and end of the NPT period, while resting-state brain activity was evaluated using MEG during the NPT period. Our results showed that the spectral properties of MEG signals predicted the changes in cognitive performance scores. High frequency oscillatory intensity at the right superior frontal gyrus medial segment, opercular part of the inferior frontal gyrus, triangular part of the inferior frontal gyrus, post central gyrus, and angular gyrus predicted the changes in cognitive performance scores. Thus, resting-state brain activity may be a powerful tool in designing personalised NPT.

Purpose: This study aimed to evaluate the risk factors, etiology, and outcomes of ischemic stroke (IS) in Japanese young adults., Methods: This was a prospective multicenter study. We enrolled patients aged 16 to 55 years with IS within seven days of the onset of symptoms. We assessed the demographic data, risk factors, stroke etiology, and outcome at discharge. The clinical characteristics were compared between sexes and among age groups., Results: We prospectively enrolled 519 patients (median age, 48 years: 139 females). The mean National Institute of Health Stroke Scale score was 3.6 ± 0.2. The most common risk factors were hypertension (HT) (55%), dyslipidemia (DL) (47%), and current smoking (42%). Body mass index, incidence of current smoking, and heavy alcohol consumption were higher in males. The prevalence of current smoking, HT, DL, and diabetes mellitus increased with aging. The most common etiologic subgroup of IS was small vessel disease (145/510, 28%). Intracranial arterial dissection (IAD) was the most common among the other determined causes (56/115, 49%). The outcome at discharge was relatively good (mRS 0-1, 71.7%); however, poor outcome (mRS ≥ 4) was observed at an incidence of 9.5%., Conclusions: Most young adults with IS had modifiable risk factors, of which prevalence increased with age. This emphasizes lifestyle improvement to prevent IS in the young population. Furthermore, we indicated that the incidence rate of IAD was high among the other determined causes., (Copyright © 2020. Published by Elsevier B.V.)

Objectives: To compare the long-term outcome and complications of living-kidney grafts with arteriosclerosis to those without abnormal findings diagnosed using pretransplant graft biopsy, and to assess the impact of the arteriosclerosis in living-donor kidneys., Methods: The influence of arteriosclerosis in pretransplant biopsy on long-term outcomes and complications was evaluated in both unmatched (n = 1351, without arteriosclerosis n = 788 vs with arteriosclerosis n = 563) and propensity score-matched cohorts (n = 984, without arteriosclerosis n = 492 vs with arteriosclerosis n = 492) of adults who underwent living-kidney transplant., Results: In both the unmatched and matched cohort, there was no significant difference in patient and death-censored graft survival at 10 years between the without arteriosclerosis and with arteriosclerosis groups. The with arteriosclerosis group had a higher incidence rate of overall rejection than did the without arteriosclerosis group in both the unmatched (P = 0.026) and matched (P = 0.060) cohorts. The with arteriosclerosis group had significantly higher chronic antibody-mediated rejection than did the without arteriosclerosis group (P = 0.006) in the unmatched cohort. The with arteriosclerosis group had a significantly lower estimated glomerular filtration rate in recipients, but there was no significant difference after matching. The incidence rates of calcineurin inhibitor nephrotoxicity and post-transplant anemia were significantly higher in the with arteriosclerosis group than in the without arteriosclerosis group in both the unmatched and matched cohorts. Long-term postoperative kidney function of living donors was lower in the with arteriosclerosis group., Conclusions: Kidney graft with arteriosclerosis might affect the incidence of rejection, complications and postoperative kidney function of donors. Long-term careful observation is required for both the recipients who received grafts with arteriosclerosis and the donors who had kidneys with arteriosclerosis., (© 2020 The Japanese Urological Association.)

Background and Purpose- We assessed whether lower-dose alteplase at 0.6 mg/kg is efficacious and safe for acute fluid-attenuated inversion recovery-negative stroke with unknown time of onset. Methods- This was an investigator-initiated, multicenter, randomized, open-label, blinded-end point trial. Patients met the standard indication criteria for intravenous thrombolysis other than a time last-known-well >4.5 hours (eg, wake-up stroke). Patients were randomly assigned (1:1) to receive alteplase at 0.6 mg/kg or standard medical treatment if magnetic resonance imaging showed acute ischemic lesion on diffusion-weighted imaging and no marked corresponding hyperintensity on fluid-attenuated inversion recovery. The primary outcome was a favorable outcome (90-day modified Rankin Scale score of 0-1). Results- Following the early stop and positive results of the WAKE-UP trial (Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke), this trial was prematurely terminated with 131 of the anticipated 300 patients (55 women; mean age, 74.4±12.2 years). Favorable outcome was comparable between the alteplase group (32/68, 47.1%) and the control group (28/58, 48.3%; relative risk [RR], 0.97 [95% CI, 0.68-1.41]; P =0.892). Symptomatic intracranial hemorrhage within 22 to 36 hours occurred in 1/71 and 0/60 (RR, infinity [95% CI, 0.06 to infinity]; P >0.999), respectively. Death at 90 days occurred in 2/71 and 2/60 (RR, 0.85 [95% CI, 0.06-12.58]; P >0.999), respectively. Conclusions- No difference in favorable outcome was seen between alteplase and control groups among patients with ischemic stroke with unknown time of onset. The safety of alteplase at 0.6 mg/kg was comparable to that of standard treatment. Early study termination precludes any definitive conclusions. Registration- URL: https://www.clinicaltrials.gov; Unique identifier: NCT02002325.

Objectives: The management of atrial fibrillation and deep venous thrombosis has evolved with the development of direct oral anticoagulants (DOAC), and oral anticoagulant (OAC) might influence the development or clinical course in both ischemic and hemorrhagic stroke. However, detailed data on the differences between the effects of the prior prescription of warfarin and DOAC on the clinical characteristics, neuroradiologic findings, and outcome of stroke are limited., Design: The prospective analysis of stroke patients taking anticoagulants (PASTA) registry study is an observational, multicenter, prospective registry of stroke (ischemic stroke, transient ischemic attack, and intracerebral hemorrhage) patients receiving OAC in Japan. This study is designed to collect data on clinical background characteristics, drug adherence, drug dosage, neurological severity at admission and discharge, infarct or hematoma size, acute therapy including recanalization therapy or reverse drug therapy, and timing of OAC re-initiation. Patient enrollment started in April 2016 and the target patient number is 1000 patients., Conclusions: The PASTA prospective registry should identify the status of stroke patients taking OAC in the current clinical practice in Japan., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Importance: The Systolic Blood Pressure Intervention Trial (SPRINT) demonstrated that a systolic blood pressure (BP) target less than 120 mm Hg was superior to less than 140 mm Hg for preventing vascular events. This trial excluded patients with prior stroke; therefore, the ideal BP target for secondary stroke prevention remains unknown., Objective: To assess whether intensive BP control would achieve fewer recurrent strokes vs standard BP control., Design, Setting, and Participants: Randomized clinical trial (RCT) of standard vs intensive BP control in an intent-to-treat population of patients who had a history of stroke. Patients were enrolled between October 20, 2010, and December 7, 2016. For an updated meta-analysis, PubMed and the Cochrane Central Library database were searched through September 30, 2018, using the Medical Subject Headings and relevant search terms for cerebrovascular disease and for intensive BP lowering. This was a multicenter trial that included 140 hospitals in Japan; 1514 patients who had a history of stroke within the previous 3 years were approached, but 234 refused to give informed consent., Interventions: In total, 1280 patients were randomized 1:1 to BP control to less than 140/90 mm Hg (standard treatment) (n = 640) or to less than 120/80 mm Hg (intensive treatment) (n = 640). However, 17 patients never received intervention; therefore, 1263 patients assigned to standard treatment (n = 630) or intensive treatment (n = 633) were analyzed., Main Outcomes and Measures: The primary outcome was stroke recurrence., Results: The trial was stopped early. Among 1263 analyzed patients (mean [SD] age, 67.2 [8.8] years; 69.4% male), 1257 of 1263 (99.5%) completed a mean (SD) of 3.9 (1.5) years of follow-up. The mean BP at baseline was 145.4/83.6 mm Hg. Throughout the overall follow-up period, the mean BP was 133.2/77.7 (95% CI, 132.5-133.8/77.1-78.4) mm Hg in the standard group and 126.7/77.4 (95% CI, 125.9-127.2/73.8-75.0) mm Hg in the intensive group. Ninety-one first recurrent strokes occurred. Nonsignificant rate reductions were seen for recurrent stroke in the intensive group compared with the standard group (hazard ratio [HR], 0.73; 95% CI, 0.49-1.11; P = .15). When this finding was pooled in 3 previous relevant RCTs in a meta-analysis, the risk ratio favored intensive BP control (relative risk, 0.78; 95% CI, 0.64-0.96; P = .02; absolute risk difference, -1.5%; 95% CI, -2.6% to -0.4%; number needed to treat, 67; 95% CI, 39-250)., Conclusions and Relevance: Intensive BP lowering tended to reduce stroke recurrence. The updated meta-analysis supports a target BP less than 130/80 mm Hg in secondary stroke prevention., Trial Registration: ClinicalTrials.gov identifier: NCT01198496.

Aims: Islet transplantation is an effective therapeutic option for type 1 diabetes. Although maintenance immunosuppression therapy is required to prevent allogeneic rejection and recurrence of autoimmunity, long-term allograft survival has not yet been achieved partly because of its adverse effects. The induction of donor-specific immunotolerance is a promising approach for long-term allograft survival without maintenance immunosuppression therapy. We previously reported that combination therapy using a liposomal ligand for invariant natural killer T cells, RGI-2001, and anti-CD154 antibody established mixed hematopoietic chimerism for the induction of donor-specific immunotolerance. This study investigated whether the protocol could promote islet allograft acceptance in experimental diabetes., Methods: Streptozotocin-induced diabetic BALB/c mice were transplanted with bone marrow cells from C57BL/6 donors and received combination therapy of RGI-2001 and anti-CD154 antibody after 3-Gy total body irradiation. 3 Weeks after bone marrow transplantation, islets isolated from C57BL/6 donors were transplanted under the kidney capsule., Results: Mixed chimerism was established in diabetic mice receiving the tolerance induction protocol. After islet transplantation, blood glucose levels improved and normoglycemia persisted for over 100 days. Hyperglycemia recurred after islet grafts were removed. Histopathological examinations showed insulin-positive staining and absence of cellular infiltration in the islet grafts. T cells of recipients showed donor-specific hyporesponsiveness, and anti-donor antibodies were not detected., Conclusions: The tolerance induction protocol with combination therapy of RGI-2001 and anti-CD154 antibody promoted islet allograft acceptance in a mouse diabetic model. This protocol may be clinically applied to islet transplantation for type 1 diabetes mellitus.

Regulatory T cells (Tregs) play a significant role in immune tolerance. Since Treg function deeply depends on Interleukin-2 signaling, calcineurin inhibitors could affect their suppressive potentials, whereas mammalian target of rapamycin (mTOR) inhibitors may have less impact, as mTOR signaling is not fundamental to Treg proliferation. We previously reported a novel mixed hematopoietic chimerism induction regimen that promotes Treg proliferation by stimulating invariant natural killer T cells under CD40 blockade. Here, we use a mouse model to show the impact of tacrolimus (TAC) or everolimus (EVL) on the establishment of chimerism and Treg proliferation in the regimen. In the immunosuppressive drug-dosing phase, peripheral blood chimerism was comparably enhanced by both TAC and EVL. After dosing was discontinued, TAC-treated mice showed gradual graft rejection, whereas EVL-treated mice sustained long-term robust chimerism. Tregs of TAC-treated mice showed lower expression of both Ki67 and cytotoxic T lymphocyte antigen-4 (CTLA-4), and lower suppressive activity in vitro than those of EVL-treated mice, indicating that TAC negatively impacted the regimen by interfering with Treg proliferation and activation. Our results suggest that the usage of calcineurin inhibitors should be avoided if utilizing the regimen to induce Tregs in vivo for the establishment of mixed hematopoietic chimerism., (© 2018 Steunstichting ESOT.)

Tolerance induction is a goal of clinical transplantation to prevent graft rejection without the lifelong use of immunosuppressive drugs. In a series of mouse studies, we previously reported that the establishment of mixed chimerism by treatment with a ligand for invariant natural killer T (iNKT) cells with CD40 signal blockade makes it possible to prevent allograft rejection without immunosuppressants, and this approach fails in thymectomized recipient mice. In this study, we showed that iNKT cells in murine thymocyte cultures are indispensable for the expansion of CD4 + CD25 + Foxp3 + regulatory T (Treg) cells as well as CD4 + CD25 + Foxp3 - cells, which contained precursor Tregs (preTregs). After the culture of BALB/c mouse-derived thymocytes in the presence of α-galactosylceramide (α-GalCer), a representative ligand for iNKT cells, the ratio of CD4 + CD25 + Foxp3 - preTregs to total CD4 + CD8 - T cells was much higher than that of CD4 + CD25 + Foxp3 + Treg cells, regardless of anti-CD40 L mAb treatment. The proliferation of CD4 + CD25 + Foxp3 - cells, but not Treg cells, was significantly augmented, and the stability of Treg cells was not affected by α-GalCer. The expansion of thymocyte-derived Tregs was not inhibited by cytokine neutralization. However, in vitro thymus-derived CD4 + CD25 + Foxp3 - cells expressed Foxp3 after IL-2 stimulation in a dose-dependent manner. These results collectively suggest that in vitro thymus-derived Treg cell expansion by α-GalCer treatment was caused by the proliferation of CD4 + CD25 + Foxp3 - preTregs but not existing Treg cells., (Copyright © 2018 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.)

Hem-o-lok clips have been widely used in laparoscopic or robot-assisted surgery. We report a case of an incidentally discovered Hem-o-lok migration into the bladder after laparoscopic radical prostatectomy. The patient was a 75-year-old man with localized prostate cancer who underwent laparoscopic radical prostatectomy in July 2009. At 3 postoperative years, follow-up ultrasonography revealed a small round mass in the bladder. No lower urinary tract symptoms were reported, and urinalysis results had never indicated hematuria or pyuria. Cystoscopy revealed a Hem-o-lok clip in the bladder, near the vesicourethral anastomotic site. We could not remove it with forceps in the outpatient clinic, so we performed the procedure again under general anesthesia and successfully removed the Hem-o-lok clip. To our knowledge, this is the first report of an asymptomatic Hem-o-lok migration into the bladder., (© 2017 Japan Society for Endoscopic Surgery, Asia Endosurgery Task Force and John Wiley & Sons Australia, Ltd.)

Transplantation-associated thrombotic microangiopathy (TA-TMA) is relatively rare and requires immediate intervention to avoid irreversible organ damage or death; however, consensus regarding the treatment approach is lacking. Atypical haemolytic uraemic syndrome (aHUS) is a rare disease caused by dysregulation of the alternative complement pathway resulting in TMA. aHUS is histologically similar to TA-TMA; approximately 60% of TA-TMA patients have complement dysregulation. Eculizumab, a humanized anti-C5 monoclonal antibody, inhibits terminal membrane-attack complex formation and TMA progression. Eculizumab has been successfully used to treat aHUS post-transplant. We present two cases of kidney TA-TMA due to unknown causes, suspected antibody-mediated rejection, or calcineurin inhibitor (CNI)-related toxicity that developed on day 1 or 2 post-kidney transplantation. Low platelet count and haemoglobin level with red cell fragments were detected. Despite steroid pulse, plasma exchange (PE), and intravenous immunoglobulin therapy, TA-TMA did not improve; therefore, eculizumab was administered despite no genetic testing. Laboratory data, including renal function, improved immediately. TA-TMA treatment primarily involves PE initiation or CNI discontinuation; eculizumab can be used to safely treat TA-TMA and then be ceased in the short term. Therefore, eculizumab administration might be beneficial for kidney TA-TMA as early as the diagnosis of refractory to PE., (© 2016 Asian Pacific Society of Nephrology.)

Focal segmental glomerulosclerosis commonly recurs following kidney transplantation. A 33-year-old man underwent living donor kidney transplantation. Proteinuria appeared two months after transplantation, and an episode biopsy on postoperative day 66 revealed recurrent focal segmental glomerulosclerosis lesions of the cellular variant by Columbia classification. We reviewed the native kidney biopsy and confirmed collapsing variant focal segmental glomerulosclerosis. Plasma exchange therapy was performed, and his proteinuria temporarily resolved. A second allograft biopsy performed on postoperative day 200 showed no evidence of focal segmental glomerurosclerosis. He experienced incomplete remission with a proteinuria of 0.5 g/day during the subsequent three years until his urinary protein level rose to 1.3 g/day. A third biopsy performed on postoperative day 1248 showed focal segmental glomerulosclerosis cellular variant lesions. Plasma exchange was resumed in combination with additional rituximab, but his proteinuria persisted. Intermittent plasma exchange was performed 42 times in total. However, his proteinuria continued, and his renal function gradually worsened. A fourth biopsy performed on postoperative day 2540 showed focal segmental glomerulosclerosis collapsing variant lesions with severe interstitial fibrosis and tubular atrophy. He ultimately required hemodialysis seven years after transplantation. Intensive therapy with long-term intermittent plasma exchange and rituximab suppressed proteinuria and preserved graft function for seven years, at which time graft failure occurred. We here present the clinical course and histological findings from consecutive allograft biopsies., (© 2015 Asian Pacific Society of Nephrology.)

Background: Acetazolamide loading has been the "gold standard" for evaluating cerebrovascular reserve capacity (CVRC). However, life-threatening side effects of acetazolamide have recently been reported. The aim of the study was to identify alternative methods for evaluating CVRC., Methods: We reviewed 6 patients who underwent both computed tomography perfusion (CTP) imaging and xenon CT (XeCT) imaging with and without acetazolamide loading during the same periods. The data were obtained as volume data using 320-row CT and applied to the automated region of interest-determining software and converted to standardized images. Correlations between CVRC and CTP parameters were analyzed by Pearson correlation coefficient analysis, and simple regression was used to assess the relationship between the data. When statistically significant, correlation between CVRC and any CTP data is identified, and cutoff points for CVRC 30% and 10% were calculated with receiver operating characteristic curves., Results: Of 4 CTP parameters evaluated, statistically significant correlations were observed between time to peak (TTP) by CTP and CVRC (P < .0001, r = -.7228) calculated from XeCT. The regression line using CVRC as outcome variable (y) and using TTP as predictor variable (x) was y = -9.062x + 140.1. The cutoff value for the TTP for CVRC less than 10% was 12.56 seconds (sensitivity of 86% and specificity of 85%) and that for CVRC less than 30% was 9.34 seconds (sensitivity of 77% and specificity of 96%)., Conclusions: TTP calculated from CTP data correlated well with the CVRC calculated from XeCT data. These results suggest that TTP calculated from CTP could be used to estimate CVRC in patients with occlusive cardiovascular disease., (Copyright © 2015 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

Cerebral blood flow (CBF) data obtained by computed tomography perfusion (CTP) imaging have been shown to be qualitative data rather than quantitative, in contrast with data obtained by other imaging methods, such as xenon CT (XeCT) imaging. Thus, interpatient comparisons of CBF values themselves obtained by CTP may be inaccurate. In this study, we have compared CBF ratios as well as CBF values obtained from CTP-CBF data to those obtained from XeCT-CBF data for the same patients to determine CTP-CBF parameters that can be used for interpatient comparisons. The data used in the present study were obtained as volume data using 320-row CT. The volume data were applied to an automated region of interest-determining software (3DSRT, version 3.5.2 ) and converted to 59 slices of 2 mm interval standardized images. In the present study, we reviewed 10 patients with occlusive cerebrovascular diseases (CVDs) undergoing both CTP and XeCT in the same period. Our study shows that ratios of CBF measurements, such as hemodynamic stress distribution (perforator-to-cortical flow ratio of middle cerebral artery [MCA] region) or the left/right ratio for the region of the MCA, calculated using CTP data have been shown to correlate well with the same ratios calculated using XeCT data. These results suggest that such CBF ratios could be useful for generating interpatient comparisons of CTP-CBF data obtained by 320-row CT among patients with occlusive CVD., (Copyright © 2015 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

Objective: The significance of early mild clinical improvement after intravenous tissue plasminogen activator (IVtPA) treatment is unclear. Therefore, we examined whether the timing of clinical improvement after IVtPA predicted the clinical outcome at 3 months., Methods: Consecutive patients with acute cerebral infarction in the anterior circulation who received IVtPA treatment within 3 hours of the onset of symptoms were enrolled in the study. Patients were classified according to the timing of clinical improvement [early responder (ER), National Institutes of Health Stroke Scale (NIHSS) score improved ≥4 points or who had a score of 0 within 2 hours after IVtPA; late responder (LR), a similar improvement between 2 and 24 hours; and non-responder (NR)] and according to the arterial occlusion site (P group, internal carotid artery and proximal middle cerebral artery M1 region; and D group, distal M1 and M2)., Results: Ninety-three patients [median age, 74 (67-79) years; 54 men (58%); median NIHSS score, 11 (7-16)] were enrolled in the study. The P group consisted of 48 (52%) patients and the D group consisted of 45 (48%) patients. Thirty-eight patients (41%) were classified as ERs, 20 (22%) as LRs, and 35 (38%) as NRs. On a multivariate regression analysis, the P group [odds ratio (OR), 3.24; 95% confidence interval (CI), 1.08-10.45; p=0.036] and NR (OR, 4.04; 95% CI, 1.29-14.27; p=0.016) were independent predictors of a poor outcome. ER (47%, p=0.01) and LR (45%, p=0.01) patients showed fewer poor outcomes than NR (77%) patients, but the rate did not differ significantly between the ER and LR patients., Conclusion: Early mild clinical recovery did not predict a good outcome. The occlusion site was a stronger predictor of clinical improvement after IVtPA administration.