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Despite the rapid introduction of androgen receptor-targeted agents (ARTA) into clinical practice for castration-resistant prostate cancer (CRPC), the optimal treatment strategy after first-line ARTA remains unclear. The object of this study was to clarify clinical outcomes of second-line therapy for CRPC after first-line ARTA.The medical records of 130 consecutive patients with CRPC with disease progression during first-line ARTA and who started second-line therapy at our Institution between 2014 and 2020 were analyzed.A total of 130 patients with CRPC were identified. Ninety patients underwent ARTA-ARTA treatment, and 40 patients underwent ARTA-docetaxel treatment. The median observation period after second-line ARTA or docetaxel administration was 14.2 months. The prostate-specific antigen response rates overall, and after second-line ARTA, and docetaxel were 26.8%, 24.7%, and 31.6%, respectively. The median progression-free survival (PFS) and 1- and 2-year PFS rates of second-line therapy were 7.9 months and 34.6% and 15.4%, respectively. The median overall survival (OS) and 1- and 2-year OS rates were 27.4 months and 81.8%, and 54.9%, respectively. Multivariate analyses for OS disclosed that a C-reactive protein over the upper limit of normal and time from first-line ARTA to progression under 12 months were associated with shorter OS. Prostate-specific antigen response, PFS and OS of second-line therapy were not significantly different between second-line ARTA and docetaxel.There was no significant difference in OS between ARTA-ARTA and ARTA-docetaxel groups in the present study, suggesting that second-line ARTA might be the preferred treatment after initial failure of ARTA.

Prostate cancer localization is reportedly associated with the laterality of lymph node metastasis. Thus, it may be feasible to predict side-specific lymph node metastasis (LNM) at radical prostatectomy (RP). To investigate whether multiparametric magnetic resonance imaging and biopsy findings can predict side-specific negative LNM and to explore the feasibility of unilateral lymph node dissection (LND) at RP.A total of 500 patients who were diagnosed with prostate cancer with prebiopsy multiparametric magnetic resonance imaging of the prostate and subsequent prostate biopsy and who underwent RP and extended LND without neoadjuvant treatment were enrolled. Multiparametric magnetic resonance imaging, biopsy findings, and LNM were assessed for each side. The negative predictive value (NPV) of multiparametric magnetic resonance imaging or biopsy or both for ipsilateral LNM was examined.LNM was found in 9.2% (46/500) and 15.6% (28/180) of patients in the overall and high-risk cohorts, respectively. Magnetic resonance imaging and biopsy findings were negative in 408 and 262 sides, respectively, in the overall cohort and 144 and 100 sides, respectively, in the high-risk cohort. The NPVs of magnetic resonance imaging, biopsy, and both for ipsilateral LNM were 98.3%, 98.5%, and 99.1%, respectively, in the overall cohort, and 95.8%, 97.1%, and 97.6%, respectively, in the high-risk cohort.Unilateral LND may be indicated based on side-specific LNM risk as assessed by prebiopsy multiparametric magnetic resonance imaging and biopsy.

Although radiation therapy is one of the most significant treatment modalities for localized prostate cancer, the prognostic factors for biochemical recurrence (BCR) regarding the treatment plan are unclear. We aimed to develop a novel dosiomics-based prediction model for BCR in patients with prostate cancer and clarify the correlations between the dosimetric factors and BCR.This study included 489 patients with localized prostate cancer (BCR: 96; no-BCR: 393) who received intensity modulated radiation therapy. A total of 2475 dosiomic features were extracted from the dose distributions on the prostate, clinical target volume (CTV), and planning target volume. A prediction model for BCR was trained on a training cohort of 342 patients. The performance of this model was validated using the concordance index (C-index) in a validation cohort of 147 patients. Another model was constructed using clinical variables, dosimetric parameters, and radiomic features for comparisons. Kaplan-Meier curves with log-rank analysis were used to assess the univariate discrimination based on the predictive dosiomic features.The dosiomic feature derived from the CTV was significantly associated with BCR (hazard ratio, 0.73; 95% CI, 0.57-0.93; P = .01). Although the dosiomics model outperformed the dosimetric and radiomics models, it did not outperform the clinical model. The performance significantly improved by combining the clinical variables and dosiomic features (C-index: 0.67; 95% CI, 0.65-0.68; P.0001). The predictive dosiomic features were used to distinguish high-risk and low-risk patients (P.05).The dosiomic feature extracted from the CTV was significantly correlated with BCR in patients with prostate cancer, and the dosiomics model outperformed the model with conventional dose indices. Hence, new metrics for evaluating the quality of a treatment plan are warranted. Moreover, further research should be conducted to determine whether dosiomics can be incorporated in a clinical workflow or clinical trial.

In 2020, we reported the "BD-checklist 92" for patients with Behcet's disease (BD) based on the International Classification of Functioning, Disability and Health. The purpose of the present study was to evaluate the validity and reliability of this checklist. Questionnaires using the "BD-checklist 92" and the 36-item Short Form Survey (SF-36) were sent to ten affiliated institutions. In total, 174 patients answered the questionnaire (response rate, 32.7%). Criterion validity was evaluated using the correlation coefficient between the number of problem categories extracted from the "BD-checklist 92" and the scores of the eight subscales and two components of the SF-36. Construct validity was assessed based on the number of problem categories extracted as an external criterion for the number of manifestations experienced and specific lesions. The comparison was performed using the Mann-Whitney U test. Cronbach's alpha coefficient was used to evaluate reliability. The number of problem categories in the "Body functions and structures", "Activities and participation", and "Environmental factors" components correlated significantly with all dimensions of the SF-36 questionnaire (P

We investigated the pathogenic relationship between cerebral microbleeds and lacunar strokes. Two cases of lacunar strokes in the region of the basal ganglia, a 72-year-old man and a 67-year-old man, were studied; both cases showed cerebral microbleeds in the stroke areas. The cerebral microbleeds were surrounded by oedema, and the oedema faded out over time, suggesting the cerebral microbleeds had developed acutely. The cerebral microbleeds were located at the ventrolateral edge of the lacunar infarctions, and the locations appeared to be at or near the sites of occlusion of the lenticulostriatal branches. Although a cerebral microbleed and a lacunar infarction may be two unrelated events on juxtapositioned vessels, or a cerebral microbleed may be haemorrhagic conversion of an infarction, a cerebral microbleed could cause an occlusion of the arterial branch, leading to lacunar infarction of its supplying territories.

In this study, we investigated the association between the early response of serum and hematological variables and the outcome of cabazitaxel therapy. The medical records of 59 consecutive patients who had previously received docetaxel chemotherapy for the treatment of metastatic castration-resistant prostate cancer (CRPC) and who received cabazitaxel at our hospital between January 2011 and March 2020 were retrospectively reviewed and statistically analyzed. The median follow-up period after cabazitaxel initiation was 15.2 months. The 30% prostate-specific antigen (PSA) response rate, median PSA progression-free survival period, and overall survival (OS) period were 45.8%, 4.3 months, and 22.6 months, respectively. Within 1 to 2 cycles of cabazitaxel, we were unable to identify hematological or serum kinetics that had a relationship with OS. Analysis of the variables after 3 cycles of cabazitaxel, however, revealed two factors, PSA decline > 30% (p = 0.016) and neutrophil–lymphocyte ratio (NLR) decline > 30% (p = 0.044), as the predictors of favorable outcome for OS. We established a prognostic model for predicting the OS period composed of these two factors, which exhibited distinctly separated OS curves (p = 0.004). The C-index of a model incorporating these two factors was 0.703. This is the first study to demonstrate that PSA and NLR decline 3 cycles after the initiation of cabazitaxel were associated with favorable outcome in patients with CRPC. Also, 3 cycles of cabazitaxel might be necessary to assess the efficacy of cabazitaxel therapy.

Glucocorticoids are important drugs used to treat rheumatoid arthritis. We recommend glucocorticoid discontinuation as soon as possible given the associated side-effects, but many patients continue to take oral glucocorticoids long-term. The present study aimed to explore factors associated with glucocorticoid discontinuation at 52 weeks after initiating biological disease-modifying antirheumatic drugs (bDMARDs). Subjects were 564 patients from a Japanese multicenter registry who were administered glucocorticoids and methotrexate (MTX) followed by initiation of the first bDMARD. We examined the status of oral glucocorticoid use at 52 weeks after initiating the first bDMARD. By 52 weeks after bDMARD initiation, 164 patients (29.1%) discontinued glucocorticoids. Multivariable analysis identified age, MTX dose, and glucocorticoid dose as factors independently associated with glucocorticoid discontinuation. After adjusting for baseline characteristics using propensity score matching, among patient groups administered MTX ≤ 8 mg/week and MTX > 8 mg/week, 105 pairs remained. A significantly higher rate of glucocorticoid discontinuation (41.0%) was noted for patients administered MTX > 8 mg/week. Our findings suggest that glucocorticoids may be discontinued after initiating bDMARDs. Moreover, higher MTX doses (>8 mg/week) at the time of bDMARD initiation were associated with glucocorticoid discontinuation among patients treated with bDMARDs.

Objective To study the efficacy of phosphodiesterase-5 inhibitor tadalafil in attenuating adverse events after low-dose-rate brachytherapy for prostate cancer. Methods This was a randomized open-label trial, conducted at two institutions. Prostate cancer patients undergoing low-dose-rate brachytherapy were randomly assigned to receive tadalafil (study group) or tamsulosin (control group). The primary endpoint was International Prostate Symptom Score for subjective evaluation of lower urinary tract symptoms. Uroflowmetry, postvoid residual urine volume, and Sexual Health Inventory for Men score were the secondary endpoints. Each clinical variable was evaluated during a follow-up period of 1 year after low-dose-rate brachytherapy. Results A total of 107 patients were enrolled in this study, with a final total of 96 patients analyzed. The mean total International Prostate Symptom Score changes at 1, 3, 6, 9, and 12 months after low-dose-rate brachytherapy were +7.4, +7.1, +4.7, +1.5, and +0.8, respectively, in the tamsulosin group, and +8.5, +9.2, +6.4, +4.1, and +1.6, respectively, in the tadalafil group. There were no statistically significant differences in International Prostate Symptom Score with the exception of the score at 9-month follow-up. Moreover, there were no statistically significant differences in any of the uroflowmetry or postvoid residual urine volume findings. The Sexual Health Inventory for Men score in the tadalafil group was significantly higher than that in the tamsulosin group at 6, 9, and 12 months after low-dose-rate brachytherapy. Conclusions Tadalafil could be an effective option for the management of lower urinary tract symptoms after low-dose-rate brachytherapy.

The case was a 76-year-old man with chronic limb-threatening ischemia. Plain old balloon angioplasty (POBA) was performed on the popliteal artery. Subsequently, he suffered from cellulitis around the POBA site, followed by reocclusion. Staphylococcus aureus was detected in a blood culture. After re-revascularization with POBA, both purulent gonitis and an infected popliteal aneurysm were observed to occur. We performed aneurysmectomy and bypass grafting with the saphenous vein and then continued antibiotic therapy. Although treatment consisted of endovascular therapy (EVT) with nothing left behind, management was difficult because of secondary infectious complications. We conclude that prophylactic antibiotics before EVT should be considered in such cases.

We compared clinical outcomes associated with seed brachytherapy (SEED-BT) alone and SEED-BT plus external-beam radiotherapy (EBRT) for intermediate-risk prostate cancer using propensity score-matched analysis. From 2006 to 2011, 993 patients diagnosed with intermediate-risk were treated with either SEED-BT alone (n = 775) or SEED-BT plus EBRT (n = 158) at 3 tertiary hospitals. In the propensity score-matched analysis (102 pairs), median follow-up was 95 months (range 18–153 months). The 8-year biochemical recurrence-free rate (bRFR) was significantly better with SEED-BT alone than with combined radiotherapy (93.3% vs. 88.4%; HR 0.396; 95% CI 0.158–0.991). Grade 2 or greater late genitourinary toxicities were significantly fewer with SEED-BT alone than with combined radiotherapy (21.0% vs. 33.2%; HR 0.521; 95% CI 0.308–0.881). Similarly, grade 2 or greater late gastrointestinal toxicities were significantly fewer with SEED-BT alone (0% vs. 12.2%; HR 0.125; 95% CI 0.040–0.390). For the unfavorable intermediate-risk subgroups, SEED-BT alone yielded a significantly better bRFR than the combined radiotherapy (HR 0.325; 95% CI 0.115–0.915). SEED-BT alone might be a better disease-management plan than SEED-BT plus EBRT for intermediate-risk prostate cancer regardless of favorable and unfavorable characteristics.

The trajectory of glomerular filtration rate (GFR) in relation to glomerular hyperfiltration (GHF) has been unknown. It was evaluated retrospectively in 23,982 GHF-free health examinees who were followed for 2−10 yr (mean: 5.1 yr). GFR was estimated by the serum creatinine concentration, and GHF was defined as age- and sex-specific estimated GFR (eGFR) ≥ 95% of the Japanese general population. The temporal profile of eGFR was plotted in a GHF-centered way, which was fitted to a random coefficient linear mixed model. Of the 23,982 subjects, 797 and 23,185 subjects developed or did not develop GHF, respectively, so that they were termed as the GHF(+)and GHF(−)groups. At baseline, median eGFR was significantly elevated in the GHF(+)group compared with in the GHF(−)group: 94.1 versus 77.3 mL/min/1.73 m2( P < 0.001). Elevation of basal eGFR lasted for a mean (SD) of 3.3 (1.9) yr in the GHF(+)group; mean eGFR then rose to the GHF range, which was 108.5 mL/min/1.73 m2. The eGFR decline after the peak was steeper in the GHF(+)group than in the GHF(−)group: −0.984 versus −0.497 mL/min/1.73 m2/yr ( P < 0.001). Baseline eGFR, but no other variable, well predicted incident GHF, with an area under the receiver operating characteristic curve of 0.87 (95% confidence interval: 0.86–0.88). In conclusion, GHF occurs as a chronic, multiphasic phenomenon: initially with a sustained GFR elevation for years, followed by a GFR surge to the GHF range, which was accompanied by accelerated GFR declining.

Because non–anthracycline-based chemotherapy with l-asparaginase has improved survival outcomes in patients with extranodal natural killer/T-cell lymphoma (ENKTL), the incidence of central nerve system (CNS) relapse can be different when compared with that in previous reports. In this research, we sought to identify the incidence of and predictors for CNS relapse and to evaluate the necessity of CNS prophylaxis with intermediate-dose methotrexate (ID-MTX). The records of 399 patients in the training cohort and 253 patients in the validation cohort with ENKTL who received non-anthracycline–based chemotherapy were reviewed. Patients were divided into 2 groups according to whether the chemotherapy regimen included ID-MTX above 2 g/m2. A new central nervous system-prognostic index of natural killer (CNS-PINK) model was developed using 1-point powerful predictors of CNS relapse (PINK; hazard ratio [HR], 2.908; P = .030 and extranodal involvement [≥2]; HR, 4.161; P = .001) and was calculated as a sum of scores. The high-risk group of CNS-PINK was defined as 2 points. The cumulative incidence of CNS relapse was different between the CNS-PINK risk groups in the training (P < .001) and validation (P = .038) cohorts. Patients in the high-risk CNS-PINK group who were treated with SMILE or SMILE-like regimens with ID-MTX (S-ID-MTX) displayed a lower incidence rate of CNS relapse than did those who received other regimens without ID-MTX in the training cohort (P = .029). The CNS-PINK was demonstrated its strong predictability of CNS relapse in ENKTL patients. The effectiveness of S-ID-MTX in preventing CNS events in high-risk CNS-PINK patients should be verified in future studies.

Protamine causes cardiac depression, which may be mediated by tumor necrosis factor alpha (TNF-α). Ulinastatin, a human urinary protease inhibitor, inhibits TNF-α. Here, we aimed to investigate whether ulinastatin prevented protamine-induced myocardial depression by inhibiting TNF-α. Rat hearts were perfused using a Langendorff system, and three protocols were followed. Protocol 1: The hearts were divided into saline, ulinastatin-low, and ulinastatin-high groups. Protamine was administered to each group, and myocardial contractility was the primary outcome. Protocol 2: The hearts were allotted to saline or ulinastatin group. Protamine was administered to each group. TNF-α expression in the coronary effluent and myocardial tissue was measured. Protocol 3: The hearts were allotted to saline and ulinastatin groups. Recombinant rat-TNF-α was administered to each group. Protamine alone reduced the maximum left ventricular pressure derivative (LV dP/dt max) by 45 ± 4%. In contrast, the reduction in LV dP/dt max was 4 ± 3% in the ulinastatin-high group. Compared with that in the saline group, the increase in TNF-α in the coronary effluent was attenuated in the ulinastatin group. Recombinant TNF-α alone reduced LV dP/dt max (- 21 ± 14%). In contrast, when TNF-α was added in the presence of ulinastatin, the decrease in LV dP/dt max was prevented significantly (- 3 ± 8%). We showed, for the first time, that ulinastatin protected against protamine-induced myocardial damage, both by inhibiting TNF-α synthesis and by directly preventing the cardiodepressant action of TNF-α.

This study was aimed at assessing the feasibility and toxicity of using stereotactic body radiation therapy (SBRT) for reirradiation of spinal metastatic tumors. We conducted a retrospective review, from our institutional database, of the data of patients who received reirradiation, with overlap of some prescribed isodose lines to the vertebra from the initial radiation therapy, between 2007 and 2019. We identified 40 patients with spinal metastatic tumors, of whom 2 had 2 metastatic vertebral lesions each, totaling up to 42 target lesions. The median dose to spinal cord at the initial radiation therapy was 30 Gy. SBRT based on the intensity-modulated radiation therapy (IMRT) technique was used for reirradiation to spare the spinal cord. All patients received a prescription dose of 25 Gy in 5 fractions to the planning target volume (PTV). Among the 40 cases who had pain, pain relief was obtained in 24 (60%) after reirradiation. Neurologic improvement was obtained in 8 of 15 cases (53%). The adverse events were evaluated using the Common Terminology Criteria for Adverse Events Version 5.0. Reirradiation was well-tolerated, with only 2 patients experiencing adverse events ≥grade 2 in severity, including 1 patient with grade 3 pain, and another patient with grade 3 spinal fracture. None of the patients developed radiation myelopathy. Our data demonstrated that reirradiation of spinal metastasis using SBRT provided effective pain relief and neurologic improvement, with minimal toxicity.

Aim: Medullary ray injury was recently reported in renal transplant biopsies. This study was performed to clarify the clinicopathological features of medullary ray injury in paediatric living renal transplant recipients. Methods: Paediatric recipients who completed a 5-year follow-up after living renal transplantation were enroled. We evaluated the clinical and pathological parameters of the presence or absence of medullary ray injury in their 1-year protocol biopsies. Results: Of 48 1-year protocol biopsies, 18 (37.5%) showed histological evidence of medullary ray injury. The 48 paediatric recipients were classified as those with medullary ray injury (n = 18; MRI-1Y [+] group) and those without medullary ray injury (n = 30; MRI-1Y [−] group) in the 1-year protocol biopsies. The prevalence of histological evidence of calcineurin inhibitor (CNI) nephrotoxicity, chronic obstruction or reflux nephropathy, and imaging findings of vesicoureteral reflux was 66.7, 22.2, and 7.7% in the MRI-1Y (+) group and 33.3, 13.3, and 15.4% in the MRI-1Y (−) group, respectively. Only the prevalence of CNI nephrotoxicity was significantly different between the 2 groups. There was no significant difference in the mean estimated glomerular filtration rate at 1, 3, or 5 years after transplantation between the 2 groups. Conclusion: In total, 37.5% of 1-year protocol biopsies showed histological evidence of medullary ray injury. This finding suggests that CNI nephrotoxicity might be the main contributor to medullary ray injury in 1-year protocol biopsies. The presence of medullary ray injury had little influence on renal function, at least during the first 5 years after transplantation.

Aim: This study evaluated the clinicopathological findings of acute/active antibody-mediated rejection (AABMR) according to the Banff 2013 classification. Methods: We analyzed 345 biopsies of 269 kidney transplant recipients. Pathological AABMR (PAABMR) was defined as histological evidence of acute tissue injury and endothelial injury by light microscopy regardless of donor-specific antibodies (DSAs). Results: Among the 345 biopsies, 29 (8.4%) were diagnosed as PAABMR. The mean g score was 1.17 ± 0.60, the mean ptc score was 1.97 ± 1.32, and DSA positivity was found in 69% of PAABMR. The mean duration after transplantation was 22.9 ± 26.7 months. Among 3 groups (DSA-high, mean fluorescence intensity (MFI) ≥ 5,000; DSA-low, MFI < 5,000 to ≥1,000; below cutoff), ABO incompatibility in DSA-high was significantly lower and second transplantation in DSA-high was significantly higher. We found 83% of PAABMR by the protocol biopsy (subclinical AABMR [SAABMR]). The short-term clinical and light microscopical changes in 8 cases of SAABMR did not show worsening during follow-up period (9–24 months). However, ultrastructural finding, including glomerular endothelial swelling, subendothelial electron-lucent widening, and early glomerular basement duplication, were found by electron microscopy (EM) in the first biopsies, and half of the SAABMR cases developed de novo circular peritubular capillary multilayering in the follow-up biopsies. Conclusion: PAABMR was mainly found by the protocol biopsy. The short-term follow-up of SAABMR patients did not show worsening clinically and light microscopically, but ultrastructural examination by EM was useful to detect early lesions of endothelial injury and progression of glomerular and peritubular capillary basement membrane alterations.

Background Remdesivir improves clinical outcomes in patients hospitalized with moderate-to-severe coronavirus disease 2019 (Covid-19). Whether the use of remdesivir in symptomatic, nonhospitalized patients with Covid-19 who are at high risk for disease progression prevents hospitalization is uncertain. Methods We conducted a randomized, double-blind, placebo-controlled trial involving nonhospitalized patients with Covid-19 who had symptom onset within the previous 7 days and who had at least one risk factor for disease progression (age ≥60 years, obesity, or certain coexisting medical conditions). Patients were randomly assigned to receive intravenous remdesivir (200 mg on day 1 and 100 mg on days 2 and 3) or placebo. The primary efficacy end point was a composite of Covid-19–related hospitalization or death from any cause by day 28. The primary safety end point was any adverse event. A secondary end point was a composite of a Covid-19–related medically attended visit or death from any cause by day 28. Results A total of 562 patients who underwent randomization and received at least one dose of remdesivir or placebo were included in the analyses: 279 patients in the remdesivir group and 283 in the placebo group. The mean age was 50 years, 47.9% of the patients were women, and 41.8% were Hispanic or Latinx. The most common coexisting conditions were diabetes mellitus (61.6%), obesity (55.2%), and hypertension (47.7%). Covid-19–related hospitalization or death from any cause occurred in 2 patients (0.7%) in the remdesivir group and in 15 (5.3%) in the placebo group (hazard ratio, 0.13; 95% confidence interval [CI], 0.03 to 0.59; P=0.008). A total of 4 of 246 patients (1.6%) in the remdesivir group and 21 of 252 (8.3%) in the placebo group had a Covid-19–related medically attended visit by day 28 (hazard ratio, 0.19; 95% CI, 0.07 to 0.56). No patients had died by day 28. Adverse events occurred in 42.3% of the patients in the remdesivir group and in 46.3% of those in the placebo group. Conclusions Among nonhospitalized patients who were at high risk for Covid-19 progression, a 3-day course of remdesivir had an acceptable safety profile and resulted in an 87% lower risk of hospitalization or death than placebo. (Funded by Gilead Sciences; PINETREE ClinicalTrials.gov number, NCT04501952; EudraCT number, 2020-003510-12.)

Tertiary lymphoid tissues (TLTs) facilitate local T- and B-cell interactions in chronically inflamed organs. However, the cells and molecular pathways that govern TLT formation are poorly defined. Here we identify TNF superfamily CD153-CD30 signaling between two unique age-dependent lymphocyte subpopulations, CD153⁺PD-1⁺CD4⁺ senescence-associated T (SAT) cells and CD30+T-bet+ age-associated B cells (ABCs), as a driver for TLT expansion. SAT cells, which produced ABC-inducing factors IL21 and IFNγ, and ABCs progressively accumulated within TLTs in aged kidneys after injury. Notably, in kidney injury models, CD153 or CD30 deficiency impaired functional SAT cell induction, which resulted in reduced ABC numbers and attenuated TLT formation with improved inflammation, fibrosis and renal function. Attenuated TLT formation after transplantation of CD153-deficient bone marrow further supported the importance of CD153 in immune cells. Clonal analysis revealed that SAT cells and ABCs in the kidneys arose from both local differentiation and recruitment from the spleen. In the synovium of aged rheumatoid arthritis patients, T peripheral helper/T follicular helper cells and ABCs also expressed CD153 and CD30, respectively. Together, our data reveal a previously unappreciated function of CD153-CD30 signaling in TLT formation and propose targeting CD153-CD30 signaling pathway as a therapeutic target for slowing kidney disease progression., 高齢者腎臓病を悪化させる原因細胞・分子の同定に成功. 京都大学プレスリリース. 2021-11-30., A new drug target for kidney disease. 京都大学プレスリリース. 2021-11-30.

In vivo calcium imaging with genetically encoded indicators has recently been applied to macaque brains to monitor neural activities from a large population of cells simultaneously. Microendoscopic calcium imaging combined with implantable gradient index lenses captures neural activities from deep brain areas with a compact and convenient setup; however, this has been limited to rodents and marmosets. Here, we developed miniature fluorescent microscopy to image neural activities from the primary visual cortex of behaving macaques. We found tens of clear fluorescent signals from three of the six brain hemispheres. A subset of these neurons showed clear retinotopy and orientation tuning. Moreover, we successfully decoded the stimulus orientation and tracked the cells across days. These results indicate that microendoscopic calcium imaging is feasible and reasonable for investigating neural circuits in the macaque brain by monitoring fluorescent signals from a large number of neurons.

To finish this special issue, some friends, colleagues and students of Prof. Chow (Emeritus Professor, the Research School of Biology, the Australian National University) have written small tributes to acknowledge not only his eminent career but to describe his wonderful personality.

To finish this special issue, some friends, colleagues and students of Prof. Chow (Emeritus Professor, the Research School of Biology, the Australian National University) have written small tributes to acknowledge not only his eminent career but to describe his wonderful personality.

Background There are few reports from Japan about the outcomes of intensity-modulated radiation therapy for localized prostate cancer. This study was aimed at assessing the efficacy and toxicity of intensity-modulated radiation therapy in patients with intermediate- or high-risk prostate cancer. Methods We conducted a review of the data, retrieved from our institutional database, of patients who had received intensity-modulated radiation therapy for localized prostate cancer at a radiation dose of 78 Gy in 39 fractions. Data of 201 patients with intermediate-risk prostate cancer and 311 patients with high-risk prostate cancer were analyzed. Results The median follow-up period after the completion of intensity-modulated radiation therapy was 100 months (range, 24–154). The rates of cause-specific survival, overall survival, metastasis-free survival and biochemical recurrence-free survival in the intermediate-risk patients were 99, 95, 95 and 94% at 5 years and 99, 91, 90 and 86% at 8 years, respectively; the corresponding rates in the high-risk patients were 100, 97, 91 and 84% at 5 years and 96, 92, 84 and 76% at 8 years, respectively. The crude incidence of late grade 2–3 genitourinary toxicity was 28.1%, and that of late grade 3 genitourinary toxicity was 2.0%. The crude incidence of late grade 2 gastrointestinal toxicity was 5.1%, and there were no cases of late grade 3 gastrointestinal toxicity. Conclusions Our data demonstrated that intensity-modulated radiation therapy is effective for patients with localized intermediate-risk or high-risk prostate cancer while having minimal toxicity.

We compared the bone strength measured via quantitative computed tomography-based finite element method (QCT/FEM) between healthy adults with and without ossification of the posterior longitudinal ligament (OPLL). No statistically significant difference was observed in the bone strength between healthy adults with and without OPLL. Hyperostosis of the posterior longitudinal ligament in OPLL may not be associated with the systemic bone strength. Although patients with OPLL have been reportedly associated with increased level of bone mineral density (BMD) using dual-energy X-ray absorptiometry (DXA), little is known about the bone strength in OPLL subjects. The aim of this study is to investigate the bone strength measured via QCT/FEM in healthy subjects with OPLL using the medical check-up data, including whole-body CT scans. We examined 796 participants (529 men and 267 women) who underwent CT scans in a single health center between January 2008 and May 2009. We identified OPLL in whole spine and divided the subjects into two groups: non-OPLL and OPLL groups. We calculated the predicted bone strength (PBS) of the proximal femur using QCT/FEM and examined the bone mineral status of the calcaneus using quantitative ultrasound (QUS). We compared the PBS and the QUS parameters between the non-OPLL and OPLL groups. Seventy-four subjects (9.3%; 57 men and 17 women) were diagnosed with OPLL in the whole spine. The OPLL group was significantly older than the non-OPLL group. No statistically significant difference was observed in the PBS and the QUS parameters between the non-OPLL and OPLL groups in both sexes. Furthermore, no statistically significant difference was noted in the PBS and the QUS parameters between two groups in age- and gender-matched analysis. Our results suggest that hyperostosis of the posterior longitudinal ligament in OPLL may not be associated with bone strength and bone mineral status at the extremities.

The purpose of this study was to use the International Classification of Functioning, Disability and Health (ICF) to identify physical and psychosocial problems associated with symptoms of Behçet’s disease (BD) in Japanese patients. Thirty patients with BD were interviewed in a pilot study using the “ICF Checklist”, and a team of medical experts selected categories related to physical and psychosocial aspects of BD. To identify specific physical and psychosocial problems of Japanese patients with BD, 100 new patients were interviewed using the selected categories. Among the 128 categories in the original ICF Checklist, 80 categories were identified as impaired, and another 12 ICF categories were added based on expert discussion of patients input. The number of problem categories was significantly greater in patients with BD with eye involvement and fatigue (eye involvement, 25.7 categories; fatigue, 25.2 categories; both P

Objective Abatacept (ABT) demonstrates good clinical efficacy and retention in rheumatoid arthritis (RA) patients. However, no rescue treatment option against inadequate response to ABT exists. Since tacrolimus (TAC) and ABT suppress T lymphocytes via different mechanisms and a combination of these agents could potentially be effective, this study aimed to examine the efficacy and safety of add-on TAC therapy in RA patients with inadequate response to ABT. Methods Of 550 patients treated with ABT and registered in a Japanese multicenter registry, 25 consecutive patients who underwent add-on TAC therapy and were followed for longer than 24 weeks were included in this study. Results Mean patient age was 67.0 years, disease duration was 16.2 years, and duration of ABT treatment was 1.2 years at the initiation of add-on TAC therapy. Mean TAC dose was 1.2 mg/d at baseline and 1.6 mg/d at week 24. Mean Disease Activity Score of 28 joints - erythrocyte sedimentation rate was significantly improved at week 24 (3.35) relative to baseline (4.97). The proportion of patients who achieved low disease activity or remission was 40.0%, and the European League Against Rheumatism moderate or good response was 72.0%. ABT retention rate was 92.0% at week 24, as calculated by Kaplan-Meier analysis. Only one patient discontinued add-on TAC therapy due to an adverse event (itching sensation). Conclusion This is the first report describing the efficacy and safety profile of add-on TAC therapy with a focus on RA patients with inadequate response to ABT. Our findings suggest that add-on TAC therapy is a worthwhile complementary treatment option in daily clinical practice.

Backgrounds: Neural biomarkers to predict motor recovery have been used in the field of rehabilitation. Functional connectivity (FC) among the brain regions recorded by functional magnetic resonance imaging systems have been reported, but convenient method to estimate FC for clinical situation has not been established.Objectives: This observational study investigated the relationship between neural functional connectivity obtained by electroencephalography (EEG) and the upper limb function in patients during recovery stage after stroke.Methods: Twenty-four patients in the recovery stage between 4 and 8 weeks after the onset of stroke (mean age: 62 ± 12 (SD)) were enrolled. The EEG signals were obtained by five electrodes placed on the motor-related areas (C3, C4, FC3, FC4, and FCz in the International 10-20 system) for 60 sec at rest and during finger movement on the affected side, and amplitude envelope correlations as measures of FC among the areas were calculated. Fugl-Meyer Assessment (FMA) was used to assess upper limb motor function.Results: The FMA scores evaluated at 4W (33 ± 24 (SD)) were improved by 8W (42 ± 23) (p < .001). The FCs in α and β bands calculated between the electrodes in the ipsi-lesional hemisphere were correlated negatively with the FMA score at 4W after stroke. The FCs obtained at 4W could be used to predict the FMA score at 8W after stroke.Conclusions: The FCs recorded at rest, as well as during the finger motor task, by the five electrodes placed on motor-related areas could be used to predict the motor function and recovery of the upper limb affected by stroke. The results indicate the possibility of using FCs recorded by conventional EEG with electrodes as biomarkers to predict motor recovery after stroke.

Discontinuation of biologic therapy in rheumatoid arthritis is attributable to various reasons, with the most important cause being insufficient response. In this study, we investigated the association between rheumatoid factor (RF) and anti-citrullinated protein autoantibody (ACPA) status and the discontinuation of tumor necrosis factor inhibitors (TNFi) therapy due to insufficient response in bio-naïve rheumatoid arthritis (RA) patients.This study included patients enrolled in the Tsurumai Biologic Communication Registry in Japan. The crude comparison of TNFi discontinuation due to ineffectiveness between seropositive and seronegative patients was analyzed using the cumulative incidence function of competing events and Gray test. We assessed the associations between baseline patient characteristics and discontinuation of TNFi therapy due to insufficient response using Fine-Gray proportional hazard regression. Fine-Gray proportional hazard analysis considered competing events of interest, including insufficient response, adverse event, palliation, and personal reasons.Of 1237 patients evaluated, 79.3% were positive for RF and 85.4% for ACPA; 72.6% were double positive and 11.1% were double negative. TNFi therapy had been discontinued because of insufficient response at 200 weeks in 19.8% RF-positive, 16.7% RF-negative, 23.0% ACPA-positive, and 13.8% ACPA-negative patients. There was a significantly higher discontinuation rate due to insufficient response in ACPA-positive patients than in ACPA-negative patients using Gray test, with a similar trend as that for RF status. RF positivity was significantly predictive of the discontinuation of TNFi therapy due to ineffectiveness using Fine-Gray proportional hazard regression analysis after adjusting for baseline characteristics, including age, sex, stage, class, disease activity at baseline, methotrexate use, and prednisolone use [hazard ratio 1.73 (95% confidence interval 1.07-2.80)].Using Fine-Gray proportional hazard regression, we demonstrated that RF positivity was related to a higher discontinuation rate of TNFi therapy due to ineffectiveness in bio-naïve RA patients. Key Points • RF positivity is related to a higher discontinuation rate of TNFi therapy due to ineffectiveness. • ACPA is not predictive of a discontinuation of TNFi therapy due to ineffectiveness.

Background Lipofuscin is an indicator of aging. We examined the clinicopathologic significance of lipofuscin deposition in the renal tubules of renal allografts. Method We analyzed allograft biopsy specimens from living kidney transplantations from January to December 2015. For controls, we analyzed native kidney biopsy specimens obtained from January 2015 to December 2016. We identified granules with a yellow-to-tan shade in renal tubules as lipofuscin. Results The donor age at transplantation was significantly older in lipofuscin deposition biopsy specimens than in those without, whereas the time after transplantation age was not different between the 2 groups with renal allografts. In native kidney biopsies, age at biopsy was significantly older in lipofuscin deposition biopsy specimens than in those without. We compared “massive lipofuscin deposition,” defined as lipofuscin deposition on both sides of 3 or more renal tubules, and donor-age matched control allograft biopsies without lipofuscin deposition. Comparing these 2 groups, recipient age at transplantation was significantly older in the massive lipofuscin deposition group. Conclusion Lipofuscin deposition on tubular epithelium is not a surrogate marker of aging of kidneys allografts, although lipofuscin deposition was significantly greater in older tissues from native kidneys. The older age of recipients may be associated with massive lipofuscin deposition in renal allografts.

To compare the clinical outcomes of abatacept between rheumatoid arthritis patients with and without concomitant methotrexate (MTX) treatment in daily clinical practice. A retrospective cohort study was performed using data from a multicentre registry. A total of 176 consecutive rheumatoid arthritis patients treated with abatacept were included. The propensity score based on multiple baseline characteristic variables was calculated, and 41 of 86 patients treated without MTX (MTX(−)) and 41 of 90 patients treated with concomitant MTX (MTX(+)) were statistically extracted and analysed. Clinical outcomes were evaluated and compared between the two groups over a 52-week period. Baseline characteristics were statistically comparable. No significant differences were observed in the following clinical outcomes from baseline throughout the 52-week period: drug retention rate (MTX(−)/MTX(+) 79.1%/80.5%), mean change in disease activity score based on 28 joints (DAS28-CRP) from baseline (− 1.35/− 1.54), low disease activity rate (48.8%/43.9%), clinical remission rate (31.7%/36.6%), moderate European League Against Rheumatism (EULAR) response rate (68.3%/68.3%), and good EULAR response rate (36.6%/41.1%) at 52 weeks. In rheumatoid arthritis patients with similar background characteristics undergoing abatacept treatment, concomitant MTX does not seem to affect clinical outcomes. Abatacept would be a suitable treatment option in daily clinical practice in patients with contraindications to MTX. • This is the first study to directly compare the clinical efficacy and safety of abatacept between patients with and without concomitant methotrexate (MTX) treatment in ‘real-world’ settings using the propensity score matching method. • There were no significant differences in clinical outcomes of abatacept between patients with and without concomitant MTX treatment. • We used data from a large Japanese multicentre registry for biologics in rheumatoid arthritis, thereby decreasing selection bias based on the personal preferences of physicians.

Purpose The study was designed to evaluate the safety and efficacy of adding oxaliplatin to py (CRT) with S-1 in patients with locally advanced rectal carcinoma (LARC). We report here the final results of the study. Patients and methods Patients with histopathologically confirmed LARC (cT3-T4, any N) were eligible. They received oral S-1 (80 mg/m2/day on days 1–5, 8–12, 22–26, and 29–33) and infusional oxaliplatin (60 mg/m2/day on days 1, 8, 22, 29) plus radiotherapy (1.8 Gy/day, total dose of 50.4 Gy in 28 fractions), with a chemotherapy gap in the third week of radiotherapy. Primary endpoint of the study was pathological complete response (pCR) rate. Secondary endpoints were rates of R0 resection, down-staging, cumulative 3-year local recurrence, 3-year disease-free survival (DFS), and toxicity. Results Forty-five patients were enrolled at six centers in Japan. All patients received CRT, and 44 underwent operation. The pCR rate was 27.3% (12/44). The R0 resection rate was 95.5% (42/44). T-down-staging rate was 59.1% (26/44), and N-down staging rate was 65.9% (29/44); the combined pathological down-staging rate was 79.5% (35/44). There were no grade 4 adverse events, but 11.1% of the patients had grade 3 adverse events. Cumulative 3-year local recurrence rate was 0%. However, 13 (30.0%) patients suffered from distant metastasis, and one patient suffered from secondary esophageal cancer that was unrelated to rectal cancer. Eight patients had lung metastasis, 4 had liver metastasis, and 3 patients died of the metastatic disease. The 3-year DFS rate of the 44 patients was 67.5% (median follow-up 36.3 months), and the 3-year overall survival (OS) rate was 93.0% (median follow-up 39.6 months). The patients were then divided into the pCR (12 patients) group and non pCR (32 patients) group. The 3-year rate of DFS for each group was 91.7% and 58.1% and that of OS was 100% and 90.3%, respectively. Conclusions The study showed a high pCR rate with no severe toxicity, good follow-up results, and good loco-regional control. Therefore, addition of oxaliplatin to preoperative CRT with S-1 in patients with LARC might be feasible and lead to better local control than standard treatment.

The aim of this study is to evaluate the safety and efficacy of induction modified 5-fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) plus bevacizumab followed by S− 1-based chemoradiotherapy in magnetic resonance imaging (MRI)-defined poor-risk locally advanced low rectal cancer. This was a prospective phase II trial at a single comprehensive cancer center. The primary endpoint was the pathological complete response (pCR) rate. Eligible patients had clinical stage II–III low rectal adenocarcinoma with any of the following MRI-defined poor-risk features: circumferential resection margin (CRM) ≤ 1 mm, cT4, positive lateral nodes, mesorectal N2 disease, and/or requiring abdominoperineal resection. Patients received six cycles of mFOLFOX6 with 5 mg/kg bevacizumab followed by oral S-1 (80 mg/m2/day on days 1–14 and 22–35) plus radiotherapy (50.4 Gy). Surgery was conducted through a laparoscopic approach. Lateral node dissection was selectively added when the patient had enlarged lateral nodes. A total of 43 patients were enrolled. Grade 3–4 adverse events occurred in nine patients during induction chemotherapy and in five patients during chemoradiotherapy. One patient declined surgery with a clinical complete response. Forty-two patients underwent surgery, and 16 had pCR [37.2%, 95% confidence interval (CI) 24.4–52.1%]. All underwent R0 resection without conversion, including combined resection of adjacent structures (n = 14) and lateral node dissection (n = 30). Clavien–Dindo grade 3–4 complications occurred in six patients (14.3%). With median follow-up of 52 months, six developed recurrences (lung n = 5, local n = 1; 3-year relapse-free survival 86.0%). This study achieved a high pCR rate with favorable toxicity and postoperative complications in poor-risk locally advanced low rectal cancer. Multicenter study is warranted to evaluate this regimen.

Background Fluorine-18-fluorodeoxyglucose-positron emission tomography (FDG-PET) uptake in primary lesions has been well studied, but little information is available about metastatic bone lesions in patients with lung cancer. The present study was performed to evaluate the relationships between metastatic bone FDG uptake and clinical parameters in patients with lung cancer. Methods FDG uptake was evaluated as the maximum standardized uptake (SUVmax) value of each targeted bone lesion, and the bone to primary lesion ratio of SUVmax (B/P ratio) was calculated. Forty-nine patients (27 men and 22 women) with a diagnosis of lung cancer (small cell lung cancer [SCLC], n = 7; non-small cell lung cancer [NSCLC], n = 42) with bone metastasis, and a total of 185 bone metastatic lesions were evaluated. Results The SUVmax in bone and the B/P ratio were significantly higher in patients with pain and subsequent development of skeletal-related events than in those without pain or skeletal-related events, respectively. In addition, the SUVmax in metastatic bone lesions and the B/P ratio in SCLC were significantly lower than those in NSCLC, despite similar FDG uptake in the primary tumor. Conclusion Our findings suggest that FDG-PET evaluation in metastatic bone lesions could be useful to predict initial pain and subsequent clinical outcomes of local bone status in initially diagnosed lung cancer patients with bone metastasis. In addition, our results suggest that there could be histological differences in the biological activity of bone metastatic lesions in lung cancer, especially between SCLC and NSCLC.

Radiotherapy (RT) can be curative in patients with localized follicular lymphoma (FL), with historical series showing a 10-year disease-free survival of 40 to 50%. As 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography with computerized tomography (PET-CT) upstages 10 to 60% of patients compared to CT, we sought to evaluate outcomes in patients staged by PET-CT, to determine if more accurate staging leads to better patient selection and results. We conducted a multicenter retrospective study under the direction of the International Lymphoma Radiation Oncology Group (ILROG). Inclusion criteria were: RT alone for untreated stage I to II FL (grade 1-3A) with dose equivalent ≥24 Gy, staged by PET-CT, age ≥18 years, and follow-up ≥3 months. End points were freedom from progression (FFP), local control, and overall survival (OS). A total of 512 patients treated between 2000 and 2017 at 16 centers were eligible for analysis; median age was 58 years (range, 20-90); 410 patients (80.1%) had stage I disease; median RT dose was 30 Gy (24-52); and median follow-up was 52 months (3.2-174.6). Five-year FFP and OS were 68.9% and 96%. For stage I, FFP was 74.1% vs 49.1% for stage II (P < .0001). Eight patients relapsed in-field (1.6%). Four had marginal recurrences (0.8%) resulting in local control rate of 97.6%. On multivariable analysis, stage II (hazard ratio [HR], 2.11; 95% confidence interval [CI], 1.44-3.10) and BCL2 expression (HR, 1.62; 95% CI, 1.07-2.47) were significantly associated with less favorable FFP. Outcome after RT in PET-CT staged patients appears to be better than in earlier series, particularly in stage I disease, suggesting that the curative potential of RT for truly localized FL has been underestimated.

OBJECTIVES Rituximab treatment strategies vary in ABOincompatible pediatric kidney transplant recipients. Here, we present the efficacy of 2 doses of rituximab and subsequent outcomes in ABO-incompatible pediatric kidney transplant patients. MATERIALS AND METHODS Our study of ABO-incompatible pediatric kidney transplant recipients included 21 who were pretreated with desensitization that included 2 doses of 100 mg rituximab (rituximab group) at 10 and 1 day pretransplant and 14 who received splenectomy without rituximab (splenectomy group). Both groups received immunosuppression. Basiliximab was administered during transplant and 4 days posttransplant. Double-filtration plasmapheresis and/or plasma exchange procedures were performed pretransplant in those with higher antidonor antibody titers. CD19-positive and CD20-positive B cells were measured sequentially in the rituximab group. Maximum titers of antidonor antibody pre- and posttransplant, patient and graft survival, biopsy-proven rejection, and complications/infections were compared between groups. RESULTS In the rituximab group, CD19- and CD20-positive B cells were depleted on transplant, persistently depleted at 3 months, and under 5% until 1 year posttransplant. Maximum titers of antidonor antibodies decreased significantly posttranplant in the rituximab (P < .001) but not in the splenectomy group (P = .174), with maximum titers posttransplant significantly lower than shown in the splenectomy group (P < .001). No rituximab patients had clinical rejection, but 5 splenectomy group patients had clinical T-cell-mediated rejection, with 2 also having antibody-mediated rejection. Six in the rituximab group had cytomegalovirus viremia but no cytomegalovirus disease; however, 5 splenectomy group recipients had cytomegalovirus disease and viremia. In the rituximab group, 3 had late-onset neutropenia. One child died of hypertrophic cardio myopathy with a functioning graft; all others survived with no failed grafts. All splenectomy group children survived, although 2 had deteriorated graft function. CONCLUSIONS Two doses of rituximab were effective in long-term B-cell depletion to suppress antidonor antibodies. The possibility of late-onset neutropenia must be considered.

Although many animals that perform sexual reproduction exhibit sexual dimorphism, individuals with intersex traits between the traits of males and females appear in some species, depending on environmental factors.

Summary: In the early fetal stage, the gonads are bipotent and only later become the ovary or testis, depending on the genetic sex. Despite many studies examining how sex determination occurs from biopotential gonads, the spatial and temporal organization of bipotential gonads and their progenitors is poorly understood. Here, using lineage tracing in mice, we find that the gonads originate from a T+ primitive streak through WT1+ posterior intermediate mesoderm and appear to share origins anteriorly with the adrenal glands and posteriorly with the metanephric mesenchyme. Comparative single-cell transcriptomic analyses in mouse and cynomolgus monkey embryos reveal the convergence of the lineage trajectory and genetic programs accompanying the specification of biopotential gonadal progenitor cells. This process involves sustained expression of epithelial genes and upregulation of mesenchymal genes, thereby conferring an epithelial-mesenchymal hybrid state. Our study provides key resources for understanding early gonadogenesis in mice and primates.

We evaluated changes in the complement system resulting from anti-vascular endothelial growth factor (VEGF) in eyes with age-related choroidal neovascularization (CNV) including neovascular age-related macular degeneration, pachychoroid neovasculopathy, and polypoidal choroidal neovasculopathy. We measured the concentrations of the complement activation products (C3a, C4a), VEGF, and monocyte chemotactic protein-1 in the aqueous humor during intravitreal anti-VEGF injections for CNV. The VEGF level decreased significantly (P P P = 0.007) and C4a (R = − 0.237, P = 0.055) levels at baseline, but the correlation between the VEGF and C3a levels (R = − 0.148, P = 0.242) changed significantly (P = 0.028 by analysis of covariance) after anti-VEGF treatment. The C3a increase after anti-VEGF therapy did not change the visual outcomes in eyes with CNV for 1 year. Dysregulation of the complement system can be induced after anti-VEGF therapy.

BACKGROUND/AIM To compare five radiotherapy methods for prostate cancer. PATIENTS AND METHODS During 2005-2018, the data of patients with non-metastatic prostate cancer were retrospectively analysed. Patients were treated with high-dose-rate brachytherapy (HDR-BT); low-dose-rate brachytherapy (LDR-BT); or external-beam radiotherapy (EBRT), including conventionally fractionated radiotherapy (CFRT), moderate-hypofractionated radiotherapy (MHRT), and ultra-hypofractionated radiotherapy (UHRT). RESULTS In total, 496 patients (149, HDR-BT; 100, LDR-BT; 100, CFRT; 97, MHRT, and 50, UHRT) with a median follow-up of 4.3 years were enrolled. The incidence of grade ≥2 acute genitourinary toxicities was significantly lower with HDR-BT (p

The lateral prefrontal cortex (LPFC) has a strong monosynaptic connection with the caudate nucleus (CdN) of the striatum. Previous human MRI studies have suggested that this LPFC-CdN pathway plays an important role in inhibitory control and working memory. We aimed to validate the function of this pathway at a causal level by pathway-selective manipulation of neural activity in non-human primates. To this end, we trained macaque monkeys on a delayed oculomotor response task with reward asymmetry and expressed an inhibitory type of chemogenetic receptors selectively to LPFC neurons that project to the CdN. Ligand administration reduced the inhibitory control of impulsive behavior, as well as the task-related neuronal responses observed in the local field potentials from the LPFC and CdN. These results show that we successfully suppressed pathway-selective neural activity in the macaque brain, and the resulting behavioral changes suggest that the LPFC-CdN pathway is involved in inhibitory control., In order to validate a previously inferred function of the lateral prefrontal cortex (LPFC)-caudate nucleus (CdN) pathway in humans in inhibitory control and working memory, Oguchi et al used pathway-selective chemogenetic manipulation of neural activity in macaques. By suppressing pathway-specific neural activity and observing resultant behavioural changes, they provided evidence that the LPFC-CdN pathway does indeed play a role in inhibitory control.

Recently, activities of daily living (ADL) were identified as a prognostic factor among elderly patients with heart disease; however, a specific association between ADL and prognosis after cardiac and aortic surgery is not well established. We aimed to clarify the impact of ADL capacity at discharge on prognosis in elderly patients after cardiac and aortic surgery. This retrospective cohort study included 171 elderly patients who underwent open operation for cardiovascular disease in a single center (median age: 74 years; men: 70%). We used the Barthel Index (BI) as an indicator for ADL. Patients were classified into 2 groups according to the BI at discharge, indicating a high (BI ≥ 85) or low (BI

Purpose This study aimed to describe recovery of dysphagia after stroke. We determined the proportion of stroke survivors with dysphagia on admission, discharge, and 6 months after stroke. Additionally, the factors affecting oral feeding 6 months after stroke were explored. Methods A total of 427 acute stroke patients were recruited prospectively. Presence of dysphagia was evaluated on admission, weekly until recovery was achieved, and at discharge. We compared stroke survivors with dysphagia who had complete recovery, who had dysphagia but achieved oral feeding, and who required tube feeding. Patient-reported eating ability was evaluated at 6 months. Patients who achieved oral feeding by 6 months were compared to those who had persistent tube feeding need. Results Fifty-five percent of stroke survivors had dysphagia on initial evaluation (3.1 ± 1.4 days after admission) and 37% at discharge (21.1 ± 12.4 days). At 6 months, 5% of patients required tube feeding. Among those who had dysphagia at initial evaluation, 32% had resolution of dysphagia within two weeks, 44% had dysphagia but started oral feeding before discharge, and 23% required alternative means of alimentation (nasogastric tube feeding, percutaneous endoscopic gastrostomy, parental nutrition) throughout hospitalization. At 6 months, 90% of stroke survivors who achieved oral feeding by discharge continued with oral feeding. Patients who achieved oral feeding after discharge had less cognitive impairments on admission and a higher speech therapist intervention rate after discharge. Conclusions More than half of stroke survivors had dysphagia but the vast majority were able to return to oral feeding by 6 months. Cognitive function and dysphagia rehabilitation interventions were associated with return to oral feeding after hospital discharge.

Objective Despite reports on the effects of ankle-brachial index (ABI) improvement following endovascular therapy (EVT) on the limb prognosis, studies evaluating cardiovascular events are limited. We investigated whether or not ABI improvement 1 year following EVT was associated with cardiovascular events. Methods The I-PAD NAGANO registry is an observational multicenter cohort study that enrolled 337 patients with peripheral artery disease (PAD) who underwent EVT between August 2015 and July 2016. From this cohort, we identified 232 patients whose ABI data 1 year following EVT were available, after excluding patients with critical limb ischemia. We divided the patients into two groups according to the degree of ABI improvement 1 year following EVT (ΔABI) - the ΔABI

BACKGROUND: The efficacy and safety of benralizumab, an interleukin-5 receptor alpha-directed cytolytic monoclonal antibody, for the prevention of exacerbations in patients with moderate to very severe chronic obstructive pulmonary disease (COPD) are not known.METHODS: In the GALATHEA and TERRANOVA trials, we enrolled patients with COPD (at a ratio of approximately 2:1 on the basis of eosinophil count [≥220 per cubic millimeter vs. RESULTS: In GALATHEA, the estimates of the annualized exacerbation rate were 1.19 per year (95% confidence interval [CI], 1.04 to 1.36) in the 30-mg benralizumab group, 1.03 per year (95% CI, 0.90 to 1.19) in the 100-mg benralizumab group, and 1.24 per year (95% CI, 1.08 to 1.42) in the placebo group; the rate ratio as compared with placebo was 0.96 for 30 mg of benralizumab (P = 0.65) and 0.83 for 100 mg of benralizumab (P = 0.05). In TERRANOVA, the estimates of the annualized exacerbation rate for 10 mg, 30 mg, and 100 mg of benralizumab and for placebo were 0.99 per year (95% CI, 0.87 to 1.13), 1.21 per year (95% CI, 1.08 to 1.37), 1.09 per year (95% CI, 0.96 to 1.23), and 1.17 per year (95% CI, 1.04 to 1.32), respectively; the corresponding rate ratios were 0.85 (P = 0.06), 1.04 (P = 0.66), and 0.93 (P = 0.40). At 56 weeks, none of the annualized COPD exacerbation rate ratios for any dose of benralizumab as compared with placebo reached significance in either trial. Types and frequencies of adverse events were similar with benralizumab and placebo.CONCLUSIONS: Add-on benralizumab was not associated with a lower annualized rate of COPD exacerbations than placebo among patients with moderate to very severe COPD, a history of frequent moderate or severe exacerbations, and blood eosinophil counts of 220 per cubic millimeter or greater (Funded by AstraZeneca [GALATHEA and TERRANOVA] and Kyowa Hakko Kirin [GALATHEA]; GALATHEA and TERRANOVA ClinicalTrials.gov numbers, NCT02138916 and NCT02155660.).

This study aimed to evaluate the effectiveness of abatacept (ABA) by anti-cyclic citrullinated peptide (ACPA) status on disease activity as well as radiographic progression in patients with rheumatoid arthritis (RA) in clinical settings. A retrospective cohort study was conducted using data from a multicenter registry. Data from a total of 553 consecutive RA patients treated with intravenous ABA were included. We primarily compared the status of disease activity (SDAI) and radiographic progression (van der Heijde modified total Sharp score: mTSS) between the ACPA-negative (N = 107) and ACPA-positive (N = 446) groups. ‘ACPA positive’ was defined as ≥ 13.5 U/mL of anti-CCP antibody. Baseline characteristics between groups were similar. The proportion of patients who achieved low disease activity (LDA; SDAI ≤ 11) at 52 weeks was significantly higher in the ACPA-positive group. Multivariate logistic regression analysis identified ACPA positivity as an independent predictor for achievement of LDA at 52 weeks. Drug retention rate at 52 weeks estimated by the Kaplan–Meier curve was significantly higher in the ACPA-positive group. Achievement rate of structural remission (ΔmTSS ≤ 0.5) at 52 weeks was similar between groups. ABA treatment demonstrated a significantly higher clinical response and higher drug retention rate in ACPA-positive patients. Progression of joint destruction was similar between the ACPA-negative and ACPA-positive groups. Close attention should be paid to joint destruction even in patients showing a favorable response to ABA, especially when the ACPA status is positive.

The cumulative intracranial tumor volume (CITV) has recently been suggested to be a more relevant predictive factor for patients with brain metastases (BM) treated with stereotactic radiosurgery (SRS). We aimed to investigate the feasibility of upfront SRS for patients with BM having a high CITV, i.e., exceeding 7 ml.Two hundred thirty-three consecutive patients with BM having a CITV 7 ml who underwent SRS as first-line treatment from 2011 to 2019 were retrospectively identified. The overall survival (OS) and intracranial disease control rates were analyzed. Multivariate proportional hazards models were used to identify prognostic factors associated with treatment outcome. Toxicity and salvage therapy were also investigated.The median OS was 8.7 months (95% confidence interval: 7.1-10.4), and 6-month and 1-year OS rates were 60 and 40%, respectively. Systemic anticancer therapy (hazard ratio (HR): 0.45, p 0.001), female sex (HR: 0.61, p = 0.001), synchronous SRS (HR: 0.57, p = 0.003), number of BM (HR: 1.04, p = 0.008), controlled extracranial disease (HR: 0.56, p = 0.009), Karnofsky performance status (HR: 0.87, p = 0.015), and staged SRS (HR: 0.71, p = 0.037) were found to be factors independently associated with OS. Post-SRS toxicities of CTCAE grades 3, 4, and 5 were observed in 14, 5, and 1 patient, respectively. As salvage management, repeat SRS, whole brain radiotherapy, and surgical resection were required for 84, 16, and 10 patients, respectively, CONCLUSIONS: With vigilant surveillance and appropriate salvage management, upfront SRS alone can be considered as a relatively safe and effective treatment strategy even for BM with CITV 7 ml.

In the multidisciplinary management of early-stage extranodal natural killer/T-cell lymphoma, nasal type (ENKTCL), with curative intent, radiation therapy is the most efficacious modality and is an essential component of a combined-modality regimen. In the past decade, utilization of upfront radiation therapy and non-anthracycline-based chemotherapy has improved treatment and prognosis. This guideline mainly addresses the heterogeneity of clinical features, principles of risk-adapted therapy, and the role and appropriate design of radiation therapy. Radiation therapy methods (including target volume definition, dose and delivery methods) are crucial for optimizing cure for patients with early-stage ENKTCL. The application of the principles of involved site radiation therapy in this lymphoma entity often leads to a more extended clinical target volume (CTV) than in other lymphoma types because it usually presents with primary tumor invasion, multifocal lesions, or extensive submucosal infiltration beyond the macroscopic disease. The CTV varies across different primary sites and is classified mainly into nasal, nonnasal upper aerodigestive tract (UADT), and extra-UADT entities. This review is a consensus of the International Lymphoma Radiation Oncology Group regarding the approach to radiation therapy, target-volume definition, optimal dose, and dose constraints in ENKTCL treatment.

Aim: Low-vacuum scanning electron microscopy (LVSEM) has been reported to aid in diagnosis of renal biopsy. This study evaluated early transplant glomerulopathy in kidney transplant recipients using LVSEM. Methods: We selected 4 biopsies of cg0, 5 biopsies of cg1a, 5 biopsies of cg1b, and 4 biopsies of cg2 lesions that had been evaluated by light microscopy (LM) and transmission electron microscopy from recipients with acute/active or chronic, active antibody-mediated rejection (AABMR or CAABMR). Renal allograft paraffin sections (1 µm thickness) were stained with periodic acid-methenamine silver and observed using LVSEM. The cg score was based on the Banff classification. The parameter “percentage of duplicated capillary number” was calculated as follows: in 1 glomerulus with glomerular basement membrane (GBM) duplication, the total duplicated capillary number/the total number of capillaries ×100. Results: In all 4 biopsy specimens with AABMR showing cg0, LVSEM revealed GBM duplication not identified by LM. The average percentage of duplicated capillary number per glomerulus with GBM duplication was higher when observed by LVSEM than when observed by LM in all cg1b and cg2 biopsy specimens. Conclusion: LVSEM revealed early GBM duplication in AABMR. Early GBM duplication might progress in the very early phase of AABMR. GBM duplication was more frequently detected by LVSEM than by LM in biopsy specimens with early chronic, active antibody mediated rejection. Thus, LVSEM may be useful in diagnosis of early transplant glomerulopathy.

Eusocial insects exhibit reproductive division of labor, in which only a fraction of colony members differentiate into reproductives. In termites, reproductives of both sexes are present in a colony and constantly engaged in reproduction. It has been suggested that the sex ratio of reproductives is maintained by social interactions. The presence of reproductives is known to inhibit the additional differentiation of same-sex reproductives, while it promotes the differentiation of opposite-sex reproductives. In this study, using the damp-wood termite Hodotermopsis sjostedti, physiological effects of male/female reproductives on the differentiation of supplementary reproductives (neotenics) were examined. The results showed that the only male-neotenic condition, i.e., the presence of male neotenics in the absence of female neotenics, accelerated the neotenic differentiation from female workers (i.e., pseudergates). Under this condition, the rise of juvenile hormone (JH) titer was repressed in females, and the application of a JH analog inhibited the female neotenic differentiation, indicating that the low JH titer leads to rapid differentiation. Thus, the only male-neotenic condition that actively promotes reproductive differentiation by manipulating physiological condition of females is suggested to be a mechanism underlying sexual asymmetry in reproductive function, which may lead the female-biased sex allocation of reproductives.

No guidelines have been established for the evaluation of swallowing function following extubation. The factors of bedside swallowing evaluations (BSEs) that are associated with the development of pneumonia have not been fully elucidated. This study aimed to retrospectively investigate the most appropriate measurements of BSEs for predicting pneumonia. The study subjects were 97 adults who underwent BSEs following cardiovascular surgery. Patients were divided into the pneumonia onset group (n = 21) and the non-onset group (n = 76). Patient characteristics, intraoperative characteristics, complications, BSE results, and postoperative progress were compared between the groups. BSEs were composed of consciousness level, modified water swallowing test (MWST) score, repetitive saliva swallowing test score, speech intelligibility score, and risk of dysphagia in the cardiac surgery score. Univariate and multivariate analyses with the BSE as the independent variable and pneumonia onset as the dependent variable were also performed to identify factors that predict pneumonia. For factors that became significant in univariate analysis, the incidence of pneumonia was shown using the Kaplan-Meier curve. No significant differences were found in patient characteristics, intraoperative characteristics, and complications between the 2 groups. The postoperative progress was significantly different between the 2 groups, the pneumonia-onset group had a significantly longer time until the start of oral intake and a significantly lower median value of Food Intake Level Scale at the time of discharge. According to univariate and multivariate analyses, MWST score was a significant factor for predicting the onset of pneumonia even after adjusting for patient characteristics and surgical factors, and the incidence of pneumonia increased approximately 3 times when the MWST score was 3 points or less. The MWST score after extubation in cardiovascular surgery was the strongest predictor of postoperative pneumonia in BSEs. Furthermore, the incidence of pneumonia increased approximately 3 times when the MWST score was 3 points or less. Predicting cases with a high risk of developing pneumonia allows nurses and attending physicians to monitor the progress carefully and take aggressive preventive measures.

Although several risk factors have been reported for cervical ossification of the longitudinal ligament (OPLL), most evaluations made in the past were based on plain X-ray, not on computed tomography (CT) scan. In this study, we aimed to clarify novel risk factors for cervical OPLL in asymptomatic subjects undergoing CT scan as their routine medical checkups. A total of 1789 Japanese asymptomatic subjects who underwent CT scan for the whole body as their routine medical checkups were retrospectively reviewed. The medical checkup also included laboratory examinations, bone mineral status, and ultrasound of the carotid artery. As a result, cervical OPLL was seen in 120 subjects (6.7%). As we compared the demographic and clinical data between subjects with and without OPLL, OPLL group showed older age, higher proportion of male sex, higher BMI, higher incidence of hypertension, higher levels of blood HbA1c and triglyceride, and higher incidence of plaques in the carotid artery. A multivariate logistic regression analysis revealed that age (Odds ratio (OR):1.03), male sex (OR: 1.91), and the presence of plaque in the carotid artery (OR: 1.71) were risk factors for OPLL. To the best of our knowledge, this is the first report to reveal an association between OPLL and arteriosclerotic lesions.