Global real-world experiences with pembrolizumab in advanced urothelial carcinoma after platinum-based chemotherapy: the ARON-2 study.

BACKGROUND: Immune checkpoint inhibitors have changed previous treatment paradigm of advanced urothelial carcinoma (UC). The ARON-2 study (NCT05290038) aimed to assess the real-world effectiveness of pembrolizumab in patients recurred or progressed after platinum-based chemotherapy. PATIENTS AND METHODS: Medical records of patients with documented metastatic UC treated by pembrolizumab as second-line therapy were retrospectively collected from 88 institutions in 23 countries. Patients were assessed for overall survival (OS), progression-free survival (PFS) and overall response rate (ORR). Cox proportional hazards models were adopted to explore the presence of prognostic factors. RESULTS: In total, 836 patients were included: 544 patients (65%) received pembrolizumab after progression to first-line platinum-based chemotherapy in the metastatic setting (cohort A) and 292 (35%) after recurring within < 12 months since the completion of adjuvant or neoadjuvant chemotherapy (cohort B). The median follow-up time was 15.3 months. The median OS and the ORR were 10.5 months and 31% in the overall study population, 9.1 months and 29% in cohort A and 14.6 months and 37% in cohort B. At multivariate analysis, ECOG-PS ≥ 2, bone metastases, liver metastases and pembrolizumab setting (cohort A vs B) proved to be significantly associated with worst OS and PFS. Stratified by the presence of 0, 1-2 or 3-4 prognostic factors, the median OS was 29.4, 12.5 and 4.1 months (p < 0.001), while the median PFS was 12.2, 6.4 and 2.8 months, respectively (p < 0.001). CONCLUSIONS: Our study confirms that pembrolizumab is effective in the advanced UC real-world context, showing outcome differences between patients recurred or progressed after platinum-based chemotherapy.

Prognostic value of micrometric substaging in pT1 bladder cancer patients treated with en-bloc transurethral resection.

AIMS: We aimed to assess the oncological impact of micrometric extent of invasion in patients with pT1 bladder cancer (BCa) who underwent en-bloc resection for bladder tumour (ERBT). METHODS AND RESULTS: We retrospectively analysed the records and specimens of 106 pT1 high-grade BCa patients who underwent ERBT. The extent of invasion, such as depth from basal membrane, number of invasive foci, maximum width of invasive focus, muscularis mucosae invasion and infiltration pattern (pattern A: solid sheet-like, nodular or nested growth, pattern B: trabecular, small cluster or single-cell pattern) were evaluated by a single genitourinary pathologist. The end-points were recurrence-free (RFS) and progression-free survival (PFS). Within a median follow-up of 23 months, overall, 36 patients experienced recurrence and 13 patients experienced disease progression. The 2-year PFS differed significantly depending on depth from basal membrane (< 1.3 mm: 94.8% versus ≧ 1.3 mm: 65.2%, P = 0.005), maximum width of invasive focus (< 4 mm: 91.7% versus ≧ 4 mm: 62.3%, P < 0.001), muscularis mucosae (MM) invasion (above MM = 96.1% versus into or beyond MM = 64.8%, P = 0.002) and infiltration pattern (pattern A: 100% versus pattern B: 83.3%, P = 0.037). In a multivariable analysis, MM invasion [hazard ratio (HR) = 4.54, 95% confidence interval (CI) = 1.25-16.5] and maximum width of invasive focus ≧ 4 mm (HR = 4.79, 95% CI = 1.25-16.5) were independent prognostic factors of progression. CONCLUSIONS: En-bloc resection facilitates the evaluation of pathologic variables that might be useful in predicting disease recurrence and progression. In particular, not only the MM invasion but also the maximum width of invasion focus, reflecting the invasive volume, appear to be reliable prognosticators for disease progression.

Improved Electrochemical Peptide Synthesis Enabled by Electron-Rich Triaryl Phosphines.

While remarkable progress has been made in the development of peptide medicines, many problems related to peptide synthesis remain unresolved. Previously, we reported electrochemical peptide synthesis using a phosphine as a potentially recyclable coupling reagent. However, there was room for improvement from the point of view of reaction efficiency, especially in the carboxylic acid activation step and the peptide bond formation step. To overcome these challenges, we searched for the optimal phosphine. Among phosphines with various electronic properties, we found that electron-rich triaryl phosphines improved the reaction efficiency. Consequently, we successfully performed electrochemical peptide synthesis on sterically hindered and valuable amino acids. We also synthesized oligopeptides that were challenging with our previous method. Finally, we examined the effect of substituents on the phosphine cations, and gained some insights into reactivity, which will aid researchers designing reactions involving phosphine cations.

Understanding Flexdispersion: Structure-Function Relationship Studies of Organic Amphiphilic Ligands.

Since inorganic nanoparticles have unique properties that differ from those of bulk materials, their material applications have attracted attention in various fields. In order to utilize inorganic nanoparticles for functional materials, they must be dispersed without agglomeration. Therefore, the surfaces of inorganic nanoparticles are typically modified with organic ligands to improve their dispersibility. Nevertheless, the relationship between the tail group structure in organic ligands and the dispersibility of inorganic nanoparticles in organic solvents remains poorly understood. We previously developed amphiphilic ligands that consist of ethylene glycol chains and alkyl chains to disperse inorganic nanoparticles in a variety of organic solvents. However, the structural requirements for amphiphilic ligands to "flexibly" disperse nanoparticles in less polar to polar solvents are still unclear. Here, we designed and synthesized several phosphonic acid ligands for structure-function relationship studies of flexdispersion. Dynamic light scattering analysis and visible light transmittance measurements revealed that the ratio of alkyl/ethylene glycol chains in organic ligands alone does not determine the dispersibility of the nanoparticles in organic solvents, but the arrangement of the individual chains also has an effect. From a practical application standpoint, it is preferable to design ligands with ethylene glycol chains on the outside relative to the particle surface.

Extracorporeal cardiopulmonary resuscitation versus conventional CPR in cardiac arrest: an updated meta-analysis and trial sequential analysis.

BACKGROUND: Extracorporeal cardiopulmonary resuscitation (ECPR) may reduce mortality and improve neurological outcomes in patients with cardiac arrest. We updated our existing meta-analysis and trial sequential analysis to further evaluate ECPR compared to conventional CPR (CCPR). METHODS: We searched three international databases from 1 January 2000 through 1 November 2023, for randomised controlled trials or propensity score matched studies (PSMs) comparing ECPR to CCPR in both out-of-hospital cardiac arrest (OHCA) and in-hospital cardiac arrest (IHCA). We conducted an updated random-effects meta-analysis, with the primary outcome being in-hospital mortality. Secondary outcomes included short- and long-term favourable neurological outcome and survival (30 days-1 year). We also conducted a trial sequential analysis to evaluate the required information size in the meta-analysis to detect a clinically relevant reduction in mortality. RESULTS: We included 13 studies with 14 pairwise comparisons (6336 ECPR and 7712 CCPR) in our updated meta-analysis. ECPR was associated with greater precision in reducing overall in-hospital mortality (OR 0.63, 95% CI 0.50-0.79, high certainty), to which the trial sequential analysis was concordant. The addition of recent studies revealed a newly significant decrease in mortality in OHCA (OR 0.62, 95% CI 0.45-0.84). Re-analysis of relevant secondary outcomes reaffirmed our initial findings of favourable short-term neurological outcomes and survival up to 30 days. Estimates for long-term neurological outcome and 90-day-1-year survival remained unchanged. CONCLUSIONS: We found that ECPR reduces in-hospital mortality, improves neurological outcome, and 30-day survival. We additionally found a newly significant benefit in OHCA, suggesting that ECPR may be considered in both IHCA and OHCA.

Impact of time to revascularization on outcomes in patients after out-of-hospital cardiac arrest with STEMI.

BACKGROUND: International guidelines recommend emergency coronary angiography in patients after out-of-hospital cardiac arrest (OHCA) with ST-segment elevation on 12­lead electrocardiography. However, the association between time to revascularization and outcomes remains unknown. This study aimed to evaluate the association between time to revascularization and outcomes in patients with OHCA due to ST-segment-elevation myocardial infarction (STEMI) who underwent percutaneous coronary intervention (PCI). METHODS: This multicenter, retrospective, nationwide observational study included patients aged ≥18 years with OHCA due to STEMI who underwent PCI between 2014 and 2020. The time of the first return of spontaneous circulation (ROSC) was defined as the time of first ROSC during resuscitation, regardless of the pre-hospital or in-hospital setting. The primary outcome was a 1-month favorable neurological outcome, defined as cerebral performance category 1 or 2. Multivariable logistic regression analysis was used to assess the association between the time to revascularization and favorable neurological outcomes. RESULTS: A total of 547 patients were included in this analysis. The multivariable logistic regression analysis showed that a shorter time from the first ROSC to revascularization was associated with 1-month favorable neurological outcomes (63/86 [73.3%] in the time from the first ROSC to revascularization ≤60 min group versus 98/193 [50.8%] in the >120 min group; adjusted OR, 0.26; 95% CI, 0.11-0.56; P for trend, 0.015). CONCLUSIONS: Shorter time to revascularization was significantly associated with 1-month favorable neurological outcomes in patients with OHCA due to STEMI who underwent PCI.

Derivation of Coagulation Phenotypes and the Association with Prognosis in Traumatic Brain Injury: A Cluster Analysis of Nationwide Multicenter Study.

BACKGROUND: The pathogenesis and pathophysiology of traumatic coagulopathy during traumatic brain injury is not well understood, and the appropriate treatment strategy for this condition has not been established. This study aimed to evaluate the coagulation phenotypes and their effect on prognosis in patients with isolated traumatic brain injury. METHODS: In this multicenter cohort study, we retrospectively analyzed data from the Japan Neurotrauma Data Bank. Adults with isolated traumatic brain injury (head abbreviated injury scale > 2; abbreviated injury scale of any other trauma < 3) who were registered in the Japan Neurotrauma Data Bank were included in this study. The primary outcome was the association of coagulation phenotypes with in-hospital mortality. Coagulation phenotypes were derived using k-means clustering with coagulation markers, including prothrombin time international normalized ratio (PT-INR), activated partial thromboplastin time (APTT), fibrinogen (FBG), and D-dimer (DD) on arrival at the hospital. Multivariable logistic regression analyses were conducted to calculate the adjusted odds ratios of coagulation phenotypes with their 95% confidence intervals (CIs) for in-hospital mortality. RESULTS: In total, 556 patients were enrolled and five coagulation phenotypes were identified. The median (interquartile range) score for the Glasgow Coma Scale was 6 (4-9). Cluster A (n = 129) had the closest to normal coagulation values; cluster B (n = 323) had a mild high DD phenotype; cluster C (n = 30) had a prolonged PT-INR phenotype with a higher frequency of antithrombotic medication in elderly patients than in younger patients; cluster D (n = 45) had a low amount of FBG, high DD, and prolonged APTT phenotype with a high incidence of skull fracture; and cluster E (n = 29) had a low amount of FBG and extremely high DD phenotype with high energy trauma and a high incidence of skull fracture. In the multivariable logistic regression analysis, the association of clusters B, C, D, and E with in-hospital mortality yielded the corresponding adjusted odds ratios of 2.17 (95% CI 1.22-3.86), 2.61 (95% CI 1.01-6.72), 10.0 (95% CI 4.00-25.2), and 24.1 (95% CI 7.12-81.3), respectively, relative to cluster A. CONCLUSIONS: This multicenter, observational study identified five different coagulation phenotypes of traumatic brain injury and showed associations of these phenotypes with in-hospital mortality.

High tibial osteotomy alone does not decrease medial meniscus extrusion in the setting of medial meniscus posterior root tear: A cadaveric study.

PURPOSE: This study investigated whether inducing valgus alignment and shifting the load laterally through high tibial osteotomy (HTO) alone decreases the extent of medial meniscus extrusion (MME) in the setting of medial meniscus posterior root tear(MMPRT) using ultrasound evaluation. METHODS: Eight fresh-frozen human cadaveric knee specimens were tested using a six-degree-of-freedom robotic testing system and ultrasound. Each specimen was tested in five conditions: (1) intact, (2) MMPRT, (3) medial meniscus repair (MMR), (4) combined medial open-wedge HTO + MMR, and (5) HTO + MMPRT. Measurements were obtained over the medial collateral ligament (MCL, central image) and posterior to the MCL (posterior image) with a 250 N axial load at 0°, 30°, and 90° of knee flexion. Statistical analysis was performed using a two-factor repeated-measures ANOVA. RESULTS: MME was significantly greater in HTO + MMPRT(0°: 2.44 ± 0.41mm, 30°: 2.47 ± 0.37mm, 90°: 2.41 ± 0.28mm) than HTO + MMR in central images (mean difference +0.83 mm, p < .001). No significant difference was found between HTO + MMPRT and MMPRT in MME . MMR had significantly less MME than MMPRT (mean difference -0.58mm, p < .001, posterior image at 0°and central image at 90°, p=.002). HTO + MMR showed significantly less MME than MMR alone at 30° and 90° knee flexion in central image (30°: -0.38 ± 0.05mm, 90°: -0.45 ± 0.06mm, p < .001) and 90° knee flexion in posterior image (-0.38 ± 0.08mm, p = .004). CONCLUSION: HTO alone did not decrease MME in the setting of MMPRT, while MMR alone decrease MME after MMPRT. Additionally, HTO + MMR decreases MME aftrer MMPRT compared to MMR alone, although the clinical significance was uncertain. CLINICAL RELEVANCE: The findings of this study provide clinicians with valuable insights for improving MME. HTO alone does not decrease MME in cases of MMPRT.

Development and validation of a scoring system for in-hospital mortality following band ligation in esophageal variceal bleeding.

OBJECTIVES: We aimed to develop and validate a simple scoring system to predict in-hospital mortality after endoscopic variceal ligation (EVL) for esophageal variceal bleeding. METHODS: Data from a 13-year study involving 46 Japanese institutions were split into development (initial 7 years) and validation (last 6 years) cohorts. The study subjects were patients hospitalized for esophageal variceal bleeding and treated with EVL. Variable selection was performed using least absolute shrinkage and selection operator regression, targeting in-hospital all-cause mortality as the outcome. We developed the Hospital Outcome Prediction following Endoscopic Variceal Ligation (HOPE-EVL) score from ß coefficients of multivariate logistic regression and assessed its discrimination and calibration. RESULTS: The study included 980 patients: 536 in the development cohort and 444 in the validation cohort. In-hospital mortality was 13.6% and 10.1% for the respective cohorts. The scoring system used five variables: systolic blood pressure (<80 mmHg: 2 points), Glasgow Coma Scale (≤12: 1 point), total bilirubin (≥5 mg/dL: 1 point), creatinine (≥1.5 mg/dL: 1 point), and albumin (<2.8 g/dL: 1 point). The risk groups (low: 0-1, middle: 2-3, high: ≥4) in the validation cohort corresponded to observed and predicted mortality probabilities of 2.0% and 2.5%, 19.0% and 22.9%, and 57.6% and 71.9%, respectively. In this cohort, the HOPE-EVL score demonstrated excellent discrimination ability (area under the curve [AUC] 0.890; 95% confidence interval [CI] 0.850-0.930) compared with the Model for End-stage Liver Disease score (AUC 0.853; 95% CI 0.794-0.912) and the Child-Pugh score (AUC 0.798; 95% CI 0.727-0.869). CONCLUSIONS: The HOPE-EVL score practically and effectively predicts in-hospital mortality. This score could facilitate the appropriate allocation of resources and effective communication with patients and their families.

Relationship between increased knee joint line obliquity after medial open-wedge high tibial osteotomy and patient-reported outcome measures.

INTRODUCTION: This study evaluated the correlation between postoperative knee joint line obliquity after medial open-wedge high tibial osteotomy and patient-reported outcome measures excluding excessively overcorrected knees. This study further identified preoperative radiological factors related to the increased postoperative knee joint line obliquity. MATERIALS AND METHODS: We retrospectively evaluated patients who underwent medial open-wedge high tibial osteotomy between March 2013 and March 2021. Postoperative excessively overcorrected knees with hip-knee-ankle angle > 7° were excluded. We investigated radiological parameters and patient-reported outcome measures preoperatively and at the last follow-up. The following radiologic parameters were measured: hip-knee-ankle angle, weight-bearing line ratio, mechanical medial proximal tibial angle, mechanical lateral distal femoral angle, lateral distal tibial angle, joint line convergent angle, knee joint line obliquity, ankle joint line obliquity, hip abduction angle, tibial posterior slope, Carton-Deschamps index, and patella tilting angle. Clinical outcomes were evaluated using Japanese knee outcome measures. This assessment criterion is based on the Western Ontario McMaster Universities Arthritis Index and MOS Short Form 36. Multiple regression analysis was performed to evaluate the association between postoperative knee joint line obliquity and patient-reported outcome measures or preoperative radiological factors (P < .05). RESULTS: A total of 52 knees were included. The mean age at the time of the surgery was 61.6 ± 9.0 years and the mean follow-up period was 30.6 ± 10.1 months. Increased postoperative knee joint line obliquity was associated with lower Japanese knee outcome measures. The preoperative hip-knee-ankle angle was significantly associated with postoperative knee joint line obliquity. CONCLUSIONS: Increased knee joint line obliquity after medial open-wedge high tibial osteotomy is associated with inferior clinical outcomes. Care should be given to the center of the rotational angulation in around-knee osteotomy to avoid postoperative increased knee joint line obliquity. LEVEL OF EVIDENCE: Retrospective comparative study, Level III.

The SYNGAP1 3'UTR Variant in ALS Patients Causes Aberrant SYNGAP1 Splicing and Dendritic Spine Loss by Recruiting HNRNPK.

Fused in sarcoma (FUS) is a pathogenic RNA-binding protein in amyotrophic lateral sclerosis (ALS). We previously reported that FUS stabilizes Synaptic Ras-GTPase activating protein 1 (Syngap1) mRNA at its 3' untranslated region (UTR) and maintains spine maturation. To elucidate the pathologic roles of this mechanism in ALS patients, we identified the SYNGAP1 3'UTR variant rs149438267 in seven (four males and three females) out of 807 ALS patients at the FUS binding site from a multicenter cohort in Japan. Human-induced pluripotent stem cell (hiPSC)-derived motor neurons with the SYNGAP1 variant showed aberrant splicing, increased isoform α1 levels, and decreased isoform γ levels, which caused dendritic spine loss. Moreover, the SYNGAP1 variant excessively recruited FUS and heterogeneous nuclear ribonucleoprotein K (HNRNPK), and antisense oligonucleotides (ASOs) blocking HNRNPK altered aberrant splicing and ameliorated dendritic spine loss. These data suggest that excessive recruitment of RNA-binding proteins, especially HNRNPK, as well as changes in SYNGAP1 isoforms, are crucial for spine formation in motor neurons.SIGNIFICANCE STATEMENT It is not yet known which RNAs cause the pathogenesis of amyotrophic lateral sclerosis (ALS). We previously reported that Fused in sarcoma (FUS), a pathogenic RNA-binding protein in ALS, stabilizes synaptic Ras-GTPase activating protein 1 (Syngap1) mRNA at its 3' untranslated region (UTR) and maintains dendritic spine maturation. To elucidate whether this mechanism is crucial for ALS, we identified the SYNGAP1 3'UTR variant rs149438267 at the FUS binding site. Human-induced pluripotent stem cell (hiPSC)-derived motor neurons with the SYNGAP1 variant showed aberrant splicing, which caused dendritic spine loss along with excessive recruitment of FUS and heterogeneous nuclear ribonucleoprotein K (HNRNPK). Our findings that dendritic spine loss is because of excess recruitment of RNA-binding proteins provide a basis for the future exploration of ALS-related RNA-binding proteins.

Real-world effectiveness of pembrolizumab as first-line therapy for cisplatin-ineligible patients with advanced urothelial carcinoma: the ARON-2 study.

BACKGROUND: The advent of immune-checkpoint inhibitors has challenged previous treatment paradigms for advanced urothelial carcinoma (UC) in the post-platinum setting as well as in the first-line setting for cisplatin-ineligible patients. In this study, we investigated the effectiveness of pembrolizumab as first-line treatment for cisplatin-ineligible UC. METHODS: Data from patients aged ≥ 18 years with cisplatin-ineligible UC and receiving first-line pembrolizumab from January 1st 2017 to September 1st 2022 were collected. Cisplatin ineligibility was defined according to the Galsky criteria. Thirty-three Institutions from 18 countries were involved in the ARON-2 study. RESULTS: Our analysis included 162 patients. The median follow-up time was 18.9 months (95%CI 15.3-76.9). In the overall study population, the median OS was 15.8 months (95%CI 11.3-32.4). The median OS was significantly longer in males versus females while no statistically significant differences were observed between patients aged < 65y versus ≥ 65y and between smokers and non-smokers. According to Recist 1.1 criteria, 26 patients (16%) experienced CR, 32 (20%) PR, 39 (24%) SD and 55 (34%) PD. CONCLUSIONS: Our data confirm the role of pembrolizumab as first-line therapy for cisplatin-unfit patients. Further studies investigating the biological and immunological characteristics of UC patients are warranted in order to optimize the outcome of patients receiving immunotherapy in this setting.

Use of concomitant proton pump inhibitors, statins or metformin in patients treated with pembrolizumab for metastatic urothelial carcinoma: data from the ARON-2 retrospective study.

BACKGROUND: Concomitant medications may potentially affect the outcome of cancer patients. In this sub-analysis of the ARON-2 real-world study (NCT05290038), we aimed to assess the impact of concomitant use of proton pump inhibitors (PPI), statins, or metformin on outcome of patients with metastatic urothelial cancer (mUC) receiving second-line pembrolizumab. METHODS: We collected data from the hospital medical records of patients with mUC treated with pembrolizumab as second-line therapy at 87 institutions from 22 countries. Patients were assessed for overall survival (OS), progression-free survival (PFS), and overall response rate. We carried out a survival analysis by a Cox regression model. RESULTS: A total of 802 patients were eligible for this retrospective study; the median follow-up time was 15.3 months. PPI users compared to non-users showed inferior PFS (4.5 vs. 7.2 months, p = 0.002) and OS (8.7 vs. 14.1 months, p < 0.001). Concomitant PPI use remained a significant predictor of PFS and OS after multivariate Cox analysis. The use of statins or metformin was not associated with response or survival. CONCLUSIONS: Our study results suggest a significant prognostic impact of concomitant PPI use in mUC patients receiving pembrolizumab in the real-world context. The mechanism of this interaction warrants further elucidation.

En Bloc Resection Versus Conventional TURBT for T1HG Bladder Cancer: A Propensity Score-Matched Analysis.

BACKGROUND: We aimed to assess the clinical, oncological, and pathological impact of en bloc resection of bladder tumors (ERBT) compared with conventional transurethral resection of bladder tumors (cTURBT) for pT1 high-grade (HG) bladder cancer. PATIENTS AND METHODS: We retrospectively analyzed the record of 326 patients (cTURBT: n = 216, ERBT: n = 110) diagnosed with pT1 HG bladder cancer at multiple institutions. The cohorts were matched by one-to-one propensity scores based on patient and tumor demographics. Recurrence-free survival (RFS), progression-free survival (PFS), cancer-specific survival (CSS), and perioperative and pathologic outcomes were compared. The prognosticators of RFS and PFS were analyzed using the Cox proportional hazard model. RESULTS: After matching, 202 patients (cTURBT: n = 101, ERBT: n = 101) were retained. There were no differences in perioperative outcomes between the two procedures. The 3-year RFS, PFS, and CSS were not different between the two procedures (p = 0.7, 1, and 0.7, respectively). Among patients who underwent repeat transurethral resection (reTUR), the rate of any residue on reTUR was significantly lower in the ERBT group (cTURBT: 36% versus ERBT: 15%, p = 0.029). Adequate sampling of muscularis propria (83% versus 93%, p = 0.029) and diagnostic rates of pT1a/b substaging (90% versus 100%, p < 0.001) were significantly better in ERBT specimen compared with cTURBT specimen. On multivariable analyses, pT1a/b substaging was a prognosticator of disease progression. CONCLUSIONS: In patients with pT1HG bladder cancer, ERBT had similar perioperative and mid-term oncologic outcomes compared with cTURBT. However, ERBT improves the quality of resection and specimen, yielding less residue on reTUR and yielding superior histopathologic information such as substaging.

Genetic factors affecting survival in Japanese patients with sporadic amyotrophic lateral sclerosis: a genome-wide association study and verification in iPSC-derived motor neurons from patients.

BACKGROUND: Several genetic factors are associated with the pathogenesis of sporadic amyotrophic lateral sclerosis (ALS) and its phenotypes, such as disease progression. Here, in this study, we aimed to identify the genes that affect the survival of patients with sporadic ALS. METHODS: We enrolled 1076 Japanese patients with sporadic ALS with imputed genotype data of 7 908 526 variants. We used Cox proportional hazards regression analysis with an additive model adjusted for sex, age at onset and the first two principal components calculated from genotyped data to conduct a genome-wide association study. We further analysed messenger RNA (mRNA) and phenotype expression in motor neurons derived from induced pluripotent stem cells (iPSC-MNs) of patients with ALS. RESULTS: Three novel loci were significantly associated with the survival of patients with sporadic ALS-FGF1 at 5q31.3 (rs11738209, HR=2.36 (95% CI, 1.77 to 3.15), p=4.85×10-9), THSD7A at 7p21.3 (rs2354952, 1.38 (95% CI, 1.24 to 1.55), p=1.61×10-8) and LRP1 at 12q13.3 (rs60565245, 2.18 (95% CI, 1.66 to 2.86), p=2.35×10-8). FGF1 and THSD7A variants were associated with decreased mRNA expression of each gene in iPSC-MNs and reduced in vitro survival of iPSC-MNs obtained from patients with ALS. The iPSC-MN in vitro survival was reduced when the expression of FGF1 and THSD7A was partially disrupted. The rs60565245 was not associated with LRP1 mRNA expression. CONCLUSIONS: We identified three loci associated with the survival of patients with sporadic ALS, decreased mRNA expression of FGF1 and THSD7A and the viability of iPSC-MNs from patients. The iPSC-MN model reflects the association between patient prognosis and genotype and can contribute to target screening and validation for therapeutic intervention.

Merger of Rotation Restriction and Symmetrical Push-Pull to Synthesize Single-Benzene Yellow Fluorophors.

Invited for the cover of this issue is the group of Yohei Okada at Tokyo University of Agriculture and Technology. The image depicts a series of single-benzene fluorophores. Constructing symmetrical push-pull motifs in combination with restricting bond rotations is the key to creating small yet brightly emitting fluorophores. Read the full text of the article at 10.1002/chem.202301411.

Merger of Rotation Restriction and Symmetrical Push-Pull to Synthesize Single-Benzene Yellow Fluorophores.

Small yet brightly emitting fluorophores should find fundamental and practical applications in both academic and industrial settings. In this report, tetrahydrobenzodifuran is used as the core architecture to create novel single-benzene fluorophores. The key for realizing unique and powerful photophysical properties is the combination of the construction of symmetrical push-pull motifs and the restriction of bond rotations to suppress molecular motions that cause non-radiative transitions.

Dispersibility of TiO2 Nanoparticles in Less Polar Solvents: Role of Ligand Tail Structures.

Nanoparticles (NPs) are inherently prone to aggregation and loss of their size-derived properties, thus it is essential to enhance their dispersibility for applications. In less polar solvents, organic ligands containing oleyl groups are known as good dispersants due to their inefficient shell packing and inhibition of chain-chain crystallization as well as interdigitation between adjacent NPs. However, reagents with oleyl structures, such as oleic acid and oleylamine, can contain trans double bonds and saturated impurities, which might affect the chemical and/or physical properties of the NPs. Nevertheless, the effect of slight differences in surface ligand structure, including isomers, on the dispersibility of NPs has been little studied. We have synthesized five phosphonic acid ligands to investigate the structure-dispersibility relationship in detail. Dynamic light scattering and visible light transmittance revealed that not only regio- but also the stereochemistries of the C=C double bond in the ligand molecule, as well as the choice of solvent, are key factors in enhancing dispersibility.

Impact of Repetitive Transcranial Magnetic Stimulation to the Cerebellum on Performance of a Ballistic Targeting Movement.

This study aimed to investigate the effects of repetitive transcranial magnetic stimulation (rTMS) of the cerebellum on changes in motor performance during a series of repetitive ballistic-targeting tasks. Twenty-two healthy young adults (n = 12 in the active-rTMS group and n = 10 in the sham rTMS group) participated in this study. The participants sat on a chair in front of a monitor and fixed their right forearms to a manipulandum. They manipulated the handle with the flexion/extension of the wrist to move the bar on the monitor. Immediately after a beep sound was played, the participant moved the bar as quickly as possible to the target line. After the first 10 repetitions of the ballistic-targeting task, active or sham rTMS (1 Hz, 900 pulses) was applied to the right cerebellum. Subsequently, five sets of 100 repetitions of this task were conducted. Participants in the sham rTMS group showed improved reaction time, movement time, maximum velocity of movement, and targeting error after repetition. However, improvements were inhibited in the active-rTMS group. Low-frequency cerebellar rTMS may disrupt motor learning during repetitive ballistic-targeting tasks. This supports the hypothesis that the cerebellum contributes to motor learning and motor-error correction in ballistic-targeting movements.

Do we need repeat transurethral resection after en bloc resection for pathological T1 bladder cancer?

OBJECTIVES: To assess the clinical significance of repeat transurethral resection (reTUR) and surgical margin status after en bloc resection of bladder tumour (ERBT) for pathological T1 (pT1) bladder cancer. PATIENTS AND METHODS: We retrospectively analysed the record of 106 patients with pT1 high-grade bladder cancer who underwent ERBT between April 2013 and February 2021 at multiple institutions. All specimens were reviewed by a genitourinary pathologist. The primary outcome measures were recurrence-free survival (RFS) and progression-free survival (PFS) between patients with and those without reTUR. We also analysed the predictive value of surgical margin on the likelihood of residual tumour on reTUR. RESULTS: A reTUR was performed in 50 of the 106 patients. The 2-year RFS and 3-year PFS were comparable between patients who underwent reTUR and those who did not (55.1% vs 59.9%, P = 0.6, 80.6% vs 82.6%, P = 0.6, respectively). No patient was upstaged to pT2 on reTUR. Regarding the surgical margin status, there were no recurrences at the original site in 51 patients with negative horizontal margins. Cox proportional hazard analysis revealed that a positive vertical margin was an independent prognostic factor of worse PFS. On reTUR, six pTa/is residues were detected in patients with a positive horizontal margin, and three pT1 residues were detected in one patient with a positive vertical margin or other adverse pathological features. CONCLUSIONS: A reTUR after ERBT for pT1 bladder cancer appears not to improve either recurrence or progression. Surgical margin status affects prognosis and reTUR outcomes. A reTUR can be omitted after ERBT in patients with pT1 bladder cancer and negative margins; for those with positive horizontal or vertical margins, reTUR should remain the standard until proven otherwise.