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Abstract Chemoradiotherapy (CRT) followed by durvalumab is standard for unresectable locally advanced non-small-cell lung cancer (LA-NSCLC). This study assesses how CRT alters the T-cell receptor (TCR) repertoire in CD8 + PD-1 + T-cells and its impact on clinical outcomes. This prospective study, conducted from November 2019 to May 2021 at three institutions in Japan, evaluated the diversity of TCR repertoire (DE50) in PD-1 + CD8 + T-cells and CD8 + T-cell phenotypes in peripheral blood before and after CRT. Forty patients treated with CRT were included. The diversity and usage of TCR beta variable chains (TRBV) and 14 junctional chains (TRBJ) were significantly and positively correlated before and after CRT. Regarding the DE50, the progression-free survival (PFS) of patients with DE50High before CRT was significantly greater than that of those with DE50Low (NR vs. NR months, HR 0.17, p = 0.01). The diversity of TCR repertoire might more accurately predict the efficacy of CRT followed by durvalumab therapy.

Duplication of chromosome 15q11–13 has been reported to be one of the most frequent cytogenetic copy number variations in autism spectrum disorder (ASD), and a mouse model of paternal 15q11–13 duplication was generated, termed 15q dup mice. While previous studies have replicated some of the behavioral and brain structural phenotypes of ASD separately, the relationship between brain structure and behavior has rarely been examined. In this study, we performed behavioral experiments related to anxiety and social behaviors and magnetic resonance imaging (MRI) using the same set of 15q dup and wild-type mice. 15q dup mice showed increased anxiety and a tendency toward alterations in social behaviors, as reported previously, as well as variability in terms of sociability. MRI analysis revealed that a lower sociability index was correlated with a smaller gray matter volume in the right medial entorhinal cortex. These results may help to understand how variability in behavioral phenotypes of ASD arises even in individuals with the same genetic background and to determine the individual differences in neurodevelopmental trajectory correlated with specific brain structures that underlie these phenotypes.

Sleep apnea is regarded as an important risk factor in the pathogenesis of Alzheimer disease (AD). Chronic intermittent hypoxia treatment (IHT) given during the sleep period of the circadian cycle in experimental animals is a well-established sleep apnea model. Here we report that transient IHT for 4 days on AD model mice causes Aβ overproduction 2 months after IHT presumably via upregulation of synaptic BACE1, side-by-side with tau hyperphosphorylation. These results suggest that even transient IHT may be sufficient to cause long-lasting changes in the molecules measured as AD biomarkers in the brain.

Abstract Introduction The safety of hyperbaric oxygen treatment (HBO2) in patients with cardiovascular implanted electronic devices (CIED) remains unclear. Methods We conducted a retrospective analysis of seven CIED patients (median age 79 [73–83] years, five males [71.4%]), including five with pacemakers and two with implantable cardioverter defibrillators (ICD), who underwent HBO2 between June 2013 and April 2023. During the initial session, electrocardiogram monitoring was conducted, and CIED checks were performed before and after the treatment. In addition, the medical records were scrutinized to identify any abnormal CIED operations. Results All seven CIED patients underwent HBO2 within the safety pressure range specified by the CIED manufacturers or general pressure test by the International Organization for Standardization (2.5 [2.5–2.5] atmosphere absolute × 18 [5–20] sessions). When comparing the CIED parameters before and after HBO2, no significant changes were observed in the waveform amplitudes, pacing thresholds, lead impedance of the atrial and ventricular leads, or battery levels. All seven patients, including two with the rate response function activated, exhibited no significant changes in the pacing rate or pacing failure. Two ICD patients did not deactivate the therapy, including the defibrillation; however, they did not experience any arrhythmia or inappropriate ICD therapy during the HBO2. Conclusion CIED patients who underwent HBO2 within the safety pressure range exhibited no significant changes in the parameters immediately after the HBO2 and had no observable abnormal CIED operations during the treatment. The safety of defibrillation by an ICD during HBO2 should be clarified.

External canal reconstruction of extensive tissue defects, including auricle or ear canal defects, is challenging. We describe the case of a 28-year-old man who underwent staged skin and nasal septum cartilage grafting for ear canal reconstruction after resectioning a giant arteriovenous malformation of the auricle. We performed arteriovenous malformation resection and reconstruction of the significant tissue defect using an anterolateral femoral skin flap. Simultaneously, a Nelaton catheter stent was placed to temporarily form an external auditory canal. Subsequently, split-thickness skin grafting was performed. Following stent removal, severe external auditory canal stenosis developed. Nasal septum cartilage grafting was performed using a stent after dilating the ear canal. Two years after surgery, the ear canal was not stenotic without the stent. Staged treatment with skin and nasal septal cartilage grafting is a simple and practical option for treating patients with total ear defects for whom a skin flap cannot be used.

The tau protein is a microtubule-associated protein that promotes microtubule stabilization. The phosphorylation of the tau protein has been linked to its dissociation from microtubules. Here, we examined the relationship between neuronal depolarization activity and tau protein phosphorylation by employing model systems in culture as well as in vivo. The KCl-evoked depolarization of cultured neurons has often been used to investigate the effects of neuronal activity. We found dephosphorylation at AT8 sites (S202, T205), T212, AT180 sites (T231, S235), and S396 in KCl-simulated cultured neurons. We also found that the KCl-induced tau protein dephosphorylation increases the level of the tau protein fractionated with stable microtubules. In an in vivo experiment, we demonstrated that the exposure of mice to a new environment activates protein phosphatase 1 in the mouse hippocampus and induces tau protein dephosphorylation. We also found an increased amount of the tau protein in a stable microtubule fraction, suggesting that the dephosphorylation of the tau protein may lead to its increased microtubule association in vivo. These results suggest that the association of microtubules with tau proteins may be regulated by the tau protein phosphorylation status affected by neuronal electrical activity.

ABSTRACT Non‐invasive radioablation using stereotactic body radiation therapy with X‐ray has been proposed as a rescue treatment for refractory ventricular tachycardia (VT). However, there are concerns about the occurrence of late valvular or coronary disease. We treated VT originating from the aortic sinus cusp using the Bragg peak principle of a heavy ion beam, minimizing the dose to the aortic valve and coronary artery and providing an anti‐arrhythmic effect and cardiac function recovery due to improved sympathetic nerve heterogeneity. We present a method for targeting sympathetic nerve distribution using 123I‐metaiodobenzylguanidine scintigraphy.

# Background After anterior cruciate ligament reconstruction (ACLR), asymmetry is likely to persist in single-leg (SL) vertical jump and drop jump performance than in SL hop distance. However, its relationship with the return to sport (RTS) remains unclear. # Hypothesis/Purpose This study aimed to determine the association between vertical jump performance after primary ACLR using hamstring tendon autograft and RTS at a pre-injury competitive level. # Study design Cross-sectional study # Methods Patients who underwent primary ACLR using hamstring tendon autograft were recruited for this study. Participants who returned to pre-injury competition after ACLR were recruited at least eight months postoperatively. Knee condition was assessed, including joint laxity, range of motion, muscle strength, and knee pain intensity during sports activities. Performance variables were also assessed, including SL hop distance, jump height in SL vertical jump, and reactive strength index (RSI; jump height/contact time) in SL drop jump. Participants were asked to subjectively report whether they had returned to the same level of competition as pre-injury and their perceived sport performance intensity. Those who answered "Yes" to the dichotomous question and had a postoperative subjective athletic performance of \> 80% were categorized into the Yes-RTS group. The primary outcome was the ability to achieve RTS at the preinjury level. # Results Sixty-five patients (female, 35; male, 30) at 13.0 (13.0) \[median (interquartile)\] months after ACLR participated in this study. Thirty-nine (60%) were assigned to the Yes-RTS group. Regarding knee conditions, the No-RTS group had a significantly higher knee pain intensity, as assessed using a numerical rating scale (p\

Abstract Loquat (Eriobotrya japonica) leaves contain many bioactive components such as ursolic acid (UA) and amygdalin. We investigated the effects of loquat leaf powder and methanol extract in human neuroglioma H4 cells stably expressing the Swedish-type APP695 (APPNL-H4 cells) and C57BL/6 J mice. Surprisingly, the extract greatly enhanced cellular amyloid-beta peptide (Aβ) 42 productions in APPNL-H4 cells. Administration of leaf powder increased Aβ42 levels after 3 months and decreased levels after 12 months compared to control mice. Leaf powder had no effect on working memory after 3 months, but improved working memory after 12 months. Administration of UA decreased Aβ42 and P-tau levels and improved working memory after 12 months, similar to the administration of leave powder for 12 months. Amygdalin enhanced cellular Aβ42 production in APPNL-H4 cells, which was the same as the extract. Three-month administration of amygdalin increased Aβ42 levels slightly but did not significantly increase them, which is similar to the trend observed with the administration of leaf powder for 3 months. UA was likely the main compound contained in loquat leaves responsible for the decrease in intracerebral Aβ42 and P-tau levels. Also, amygdalin might be one of the compounds responsible for the transiently increased intracerebral Aβ42 levels.

Introduction: This study validated real-world pharmacokinetic (PK) data using an established population PK (PopPK) model for atezolizumab in Japanese patients with NSCLC and explored the relationship between PK parameters, effectiveness, and adverse events (AEs) for the 1200 mg once every three weeks regimen. Methods: A subgroup of 262 of 1039 patients from J-TAIL consented to this exploratory research for PK evaluation of atezolizumab monotherapy for unresectable advanced/recurrent NSCLC (August 2018 to October 2019; 197 institutions). We evaluated plasma concentrations before the start of the third cycle of atezolizumab infusion classified into quartiles 1 to 4, their association with effectiveness, and the association between atezolizumab maximum plasma concentrations (Cmax) calculated using the existing PopPK model and AEs of special interest (AESIs). Results: Overall, 175 of 262 patients were included; baseline characteristics were similar to those of patients enrolled in J-TAIL (Eastern Cooperative Oncology Group performance status ≥ 2, 12.0%; age ≥ 75 y, 28.9%; atezolizumab as more than or equal to third-line treatment, 57.5%). Atezolizumab plasma concentrations were similar to previously reported data among Japanese/non-Japanese patients. The overall survival was significantly shorter in patients with lower atezolizumab plasma concentrations in Q1 versus Q2 to Q4, although progression-free survival remained the same. The PK data adequately fit the PopPK model, with the frequency of AESIs increasing as the calculated Cmax at cycle 1 increased. Conclusions: In real-world Japanese patients with unresectable advanced/recurrent NSCLC, PKs were similar to previous reports. Certain patient populations had shorter overall survival, and atezolizumab plasma concentrations in cycle 3 were lower in this population. Elevated Cmax at cycle 1 may be associated with an increased frequency of AESIs.

Abstract Aims This study investigated fatigue in individuals with 22q11.2 deletion syndrome (22q11.2DS), identifying both physical and psychosocial factors. Methods We conducted a cross‐sectional web‐based survey of 125 parents of individuals with 22q11.2DS. Significant factors of fatigue were identified using bivariate analysis and forward stepwise binary logistic regression. Results Overall, 34% (42 of 125) of the participants reported fatigue. Bivariate analysis identified 37 variables linked with fatigue, of which 11 were significant in multivariable analysis: older age (odds ratio [OR] = 1.28, 95% confidence interval [CI] [1.07, 1.53], P = 0.008), history of auditory hypersensitivity (OR = 36.4, 95% CI [4.08, 323.8], P = 0.001), delayed motor development (OR = 10.4, 95% CI [1.78, 61.0], P = 0.009), difficulty participating in events (OR = 33.5, 95% CI [1.1, 1068.2], P = 0.047), inability to join groups (OR = 47.9, 95% CI [4.8, 481.7], P = 0.001), concerns about marriage (OR = 17.0, 95% CI [2.6, 112.7], P = 0.003), inability to attend facilities (OR = 20.4, 95% CI [1.4, 308.0], P = 0.029), poor coordination when changing medical facilities (OR =

Abstract Philadelphia chromosome (Ph)-like acute lymphoblastic leukemia (ALL) is a subset of ALL that demonstrated a high treatment failure rate. One of the hallmarks of Ph-like ALL is PDGFRB gene fusion, with fusion partner proteins often harboring dimerization domains and enhancing the kinase activity of PDGFRB. We determined a novel oncogenic PDGFRB fusion gene, NRIP1::PDGFRB, from a pediatric patient with ALL, encoding a protein with the carboxy-terminal kinase domain of PDGFRB, without the partner peptide. We confirmed the oncogenic potential of NRIP1::PDGFRB in vitro and the efficacy of all ABL1-specific inhibitor generations, including imatinib, dasatinib, nilotinib, and ponatinib, in suppressing this potential. PDGFRB activation mechanism may include juxtamembrane domain truncation in the predicted peptide. In conclusion, we determined a novel fusion gene pattern in Ph-like ALL.

ObjectivesThe goal of this study was to evaluate whether intermittent VNS reduces electrical heterogeneities and arrhythmia inducibility during sympathoexcitation.BackgroundSympathoexcitation increases the risk of ventricular tachyarrhythmias (VT). Vagal nerve stimulation (VNS) has been antiarrhythmic in the setting of ischemia-driven arrhythmias, but it is unclear if it can overcome the electrophysiological effects of sympathoexcitation in the setting of chronic myocardial infarction (MI).MethodsIn Yorkshire pigs after chronic MI, a sternotomy was performed, a 56-electrode sock was placed over the ventricles (n = 17), and a basket catheter was positioned in the left ventricle (n = 6). Continuous unipolar electrograms from sock and basket arrays were obtained to analyze activation recovery interval (ARI), a surrogate of action potential duration. Bipolar voltage mapping was performed to define scar, border zone, or viable myocardium. Hemodynamic and electrical parameters and VT inducibility were evaluated during sympathoexcitation with bilateral stellate ganglia stimulation (BSS) and during combined BSS with intermittent VNS.ResultsDuring BSS, global epicardial ARIs shortened from 384 ± 59 milliseconds to 297 ± 63 milliseconds and endocardial ARIs from 359 ± 36 milliseconds to 318 ± 40 milliseconds. Dispersion in ARIs increased in all regions, with the greatest increase observed in scar and border zone regions. VNS mitigated the effects of BSS on border zone ARIs (from -18.3% ± 6.3% to -2.1% ± 14.7%) and ARI dispersion (from 104 ms2 [1 to 1,108 ms2] to -108 ms2 [IQR: -588 to 30 ms2]). VNS reduced VT inducibility during sympathoexcitation (from 75%-40%; P < 0.05).ConclusionsAfter chronic MI, VNS overcomes the detrimental effects of sympathoexcitation by reducing electrophysiological heterogeneities exacerbated by sympathetic stimulation, decreasing VT inducibility.

The diagnostic accuracy of cerebrospinal fluid (CSF) anti-human T-cell leukemia virus type I (HTLV-1) antibody testing for HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM) remains unclear. Therefore, we measured the anti-HTLV-1 antibody levels in CSF using various test kits, evaluated the stability of CSF antibodies, and performed a correlation analysis using the particle agglutination (PA) method, as well as a receiver operating characteristic (ROC) analysis between patients with HAM and carriers. The CSF anti-HTLV-1 antibody levels were influenced by freeze–thaw cycles but remained stable when the CSF was refrigerated at 4 °C for up to 48 h. Measurements from 92 patients (69 patients with HAM and 23 carriers) demonstrated a strong correlation (r > 0.9) with the PA method across all six quantifiable test kits. All six test kits, along with CSF neopterin and CXCL10, exhibited areas under the ROC curve greater than 0.9, indicating a high diagnostic performance for HAM. Among these, five test kits, Lumipulse and Lumipulse Presto HTLV-I/II, HISCL-UD (a kit under development), HTLV-Abbott, and Elecsys HTLV-I/II, established a cutoff with 100% sensitivity and maximum specificity, achieving a sensitivity of 100% and a specificity ranging from 43.5% to 56.5%. This cutoff value, in combination with clinical findings, will aid in the accurate diagnosis of HAM.

Corticosteroids are most commonly used to treat HTLV-1-associated myelopathy (HAM); however, their clinical efficacy has not been tested in randomized clinical trials. This randomized controlled trial included 8 and 30 HAM patients with rapidly and slowly progressing walking disabilities, respectively. Rapid progressors were assigned (1:1) to receive or not receive a 3-day course of intravenous methylprednisolone in addition to oral prednisolone therapy. Meanwhile, slow progressors were assigned (1:1) to receive oral prednisolone or placebo. The primary outcomes were a composite of ≥1-grade improvement in the Osame Motor Disability Score or ≥30% improvement in the 10 m walking time (10 mWT) at week 2 for rapid progressors and changes from baseline in 10 mWT at week 24 for slow progressors. In the rapid progressor trial, all four patients with but only one of four without intravenous methylprednisolone achieved the primary outcome (p = 0.14). In the slow progressor trial, the median changes in 10 mWT were -13.8% (95% CI: -20.1--7.1; p < 0.001) and -6.0% (95% CI: -12.8-1.3; p = 0.10) with prednisolone and placebo, respectively (p for between-group difference = 0.12). Whereas statistical significance was not reached for the primary endpoints, the overall data indicated the benefit of corticosteroid therapy. (Registration number: UMIN000023798, UMIN000024085).