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The objective of this study is to investigate the effects of neutron (n) irradiation on hydrogen isotope transport in tungsten (W). W samples were irradiated with neutrons in a fission reactor and then exposed to high flux deuterium (D) plasma at 563 K in a linear plasma device. The fraction of D release increased with increasing exposure time. In addition, the D retention in n-irradiated W increased in proportion to the square root of the plasma exposure time. These observations were explained by increase in the penetration depth of D with filling up displacement damages acting as strong trapping sites.

Background: Pulmonary nocardiosis is a rare opportunistic infection, with approximately 15 % of patients being immunocompetent. The isolation rate of Nocardia spp. has recently increased, indicating rising clinical concern. This study aimed to summarize computed tomography (CT) findings, evaluate treatment outcomes, and improve disease recognition., Methods: We retrospectively analyzed 12 pulmonary nocardiosis cases recorded over 10 years in three hospitals, excluding two unclear cases. All pathogens were detected on smears and isolated from respiratory specimens., Results: The mean age was 73.0 ± 12.9 years, with 9 men and 6 smokers. Among the included patients, 8 had underlying pulmonary diseases, 4 had non-pulmonary diseases, and 3 were on steroids. The most common species were N. cyriacigeorgica and N. nova. CT findings included cavitary, consolidation/infiltrative, and nodular-bronchiectatic (NB) patterns. The NB pattern, particularly common in immunocompetent patients, was associated with significantly better treatment outcomes than non-NB patterns (Fisher's exact test, p = 0.0476). All isolates were susceptible to trimethoprim/sulfamethoxazole. Eight patients recovered with appropriate antimicrobial therapy, while two patients died., Conclusions: Pulmonary nocardiosis presented three CT patterns, with the NB pattern being the most frequent and showing favorable treatment outcomes, especially in immunocompetent patients. While Nocardia spp. can develop in patients with preexisting bronchiectasis, it may also independently cause bronchiectasis. Nocardia infection should be considered as a differential diagnosis in patients exhibiting the NB pattern, resembling that of nontuberculous mycobacterial pulmonary diseases., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes severe illness and mortality in patients with immunodeficiency. Although vaccination has been recommended, the induction of protective antibodies by immunization, and thus the disease-preventive effect, has proven insufficient in immunodeficient patients, especially in those with predominantly antibody deficiency. A monoclonal antibody combination of tixagevimab and cilgavimab (TIX/CIL) was developed as a pre-exposure prophylaxis (PrEP). In this study, we investigated the post-PrEP increase in antiviral antibody titers and detailed the breakthrough infections that occurred despite PrEP in Japanese immunodeficient patients who had received TIX/CIL., Methods: Blood samples were collected before and after TIX/CIL administration between November 2022 and August 2023. Antibody titers against the S-protein of SARS-CoV-2 were measured to evaluate TIX/CIL-induced protection. Information regarding breakthrough infection, as evidenced by positive antigen and/or PCR tests, was collected., Results: A significant increase in the anti-S antibody titer was observed in all 89 immunodeficient patients who had received TIX/CIL. However, 14 (16 %) patients experienced breakthrough SARS-CoV-2 infections, of which one died of respiratory failure., Conclusion: The shift in the SARS-CoV-2 circulating strain might have reduced the efficacy of TIX/CIL, leading to an increased number of breakthrough infections., (Copyright © 2024 Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases, and Japanese Society for Infection Prevention and Control. Published by Elsevier Ltd. All rights reserved.)

Objectives: To investigate the impact of early intensive in-hospital rehabilitation, initiated within 2 days of surgery and lasting up to 7 days, on the recovery of activities of daily living in patients with and without dementia., Study Design and Setting: Medical claims data from 925 hospitals in Japan were analyzed. We enrolled patients aged ≥50 years who underwent hip fracture surgery within 2 days of admission between April 1, 2018, and December 31, 2019. Low- (20 minutes per day starting on day 2), highest- (60 minutes per day starting on day 1), and gradually increasing (20 minutes on day 1, 40 minutes on days 2-4, and 60 minutes per day thereafter) intensity regimens were used as exposures. The outcomes were Barthel Index (BI) scores at 14 and 30 days postoperatively. For per-protocol analysis, a target trial emulation framework with the sequential doubly robust estimator was used., Results: Among patients without dementia (N = 11,461), no significant differences in BI scores were observed at 14 days postoperatively across regimens. At 30 days postoperatively, significant differences in BI scores were noted between highest- and low-intensity regimens and between gradually increasing intensity and low-intensity regimens, with additive BI scores of 15.2 (95% CI, 10.7-19.7) and 14.7 (95% CI, 9.2-20.2), respectively. In patients with dementia (N = 14,302), significant differences in BI scores were noted at 14 days postoperatively between highest- and low-intensity regimens and between gradually increasing intensity and low-intensity regimens, with additive BI scores of 8.7 (95% CI, 5.2-12.2) and 10.7 (95% CI, 5.8-15.6), respectively. At 30 days postoperatively, a significant difference in BI scores was observed between gradually increasing intensity and low-intensity regimens, with an additive BI score of 17.9 (95% CI, 11.3-24.5)., Conclusion: Early intensive in-hospital rehabilitation is highly relevant and beneficial for dementia patients., Competing Interests: Declaration of competing interest There are no competing interests for any author., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Human adenovirus infection (HAdV) may be fatal in patients undergoing allogeneic hematopoietic cell transplantation (HCT). Cidofovir is effective in only a part of the post-HCT HAdV infection. Therefore, posttransplant immune reconstitution is important for HAdV clearance. We describe the detailed immune reconstitution and response of adenovirus-specific T cells in a patient with inborn errors of immunity who had disseminated HAdV infection with hepatitis post-HCT and was treated with cidofovir. Though the patient received cidofovir for only 19 days starting from Day 72 after HCT because of renal dysfunction, we observed T-cell reconstitution, a decrease in HAdV copy number, and amelioration of the symptoms of HAdV infection after Day 90. We initially observed expanded NK and CD8 + CD45RO + memory subsets and later gradual increase of naïve T cells eveloped after cessation of cidofovir treatment. An increase in adenovirus-specific IFN-γ secretion from 2 to 4 months after HCT was confirmed by ELISpot assay. The progression of immune reconstitution and cidofovir treatment are considered to have contributed to survival in this patient. Optimization of transplantation methods, prompt appropriate antiviral medication, and virus-specific T-cell therapy would be necessary as the better strategy for systemic HAdV infection., Competing Interests: Declaration of competing interest We have no conflict of interest to disclose concerning this study., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Chitin, an N-acetyl-D-glucosamine polymer, has multiple functions in living organisms, including the induction of disease resistance and growth promotion in plants. In addition, chitin oligosaccharides (COs) are used as the backbone of the signaling molecule Nod factor secreted by soil bacteria rhizobia to establish a mutual symbiosis with leguminous plants. Nod factor perception triggers host plant responses for rhizobial symbiosis. In this study, the effects of chitins on rhizobial symbiosis were examined in the leguminous plants Lotus japonicus and soybean. Chitin nanofiber (CNF), retained with polymeric structures, and COs elicited calcium spiking in L. japonicus roots expressing a nuclear-localized cameleon reporter. Shoot growth and symbiotic nitrogen fixation were significantly increased by CNF but not COs in L.japonicus and soybean. However, treatments with chitin and cellulose nanofiber, structurally similar polymers to CNF, did not affect shoot growth and nitrogen fixation in L.japonicus. Transcriptome analysis also supported the specific effects of CNF on rhizobial symbiosis in L.japonicus. Although chitins comprise the same monosaccharides and nanofibers share similar physical properties, only CNF can promote rhizobial nitrogen fixation in leguminous plants. Taking the advantages on physical properties, CNF could be a promising material for improving legume yield by enhancing rhizobial symbiosis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Risk stratification in patients with Brugada syndrome (BrS) is challenging, especially in those at intermediate risk. The Predicting Arrhythmic evenT (PAT) score has recently been demonstrated to be excellent for predicting future arrhythmic events in patients without prior ventricular fibrillation (VF). However, validation studies are lacking., Objective: This study aimed to assess the performance of a novel risk stratification model in predicting future VF events in patients with BrS in a Japanese multicenter cohort., Methods: The PAT score was calculated for 413 patients with BrS (mean age, 50.9 ± 13.6 years; 395 men) from 59 hospitals in Japan, including 314 patients without prior VF. The incidence of developing VF during the follow-up period was investigated., Results: During the 106.8-month follow-up period, 54 patients (13.1%) experienced VF events. Of the 314 patients without prior VF at enrollment, 14 (4.5%) experienced VF events. The incidence of VF events during the follow-up period was significantly higher in patients with PAT scores ≥ 10 than in those with scores < 10 (41/173 [23.7%] vs 13/240 [5.4%]; P < .0001) in the total cohort. No difference was observed in the incidence of VF events between patients with PAT scores ≥ 10 and < 10 among the 314 patients without prior VF (6/86 [7.0%] vs 8/228 [3.5%]; P = .22). PAT scores ≥ 10 predicted future VF events with a sensitivity and specificity of 42.9% and 73.3%, respectively., Conclusion: This Japanese multicenter registry demonstrated that the novel risk stratification model could not accurately predict future VF events in patients with BrS but without prior VF., Competing Interests: Disclosures The authors have no conflicts of interest to disclose., (Copyright © 2024 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Abstract: Ataxia-telangiectasia (A-T) is an autosomal-recessive disorder caused by pathogenic variants (PVs) of the ATM gene, predisposing children to hematological malignancies. We investigated their characteristics and outcomes to generate data-based treatment recommendations. In this multinational, observational study we report 202 patients aged ≤25 years with A-T and hematological malignancies from 25 countries. Ninety-one patients (45%) presented with mature B-cell lymphomas, 82 (41%) with acute lymphoblastic leukemia/lymphoma, 21 (10%) with Hodgkin lymphoma and 8 (4%) with other hematological malignancies. Four-year overall survival and event-free survival (EFS) were 50.8% (95% confidence interval [CI], 43.6-59.1) and 47.9% (95% CI 40.8-56.2), respectively. Cure rates have not significantly improved over the last four decades (P = .76). The major cause of treatment failure was treatment-related mortality (TRM) with a four-year cumulative incidence of 25.9% (95% CI, 19.5-32.4). Germ line ATM PVs were categorized as null or hypomorphic and patients with available genetic data (n = 110) were classified as having absent (n = 81) or residual (n = 29) ATM kinase activity. Four-year EFS was 39.4% (95% CI, 29-53.3) vs 78.7% (95% CI, 63.7-97.2), (P < .001), and TRM rates were 37.6% (95% CI, 26.4-48.7) vs 4.0% (95% CI, 0-11.8), (P = .017), for those with absent and residual ATM kinase activity, respectively. Absence of ATM kinase activity was independently associated with decreased EFS (HR = 0.362, 95% CI, 0.16-0.82; P = .009) and increased TRM (hazard ratio [HR] = 14.11, 95% CI, 1.36-146.31; P = .029). Patients with A-T and leukemia/lymphoma may benefit from deescalated therapy for patients with absent ATM kinase activity and near-standard therapy regimens for those with residual kinase activity., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Background: Mucoid degeneration of the anterior cruciate ligament is a pathological condition that may impair knee mechanics and contribute to the symptomatology of osteoarthritis. This study aimed to evaluate whether preoperative magnetic resonance imaging can predict anterior cruciate ligament degeneration, specifically mucoid degeneration, and to elucidate the histopathological characteristics of mucoid degeneration in knee osteoarthritis patients., Methods: We evaluated a total of 95 knees of osteoarthritis patients (23 males, 72 females; mean age: 72.7 ± 7.5) scheduled for total knee arthroplasty. The relationship between preoperative magnetic resonance imaging findings and the histopathological evidence of anterior cruciate ligament mucoid degeneration was examined. Immunohistochemical analysis was employed for collagen types (COL-I, COL-II), chondrogenesis (SOX9), and vascularity (CD31)., Results: High signal intensity on magnetic resonance imaging showed a positive correlation with Alcian Blue staining areas (rs = 0.59, p < 0.01) and the swelling index (rs = 0.62, p < 0.01), indicating advanced mucoid degeneration. The absence of synovial lining around the anterior cruciate ligament was associated with more severe degeneration. In the histological evaluations, advanced degeneration was characterized by an increase in chondroid metaplasia and collagen disorientation. The Alcian Blue and SOX9 correlation was positive (rs = 0.69, p < 0.01), but negative with COL-I (rs = -0.38, p = 0.03) and vascularity (CD31) (rs = -0.60, p < 0.01)., Conclusions: Preoperative magnetic resonance imaging is an effective tool in assessing the severity of anterior cruciate ligament degeneration; it influences surgical decisions. High signal intensity on magnetic resonance images denotes advanced mucoid degeneration. The absence of synovial lining around the anterior cruciate ligament is associated with more severe degeneration and may accelerate degenerative changes. Chondroid metaplasia and collagen disorientation mark advanced degeneration. Magnetic resonance imaging can be used to gauge the degree of anterior cruciate ligament degeneration in osteoarthritis., Competing Interests: Declaration of competing interest The authors have no competing financial interests., (Copyright © 2024 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.)

Background: The most recommended treatment for stage IV EGFR-positive lung cancer is osimertinib monotherapy. The dosage of osimertinib is fixed at 80 mg/day regardless of body surface area (BSA), however some patients withdraw or reduce the dosage due to adverse events (AEs)., Methods: We performed a retrospective cohort study of 98 patients with EGFR mutation-positive non-small cell lung cancer (NSCLC), who received 80 mg osimertinib as the initial treatment. We investigated the impact of BSA on efficacy and safety of osimertinib., Results: The cut-off value of BSA was estimated using the receiver operating characteristics curve, and was determined to be 1.5 m 2 . There were 44 patients in the BSA < 1.5 group and 54 patients in the BSA ≥ 1.5 group. There was no significant difference in the incidence of AEs (hematologic toxicity of ≥grade 3 or higher, and non-hematologic toxicity of ≥grade 3) between the two groups. However, the incidence of dose reduction due to AEs was significantly higher in the BSA < 1.5 group compared with the BSA ≥ 1.5 group (16 patients vs 5 patients, p = 0.003). The main reasons were fatigue, anorexia, diarrhea, and liver disfunction. Median progression-free survival (PFS) was not significantly different (16.9 months in the BSA < 1.5 group vs 18.1 months in the BSA ≥ 1.5 group, p = 0.869)., Conclusion: Differences in BSA affected the optimal dose of osimertinib. However, the PFS with osimertinib treatment was not affected by BSA. Therefore, when using osimertinib as an initial treatment for patients with EGFR-mutant NSCLC, dose reduction to control AEs should be considered, especially in the BSA<1.5 group., Competing Interests: Declaration of competing interest Motohiro Tamiya has received lecture fees from Chugai Pharmaceutical, Boehringer Ingelheim, AstraZeneca, Taiho Pharmaceutical, Eli Lilly, Novartis, Pfizer, Asahi Kasei Pharmaceutical, Ono Pharmaceutical, Bristol-Myers Squibb, MSD, Bayer, Amgen, Kyowa-Kirin, and Nippon Kayaku. Kei Kunimasa has received lecture fees from AstraZeneca, Chugai Pharma and Novartis. Kazumi Nishino has received lecture fees from AstraZeneca, Chugai Pharmaceutical, Boehringer Ingelheim, Eli Lilly, Roche Diagnostics, Novartis, Pfizer, Merk, Janssen Pharmaceutical K.K., Bristol Myers Squibb, and Nippon Kayaku. Mari Takagi has received lecture fees from Eli Lilly, Yakult, Terumo, Chugai Pharmaceutical, Towa Pharmaceutical, Daiichi-Sankyo, Becton Dickinson and Company, MSD, Taiho Pharmaceutical, Nippon Kayaku, AstraZeneca, Sando, and Ono Pharmaceutical. Other authors have no conflicts of interest to declare., (Copyright © 2024. Published by Elsevier Ltd.)

Background: The efficacy of therapeutic modalities for hair disease can be evaluated globally by photo assessment and more precisely by phototrichogram (PTG). However, the latter procedure is laborious, time consuming, subject to inter-observer variation, and requires hair clipping., Objective: To establish an automated and patient/investigator friendly methodology enabling quantitative hair amount evaluation for daily clinical practice., Methods: A novel automated numerical algorithm (aNA) adopting digital image binarization (i.e., black and white color conversion) was invented to evaluate hair coverage and measure PTG parameters in scalp images. Step-by-step improvement of aNA was attempted through comparative analyses of the data obtained respectively by the novel approach and conventional PTG/global photography assessment (GPA)., Results: For measuring scalp hair coverage, the initial version of aNA generally agreed with the cumulative hair diameter as assessed using PTG, showing a coefficient of 0.60. However, these outcomes were influenced by the angle of hair near the parting line. By integrating an angle compensation formula, the standard deviation of aNA data decreased from 5.7% to 1.2%. Consequently, the coefficient of determination for hair coverage calculated using the modified aNA and cumulative hair diameter assessed by PTG increased to 0.90. Furthermore, the change in hair coverage as determined by the modified aNA protocol correlated well with changes in the GPA score of images obtained using clinical trials., Conclusion: The novel aNA method provides a valuable tool for enabling simple and accurate evaluation of hair growth and volume for clinical trials and for treatment of hair disease., (Copyright © 2023 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.)

Background: Hip fracture is among the most common injuries in elderly people. We aimed to investigate the decennial trends in hip fractures in patients ≥65 years of age., Methods: A questionnaire was distributed to all hospitals with a Department of Orthopaedic Surgery in Yamagata Prefecture to collect data on hip fractures occurring in 1996, 2006 and 2016., Results: The response rate was 100%. The total numbers of hip fractures in 1996, 2006 and 2016 were 665, 1169 and 1,728, respectively (crude incidence: 258, 373 and 494 per 100,000 person-year, respectively). Injuries frequently occurred in the early morning and daytime morning in 1996. In contrast, they frequently occurred in activity times (e.g., morning and afternoon) in 2006 and 2016. Among the patients, 80-90% were injured by simple falls, and 70-80% were injured indoors. The incidence of trochanteric fractures was approximately 1.8-1.9 times greater than incidence of neck fractures in all years. Especially, trochanteric fractures in females of ≥90 years of age markedly increased. The rate of surgical treatment was the same in 1996 and 2006, but was lower in 2016. In 1996, the percentage of independent walkers at discharge and 1 year later was almost the same. In 2006 and 2016, the rate of independent walkers was low at discharge, but increased 1 year later. The rate of discharge to home decreased gradually. The combined percentage of patients discharged to home and to rehabilitation institutions in 2006 and the percentage of patients who entered the regional referral clinical pathway in 2016 were both approximately 70%, with no marked changes observed., Conclusions: Hip fractures, especially trochanteric fractures in super-aged females, increased. Discharge to home decreased, and the use of the regional referral clinical pathway was widespread. Ambulation ability was reduced at discharge, but improved after 1 year., Competing Interests: Declaration of competing interest All authors declare no conflicts of interest in association with the present study., (Copyright © 2022 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.)

Backgrounds: The efficacy of nusinersen and its evaluation in patients with spinal muscular atrophy (SMA) has been established in clinical trials only for pediatric patients, not for adolescent and adult patients who developed SMA in infancy or early childhood. We report a long-term follow-up in adolescent and adult patients with SMA types 1 and 2., Methods: Nusinersen-treated patients with SMA types 1 and 2 between 2017 and 2022 were retrospectively reviewed. We compared baseline motor function tests with those after the final treatment. Physical and occupational therapists performed Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND), Hammersmith Functional Motor Scale-Expanded (HFMSE), and Revised Upper Limb Module (RULM). The Landau and Galant reflexes were not performed in CHOP-INTEND. Meaningful improvement was defined as CHOP-INTEND, 4; HFSME, 3; and RULM, 2., Results: Seven patients with SMA (type 1, 1; type 2, 6) with a median age of 23 (range, 12-40)years were treated with nusinersen for 3.55 (1.78-4.53)years. Improvement was detected in CHOP-INTEND (pre, 5 [0-31]; post, 21 [0-39]; difference, 5 [0-26]; p = 0.100) without significance, although not in HFMSE (pre, 0 [0-3]; post, 0 [0-5]; difference, 0 [0-2]; p = 0.346) and RULM (pre, 1 [0-20]; post, 3 [0-21]; difference, 1 [0-2]; p = 0.089). Owing to prolonged treatment intervals with the COVID-19 pandemic, RULM worsened in two patients., Conclusion: Nusinersen was effective in long-term follow-up. Only CHOP-INTEND showed meaningful improvement. The interval between doses of nusinersen should not be prolonged even with the COVID-19 pandemic., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: HI received honoraria for 5 lectures (2019: 400,376 yen; 2020: 192,367 yen), and 2 manuscript writings (2019: 175,307 yen). AO received honoraria for 1 speakers bureau (2019: 47,080 yen). The other authors declare no competing interests., (Copyright © 2022 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Background: Knowledge regarding the normal alignment of the lower limb is important when considering alignment for total knee arthroplasty. However, few studies have explored the lower limb alignment of healthy Japanese subjects., Methods: Between July and October 2020, we performed whole leg standing radiography of 120 legs of 60 healthy adult Japanese volunteers aged <50 years in the closed-leg stance. The measurement parameters were hip knee ankle angle (positive for varus), percentage of constitutional varus (hip knee ankle angle ≥ 3°), mechanical axis deviation ratio, mechanical lateral distal femoral angle, medial proximal tibial angle, joint line convergence angle (positive for lateral opening), and tibial joint line angle (positive for medial inclination)., Results: The mean measured values for all volunteers, men and women, were as follows: hip knee ankle angle (°), 2.3, 2.6, and 2.0; mechanical axis deviation ratio, 35.8, 35.6, and 36.9; mechanical lateral distal femoral angle (°), 86.7, 87.0, and 86.7; medial proximal tibial angle (°), 85.6, 85.0, and 86.2; joint line convergence angle (°), 0.6, 0.3, and 0.8; and tibial joint line angle (°), -1.0, -0.7, -1.4, respectively. The percentage of constitutional varus was 35.8% overall, 35.8% in men and 35.3% in women. Only the medial proximal tibial angle was smaller in men than that in women (p = 0.003)., Conclusions: The mechanical lateral distal femoral and medial proximal tibial angles were smaller, hip knee ankle angle was larger, and percentage of constitutional varus was higher in Japanese subjects than those reported for subjects in other countries. Our findings improve the understanding of Japanese-specific alignments when considering alignment for lower limb surgery, especially, total knee arthroplasty., Competing Interests: Declaration of competing interest None., (Copyright © 2021 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.)

Diffusion-Weight Imaging (DWI) is increasingly used to explore a range of outcomes in pediatric concussion, particularly the neurobiological underpinnings of symptom recovery. However, the DWI findings within the broader pediatric concussion literature are mixed, which can largely be explained by methodological heterogeneity. To address some of these limitations, the aim of the present study was to utilize internationally- recognized criteria for concussion and a consistent imaging timepoint to conduct a comprehensive, multi-parametric survey of white matter microstructure after concussion. Forty-three children presenting with concussion to the emergency department of a tertiary level pediatric hospital underwent neuroimaging and were classified as either normally recovering (n = 27), or delayed recovering (n = 14) based on their post-concussion symptoms at 2 weeks post-injury.We combined multiple DWI metrics across four modeling approaches using Linked Independent Component Analysis (LICA) to extract several independent patterns of covariation in tissue microstructure present in the study cohort. Our analysis did not identify significant differences between the symptomatic and asymptomatic groups and no component significantly predicted delayed recovery. If white matter microstructure changes are implicated in delayed recovery from concussion, these findings, alongside previous work, suggest that current diffusion techniques are insufficient to detect those changes at this time., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Inc.)

Background: Patients with perforated colorectal cancer (PCRC) experience higher recurrence rates than those with non-perforated tissue. We identified the promoting factors of stage II PCRC recurrence after R0 surgery., Method: This retrospective observational study included patients treated for colorectal cancer at a single facility between 2007 and 2016, and compared the clinicopathological features of patients with perforating versus non-perforating stage II tumors who underwent R0 resection, while focusing on recurrences., Results: Thirty-two and 112 patients (predominantly men) with perforating and non-perforating tumors, respectively, were included. The perforated group had significantly higher proportions of T4 tumors than the non-perforated group (44% vs. 15%). The perforated group had significantly lower numbers of resected lymph nodes than the non-perforated group (6 vs. 17). Seven of 17 patients with follow-up data in the perforated group experienced recurrence (41%), versus 19 of 104 in the non-perforated group (18%). In the non-perforated group, male sex (89% vs. 60%, p = 0.030), T4 stage (32% vs. 9%, p = 0.029), and fewer resected lymph nodes (12.5 vs. 18.6, p = 0.003) were significantly associated with recurrence; however, no such influences on recurrence were observed in the perforated group. The recurrence sites in the perforated group were mostly local (6 patients, 86%). Conversely, recurrences in the non-perforated group were mostly distant; 8 of 19 patients (42%) had liver metastasis and 1 (5%) had lung metastasis., Conclusion: Patients with stage II PCRC experienced higher recurrence rates regardless of clinicopathological features and had high local recurrence rates indicating possible local tumor cell dispersal owing to perforation., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2022 Asian Surgical Association and Taiwan Robotic Surgery Association. Published by Elsevier B.V. All rights reserved.)

Bromovalerylurea (BU), an acyl urea derivative, was originally developed as a hypnotic/sedative. We recently reported that BU at a dose of 50 mg/kg ameliorates sepsis, Parkinson's disease, and traumatic brain injury in Wistar rat models through its anti-inflammatory actions on microglia and macrophages. However, since BU was developed more than 100 years ago, its hypnotic mechanism and characteristics are poorly understood. Herein, we conducted an electroencephalogram (EEG) study and found that BU, when administered at a dose of more than 125 mg/kg but not at a dose of 50 mg/kg in Wistar rats, significantly increased non-rapid eye movement (NREM) sleep duration and dose-dependently decreased rapid eye movement (REM) sleep duration. This characteristic of sleep induced by BU is similar to the effect of compounds such as barbiturate, benzodiazepine, and z-drugs, all of which require γ-aminobutyric acid A receptors (GABA A R) for hypnotic/sedative activity. To investigate whether BU could potentiate GABA A ergic neurotransmission, we conducted a whole-cell patch-clamp recording from pyramidal neurons in rat cortical slices to detect spontaneous GABA A R-mediated inhibitory postsynaptic currents (IPSCs). We found that BU dose-dependently prolonged IPSCs. Importantly, the prolonged IPSCs were not attenuated by flumazenil, a benzodiazepine receptor antagonist, suggesting that modulation of IPSCs by BU is mediated by different mechanisms from that of benzodiazepine. Taken together, these data elucidate the basic characteristics of the hypnotic effects of BU and suggest that the enhancement of GABA A R-mediated Cl - flux may be a possible mechanism that contributes to its hypnotic/sedative activity., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Curly/underlapping toe involves flexion, adduction, and varus deformity of the interphalangeal joints. There are no previous reports showing the relationship between physical examination and X-ray findings among patients with curly toe deformity., Methods: We investigated the clinical findings of 116 consecutive patients associated with 239 underlapping toes. We compared the age and affected toes between patients whose deformities were pointed out at a pediatric medical examination (group 1) and those referred for medical treatment (group 2). The degree of curly toe deformity was graded by a physical examination and X-ray., Results: The average age at presentation was 2.7 years. The affected toes were significantly different between groups 1 and 2 (p < .001). The morbidity of each toe differed significantly in group 2 (p < .005) but not in group 1. The correlation between the appearance grading and classification by X-ray was very strong using Spearman's rank correlation coefficient. The severity of curly toe was divided into mild in 104 toes, moderate in 105 toes, and severe in 17 toes. The methods of conservative treatment were observation only in 15 cases, manipulations in 30 cases, taping in 67 cases, and a brace in 9 cases. Surgery was performed in 8% of cases., Conclusion: Curly toe deformity of the third or fourth toes tend to be referred for medical treatment because of the abnormality. Our grading system using a physical examination and classification by X-ray was useful for assessing the severity of curly toe., Competing Interests: Declaration of competing interest The authors declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (Copyright © 2021 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.)

Background: Hip-to-calcaneus (HC) view is a whole-leg standing view that can visualize the hindfoot in detail. The aim of this study was to investigate the reliability and validity of tibiocalcaneal angle in HC view (H-TCA) by comparing it with that in long axial view (L-TCA). We also verified whether periarticular knee alignment parameters, measured conventionally in whole-leg standing radiography, could be measured in HC view., Method: Sixty healthy volunteers and 61 patients with medial knee osteoarthritis were included. H-TCA was measured by two examiners in the healthy group, and intra-class correlation coefficients (ICCs) were evaluated. H-TCA and L-TCA were then measured in the healthy and osteoarthritis groups and correlated. Finally, we measured hip-knee-ankle angle, mechanical axis deviation ratio, mechanical lateral distal femoral angle, medial proximal tibial angle, and joint-line convergence angle in HC view and conventional whole-leg standing radiography to evaluate statistical differences and correlations., Results: The intra-observer and inter-observer ICCs were 0.86 and 0.76, respectively. Correlation coefficients (r) between H-TCA and L-TCA were r = 0.87 in healthy group and r = 0.81 in osteoarthritis group, indicating a strong positive correlation in both groups. There was no significant difference in periarticular knee alignment parameters between HC view and conventional whole-leg radiography., Conclusions: Hindfoot evaluation in HC view showed high intra-observer and inter-observer reliabilities and strong positive correlation with TCA in long axial view. By using HC view before knee surgery, such as total knee arthroplasty, other necessary alignments can be evaluated simultaneously., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: The utility of late potentials on signal-averaged electrocardiography (SAECG) for risk stratification in patients with Brugada syndrome (BrS) remains controversial. Late potentials on conventional SAECG with Frank leads may be insufficiently sensitive to detect site-specific late potentials in right precordial leads., Objective: The purpose of this study was to evaluate the utility of site-specific late potentials using a novel unipolar Holter-SAECG system for risk stratification in patients with BrS., Methods: Consecutive symptomatic (n = 20) and asymptomatic (n = 21) patients with BrS who underwent investigation using conventional SAECG and a novel unipolar Holter-SAECG system were enrolled. We evaluated clinical characteristics and outcomes and compared late potentials on the 2 SAECGs between both groups and patients with and without cardiac events (CEs) (sudden cardiac death or sustained ventricular tachyarrhythmias) during the follow-up period., Results: During mean follow-up of 76 months, 10 patients (24%) had CEs. There were no significant differences in late potentials on conventional SAECG between symptomatic and asymptomatic patients. On the Holter-SAECG system, RMS40 in lead V 2 in the third intercostal space (3L-V 2 ) at the nighttime was significantly lower in the symptomatic group than in the asymptomatic group (5.5 ± 0.8 μV and 8.2 ± 0.8 μV, respectively; P = .027). Univariate analysis of predictive values for CE showed that hazard ratios of daytime and nighttime RMS40 in lead 3L-V 2 of <7.7 μV and <6.1 μV were 7.58 and 6.14, respectively., Conclusion: Site-specific late potentials in lead 3L-V 2 measured using the novel Holter-SAECG system may be a useful marker for high-risk patients with BrS., (Copyright © 2022 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: Anti-aquaporin-4 (AQP4) antibody is an autoantibody marker often observed in patients with neuromyelitis optica spectrum disorder (NMOSD). The pathological relevance of complicated pulmonary disorders in anti-AQP4 antibody-positive NMOSD remains unclear. We aimed to assess the clinical and histological relevance of complicated pulmonary disorders in anti-AQP4 antibody-positive NMOSD., Methods: We retrospectively reviewed the medical records of 52 patients with anti-AQP4 antibody-positive NMOSD and conducted immunohistochemical evaluations of the lung biopsy specimens., Results: Among 52 patients with anti-AQP4 antibody-positive NMOSD, 4 patients showed pulmonary involvement with a diagnosis of organizing pneumonia (OP). The proportion of males was larger (75% vs. 12.5%; p = 0.013) and creatine kinase levels were higher (458.3 U/L vs. 83.9 U/L; p = 0.003) in patients with OP than in those without OP. OP development preceded or coincided with the NMOSD symptoms. Chest computed tomography findings were consistent with OP in all four patients. Bronchoalveolar lavage fluid predominantly contained lymphocytes. Transbronchial lung biopsy revealed intraluminal plugs of inflammatory debris within the alveoli. Alveolar epithelial cells covering the OP lesions exhibited AQP4 loss, immunoglobulin G deposition, and complement activation. Corticosteroid treatment resulted in clinical improvement of OP., Conclusion: OP may be considered a pulmonary manifestation of anti-AQP4 antibody-positive NMOSD beyond the central nervous system. Complement-dependent cytotoxicity of the lung epithelial cells caused by anti-AQP4 antibody is at least partly involved in OP development. When diagnosing NMOSD, the possibility of OP should be carefully evaluated based on the detailed history and chest imaging findings., Competing Interests: Conflict of interest The authors declare no competing interests., (Copyright © 2022 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

This study aimed to determine the effectiveness of triamcinolone acetonide in suppressing inflammation after blepharoptosis surgery. The study was designed as prospective, randomized, two medical centers' clinical trial. Thirty-two patients with involutional blepharoptosis of the same degree in both eyelids underwent bilateral transcutaneous levator advancement. At the end of the surgery, 4 mg/0.1 ml of triamcinolone acetonide was injected into a randomly selected upper eyelid. The fellow eyelid was not injected and was used as control. Facial photographs were taken on day 1, week 1, month 1, and month 3, and the degree of inflammation, the margin reflex distance 1 (MRD-1), and levator function (LF) between the two eyelids of each patient were compared. The primary outcome was the selection of the less inflamed eyelid decided by the majority of three individuals unrelated to the study. MRD-1 and LF were analyzed for secondary outcomes. As a result, the injected eyelid was judged to be the less inflamed eyelid in all cases. The MRD-1 in the postoperative period less than 1 month was significantly larger in the injected eyelids than the control eyelids (P<0.03). The postsurgical MRD-1 at month 3, the postsurgical LF at all postsurgical examination times were not statistically different. Adverse complications by the injection, including ptosis, levator dysfunction, increase of the intraocular pressure, and visual disturbance were not observed. In conclusion, a triamcinolone acetonide injection after ptosis surgery is both safe and effective in reducing the early postsurgical inflammation and helpful in an earlier return to a daily routine for the patients., Competing Interests: Declaration of Competing Interest None., (Copyright © 2021 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.)

Tuberculosis remains the leading cause of infectious disease related death worldwide with extrapulmonary tuberculosis being particularly difficult to diagnose. Here, we report a case of pancreatic tuberculosis (PTB) in an immunocompetent young female, which mimicked a malignant tumor diagnosed by endoscopic ultrasound-guided fine needle aspiration and biopsy (EUS-FNAB). A 19-year-old Japanese female with no prior medical history presented with abdominal epigastralgia and appetite loss lasting 2 months. A solid lobular mass was observed in the pancreatic head with enhanced abdominal computed tomography and magnetic resonance imaging suggested it was a malignant pancreatic tumor. Using EUS-FNAB, granulomas with caseous necrosis and acid-fast bacilli were observed. Polymerase chain reaction results were positive for Mycobacterium tuberculosis but negative for Mycobacterium avium complex. Therefore, the patient was diagnosed with PTB. Her symptoms and radiological findings improved with a standard antituberculosis therapy. PTB is difficult to differentiate from other pancreatic diseases with Magnetic resonance imaging (MRI) patterns of T1, T2 weighted, or diffusion-weighted image (DWI) images. To investigate novel radiological diagnostics for PTB, we focused on MRI apparent diffusion coefficient (ADC) values, which have not been investigated in this context. The present case showed 0.52 × 10 -3  mm 2 /s; additionally, the mean value of other mass-forming pancreatic diseases, such as pancreatic cancer was 1.592 × 10 -3  mm 2 /s (the range: 1.015-3.025 × 10 -3  mm 2 /s). The range does not overlap with the present PTB case or other pancreatic diseases. Therefore, ADC values may be useful as a noninvasive radiological diagnostic method for PTB., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: To examine the efficacy and tolerance of the antiseizure medications lacosamide (LCM) and levetiracetam (LEV) in patients with benign infantile epilepsy (BIE)., Methods: The clinical data of 24 children with BIE seen between 2014 and 2020 were collected retrospectively, and treatment, effectiveness, and adverse effects were examined. PRRT2 gene analysis was performed using Sanger sequencing., Results: Of the 24 children with BIE, 14 were treated with antiseizure medications. PRRT2 gene analysis was performed in 14 children, and mutations were identified in 4, including a pair of siblings. All five children treated with LCM became seizure-free, similar to those treated with carbamazepine. The LCM does was 2 mg/kg/day in all cases. There were no adverse effects in any patient treated with LCM. By contrast, both patients treated with LEV had seizure recurrence. In one patient, LEV was replaced with CBZ, resulting in seizure freedom., Conclusions: Low-dose LCM was effective and well tolerated in patients with BIE, whereas LEV was insufficiently effective., (Copyright © 2021. Published by Elsevier Ltd.)

Background/Objective: Core decompression (CD) with scaffold and cell-based therapies is a promising strategy for providing both mechanical support and regeneration of the osteonecrotic area for early stage osteonecrosis of the femoral head (ONFH). We designed a new 3D printed porous functionally-graded scaffold (FGS) with a central channel to facilitate delivery of transplanted cells in a hydrogel to the osteonecrotic area. However, the optimal porous structural design for the FGS for the engineering of bone in ONFH has not been elucidated. The aim of this study was to fabricate and evaluate two different porous structures (30% or 60% porosity) of the FGSs in corticosteroid-associated ONFH in rabbits., Methods: Two different FGSs with 30% or 60% porosity containing a 1-mm central channel were 3D printed using polycaprolactone and β-tricalcium phosphate. The FGS was 3-mm diameter and 32-mm length and was composed of three segments: 1-mm in length for the non-porous proximal segment, 22-mm in length for the porous (30% versus 60%) middle segment, and 9-mm in length for the 15% porous distal segment. Eighteen male New Zealand White rabbits were given a single dose of 20 ​mg/kg methylprednisolone acetate intramuscularly. Four weeks later, rabbits were divided into three groups: the CD group, the 30% porosity FGS group, and the 60% porosity FGS group. In the CD group, a 3-mm diameter drill hole was created into the left femoral head. In the FGS groups, a 30% or 60% porosity implant was inserted into the bone tunnel. Eight weeks postoperatively, femurs were harvested and microCT, mechanical, and histological analyses were performed., Results: The actual porosity and pore size of the middle segments were 26.4% ​± ​2.3% and 699 ​± ​56 ​μm in the 30% porosity FGS, and 56.0% ​± ​4.5% and 999 ​± ​71 ​μm in the 60% porosity FGS, respectively using microCT analysis. Bone ingrowth ratio in the 30% porosity FGS group was 73.9% ​± ​15.8%, which was significantly higher than 39.5% ​± ​13.0% in the CD group on microCT (p ​< ​0.05). Bone ingrowth ratio in the 60% porosity FGS group (61.3% ​± ​30.1%) showed no significant differences compared to the other two groups. The stiffness at the bone tunnel site in the 30% porosity FGS group was 582.4 ​± ​192.3 ​N/mm 3 , which was significantly higher than 338.7 ​± ​164.6 ​N/mm 3 in the 60% porosity FGS group during push-out testing (p ​< ​0.05). Hematoxylin and eosin staining exhibited thick and mature trabecular bone around the porous FGS in the 30% porosity FGS group, whereas thinner, more immature trabecular bone was seen around the porous FGS in the 60% porosity FGS group., Conclusion: These findings indicate that the 30% porosity FGS may enhance bone regeneration and have superior biomechanical properties in the bone tunnel after CD in ONFH, compared to the 60% porosity FGS., Translation Potential Statement: The translational potential of this article: This FGS implant holds promise for improving outcomes of CD for early stage ONFH., Competing Interests: The author(s) have no conflicts of interest relevant to this article., (© 2021 The Authors.)

5-Aminolevulinic acid (ALA) is the rate-limiting intermediate in heme biosynthesis in vertebrate species; a reaction catalyzed by the mitochondrial ALA synthase 1 (ALAS1) enzyme. Previously we reported that knockdown of the ubiquitously expressed ALAS1 gene in mice disrupts normal glucose metabolism, attenuates mitochondrial function and results in a prediabetic like phenotype when animals pass 20-weeks of age (Saitoh et al., 2018). Contrary to our expectations, the cytosolic and mitochondrial heme content of ALAS1 heterozygous (A1+/-) mice were similar to WT animals. Therefore, we speculated that regulatory "free heme" may be reduced in an age dependent manner in A1+/- mice, but not total heme. Here, we examine free and total heme from the skeletal muscle and liver of WT and A1+/- mice using a modified acetone extraction method and examine the effects of aging on free heme by comparing the amounts at 8-12 weeks and 30-36 weeks of age, in addition to the mRNA abundance of ALAS1. We found an age-dependent reduction in free heme in the skeletal muscle and liver of A1+/- mice, while WT mice showed only a slight decrease in the liver. Total heme levels showed no significant difference between young and aged WT and A1+/- mice. ALAS1 mRNA levels showed an age-dependent reduction similar to that of free heme levels, indicating that ALAS1 mRNA expression levels are a major determinant for free heme levels. The free heme pools in skeletal muscle tissue were almost 2-fold larger than that of liver tissue, suggesting that the heme pool varies across different tissue types. The expression of heme oxygenase 1 (HO-1) mRNA, which is expressed proportionally to the amount of free heme, were similar to those of free heme levels. Taken together, this study demonstrates that the free heme pool differs across tissues, and that an age-dependent reduction in free heme levels is accelerated in mice heterozygous for ALAS1, which could account for the prediabetic phenotype and mitochondrial abnormality observed in these animals., (Copyright © 2020. Published by Elsevier Inc.)

Objective: To determine the predictors of unfavorable outcomes in acute minor ischemic stroke patients with large vessel occlusion., Methods: The derivation cohort included ischemic stroke patients admitted to a comprehensive stroke center within 7 days after onset with large vessel occlusion and an initial National Institutes of Health Stroke Scale score of 5 or less. An unfavorable outcome was defined as dependency (modified Rankin Scale score of 3 to 6) at 3 months from the onset. The predictive values of factors related to an unfavorable outcome were evaluated. External validation was performed from a stroke registry of a tertiary medical center., Results: In the derivation cohort, 3839 consecutive patients were screened; a total of 130 patients were included. Twenty-four (18%) patients had unfavorable outcomes. In multivariate analysis, D-dimer ≥1900 μg/l (odds ratio (OR) 3.31, 95% confidence interval (CI) 1.14-9.61, p = .028) and age (OR 2.01, 95% CI 1.05-3.86, p = .035) were independently associated with an unfavorable outcome. No significant differences were observed regarding occluded vessel sites. In the validation cohort, 850 consecutive patients were screened; a total of 74 patients were included. D-dimer ≥1900 μg/l (OR 8.78, 95% CI 1.41-54.61, p = .020) was the only factor independently associated with an unfavorable outcome, as in the derivation cohort., Conclusions: A high D-dimer level on admission could help predict unfavorable outcomes in patients with a minor ischemic stroke with large vessel occlusion., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Neoadjuvant chemotherapy (NAC) is increasingly used for resectable locally advanced gastric cancer (LAGC). JCOG1302A investigated the diagnostic criteria of LAGC patients with cT3-4/N1-3 to minimize contamination of pathological stage I as a candidate for NAC. In JCOG1302A, 77.2% of cT3-4 tumors diagnosed via a combination of endoscopy and computed tomography (CT) were pT3-4. However, the role of endoscopic ultrasonography (EUS) and additional diagnostic procedures/modalities remains unclear. Here, we investigated whether EUS, thin-slice CT, and foaming agent (FA) in CT contribute to accurate diagnosis of AGC invasion depth., Methods: Using JCOG1302A study data, we compared positive predictive value (PPV), negative predictive value (NPV), and kappa index (KI) between conventional and additional diagnostic procedures to identify pT3-4: conventional endoscopy (CE) with versus without EUS, 1-mm versus 5-mm CT slice, and CT with versus without FA., Results: We analyzed 1232 patients' data. PPV, NPV, and KI were 79.2%/73.7%, 59.2%/58.8%, and 0.38/0.39 (CE alone/CE with EUS), 77.8%/75.5%, 62.9%/71.2%, and 0.38/0.39 (5-mm CT/1-mm CT), and 78.6%/75.1%, 60.9%/69.7%, and 0.38/0.40 (CT without FA/CT with FA), respectively. Overall, there were no remarkable differences in any comparison. More specifically, PPV and KI were slightly higher with CE alone rather than CE with EUS. Although NPV was higher for 1-mm CT and CT with FA, PPV was rather higher for 5-mm CT and CT without FA., Conclusion: Additional diagnostic procedures/modalities, like EUS, 1-mm slice CT, or FA in CT may not improve the diagnostic accuracy of invasion depth in resectable LAGC., Competing Interests: Declaration of competing interest No., (Copyright © 2020 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Precipitation has been widely applied to purification and fractionation of biological macromolecules. Several physical-chemical factors contribute to the destabilization of those solutions, such as the nature of solvent employed, presence of salts, temperature, and concentration of the macromolecule. In the case of charged biopolymers, electrostatic forces are the major contributors to their stability in solution. However, the role of each variable and the exact mechanism of precipitation are not completely understood yet. The aim of this work was to study the precipitation of polyribosyl-ribitol-phosphate (PRP, a linear homogeneous anionic biopolymer) in presence of salts and non-solvents, in order to contribute to the elucidation of its precipitation mechanism. The solvents tested (acetone, ethanol, and isopropanol) presented distinct dielectric constants. The salts used (NH 4 Cl, NaCl, KCl, MgCl 2 , and CaCl 2 ) differ by their cations. For each salt concentration, the solvent fraction that induces precipitation was identified and the dielectric constant of the bulk solution was calculated. Precipitation always occurred at well-defined combinations of solvents and salts. At low concentration of monovalent salts, there was a linear correlation between the logarithm of the salt concentration and the inverse of the medium dielectric constant at a defined precipitation point. This is a strong indication that the stability of the solution depends almost exclusively on the balance of electrostatic forces. This behavior is compatible with the DLVO modeling of colloidal systems. When divalent salts were used, low concentrations of the counterion were sufficient to induce precipitation, due to a phenomenon called ionic condensation. Apparently, PRP precipitates when around 90% of its charges are neutralized, value that is similar to charge neutralization for DNA precipitation., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: There is limited information on ethnic differences between patients with Brugada syndrome (BrS) and arrhythmic events (AEs)., Objective: The purpose of this study was to compare clinical, electrocardiographic (ECG), electrophysiological, and genetic characteristics between white and Asian patients with BrS and AEs., Methods: The Survey on Arrhythmic Events in Brugada Syndrome is a multicenter survey from Western and Asian countries, gathering 678 patients with BrS and first documented AE. After excluding patients with other (n = 14 [2.1%]) or unknown (n = 30 [4.4%]) ethnicity, 364 (53.7%) whites and 270 (39.8%) Asians comprised the study group., Results: There was no difference in AE age onset (41.3 ± 16.1 years in whites vs 43.3 ± 12.3 years in Asians; P = .285). Higher proportions of whites were observed in pediatric and elderly populations. Asians were predominantly men (98.1% vs 85.7% in whites; P < .001) and frequently presented with aborted cardiac arrest (71.1% vs 56%; P < .001). Asians tended to display more spontaneous type 1 BrS-ECG pattern (71.5% vs 64.3%; P = .068). A family history of sudden cardiac death was noted more in whites (29.1% vs 11.5%; P < .001), with a higher rate of SCN5A mutation carriers (40.1% vs 13.2% in Asians; P < .001), as well as more fever-related AEs (8.5% vs 2.9%; P = .011). No difference was observed between the 2 groups regarding history of syncope and ventricular arrhythmia inducibility., Conclusion: There are important differences between Asian and white patients with BrS. Asian patients present almost exclusively as male adults, more often with aborted cardiac arrest and spontaneous type 1 BrS-ECG. However, they have less family history of sudden cardiac death and markedly lower SCN5A mutation rates. The striking difference in SCN5A mutation rates should be tested in future studies., (Copyright © 2019 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: Spinocerebellar ataxia type 5 (SCA5), a dominant spinocerebellar ataxia is caused by spectrin beta nonerythrocytic 2 gene (SPTBN2) mutation. It typically consists of a slow progressive cerebellar ataxia with an onset principally in adulthood. Here, we report on the first Japanese patient with infantile-onset SCA5 associated with a novel heterozygous SPTBN2 mutation., Case Report: The patient, a 6-year-old girl, developed delayed motor development and unsteady arm movement during infancy. She also showed gaze-evoked nystagmus, saccadic eye pursuit, dysarthria, dysmetria, intention tremor and mild intellectual disability. Brain MRI revealed moderate cerebellar atrophy and mild pontine atrophy. Comprehensive target capture sequencing to identify the causative gene identified a novel missense mutation in SPTBN2 (c.1309C

Objectives: Defects in DNA damage responses or repair mechanisms cause numerous rare inherited diseases, referred to as "DNA-repair defects" or "DNA damage deficiency", characterized by neurodegeneration, immunodeficiency, and/or cancer predisposition. Early accurate diagnosis is important for informing appropriate clinical management; however, diagnosis is frequently challenging and can be delayed, due to phenotypic heterogeneity. Comprehensive genomic analysis could overcome this disadvantage. The objectives of this study were to determine the prevalence of ataxia-telangiectasia (A-T) and A-T-like DNA-repair defects in Japan and to determine the utility of comprehensive genetic testing of presumptively diagnosed patients in facilitating early diagnosis., Methods: A nationwide survey of diseases presumably caused by DNA-repair defects, including A-T, was performed. Additionally, comprehensive next-generation sequencing (NGS) analysis, targeting known disease-causing genes, was conducted., Results: Sixty-three patients with A-T or other diseases with characteristics of DNA-repair defects were identified. Thirty-four patients were genetically or clinically definitively diagnosed with A-T (n = 22) or other DNA-repair defects (n = 12). Genetic analysis of 17 presumptively diagnosed patients revealed one case of ataxia with oculomotor apraxia type 1 (AOA1); one ataxia with oculomotor apraxia type 2 (AOA2); two types of autosomal dominant spinocerebellar ataxia (SCA5, SCA29); two CACNA1A-related ataxias; one microcephaly with or without chorioretinopathy, lymphedema, or mental retardation (MCLMR); and one autosomal dominant KIF1A-related disorder with intellectual deficit, cerebellar atrophy, spastic paraparesis, and optic nerve atrophy. The diagnostic yield was 58.8%., Conclusion: Comprehensive genetic analysis of targeted known disease-causing genes by NGS is a powerful diagnostic tool for subjects with indistinguishable neurological phenotypes resembling DNA-repair defects., (Copyright © 2018 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Background: There is limited information on gender differences in patients with Brugada syndrome (BrS) who experienced arrhythmic events (AEs)., Objective: The purpose of this study was to compare clinical, electrocardiographic (ECG), electrophysiological, and genetic characteristics between males and females in patients with BrS with their first AE., Methods: The multicenter Survey on Arrhythmic Events in BRUgada Syndrome collected data on the first AE in 678 patients with BrS including 619 males (91.3%) and 59 females (8.7%) aged 0.27-84 years (mean age 42.5 ± 14.1 years) at the time of AE occurrence., Results: After excluding pediatric patients, it was found that females were older than males (49.5 ± 14.4 years vs 43 ± 12.7 years, respectively; P = .001). Higher proportions of females were observed in the pediatric and elderly populations. In Asians, the male to female ratio for AEs was ≈9-fold higher than that in White. Spontaneous type 1 BrS ECG was associated with an earlier onset of AEs in pediatric females. A similar prevalence (≈65%) of spontaneous type 1 BrS ECG was present in males and females above the age of 60 years. Females less frequently showed spontaneous type 1 BrS ECG (41% vs 69%; P < .001) or arrhythmia inducibility at electrophysiology study (36% vs 66%; P < .001). An SCN5A mutation was more frequently found in females (48% vs 28% in males; P = .007)., Conclusion: This study confirms that female patients with BrS are much rarer, display less type 1 Brugada ECG, and exhibit lower inducibility rates than do males. It shows for the first time that female patients with BrS with AE have higher SCN5A mutation rates as well as the relationship between gender vs age at the onset of AEs and ethnicity., (Copyright © 2018 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: The literature on fever-related arrhythmic events (AEs) in Brugada syndrome (BrS) is currently limited to few case reports and small series., Objective: The present study aimed to describe the characteristics of fever-related AE in a large cohort of patients with BrS., Methods: The Survey on Arrhythmic Events in Brugada Syndrome is a multicenter study on 678 patients with BrS with first AE documented at the time of aborted cardiac arrest (n = 426) or after prophylactic implantable cardioverter-defibrillator implantation (n = 252)., Results: In 35 of 588 patients (6%) with available information, the AE occurred during a febrile illness. Most of the 35 patients were male (80%), Caucasian (83%), and proband (70%). The mean age at the time of AE was 29 ± 24 years (range 0.3-76 years). Most patients (80%) presented with aborted cardiac arrest and 6 (17%) with arrhythmic storm. Family history of sudden death, history of syncope, and spontaneous type 1 Brugada electrocardiogram were noted in 17%, 40%, and 71% of patients, respectively. Ventricular fibrillation was induced at electrophysiology study in 9 of 19 patients (47%). An SCN5A mutation was found in 14 of 28 patients (50%). The highest proportion of fever-related AE was observed in the pediatric population (age <16 years), with a disproportionally higher event rate in the very young (age 0-5 years) (65%). Males were involved in all age groups and females only in the pediatric and elderly groups. Fever-related AE affected 17 Caucasians aged <24 years, but no Asians aged <24 years., Conclusion: The risk of fever-related AE in BrS markedly varies according to age group, sex, and ethnicity. Taking these factors into account could help the clinical management of patients with BrS with fever., (Copyright © 2018 Heart Rhythm Society. All rights reserved.)

Nanoemulsions of a lipophilic vitamin, retinol palmitate (vitamin A; VA), have a therapeutic effect on corneal damage. The nanoemulsion based on a triblock-type polymer surfactant with polyoxyethylene and polypropylene, EO 100 PO 70 EO 100 (EOPO) showed superior efficacy, as compared with a nanoemulsion based on polyoxyethylene (60) hydrogenated castor oil (HCO). We studied the mechanism of VA nanoemulsions related to efficacy from the viewpoint of the interaction with plasma membrane-mimicking giant unilamellar vesicles (GUVs) and the plasma membrane permeation in corneal epithelial cells. When nanoemulsions and GUVs doped with fluorescent compounds were mixed each other, and observed by confocal laser microscopy, EOPO nanoemulsions induced endocytic morphological changes like strings and vesicles of the bilayer drawn inside a GUV by budding. Judging by isothermal titration calorimetry and ζ potential measurements, the EOPO nanoemulsions seemed to have stronger hydrophobic interactions with the lipid bilayer because of lower coverage of the core interface. Next, when the nanoemulsions prepared with a pyrene derivative of retinol (VApyr) were applied to corneal epithelial cells, the EOPO nanoemulsions greatly permeated the cells and gathered around the cell nucleus, as compared with HCO nanoemulsions. Furthermore, according to the three-dimensional images of the cell, it was found that the vesicles that absorbed nanoemulsions formed from the plasma membrane as real endocytosis, and were transported to the area around the nucleus. Consequently, it is likely that EOPO nanoemulsions entered the cell by membrane-mediated transport, delivering VA to the cell nucleus effectively and enhancing the effects of VA., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Silicate is an excellent adsorbent because of its large surface area and amenability to surface modification. In this study, the representative liposome nanomedicines DOXIL ® and AmBisome ® were enriched using a silica monolith disc (diameter 4.2 mm, length 1.5 mm) with bimodal pores. Although the nanoparticles passed through the disc without retention when water was used as the preactivation solution, they were strongly retained by the disc when a 1 M bivalent metal (such as Mg 2+ , Ca 2+ , and Ni 2+ ) solution was used. Notably, strong affinity was observed to DOXIL, a pegylated liposomal nanoparticle, by the disc composed of 5 μm and 10 nm through- and meso pores, respectively, and nearly 100% of DOXIL was recovered from a 40× diluted solution. Overall, the results demonstrate that monolithic discs are effective for the enrichment of liposomal nanomedicines., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Thiopurines (eg, 6-mercaptopurine [MP]) are highly efficacious antileukemic agents, but they are also associated with dose-limiting toxicities. Recent studies by us and others have identified inherited NUDT15 deficiency as a novel genetic cause of thiopurine toxicity, and there is a strong rationale for NUDT15- guided dose individualization to preemptively mitigate adverse effects of these drugs. Using CRISPR-Cas9 genome editing, we established a Nudt15 -/- mouse model to evaluate the effectiveness of this strategy in vivo. Across MP dosages, Nudt15 -/- mice experienced severe leukopenia, rapid weight loss, earlier death resulting from toxicity, and more bone marrow hypocellularity compared with wild-type mice. Nudt15 -/- mice also showed excessive accumulation of a thiopurine active metabolite (ie, DNA-incorporated thioguanine nucleotides [DNA-TG]) in an MP dose-dependent fashion, as a plausible cause of increased toxicity. MP dose reduction effectively normalized systemic exposure to DNA-TG in Nudt15 -/- mice and largely eliminated Nudt15 deficiency-mediated toxicity. In 95 children with acute lymphoblastic leukemia, MP dose adjustment also directly led to alteration in DNA-TG levels, the effects of which were proportional to the degree of NUDT15 deficiency. Using leukemia-bearing mice with concordant Nudt15 genotype in leukemia and host, we also confirmed that therapeutic efficacy was preserved in Nudt15 -/- mice receiving a reduced MP dose compared with Nudt15 +/+ counterparts exposed to a standard dose. In conclusion, we demonstrated that NUDT15 genotype-guided MP dose individualization can preemptively mitigate toxicity without compromising therapeutic efficacy., (© 2018 by The American Society of Hematology.)

Background: Detailed information on the profile of patients with Brugada syndrome (BrS) presenting their first arrhythmic event (AE) after prophylactic implantation of an implantable cardioverter-defibrillator (ICD) is limited., Objectives: The objectives of this study were (1) to compare clinical, electrocardiographic, electrophysiologic, and genetic profiles of patients who exhibited their first documented AE as aborted cardiac arrest (group A) with profiles of those in whom the AE was documented after prophylactic ICD implantation (group B) and (2) to characterize group B patients' profile using the class II indications for ICD implantation established by HRS/EHRA/APHRS expert consensus statement in 2013., Methods: A survey of 23 centers from 10 Western and 4 Asian countries enabled data collection of 678 patients with BrS who exhibited their AE (group A, n = 426; group B, n = 252)., Results: The first AE occurred in group B patients 6.7 years later than in group A (mean age 46.1 ± 13.3 years vs 39.4 ± 15.1 years; P < .001). Group B patients had a higher incidence of family history of sudden cardiac death and SCN5A mutations. Of the 252 group B patients, 189 (75%) complied with the HRS/EHRA/APHRS indications whereas the remaining 63 (25%) did not., Conclusion: Patients with BrS with the first AE documented after prophylactic ICD implantation exhibited their AE at a later age with a higher incidence of positive family history of sudden cardiac death and SCN5A mutations as compared with those presenting with aborted cardiac arrest. Only 75% of patients who exhibited an AE after receiving a prophylactic ICD complied with the 2013 class II indications, suggesting that efforts are still required for improving risk stratification., (Copyright © 2018 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: The reliability of the cobas EGFR assay to detect epidermal growth factor receptor (EGFR) mutations in non-small-cell lung cancer (NSCLC) as an in vitro diagnostic test was compared with 3 laboratory-developed tests (LDTs)., Materials and Methods: After screening for EGFR mutations using formalin-fixed-paraffin-embedded NSCLC tissue sections using the cobas EGFR assay, 151 samples were further tested with 3 LDTs; the peptide nucleic acid-locked nucleic acid polymerase chain reaction (PCR) clamp, PCR invader, and Cycleave assays. The cobas EGFR assay performance was evaluated by determining the concordance rate and κ-coefficient between the assays. In samples exhibiting discrepancies in the EGFR mutation status in the 4 assays, next-generation sequencing was performed to confirm mutated sequences., Results: Concordance rates and κ-coefficients between the cobas EGFR assay and the other tests were 96.0% and 0.921 for the peptide nucleic acid-locked nucleic acid PCR clamp assay, 94.0% and 0.881 for the PCR invader assay, and 96.7% and 0.934 for the Cycleave assay, respectively. Data showed very good agreement with the other assays. Precise mutated sequences or exons in the EGFR gene matched in 137 samples (90.7%). Different results were obtained in 4 samples (2.6%), owing to systemic limitations of the assay. Next-generation sequencing of 10 (6.6%) samples with discordant results exhibited a concordance rate of 60% to 80% in each assay., Conclusions: The cobas EGFR assay showed high concordance rates and κ-coefficients between the 3 compared LDTs and can be used to select patients who would benefit from EGFR-tyrosine kinase inhibitors., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background and Objective: Marinesco-Sjögren syndrome (MSS) is an autosomal recessive infantile-onset disorder characterized by cataracts, cerebellar ataxia, and progressive myopathy caused by mutation of SIL1. In mice, a defect in SIL1 causes endoplasmic reticulum (ER) chaperone dysfunction, leading to unfolded protein accumulation and increased ER stress. However, ER stress and the unfolded protein response (UPR) have not been investigated in MSS patient-derived cells., Methods: Lymphoblastoid cell lines (LCLs) were established from four MSS patients. Spontaneous and tunicamycin-induced ER stress and the UPR were investigated in MSS-LCLs. Expression of UPR markers was analyzed by western blotting. ER stress-induced apoptosis was analyzed by flow cytometry. The cytoprotective effects of ER stress modulators were also examined., Results: MSS-LCLs exhibited increased spontaneous ER stress and were highly susceptible to ER stress-induced apoptosis. The inositol-requiring protein 1α (IRE1α)-X-box-binding protein 1 (XBP1) pathway was mainly upregulated in MSS-LCLs. Tauroursodeoxycholic acid (TUDCA) attenuated ER stress-induced apoptosis., Conclusion: MSS patient-derived cells exhibit increased ER stress, an activated UPR, and susceptibility to ER stress-induced death. TUDCA reduces ER stress-induced death of MSS patient-derived cells. The potential of TUDCA as a therapeutic agent for MSS could be explored further in preclinical studies., (Copyright © 2017 Elsevier B.V. All rights reserved.)