Search

Background: Since lung transplant recipients (LTRs) exhibit low immunogenicity after two doses of SARS-CoV-2 mRNA vaccines, optimal vaccine strategies for SARS-CoV-2 are required in LTRs. This study aimed to investigate the efficacy and safety of the third and fourth doses of the SARS-CoV-2 mRNA vaccines in LTRs., Methods: We conducted a single-center study of 73 LTRs and 23 healthy controls (HCs). Participants received two-to-four doses of SARS-CoV-2 mRNA vaccines. The LTRs were divided into three groups based on the number of vaccine dose. IgG titers against SARS-CoV-2 spike protein were measured, and adverse events were assessed. Factors associated with humoral response were analyzed using univariate and multivariate analyses., Results: The Dose 4 group (n = 27) had a higher humoral response rate (P = 0.018) and higher levels of anti-SARS-CoV-2 IgG antibody (P = 0.04) than the Dose 2 group (n = 14). The Dose 3 group (n = 32) had lower humoral response rates (P = 0.005) and levels of anti-SARS-CoV-2 IgG antibody (P = 0.0005) than the HCs (n = 23) even after the same dose. Systemic adverse events were milder in the LTRs than in the HCs (P < 0.05). Increased number of vaccine dose was identified as a predictor of positive humoral response (P = 0.021)., Conclusion: Booster doses of SARS-CoV-2 mRNA vaccines may enhance humoral response with mild adverse events in LTRs. Repeated vaccination might be warranted for LTRs to prevent SARS-CoV-2 infection., Competing Interests: Declaration of competing interest The authors have no conflicts of interest., (Copyright © 2024 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Objective: Acute Physiology and Chronic Health Evaluation II (APACHE II) is based on the data of intensive care unit (ICU) patients and often correlates with disease severity and prognosis. However, no prognostic predictors exist based on ICU admission data for patients with brain tumors, and no studies have reported an association between APACHE II and prognosis in patients with brain tumors. The Japanese Intensive Care Patients Database (JIPAD) was established to improve the quality of care delivered in intensive care medicine in Japan. We used JIPAD to examine factors associated with in-hospital mortality based on available data of postoperative patients with brain tumors admitted to the ICU., Methods: Patients aged ≥16 years enrolled in JIPAD between April 2015 and March 2018 after surgical brain tumor resection or biopsy of brain tumors. We examined factors related to outcomes at discharge based on blood tests and medical procedures performed during ICU admission, tumor type, and APACHE II score., Results: Among the 1454 patients (male:female ratio: 1:1.1, mean age: 62 years) in the study, 32 (2.2 %) died during hospital stay. In multivariate analysis, male sex (odds ratio [OR] 2.70, [95 % confidence interval, CI 1.22-6.00]), malignant tumor (OR 2.51 [95 % CI 1.13-5.55]), and APACHE II score ≥15 (OR 2.51 [95 % CI 3.08-14.3]) were significantly associated with in-hospital mortality., Conclusion: By picking up cases with a high risk of in-hospital death at an early stage, it is possible to improve methods of treatment and support for the patient's family., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The present monograph discusses the possibility of BCS-based biowaivers for immediate release pharmaceutical products containing raltegravir potassium, which is used to treat human immunodeficiency virus (HIV) infections. Raltegravir potassium can be assigned to BCS class II or IV since this compound has low solubility and uncertain permeability. Therefore, according to the ICH M9 guideline, it is not recommended to apply BCS-based biowaiver to approval of immediate release solid dosage forms of raltegravir potassium, either for new generic versions or when moderate to major changes in composition and/or the manufacturing method of the product are made., Competing Interests: Conflict of Interest This article is a part of the project of the Focus Group BCS & Biowaiver. The contents of this monograph are based on the data available in the literature and represent the scientific opinion of the authors but not necessarily the policies of regulatory authorities., (Copyright © 2024 American Pharmacists Association. All rights reserved.)

Objective: This study aimed to elucidate postoperative outcomes in patients with spinal metastases of prostate cancer, with a focus on patient-oriented assessments., Methods: This was a prospective multicenter registry study involving 35 centers. A total of 413 patients enrolled in the Japanese Association for Spine Surgery and Oncology Multicenter Prospective Study of Surgery for Metastatic Spinal Tumors were evaluated for inclusion. The eligible patients were followed for at least 1 year after surgery. The Frankel Classification, Eastern Cooperative Oncology Group Performance Status, visual analog scale for pain, face scale, Barthel Index, vitality index, indications for oral pain medication, and the EQ-5D-5L questionnaire were used for evaluating functional status, activities of daily living, and patient motivation., Results: Of the 413 eligible patients, 41 with primary prostate cancer were included in the study. The patient-oriented assessments indicated that the patients experienced postoperative improvements in quality of life and motivation in most items, with the improvements extending for up to 6 months. More than half of the patients with Frankel classifications B or C showed improved neurological function at 1 month after surgery, and most patients presented maintained or improved their classification at 6 months., Conclusion: Surgical intervention for spinal metastases of prostate cancer significantly improved neurological function, quality of life, and motivation of the patients. Consequently, our results support the validity of surgical intervention for improving the neurological function and overall well-being of patients with spinal metastases of prostate cancer., Competing Interests: Declaration of competing interest The Authors declare that there is no conflict of interest., (Copyright © 2024 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.)

Background: Current antiretroviral therapy (ART) regimens are highly effective; therefore, to differentiate between various regimens, considering patient-reported outcomes is essential. This study aimed to assess patient satisfaction with their current ART regimens and investigate factors associated with the Human Immunodeficiency Virus Treatment Satisfaction Questionnaire: Status (HIVTSQs) score., Methods: This cross-sectional, multicenter study was conducted in Japan between April and December 2021. Patient-reported satisfaction with ART was assessed using the Japanese version of the HIVTSQs. Binary logistic regression was used to identify factors associated with a low total HIVTSQs score., Results: A total of 679 patients completed the questionnaire. The median total HIVTSQs score was 58 (interquartile range: 52.5-64). In the multivariable logistic regression analyses, a total HIVTSQs score in the lowest quartile (indicating low satisfaction) was independently associated with twice- or thrice-daily regimens compared with single-tablet, once-daily regimens (adjusted odds ratio: 2.80, 95% confidence interval: 1.29-6.06, p = 0.009) and depression (adjusted odds ratio: 2.30, 95% confidence interval: 1.32-4.01, p = 0.003)., Conclusions: Satisfaction with the current ART regimen was high. Depression and twice- or thrice-daily ART regimen were associated with low HIVTSQ. Switching to a single-tablet, once-daily regimen may improve patient satisfaction in patients receiving twice- or thrice-daily regimens., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (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.)

Background: Information regarding the status of surgical antimicrobial prophylaxis (SAP) in Japanese hospitals is lacking. This study aimed to explore the status of SAP prescriptions for surgeries and adherence to Japanese SAP guidelines., Methods: From February to July 2020, a 1-day multicentre point prevalent survey was conducted at 27 hospitals in Aichi Prefecture, Japan. Patients prescribed SAP were included in this study. The appropriateness of the SAP was evaluated based on the guidelines for selection of antimicrobials and their duration. Surgery was defined as appropriate when all the items were appropriate., Results: A total of 728 patients (7.1 %; 728/10,199) received antimicrobials for SAP. Among them, 557 patients (76.5 %, 557/728) underwent the surgeries described in the guidelines. The overall appropriateness of all surgeries was 33.9 % (189/557). The appropriate selection of antimicrobial before/during and after surgery and their durations were 67.5 % (376/557), 67.5 % (376/557), and 43.3 % (241/557), respectively. The overall appropriateness ranged from 0 % (0/37, oral and maxillofacial surgery) to 58.7 % (88/150, orthopaedic surgery) and 27.7 % (36/130, community hospitals with 400-599 beds) to 47.2 % (17/36, specific hospitals). Cefazolin was the most prevalent antimicrobial prescribed before/during (55.5 %, 299/539), and after (45.1 %, 249/552) surgery. In total, 101 oral antimicrobials were prescribed postoperatively., Conclusions: SAP adherence by specific surgical fields and hospitals was shown in this study. Intensive intervention and repeated surveillance are necessary to improve SAP prescriptions in Japanese hospitals., Competing Interests: Declaration of competing interest All authors declare no conflicts of interest relevant to this article., (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.)

Background: Life-long immunosuppressive therapy after lung transplantation (LT) may lead to end-stage renal disease (ESRD), requiring renal replacement therapy (RRT). We aimed to investigate the characteristics and long-term outcomes of patients undergoing LT and requiring RRT., Methods: This study was a single-center, retrospective cohort study. The patients were divided into the RRT (n = 15) and non-RRT (n = 170) groups. We summarized the clinical features of patients in the RRT group and compared patient characteristics, overall survival, and chronic lung allograft dysfunction (CLAD)-free survival between the two groups., Results: The cumulative incidences of ESRD requiring RRT after LT at 5, 10, and 15 years were 0.8 %, 7.6 %, and 25.2 %, respectively. In the RRT group, all 15 patients underwent hemodialysis but not peritoneal dialysis, and two patients underwent living-donor kidney transplantation. The median follow-up period was longer in the RRT group than in the non-RRT group (P < 0.001). The CLAD-free survival and overall survival did not differ between the two groups. The 5-year survival rate even after the initiation of hemodialysis was 53.3 %, and the leading cause of death in the RRT group was infection., Conclusions: Favorable long-term outcomes can be achieved by RRT for ESRD after LT., Competing Interests: Declaration of competing interest The authors have no conflicts of interest., (Copyright © 2024 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Background: Although previous studies have demonstrated the advantages of early surgery for traumatic spinal cord injury (SCI), the appropriate surgical timing for cervical SCIs (CSCIs) without bone injury remains controversial. Here, we investigated the influence of relatively early surgery within 48 h of injury on the neurological recovery of elderly patients with CSCI and no bone injury., Methods: In this retrospective multicenter study, we reviewed data from 159 consecutive patients aged ≥65 years with CSCI without bone injury who underwent surgery in participating centers between 2010 and 2020. Patients were followed up for at least 6 months following CSCI. We divided patients into relatively early (≤48 h after CSCI, n = 24) and late surgery (>48 h after CSCI, n = 135) groups, and baseline characteristics and neurological outcomes were compared between them. Multivariate analysis was performed to identify factors associated with neurological recovery., Results: The relatively early surgery group demonstrated a lower prevalence of cardiac disease, poorer baseline American Spinal Injury Association (ASIA) impairment scale grade, and lower baseline ASIA motor score (AMS) than those of the late surgery group (P < 0.030, P < 0.001, and P < 0.001, respectively). Although the AMS was lower in the relatively early surgery group at 6 months following injury (P = 0.001), greater improvement in this score from baseline to 6-months post injury was observed (P = 0.010). Multiple linear regression analysis revealed that relatively early surgery did not affect postoperative improvement in AMS, rather, lower baseline AMS was associated with better AMS improvement (P < 0.001). Delirium (P = 0.006), pneumonia (P = 0.030), and diabetes mellitus (P = 0.039) negatively influenced postoperative improvement., Conclusions: Although further validation by future studies is required, relatively early surgery did not show a positive influence on neurological recovery after CSCI without bone injury in the elderly., (Copyright © 2023 The Japanese Orthopaedic Association. All rights reserved.)

Introduction: Ensuring adequate fetal oxygenation is an essential aim of fetal monitoring. The purpose of this study was to establish a basic technique for real-time measurement of blood oxygen saturation of the placenta by photoacoustic (PA) technique as a new fetal monitoring method., Methods: The hypoxia model established in our previous study was applied to 7 pregnant rabbits. Three phases were induced: normal phase, hypoxia phase, and recovery phase. Three methods were simultaneously used for real-time fetal monitoring: fetal heat rate (FHR) monitoring, oxygen saturation (SO 2 ) measurement by near-infrared spectroscopy (S N O 2 ), and placenta SO 2 measured by PA technique (S pl O 2 ). The maternal hypoxia was assessed by skin SO 2 measured by PA technique (SsO 2 ), and arterial blood SO 2 by blood gas analysis (SaO 2 )., Results: The average of S pl O 2 in normal phase was 52.6 ± 13.9 %. The averages of S N O 2 , S S O 2 , and S pl O 2 in the seven rabbits changed in parallel from the normal phase to hypoxia phase. In the recovery phase, the S pl O 2 rose in parallel with recovery of SaO 2 . There was lag in increase of the FHR compared to the change in the other values. In the detailed analysis of PA signals from the labyrinth and decidua, a unique change in oxygen saturation was seen in one case., Discussion: Results of this study showed that sensitivity of our novel PA technique in detecting tissue hypoxia was similar to near-infrared spectroscopy (NIRS). As an advantage, unlike NIRS, monitoring with PA technique was unaffected by ischemia and surface changes in oxygen saturation because of its higher spatial resolution. We conclude that PA technique provides more accurate information about fetal blood placenta than NIRS. Ultrasound imaging, combined with oxygen saturation monitoring by PA technique, would improve fetal monitoring and fetal diagnosis in the future., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Kiguna Sei Okawa reports financial support was provided by National Defense Medical College. Shinpei Okawa reports financial support was provided by Japan Society for the Promotion of Science. Miya Ishihara reports financial support was provided by Japan Society for the Promotion of Science, Grant-in Aid for Scientific Research on Innovative Areas., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: According to the results of the KEYNOTE-407 trial, pembrolizumab plus platinum-based chemotherapy is the standard of care for patients with previously untreated advanced squamous non-small-cell lung cancer (NSCLC). Ubenimex, a potent aminopeptidase inhibitor, is an oral drug with immunostimulatory and antitumor activities. We aim to assess the safety and efficacy of ubenimex in combination with pembrolizumab, nab-paclitaxel, and carboplatin in patients with previously untreated advanced squamous NSCLC., Patients and Methods: This prospective, single-arm, multicenter, phase II clinical trial is conducted to confirm the tolerability and efficacy of the tested drugs. Patients with previously untreated advanced squamous NSCLC will receive a predetermined daily dose of ubenimex orally plus 4 cycles of pembrolizumab, nab-paclitaxel, and carboplatin, followed by continuous administration of ubenimex and pembrolizumab for a maximum of 2 years. To confirm tolerability, the daily dose of ubenimex will begin at level 1 (30 mg), which will be increased to levels 2 (60 mg) and 3 (120 mg) according to the escalation criteria, with a standard 3 + 3 design for achieving the target dose-limiting toxicity rate of 33%. The efficacy, safety, and tolerability of ubenimex at the determined dose level will be analyzed. The primary endpoint of the efficacy evaluation will be the objective response rate assessed by an independent review committee., Conclusions: This is the first study to evaluate the efficacy and safety of ubenimex combined with pembrolizumab, nab-paclitaxel, and carboplatin in patients with previously untreated advanced squamous NSCLC. The results will help devise future treatment strategies., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Chemical O-glycosylation is a key step for the synthesis of sugar-containing molecules such as glycolipids. However, traditional carbohydrate chemistry is characterized by extensive use of protective groups, resulting in laborious manipulations and poor atom economy. Here, we present a protecting-group-free glycosylation strategy employing dibenzyloxy-1,3,5-triazin-2-yl glycosides (DBT-glycosides) as glycosyl donors. The DBT-glycosyl donors could be prepared directly through an alkaline nucleophilic substitution from unprotected sugars in aqueous media. The O-glycosylation of alcohols by using DBT-glycosyl donors has been carried out under mild hydrogenolytic conditions, affording the corresponding alkyl glycosides stereo-selectively in good yields., 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 Elsevier Ltd. All rights reserved.)

Competing Interests: The authors declare they have no conflict of interest.

Objective: We present the surgical approaches and short-term (2 years postoperative) results pertaining to circumferential minimally invasive spine surgery (CMIS) with lateral lumbar interbody fusion (LLIF) and percutaneous pedicle screw application for adult idiopathic scoliosis (AS)., Methods: We enrolled eight patients with AS who underwent CMIS (2018-2020) and examined the number of fused levels, upper instrumented vertebra, lower instrumented vertebra, number of LLIF-treated segments, number of preoperative intervertebral fusions, intraoperative blood loss, operative time, various spinopelvic parameters, Oswestry Disability Index, low back pain, visual analog scale (VAS), leg VAS, bone fusion rate, and perioperative complications., Results: The upper instrumented vertebra was T4, T7, T8, and T9 in two cases, whereas lower instrumented vertebra was the pelvis in all the cases. The average numbers of fixed vertebrae and segments that underwent LLIF were 13.3 ± 2.0 and 4.6 ± 0.7, respectively. All spinopelvic parameters improved significantly after surgery (thoracic kyphosis: P < 0.05, lumbar lordosis, cobb angle, pelvic tilt, pelvic incidence-lumbar lordosis, sagittal vertical axis: P < 0.001), and good alignment was achieved. The Oswestry Disability Index and VAS scores improved significantly (P < 0.001). The bone fusion rates achieved in the lumbosacral and thoracic spine were 100% and 88%, respectively. Only 1 patient showed postoperative coronal imbalance., Conclusions: The 2-year postoperative results of CMIS for AS were good, and spontaneous bone fusion was confirmed in the thoracic spine without bone grafting. In this procedure, sufficient intervertebral release with LLIF and a percutaneous pedicle screw device translation technique enabled adequate global alignment correction. Therefore, correcting the global imbalance of the coronal and sagittal planes is more crucial than correcting scoliosis., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Curved periacetabular osteotomy (CPO) is indicated for patients with developmental dysplasia of hip (DDH) to prevent progressive osteoarthritis. Patients with DDH have not only lateral acetabulum dysplasia but also anterior and posterior dysplasia. The full circumference acetabular coverage angle (ACA) of the femoral head should be evaluated preoperatively. This study aimed to determine the full circumference ACA in the patients with DDH before and after CPO compared with the coverage in normal patients., Methods: Twenty-three patients (a total of 24 hips) with DDH undergoing CPO between February 2006 and March 2014 were included in this study. The normal group was defined as the normal side in patients with unilateral osteonecrosis of the femoral head (ONFH) and the non-collapsed femoral head side in patients with bilateral ONFH. Pre- and postoperative hip functions were evaluated using the Japanese Orthopedic Association (JOA) hip score. ACA was measured using pre- and postoperative three-dimensional computed tomography (3DCT) and described as a clock using a radar chart. The ACA of the normal group was evaluated in the same manner as that for patients who underwent CPO. The ACA before CPO was compared with the ACA after CPO, the ACA before CPO was compared with that of the normal group and the ACA after CPO was compared with that of the normal group at each location., Results: The mean JOA hip scores improved significantly from 69 preoperatively to 88 postoperatively. The superior, posterior, and anterior ACA after CPO significantly increased and the inferior ACA decreased compared with ACA before CPO. The superior, posterior, and anterior ACA before CPO were significantly smaller than ACA in the normal group. The ACA after CPO were similar to the normal group., Conclusions: CPO improved the anterosuperior coverage of the femoral head but reduced its inferior coverage. The radar chart could visualize acetabulum full circumference and was useful for three-dimensional pre-postoperative evaluation., Competing Interests: Declaration of competing interest None declared., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: Reconstruct compound median nerve action currents using magnetoneurography to clarify the physiological characteristics of axonal and volume currents and their relationship to potentials., Methods: The median nerves of both upper arms of five healthy individuals were investigated. The propagating magnetic field of the action potential was recorded using magnetoneurography, reconstructed into a current, and analyzed. The currents were compared with the potentials recorded from multipolar surface electrodes., Results: Reconstructed currents could be clearly visualized. Axonal currents flowed forward or backward in the axon, arcing away from the depolarization zone, turning about the subcutaneous volume conductor, and returning to the depolarization zone. The zero-crossing latency of the axonal current was approximately the same as the peak of its volume current and the negative peak of the surface electrode potential. Volume current waveforms were proportional to the derivative of axonal ones., Conclusions: Magnetoneurography allows the visualization and quantitative evaluation of action currents. The currents in axons and in volume conductors could be clearly discriminated with good quality. Their properties were consistent with previous neurophysiological findings., Significance: Magnetoneurography could be a novel tool for elucidating nerve physiology and pathophysiology., (Copyright © 2023 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Background: Poor health-related quality of life (HRQL) at the registration for lung transplantation is related to waitlist mortality. We investigated the relationship between 1-year change in HRQL and subsequent outcomes in patients waitlisted for lung transplantation., Methods: In a 5-year longitudinal study, we analyzed the factors related to waitlist mortality in 197 lung transplant patients registered on the Japan Organ Transplant Network. HRQL was assessed using St. George's Respiratory Questionnaire (SGRQ), and factors related to changes in SGRQ scores were evaluated after 1 year. We assessed the relationship between the 1-year change in SGRQ score and subsequent mortality or hospitalization., Results: Among 197 patients, 108 remained waitlisted during the first-year assessment. During the median follow-up period of 469 d, 28 patients died, and 54 underwent lung transplantation. Univariate Cox proportional hazards analysis revealed that the changes in all components and total score of the SGRQ after 1 year were associated with waitlist mortality (p < 0.05). Stepwise multivariate analysis revealed that the 1-year changes in SGRQ scores were significantly related to waitlist mortality. Forty-three patients with worsened HRQL after 1 year had higher likelihoods of hospitalization (p = 0.038) and mortality (p = 0.026) after 1 and 4 years of follow-up, respectively, than 61 patients without worsened HRQL., Conclusions: Patients with worsened health status during the first year after registration had higher likelihoods of hospitalization and mortality after 1 and 4 years of follow-up, respectively, than those without worsened HRQL. Strategies to improve health status while waiting are needed to reduce waitlist hospitalization or mortality., Competing Interests: Conflict of Interest The authors have no conflicts of interest., (Copyright © 2023 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Objective: The mechanism underlying the generation of P9 far-field somatosensory evoked potentials (SEPs) is unresolved. Accordingly, we used magnetoneurography to visualize the current distribution in the body at the P9 peak latency and elucidate the origin of P9 generation., Methods: We studied five healthy male volunteers without neurological abnormalities. We recorded far-field SEPs after median nerve stimulation at the wrist to identify the P9 peak latency. Using magnetoneurography, we recorded the evoked magnetic fields in the whole body under the same stimulus conditions as the SEP recording. We analyzed the reconstructed current distribution at the P9 peak latency., Results: At the P9 peak latency, we observed the reconstructed current distribution dividing the thorax into two parts, upper and lower. Anatomically, the depolarization site at the P9 peak latency was distal to the interclavicular space and at the level of the second intercostal space., Conclusions: By visualizing the current distribution, we proved that P9 peak latency originates in the change in volume conductor size between the upper and lower thorax., Significance: We clarified that magnetoneurography analysis is affected by the current distribution due to the junction potential., (Copyright © 2023 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Background: The impact of shorter door-to-balloon (DTB time on long-term outcomes in ST-segment elevation myocardial infarction (STEMI treated with primary percutaneous coronary intervention (PPCI has not been fully elucidated., Methods: We investigated 3283 consecutive patients with acute myocardial infarction selected from a prospective, nationwide, multicenter registry (J-MINUET database comprising 28 institutions in Japan between July 2012 and March 2014. Among the study population, we analyzed 1639 STEMI patients who had PPCI within 12 h of onset. Patients were stratified into four groups (DTB time < 45 min, 45-60 min, 61-90 min, >90 min. The primary endpoint was a composite of all-cause death, non-fatal MI, non-fatal stroke, cardiac failure, and urgent revascularization for unstable angina up to 3 years. We performed landmark analysis for incidence of the primary endpoint from 31 days to 3 years among the four groups., Results: The primary endpoint rate from 31 days to 3 years increased significantly and time-dependently with DTB time (10.2 % vs. 15.3 % vs. 16.2 % vs. 19.3 %, respectively; log-rank p = 0.0129. Higher logarithm-transformed DTB time was associated with greater risk of a primary endpoint from 31 days to 3 years, and the increased number of adverse long-term clinical outcomes persisted even after adjusting for other independent variables., Conclusion: Shorter DTB time was associated with better long-term clinical outcomes in STEMI patients treated with PPCI in contemporary clinical practice. Further efforts to shorten DTB time are recommended to improve long-term clinical outcomes in STEMI patients., Trial Registration: UMIN Unique trial Number: UMIN000010037., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. Yukio Ozaki has received several research grants from Bayer Yakuhin, Ltd., Research Institute for Production Development, Daiichi-Sankyo Co., Ltd., and Dainippon Sumitomo Co., Ltd. Kazuo Kimura has received honoraria from AstraZeneca, Toa Eiyo Ltd., MSD K.K., Bayer Yakuhin, Ltd., and Daiichi-Sankyo Co., Ltd., and has received several research grants from MSD K.K., Daiichi-Sankyo Co., Ltd., Ono Pharmaceutical Co., Pfizer Japan Inc., Bayer Yakuhin Ltd., Takeda Pharmaceutical Co., Ltd., Boehringer Ingelheim Japan, Tanabe Mitsubishi, and Astellas Pharma Inc. Wataru Shimizu has received honoraria from Daiichi-Sankyo Co., Ltd., Boehringer Ingelheim Japan, Bayer Yakuhin Ltd., Bristol, and Ono Pharmaceutical Co., and has received several research grants from Daiichi-Sankyo Co., Ltd., Boehringer Ingelheim Japan, Ono Pharmaceutical Co., Otsuka Pharmaceutical Co., Eisai Co., Mitsubishi Tanabe Pharma Co., Asterllas Pharma Inc., and St Jude Medical. Yoshihiko Saito has received honoraria from Otsuka Pharmaceutical Co., Ltd., Kowa Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Mitsubishi Tanabe Pharma Co., Pfizer Japan Inc., and Novartis Pharma K.K., and has received several research grants from Takeda Pharmaceutical Co., Ltd., Teijin Pharma Ltd., Ono Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Co., Eisai Co., Ltd., ZERIA Pharmaceutical Co., Ltd., Shionogi & Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Dainippon Sumitomo Pharma Co., Ltd., Kyowa Hakko Kirin Co., Ltd., Astellas Pharma Inc., Daiichi Sankyo Co., Ltd., and Boston Scientific Japan K.K. Toshiaki Mano has received a research grant from Abbot Vascular Japan. Kengo Tanabe has received honoraria from Abbot Vascular Japan, Mitsubishi Tanabe Pharma Co., and Daiichi Sankyo Co., Ltd. and has received several research grants from Kaneka and Terumo. Kenichi Tsujita has received honoraria from Amgen Astellas Bio Pharma K.K., Bayer Yakuhin, Ltd., Daiichi Sankyo Co., Ltd., MSD K.K., and Sanofi K.K., and has received several research grants from AstraZeneca K.K., Astellas Pharma Inc., Bayer Yakuhin, Ltd., Boehringer Ingelheim Japan, Boston Scientific Japan K.K., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Eisai Co., Ltd., Kowa Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Co., MSD K.K., Pfizer Japan Inc., Sanofi K.K., Shionogi & Co., Ltd., and Takeda Pharmaceutical Co., Ltd. Masaharu Ishihara has received honoraria from Bayer Yakuhin Ltd., MSD K.K., Astra Zeneca, and Astellas Pharma Inc. and has received several research grants from Abbott Vascular Japan, Boston Scientific Japan K.K., Sanofi K.K., MSD K.K., Astellas Pharma Inc., Bayer Yakuhin Ltd., Pfizer, Daiichi Sankyo Co., Ltd., MID, and Goodman. No funders played any role in this study., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Platelet glycoprotein (GP) Ibα is the major ligand-binding subunit of the GPIb-IX-V complex that binds von Willebrand factor. GPIbα is heavily glycosylated, and its glycans have been proposed to play key roles in platelet clearance, von Willebrand factor binding, and as target antigens in immune thrombocytopenia syndromes. Despite its importance in platelet biology, the glycosylation profile of GPIbα is not well characterized., Objectives: The aim of this study was to comprehensively analyze GPIbα amino acid sites of glycosylation (glycosites) and glycan structures., Methods: GPIbα ectodomain that was recombinantly expressed or that was purified from human platelets was analyzed by Western blot, mass spectrometry glycomics, and mass spectrometry glycopeptide analysis to define glycosites and the structures of the attached glycans., Results: We identified a diverse repertoire of N- and O-glycans, including sialoglycans, Tn antigen, T antigen, and ABO(H) blood group antigens. In the analysis of the recombinant protein, we identified 62 unique O-glycosites. In the analysis of the endogenous protein purified from platelets, we identified 48 unique O-glycosites and 1 N-glycosite. The GPIbα mucin domain is densely O-glycosylated. Glycosites are also located within the macroglycopeptide domain and mechanosensory domain., Conclusions: This comprehensive analysis of GPIbα glycosylation lays the foundation for further studies to determine the functional and structural roles of GPIbα glycans., Competing Interests: Declaration of competing interests M.A.H. received consulting fees from Dova Pharmaceuticals, Janssen Pharmaceuticals, and Sonder Capital. C.R.B. is a co-founder and scientific advisory board member of Lycia Therapeutics, Palleon Pharmaceuticals, Enable Bioscience, Redwood Biosciences (a subsidiary of Catalent), OliLux Bio, Grace Science LLC, and InterVenn Biosciences. S.A.M. is a consultant for InterVenn Biosciences and Arkuda Therapeutics. S.A.M. and C.R.B. are inventors on a Stanford patent related to the use of mucinases for glycoproteomic analysis. The remaining co-authors have no conflicts of interest to disclose., (Copyright © 2023 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)

Background: Beta-blockers are associated with several clinical benefits in patients with reduced left ventricular ejection fraction (REF) after acute myocardial infarction (AMI), such as lower rates of mortality, recurrence of myocardial infarction, and heart failure. However, the long-term prognosis of beta-blockers has rarely been investigated in patients with non-REF after AMI. This study aimed to investigate the clinical benefits of beta-blockers in these patients., Methods: A total of 3281 consecutive patients who were hospitalized within 48 h after AMI were registered in the J-MINUET study. Patients who underwent primary percutaneous coronary intervention (PCI) and had a left ventricular ejection fraction ≥40 % were enrolled, and patients who died during admission were excluded. Included patients were divided into two groups according to the prescription of beta-blockers at discharge. Their characteristics and clinical outcomes were compared., Results: The number of AMI patients treated with beta-blockers was 1353 (70.4 %). Patients who received beta-blockers were younger and had a higher incidence of hypertension, dyslipidemia, and ST-segment elevation myocardial infarction than those who did not receive beta-blockers. The peak creatine kinase level after primary PCI was significantly higher in patients who received beta-blockers. These patients also had a lower incidence of a composite of all-cause death, myocardial infarction, and stroke compared to those that did not receive beta-blockers (7.3 % vs. 11.9 %, p = 0.001). Multivariate analysis showed that beta-blocker use was an independent factor for better clinical outcomes., Conclusions: The J-MINUET study revealed the clinical benefit of beta-blockers in AMI patients with non-REF after primary PCI., Competing Interests: Declaration of competing interest Yoshihiko Saito: grants from MEXT KAKENHI Grant Number JP19155855, grants from Health Labour Sciences Research Grant Number 19189094, grants from Health Labour Sciences Research Grant Number 17933459, grants from AMED under Grant Number JP19ek0210080, grants from AMED under Grant Number JP19ek0210118, grants from AMED under Grant Number JP19ek0210121, grants from AMED under Grant Number JP19ek0210115, grants from AMED under Grant Number JP19ek0109367, grants from AMED under Grant Number JP19ek0109406, grants from AMED under Grant Number JP19km0405009, during the conduct of the study; grants and personal fees from Otsuka Pharmaceutical Co., Ltd., grants and personal fees from Ono Pharmaceutical Co., Ltd., grants from Takeda Pharmaceutical Co., Ltd., grants and personal fees from Daiichi Sankyo Co., Ltd., grants and personal fees from Mitsubishi Tanabe Pharma Corporation, grants and personal fees from Bristol-Myers Squibb Company, grants from Actelion Pharmaceuticals Japan Ltd., grants from Kyowa Kirin Co., Ltd., grants and personal fees from Kowa Pharmaceutical Co., Ltd., grants from Shionogi & Co., Ltd., grants from Dainippon Sumitomo Pharma Co., Ltd., grants and personal fees from Teijin Pharma Ltd., grants from Chugai Pharmaceutical Co., Ltd., grants from Eli Lilly Japan K.K., grants from Nihon Medi-Physics Co., Ltd., grants, personal fees and other from Novartis Pharma K.K., grants and personal fees from Pfizer Japan Inc., grants from Fuji Yakuhin Co., Ltd., grants, personal fees and other from Bayer Yakuhin, Ltd., other from Amgen Astellas BioPharma K.K., other from Actelion Pharmaceuticals Japan Ltd., other from Roche Diagnostics K.K., personal fees from Alnylam Japan K.K., personal fees from AstraZeneca K.K., personal fees from Tsumura & Co., personal fees from Toa Eiyo Ltd., personal fees from Nippon Shinyaku Co., Ltd., personal fees from Nippon Boehringer Ingelheim Co., Ltd., personal fees from Mochida Pharmaceutical Co., Ltd. Kengo Tanabe: personal fees from Abbott Vascular, personal fees from Boston Scientific, personal fees from Medtronic, personal fees from Terumo, personal fees from Kaneka, from Japan Lifeline. Hisao Ogawa: personal fees from Towa Pharmaceutical Co., Ltd., personal fees from Bristol-Meyers Squibb Co., Ltd., personal fees from Pfizer Co., Ltd., personal fees from Toa Eiyo Co., Ltd., personal fees from Bayer Yakuhin Co., Ltd., personal fees from Novartis Pharma Co., Ltd. Masaharu Ishihara: grants from Abbott Vascular Japan Co., Ltd., grants and personal fees from Amgen Astellas Bio Pharma K.K., grants from Astellas Pharma Inc., grants and personal fees from Bayer Yakuhin, Ltd., grants from Boston Scientific Japan K.K., grants and personal fees from Daiichi Sankyo Company, Limited, grants from Fukuda Denshi Co., Ltd., grants from Goodman Co., LTD., grants from Japan Lifeline Co., Ltd., grants from Kowa Pharmaceutical Co., Ltd., grants from MID, Inc., grants from Mitsubishi Tanabe Pharma Corporation, grants and personal fees from MSD K.K., grants from Nippon Shinyaku Co., Ltd., grants from Nipro Corporation, grants from Otsuka Pharmaceutical Co., Ltd., grants from Ono Pharmaceutical Co., Ltd., grants from Pfizer Japan Inc., grants and personal fees from Sanofi K.K., grants from Shionogi & Co., Ltd., grants from Sumitomo Dainippon Pharma Co., Ltd., grants from Takeda pharmaceutical Co. Ltd., grants from Teijin Pharma Ltd., grants from Terumo Corporation, grants from Abbott Medical Japan Co., Ltd., grants from Medtronic Japan Co., Ltd., grants from Nippon Boehringer Ingelheim Co., Ltd., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Breast cancer is a complex heterogeneous disease with unique molecular subtypes, which limits the development of optimized treatment strategies for each subtype. Cancer gene therapy and potential therapeutics for advanced/refractory cancers can be promising for breast cancer. Combining tumor-tropic lipid nanoparticles (LNPs) and inducible caspase-9 (iC9) mRNA, we aimed to develop a novel treatment strategy for refractory breast cancer. LNP's anti-tumor effects were tested in vitro in three breast cancer cell lines: MDA-MB231, SKBR3, and MCF-7. Tumor cells were treated with LNPs encapsulated with eGFP or iC9 mRNA and chemical inducers of dimerization (CID). Apoptosis-related genes were evaluated by reverse transcriptase quantitative PCR. LNPs could efficiently deliver encapsulated GFP mRNA to all three cancer cell lines (>80% GFP expression. in target cells). Furthermore, LNPs encapsulated with iC9 mRNA (iC9-LNPs) and CID showed cytotoxic activity against all cancer cell lines in vitro. Interestingly, susceptibility to iC9 gene therapy was heterogeneous among cancer cell lines. iC9-LNPs with CID-induced potent cytotoxic effects against SKBR3 and MDA-MB231 cells, but only a mild cytotoxic effect on MCF7 cells. Quantification of apoptosis-related genes suggested that a high BAX/Bcl-2 ratio might be associated with iC9-LNP + CID susceptibility. Thus, cancer gene therapy using iC9-LNPs and CID could be a promising alternative for the treatment of breast cancers, especially for aggressive breast cancers., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Yozo Nakazawa reports financial support was provided by Toshiba Corporation. Yozo Nakazawa reports a relationship with Toshiba Corporation that includes: funding grants. Mitsuko Sugano-Ishihara has patent #PCT/IB2020/058307 pending to Shoji Saito, Eiichi Akahoshi, and Yozo Nakazawa. Eiichi Akahoshi and Mitsuko Sugano-Ishihara are employees of Toshiba Corporation., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Percutaneous pedicle screw (PPS) placements in the lumbosacral spine generally rely on fluoroscopy at the expense of radiation exposure. Our accumulated experience in open PS placements without fluoroscopic guidance realized a consistent shift toward PPS insertion with newly developed devices, which require neither fluoroscopy nor navigation. We wish to report our new technique and evaluations of its accuracy., Methods: Our equipment consisted of a pedicle targeting tool to identify and escort the cannulated awl to the correct starting point for cortical bone perforation and a cannulated awl-probe system with a guidewire to maintain the optimal position throughout the subsequent surgical steps. The surgeon could advance the blunt-tipped probe searching for the cancellous bone track using tactile feedback as experienced in open techniques. A 2-year period of transition from a free-hand (1169 screws in 286 patients) to the new PPS technique (1933 screws in 413 patients) allowed accuracy comparison between the two procedures using postoperative CT scans., Results: Compared with the open-group, the PPS-group showed a lower rate of fully contained intrapedicular PS placements at L1 through S1, as a whole (90.7% vs 85.4%), but not at L4 through S1 (89.9% vs 90.2%). Less-accurate PPS placements at upper than lower lumbar spines in part reflect intended pedicle perforations laterally as a trade-off for avoiding facet violation immediately above the most cephalad screw. The PPS-group also had a higher incidence of PS-related transient nerve root complications (0% vs 1.7%). These values for the PPS-group, however, fell within those previously reported for free-hand or fluoroscopy techniques., Conclusions: Our new PPS technique, although useful for eliminating the potential risk of repeated radiation exposure, fell short of reaching the accuracy of the free-hand technique. Nerve integrity monitoring with PS stimulation, which we currently use, will help further improve the technical precision., Study Design: Original Article. The study was approved by our institutional review boad (2,019,231)., Competing Interests: Declaration of competing interest The authors declare that no benefits in any form that are related directly or indirectly to the subject on this manuscript have been or will be received from a commercial party., (Copyright © 2021 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.)

Objective: The management of cervical spine injuries in the elderly is often complicated by the presence of multiple medical comorbidities, and it is not uncommon for preoperative testing to reveal other conditions that require the postponement of surgery. However, the factors that affect the waiting time from injury to surgery have not been clarified. The purpose of this multicenter database study was to analyze the clinical features and identify the factors affecting the number of days waited between injury and surgery in elderly patients with a cervical spine injury., Methods: We retrospectively reviewed the case histories of 1512 Japanese patients with a cervical spinal injury, who were seen at 33 institutions. After excluding patients who were not initially receiving a surgery for cervical spinal injury, 694 patients were ultimately analyzed. Based on a multivariate mixed model, we determined the factors related to the number of days from injury to surgery., Results: The mean time from injury to surgery was 12.3 days. Multivariate analysis revealed delays of 10.7 days for a renal disorder, 7.3 days for anticoagulant use, and 15.2 days for non-surgical thoracolumbar fracture as factors prolonging wait time. In contrast, a C3 or lower spine injury was significantly associated with a shortening of 9.5 days to surgery., Conclusions: This multicenter database study identified several factors influencing the time between injury and cervical spine surgery in elderly patients. While renal impairment, anticoagulant use, and non-surgical thoracolumbar fracture may increase the number of days to surgery, trauma to C3 or lower may expedite surgical treatment., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: High lipoprotein (a) [Lp (a)] levels are associated with worse long-term outcomes in patients undergoing percutaneous coronary intervention (PCI). However, there are limited studies investigating association between Lp (a) levels and long-term outcomes in the era of new generation drug-eluting stents (DES)., Methods: A total of 495 patients with available data on Lp (a) who underwent PCI for de novo lesions with new generation DES were enrolled between 2013 and 2017. The primary endpoint was the major adverse cardiovascular event (MACE), which was defined as a composite of cardiac death, myocardial infarction, stent thrombosis, clinically driven target lesion revascularization, and revascularization for new lesions during 3 years. Patients were divided into 2 groups according to the Lp (a) level: high Lp (a) group (≥30 mg/dL: n = 109) and low Lp (a) group (30 mg/dL>: n = 386). Multivariate Cox regression analysis was performed to identify the predictors for 3-year MACE., Results: The incidence of 3-year MACE was significantly higher in high Lp (a) group than low Lp (a) group (33.0% vs. 15.9%, p < 0.001). Multivariable analysis showed that Lp (a) level of ≥30 mg/dL was an independent predictor for 3-year MACE (HR 2.01, 95%CI 1.30-3.11, p = 0.002)., Conclusion: High Lp (a) level was associated with worse long-term outcome even in the era of new generation DES., Competing Interests: Declaration of competing interest The authors declare that there is no conflict of interest., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Introduction: Because of thrombocytopenia, linezolid treatment tends to be stopped before the completion of therapy for complicated infections that require prolonged antimicrobial administration. In contrast, tedizolid shows a favorable hematologic profile. The primary end-point of this study was to evaluate the efficacy of switching treatment to tedizolid in patients who developed thrombocytopenia during linezolid therapy., Methods: This retrospective study was conducted in patients with vertebral osteomyelitis (VO) caused by antibiotic-resistant Gram-positive bacteria. Treatment failure was defined as the reappearance of infection signs within 2 weeks after stopping tedizolid and discontinuation of tedizolid because of continued thrombocytopenia or other adverse effects., Results: Eight patients with native VO (n = 3) and postoperative VO (n = 5) were included in the study. The causative organisms were MRSA in all patients except one. Platelet counts decreased from 35.2 ± 11.5 × 10 4 /mm 3 to 17.8 ± 6.2 × 10 4 /mm 3 during linezolid therapy and improved without washout period in all patients after switching to tedizolid on days 5-7 (28.6 ± 4.9 × 10 4 /mm 3 , p = 0.002). Tedizolid therapy was completed and treatment failure was not observed in any patient. The duration of treatment was 20.0 ± 11.2 days for linezolid and 30.3 ± 9.5 days for tedizolid (total, 50.3 ± 10.7 days). One patient died because of underlying disease, and there was no recurrence in the remaining 7 patients (median follow-up 501 days)., Conclusions: Switching therapy to tedizolid improved thrombocytopenia that occurred during linezolid therapy, and it enabled the completion of therapy for VO patients., (Copyright © 2022 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Sperm cryopreservation is an effective method of preserving male fertility in humans, as well as domestic and experimental animals. However, various factors such as ice crystal formation, osmotic stress, and oxidative stress, negatively influence the motility and viability of post-thawed spermatozoa. Betaine, which works as an osmoprotectant is known to work as a nontoxic cryoprotectant. However, the protective effects during mouse sperm cryopreservation are still unclear. Thus, the purpose of this study was to investigate whether betaine has protective effects during the process of mouse sperm cryopreservation. In this study, betaine was found to be effective in maintaining sperm motility during the freezing procedure and 1% (85.4 mM) betaine was identified as the optimal concentration to be added to cryopreservation solutions. It was also found that betaine improves the integrity of the plasma membranes of sperm tails, suggesting that betaine has a positive effect on sperm motility., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Accurate cup placement during total hip arthroplasty (THA) is difficult because the intraoperative pelvic position changes even in supine patient position. We developed a device known as HipPointer; it corrects pelvic rotation and creates a functional pelvic plane as a reference. The aim of this study was to determine the device placement accuracy and investigate causes of error., Material and Methods: HipPointer was used for cup placement in 353 hips of 308 patients who underwent direct-anterior-approach THA in supine position. The mean age at surgery and body mass index were 63.9 (17-90) years and 24.9 (16.6-42.0) kg/m 2 , respectively. The mean observation period was 40.5 (12-73) months. To investigate the accuracy of HipPointer, preoperative planning and postoperative cup placement angles relative to the functional pelvic plane were evaluated using a three-dimensional analysis software, and absolute errors were determined., Results: The means ± standard deviations of radiographic inclination (RI) and radiographic anteversion (RA) were 40.2 ± 3.0° and 15.8 ± 3.6°, respectively. The absolute errors of RI and RA were 2.2 ± 2.0° and 2.7 ± 2.3°, respectively. The ratio of the cup placement angle for which both RI and RA are ≤10° in the target zone was 99% (350/353 hips), and the ratio of the absolute errors for which both RI and RA are ≤5° was 80.4% (284/353 hips)., Conclusions: HipPointer is simple in structure, easy to use, and useful for direct-anterior-approach THA in supine position. It provides good cup placement accuracy.

Introduction: Because of its lower risk of renal toxicity than vancomycin, teicoplanin is the preferred treatment for methicillin-resistant Staphylococcus aureus infection in patients undergoing continuous venovenous haemodiafiltration (CVVHDF) in whom renal function is expected to recover. The dosing regimen for achieving a trough concentration (C min ) of ≥20 μg/mL remains unclear in patients on CVVHDF using the low flow rate adopted in Japan., Methods: The study was conducted in patients undergoing CVVHDF with a flow rate of <20 mg/kg/h who were treated with teicoplanin. We adopted three loading dose regimens for the initial 3 days: the conventional regimen, a high-dose regimen (four doses of 10 mg/kg), and an enhanced regimen (four doses of 12 mg/kg). The initial C min was obtained at 72 h after the first dose., Results: Overall, 60 patients were eligible for study inclusion. The proportion of patients achieving the C min target was significantly higher for the enhanced regimen than for the high-dose regimen (52.9% versus 8.3%, p = 0.003). In multivariate analysis, the enhanced regimen (odds ratio [OR] = 39.93, 95% confidence interval [CI] = 5.03-317.17) and hypoalbuminaemia (OR = 0.04, 95% CI = 0.01-0.44) were independent predictors of the achievement of C min ≥ 20 μg/mL., Conclusions: An enhanced teicoplanin regimen was proposed to treat complicated or invasive infections by methicillin-resistant Staphylococcus aureus in patients receiving CVVHDF even with a low flow rate., (Copyright © 2021 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Percutaneous coronary intervention (PCI) is a standard treatment in patients with stable coronary artery disease (CAD); however, periprocedural myocardial infarction (PMI) remains a common complication of PCI. Aggressive lipid-lowering therapy with statin has shown to reduce the incidence of PMI by preventing coronary microvascular dysfunction. It is unclear whether evolocumab, a potent lipid-lowering agent, could diminish microvascular damage after PCI. The EVOCATION trial (jRCTs051180022) is a multicenter, randomized, open-label, active-controlled, parallel-group, exploratory, investigator-initiated clinical study to evaluate whether pretreatment with evolocumab could decrease the index of microvascular resistance (IMR) after PCI in patients with stable CAD. This study population consists of 100 patients with stable CAD who will undergo PCI and have high low-density lipoprotein cholesterol levels despite administration of maximum tolerated dose of statins for at least 2 weeks. Eligible patients are randomized in a 1:1 ratio to receive either evolocumab 140 mg every 2 weeks in addition to standard of care treatment or standard of care treatment only for 2-6 weeks before PCI. The primary endpoint is IMR after PCI. The EVOCATION trial will evaluate whether pretreatment with evolocumab reduces periprocedural microvascular damage in patients with stable CAD undergoing PCI., (Copyright © 2021. Published by Elsevier Ltd.)

Background: Cerebral arteriovenous malformations (cAVMs) represent tangles of abnormal vasculature without intervening capillaries. High-pressure vascular channels due to abnormal arterial and venous shunts can lead to rupture. Multiple pathways are involved in the pathobiology of cAVMs including inflammation and genetic factors such as KRAS mutations. Neutrophil release of nuclear chromatin, known as neutrophil extracellular traps (NETs), plays a multifunctional role in infection, inflammation, thrombosis, intracranial aneurysms, and tumor progression. However, the relationship between NETs and the pathobiology of cAVMs remains unknown. We tested whether NETs play a role in the pathobiology of cAVMs., Methods: We analyzed samples from patients who had undergone surgery for cAVM and immunohistochemically investigated expression of citrullinated histone H3 (CitH3) as a marker of NETs. CitH3 expression was compared among samples from cAVM patients, epilepsy patients, and normal human brain tissue. Expressions of thrombotic and inflammatory markers were also examined immunohistochemically in samples from cAVM patients., Results: Expression of CitH3 derived from neutrophils was observed intravascularly in all cAVM samples but not other samples. Nidi of AVMs showed migration of many Iba-I-positive cells adjacent to the endothelium and endothelial COX2 expression, accompanied by expression of IL-6 and IL-8 in the endothelium and intravascular neutrophils. Unexpectedly, expression of CitH3 was not necessarily localized to the vascular wall and thrombus., Conclusions: Our results offer the first evidence of intravascular expression of NETs, which might be associated with vascular inflammation in cAVMs., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: This study evaluated the mechanism of decline in coronary pressure from the proximal to the distal part of the coronary arteries in the left anterior descending (LAD) versus the right coronary artery (RCA) from the insight of coronary hemodynamics using wave intensity analysis (WIA)., Methods: Twelve patients with angiographically normal LAD and RCA were prospectively enrolled. Distal coronary pressure, mean aortic pressure, and average peak velocity were measured at 4 different positions: 9, 6, 3, and 0 cm distal from each coronary ostium., Results: The distal-to-proximal coronary pressure ratio during maximum hyperemia gradually decreased in proportion to the distance from the ostium (0.92±0.03 and 0.98±0.03 at 9 cm distal to the LAD and RCA ostium). WIA showed the dominant forward-traveling compression wave gradually decreased and the backward-traveling suction wave gradually decreased in proportion to the decrease in coronary pressure through the length of the non-diseased LAD but not the RCA., Conclusions: The pushing wave and suction wave intensities on WIA were diminished in proportion to the distance from the ostium of the LAD despite the wave intensity not changing across the length of the RCA, which may lead to gradual intracoronary pressure drop in the angiographically normal LAD., Competing Interests: Declaration of Competing Interest The authors declare that there is no conflict of interest., (Copyright © 2021. Published by Elsevier Ltd.)

Competing Interests: Declaration of interests We declare no competing interests.

We report a case of prolonged motivational deficit as a sequela of high altitude cerebral edema (HACE), the most severe form of neuropsychiatric dysfunction arising from traveling to high altitude. Magnetic resonance imaging of the brain showed hyperintense lesions in the globi pallidi bilaterally on T2-weighted images. Single-photon emission computed tomography showed hypoperfusion in dorsolateral and orbital prefrontal cortices bilaterally and in the anterior cingulate cortex. This case suggests that a prolonged motivational deficit can occur in patients with HACE. The case may also suggest that HACE can cause network disturbances between the prefrontal cortex and the globi pallidi., (Copyright © 2020 Wilderness Medical Society. Published by Elsevier Inc. All rights reserved.)

Background: Cardiac implantable electronic device-detected atrial high-rate episodes (AHREs) have been reported to be associated with thromboembolic risks. The present study aimed to investigate the association of echocardiographic and clinical parameters with the occurrence of AHREs in patients with a dual-chamber pacemaker (PMI)., Methods: One hundred forty-seven patients (76 males, 75.2 ± 8.9 years) who did not show atrial tachyarrhythmia before the implantation of the PMI were studied. Diastolic wall strain (DWS) and other measurements were assessed during sinus rhythm using transthoracic echocardiography before the PMI. DWS was calculated from the M-mode echocardiographic measurement of the left ventricular (LV) posterior wall thickness at end-systole (PWs) and end-diastole (PWd), and DWS was defined as (PWs-PWd) / PWs., Results: AHREs (defined as AHREs duration >6 min and atrial rate >180 bpm) were detected in 50 / 147 patients during follow up (38.3 ± 13.8 months). Patients in the AHREs group had reduced DWS (0.29 ± 0.07 vs. 0.39 ± 0.06, p < 0.0001), larger left atrial volume index, thicker LV posterior diameter, higher rate of patients taking β-blocker / diuretics, and higher prevalence of sinus node dysfunction. On multivariable analysis, only DWS was independently associated with AHREs. Patients with reduced DWS (<0.33) had a higher risk of incidences of AHREs., Conclusion: LV stiffness assessed by DWS was associated with AHREs in patients with a PMI., (Copyright © 2020. Published by Elsevier Ltd.)

Iron is a necessary element for life; however, excess iron leads to oxidative stress by the Fenton reaction. Iron deficiency is prevalent in patients with heart failure, while iron overload is associated in the pathogenesis of atherosclerosis. These findings suggest the "iron paradox" in cardiovascular diseases. Iron metabolism in cardiovascular diseases is complex, and the mechanisms regulating systemic and cellular iron metabolism in cardiovascular diseases remain completely unknown. In this review, we focus on the role of iron in cardiovascular diseases., (Copyright © 2020 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Background: The prevalence of acute myocardial infarction (AMI) in elderly people is increasing worldwide. However, their characteristics and prognosis have been rarely investigated. This study aimed to investigate the characteristics and prognosis in elderly patients with cardiac troponin-positive AMI., Methods: Consecutive patients with AMI from the J-MINUET study were divided into the following 3 groups: patients aged less than 65 years, those aged between 65 and 79 years, and those aged 80 years or over. Their characteristics and in-hospital outcomes were compared., Results: Patients with AMI aged 80 years or over had the highest incidence of female gender, and the highest incidence of hypertension, chronic kidney disease, and cardiovascular disease, such as peripheral artery disease, atrial fibrillation, and stroke, whereas they had the lowest body mass index, and the lowest incidence of current smoker, diabetes mellitus, and dyslipidemia. Patients with AMI aged 80 years or over had significantly longer onset to door time and longer door to device time, and lower peak creatine kinase (CK). The incidence of ST-segment elevation myocardial infarction (STEMI) was the lowest in the AMI patients aged 80 years or over, but the patients had a higher incidence of in-hospital death and cardiac failure than the other two groups. In addition, the presentation with STEMI and non-ST-segment elevation myocardial infarction with CK elevation among patients aged 80 years or over showed the highest incidence of in-hospital death and cardiac failure., Conclusions: J-MINUET showed different clinical characteristics between the aged and younger populations. The incidence of in-hospital death and cardiac failure in patients aged 80 years or over with AMI was poorer than their younger counterparts., (Copyright © 2020. Published by Elsevier Ltd.)

Background: Patients with peripheral artery disease (PAD) are at high risk of cardiovascular events, including myocardial infarction (MI), stroke, and cardiovascular death. However, the impact of PAD on prognosis in Japanese patients with acute MI remains unclear., Methods: The Japanese registry of acute Myocardial INfarction diagnosed by Universal dEfiniTion (J-MINUET) is a prospective multicenter registry that registered 3283 patients with acute MI. Among them, 2970 patients with available data of PAD were divided into the following 4 groups: 2513 patients without prior MI or PAD (None group), 320 patients with only prior MI (Prior MI group), 100 patients with only PAD (PAD group), and 37 patients with both previous MI and PAD (Both group). The primary endpoint was a composite of all-cause death, non-fatal MI, non-fatal stroke, cardiac failure, and urgent revascularization for unstable angina., Results: The 3-year cumulative incidence of the primary endpoint was 26.9% in None group, 41.4% in Prior MI group, 48.0% in PAD group, and 60.3% in Both group (p < 0.001). In multivariate analysis, hazard ratio using None group as reference was 1.55 (95% confidence intervals 1.25-1.91; p < 0.001) for MI group, 2.26 (1.61-3.07; p < 0.001) for PAD group, and 2.52 (1.52-3.90; p < 0.001) for Both group., Conclusions: Concomitant PAD was associated with poor prognosis in Japanese patients with acute MI., (Copyright © 2020 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

G protein-coupled receptors (GPCRs) are seven-transmembrane proteins, which transmit extracellular signals inside cells via activating G proteins. GPCRs are involved in a wide variety of physiological functions, such as signal sensing, immune system processes, and neurotransmission. Although the structures and functions of GPCRs have been well studied, little has been known about their real-time dynamics on live cells. In this study, we used Diffracted X-ray Tracking (DXT) and Diffracted X-ray Blinking (DXB) techniques for analysis. These methods are very precise single-molecular analytical techniques that elucidate protein dynamics by analyzing the diffraction spots from the gold nanocrystals labeled on the protein surface. DXT tracks diffraction spot movements, whereas DXB analyzes continuation of signals by calculating the autocorrelation function of each pixel from the recorded data. Serotonin receptor subtype 2A (5-HT 2A receptors) were transiently expressed on HEK 293 cells, and the gold nanocrystals were attached to the N-terminally introduced FLAG-tag via anti-FLAG antibodies. Fast- and mid-range motions were recorded by DXT with 100μs and 1.25 ms/frame rate, respectively. Slow-range motion was obtained using the DXB method with 100 ms/frame rate. An agonist interestingly suppressed the fluctuations of 5-HT 2A receptors at the microsecond-ranged fast measurement. On the contrary, the motion was enhanced by the agonist in the hundred-millisecond-ranged slow time scale. These dual-natured data may suggest that we succeeded in extracting different modes of receptor's motion on live cells; microsecond ranged fluctuation on the cell membrane, and millisecond-ranged dynamic movement comprising interactions with intracellular signaling molecules., 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 © 2020 Elsevier Inc. All rights reserved.)

Transverse aortic constriction (TAC) has been widely used to create pressure overload induced heart failure in mice. However, this conventional model has some limitations such as low reproducibility and long creation period of cardiac failure. In order to establish a highly reproducible cardiac failure model that mimics adverse cardiac remodeling (ACR) we combined pressure overload and beta-adrenergic receptor stimuli using isoproterenol (ISO) and explored the optimal TAC model by changing the durations of TAC and the doses of ISO. Thus we constructed a suitable model for ACR with an effective combination of 3-week TAC and subsequent one-week ISO (3 mg/kg/day) infusion. Using RNA-Seq analyses, we identified that the up-regulated genes were mainly related to fibrosis including Fbn1, C1qtnf6 and Loxl2; and that the down-regulated genes were associated with mitochondrial function including Uqcrc1, Ndufs3, and Idh2 in failing hearts of our ACR model. Next, we followed the changes in cardiac function after ceasing ISO infusion. Left ventricular function gradually recovered after cessation of ISO, suggesting cardiac reverse remodeling (CRR). Gene expression signatures of hearts, which exhibited CRR, were almost identical to that of TAC hearts without ISO. In conclusion, our new model exhibits a transition to ACR and subsequent CRR with high reproducibility. This murine model might add new insights into the experiments of heart failure technically as well as scientifically., 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 © 2020 Elsevier Inc. All rights reserved.)

Background: The relationship between long-term outcome in patients with lower extremity artery disease (LEAD) and left ventricular (LV) diastolic dysfunction has not been systematically studied. The aim of this study was to assess the impact of LV diastolic dysfunction on the long-term outcome in patients with LEAD., Methods: Two hundred LEAD patients (male 66 %, mean age 76±9 years) with preserved LV systolic function assessed by echocardiography (ejection fraction ≥50 %) were enrolled from a single center database between January 2013 and May 2015. We divided the patients into two groups on the basis of LV diastolic dysfunction, which was diagnosed based on the American Society of Echocardiography/European Association of Cardiovascular Imaging guidelines. The 3-year cumulative incidence of the primary endpoint was compared between LEAD patients with LV diastolic dysfunction and those without. The primary endpoint was a composite of major adverse cardiac and cerebrovascular events (MACCE: death, hospitalization for heart failure, myocardial infarction, and stroke). Multivariate analysis was performed to determine whether LV diastolic dysfunction was independently associated with the MACCE., Results: LV diastolic dysfunction was identified in 31 % of LEAD patients. The mean observation period was 32±21 months. The 3-year cumulative incidence of MACCE occurred more frequently in patients with LV diastolic dysfunction than those without (35 % vs 23 %, p=0.01). In multivariate analysis, LV diastolic dysfunction (HR=1.96, 95 % CI 1.09-3.55, p=0.03) and critical limb ischemia (HR=2.52, 95 % CI 1.24-5.10, p=0.01) were an independent predictor for MACCE., Conclusion: LV diastolic dysfunction increased the risk for MACCE in patients with LEAD., (Copyright © 2020 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Pseudoaneurysm of below-the-knee arteries after a high tibial osteotomy (HTO) is rare. A 69-year-old woman with history of right HTO a half year ago had performed a left HTO for osteoarthritis. Postoperatively, she had swelling and pain of the left lower leg. Computed tomography and echocardiography revealed the pseudoaneurysm of peroneal artery (PA). After the release of the covered stent graft, the pseudoaneurysm of the PA did not disappear, it was completely excluded in the completion angiogram., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Peripheral artery disease (PAD) is often accompanied by heart failure with preserved ejection fraction (HFpEF). Left ventricular (LV) diastolic dysfunction is related to HFpEF. The aim of this study was to compare LV diastolic function between patients with or without PAD., Methods: One thousand one hundred twenty-one patients (male 56%, mean age 68±13 years) with available preserved LV systolic function assessed by echocardiography (ejection fraction ≥50%) were enrolled from a single-center database between January 2013 and May 2015. PAD was defined as ankle brachial index <0.9 or previous history of lower extremity bypass and/or endovascular therapy. Diagnosis of LV diastolic dysfunction was based on the American Society of Echocardiography and European Association of Cardiovascular Imaging guidelines. The prevalence of LV diastolic dysfunction was compared between patients with PAD and those without PAD. Multivariate analysis was performed by logistic regression analyses to assess predictors of LV diastolic dysfunction., Results: Two hundred patients (18%) had PAD. Patients with PAD had higher E/e' (15.3±7.4 vs 11.8±5.5, p<0.01), tricuspid regurgitation velocity (2.37±0.33 vs 2.19±0.28m/s, p<0.01), left atrial volume index (40.6±20.2 vs 32.1±13.6mL/m 2 , p<0.01), and lower e' (5.68±1.70 vs 6.38±2.07cm/s, p<0.01) than patients without PAD. The prevalence of LV diastolic dysfunction was higher (31% vs 12%, p<0.01) in patients with PAD compared to patients without PAD. Multivariate analysis showed that PAD was an independent predictor of LV diastolic dysfunction (adjusted odds ratio: 1.77, 95% confidence interval: 1.13-2.65, p=0.01)., Conclusion: The prevalence of LV diastolic dysfunction was higher in patients with PAD than patients without PAD., (Copyright © 2019 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Background: The immune checkpoint inhibitor nivolumab is entering routine oncologic practice. We investigated the safety and efficacy of nivolumab in the real world and alternative predictive factors for survival in patients with advanced non-small-cell lung cancer (NSCLC)., Patients and Methods: We performed a prospective observational study to evaluate the activity of nivolumab treatment for chemotherapy-refractory NSCLC. Patients were treated with nivolumab once every 2 weeks, and the efficacy was assessed every 8 ± 2 weeks., Results: Fifty-two patients were enrolled after nivolumab approval in Japan. These patients received a median of 4 (range, 1-43) cycles of nivolumab. Overall objective response was observed in 12 patients (23.1%). Median progression-free survival was 2.1 (95% confidence interval, 1.0-3.2) months, and 1-year overall survival rate was 59.9%. A total of 23 immune-related adverse events occurred in 20 patients, as follows: 7 cases of pneumonitis, 6 of oral mucositis, 5 of hypothyroidism, 2 of colitis, 2 of liver dysfunction, and 1 of arthritis. All patients recovered after appropriate management. A pretreatment neutrophil-to-lymphocyte ratio (NLR) of ≥ 5 was significantly associated with poor prognosis compared to NLR < 5 (hazard ratio, 4.52; 95% confidence interval, 1.84-11.14; P = .013), independently., Conclusion: Nivolumab showed promising activity with a manageable safety profile in clinical practice, consistent with effects of previous clinical trials. This drug could affect a specific population of patients with advanced NSCLC, and pretreatment NLR was a candidate for surrogate markers for survival benefit of patients with NSCLC treated with nivolumab., (Copyright © 2018 Elsevier Inc. All rights reserved.)