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Study Objectives: Catathrenia has been classified as a sleep-related breathing disorder variant in the third edition of the International Classification of Sleep Disorders , but its validity remains unverified. We analyzed the clinical descriptive variables and polysomnographic findings of catathrenia and discussed the similarities and differences to those of obstructive sleep apnea (OSA), non-REM parasomnias, and sleep bruxism (SB)., Methods: A retrospective analysis was conducted on 47 patients diagnosed with nocturnal groaning through polysomnography. We examined sex, body mass index, age at symptom onset, weekly symptom frequency, and presence/absence of comorbidities, including OSA, periodic limb movement disorder, non-REM parasomnia, and SB. The groaning event (GE) index was calculated according to sleep position and sleep stage., Results: The distribution of patients with catathrenia did not show sex difference (male/female = 20:27), body mass index was 20.6 ± 3.0 kg/m 2 , and age of onset was 18.2 ± 7.4 years. The GE index was higher in stages N1 and R than in stage N3 and in the supine position than in the lateral position. There were no cases complicated with non-REM parasomnia, but the complication of SB was observed in 30% of the participants, and SB events appeared immediately before or during the interictal period of the GE episodes in these cases., Conclusions: Given the clinical background, posture- and sleep stage-dependent appearance of GEs, and the relatively high complication rate of SB, catathrenia pathogenesis may be heterogeneous or comprise elements of different sleep disorders., (© 2024 American Academy of Sleep Medicine.)

Background: It is unclear whether the development of the branches of the subclavian artery is dependent on the proximal part of this artery since great vessel formation is partially regulated by haemodynamic stress. For example, the vertebral artery that usually arises from the subclavian artery might be affected by anomalies in the aortic arch branches. This uncertainty is partly due to the limited reports of highly anomalous cases of proximal and distal branching morphologies. Here, we report an Adachi-Williams type CG plus H aortic arch case found during student dissection and discuss the development of the cervicothoracic circulation., Case Report: Here, we report an aberrant right subclavian artery that arose from the aorta distal to the left subclavian artery, via a retroesophageal course, whereas the right and left common carotid arteries arose from a short common trunk from the aorta (the carotid trunk) (Adachi-Williams type H). In addition, the left vertebral artery arose directly from the aortic arch between the carotid trunk and the left subclavian artery (Adachi-Williams type CG). Anomalies in the branching arteries from this aberrant right subclavian artery (the right vertebral artery, internal thoracic artery, thyrocervical trunk, costocervical trunk and thoracoacromial artery) were unidentifiable. The right vagus nerve directly innervates the laryngeal muscles without forming the recurrent nerve., Conclusions: The development of an aberrant right subclavian artery might affect haemodynamic stress in both the proximal and distal regions of the anterior limb region. The distal branching morphology, however, was normal, suggesting an independence of proximal and distal vasculature development. Since the concomitance of Adachi-Williams-type CG and H is rare, rather than sequentially develop, the distal arteries develop in a fine-tuned manner to adapt to anomalies in the proximal arteries.

Background: We previously demonstrated the applicability of the concept of "platinum sensitivity" in recurrent endometrial cancer. Although immune checkpoint inhibitors have been widely incorporated into endometrial cancer treatment, the debate continues regarding treatment options in patients with recurrent endometrial cancer who have previously received platinum-based chemotherapy. In this study, we assessed the duration of response to secondary platinum-based treatment using pooled data from the SGSG-012/GOTIC-004/Intergroup study., Methods: Among the 279 participants in the SGSG-012/GOTIC-004/Intergroup study wherein platinum-based chemotherapy was re-administered for managing recurrent endometrial cancer between January 2005 and December 2009, 130 (47%) responded to chemotherapy. We compared the relationship between platinum-free interval and duration of secondary platinum-based treatment using pooled data., Results: In 40 patients (31%), the duration of response to secondary platinum-based treatment exceeded the platinum-free interval. The duration of response to secondary platinum-based treatment exceeded 12 months in 51 patients (39%) [platinum-free interval: < 12 months, 14/48 (29%); 12-23 months, 18/43 (42%); 24-35 months, 8/19 (42%); ≥ 36 months, 11/20 (55%)]. In particular, in eight patients (6%), the duration of response to secondary platinum-based treatment exceeded 36 months [platinum-free interval: < 12 months, 3/48 (6%); 12-23 months, 0/19 (0%); 24-35 months, 2/19 (11%); ≥ 36 months, 3/20 (15%)]., Conclusions: Re-administration of platinum-based chemotherapy for recurrent endometrial cancer may result in a long-term response exceeding the platinum-free interval in some patients. Even in the current situation, where immune checkpoint inhibitors have been introduced, re-administration of platinum-based chemotherapy is worth considering., (© 2024. The Author(s).)

Risperidone is a second-generation antipsychotic for treating schizophrenia and bipolar disorder. It can potently inhibit I Kr , but is classified into conditional risk for torsade de pointes (TdP) by CredibleMeds®. Our previous studies using chronic atrioventricular block dogs showed that risperidone alone did not induce TdP, and that dl-sotalol (β-adrenoceptor blockade plus I Kr inhibition) induced TdP three times more frequently than d-sotalol (I Kr inhibition alone). Since risperidone can block α 1 -adrenoceptor and decrease blood pressure, the resulting reflex-mediated increase of sympathetic tone on β-adrenoceptor might protect the heart from its I Kr inhibition-associated TdP. To validate this hypothesis, risperidone was administered to chronic atrioventricular block dogs after β-adrenoceptor blocker atenolol infusion with monitoring J-T peak and T peak -T end , which are proarrhythmic surrogate markers of "substrate" and "trigger" toward TdP, respectively. Atenolol alone induced TdP in 1 out of 5 dogs; moreover, an additional infusion of risperidone induced TdP in 3 out of 4 dogs. Risperidone prolonged QT interval, J-T peak and T peak -T end in animals that induced TdP. These findings indicate that β-adrenoceptor blockade can diminish repolarization reserve to augment risperidone's torsadogenic potential, thus advising caution when using β-adrenoceptor blockers in patients with I Kr inhibition-linked labile repolarization., (Copyright © 2024 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

Aims: Schizophrenia (SZ) is a brain disorder characterized by psychotic symptoms and cognitive dysfunction. Recently, irregularities in sharp-wave ripples (SPW-Rs) have been reported in SZ. As SPW-Rs play a critical role in memory, their irregularities can cause psychotic symptoms and cognitive dysfunction in patients with SZ. In this study, we investigated the SPW-Rs in human SZ., Methods: We measured whole-brain activity using magnetoencephalography (MEG) in patients with SZ (n = 20) and sex- and age-matched healthy participants (n = 20) during open-eye rest. We identified SPW-Rs and analyzed their occurrence and time-frequency traits. Furthermore, we developed a novel multivariate analysis method, termed "ripple-gedMEG" to extract the global features of SPW-Rs. We also examined the association between SPW-Rs and brain state transitions. The outcomes of these analyses were modeled to predict the positive and negative syndrome scale (PANSS) scores of SZ., Results: We found that SPW-Rs in the SZ (1) occurred more frequently, (2) the delay of the coupling phase (3) appeared in different brain areas, (4) consisted of a less organized spatiotemporal pattern, and (5) were less involved in brain state transitions. Finally, some of the neural features associated with the SPW-Rs were found to be PANSS-positive, a pathological indicator of SZ. These results suggest that widespread but disorganized SPW-Rs underlies the symptoms of SZ., Conclusion: We identified irregularities in SPW-Rs in SZ and confirmed that their alternations were strongly associated with SZ neuropathology. These results suggest a new direction for human SZ research., (© 2024 The Author(s). Psychiatry and Clinical Neurosciences published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Psychiatry and Neurology.)

Objective: The study aimed to investigate treatment options for older women with pelvic organ prolapse (POP) and postoperative outcomes based on their long-term care (LTC) status., Methods: We used the medical and LTC insurance claims databases of Tochigi Prefecture in Japan, covering 2014 to 2019. We included women 65 years and older with POP and evaluated their care status and treatment, excluding women with an observation period <6 months. Among women with a postsurgical interval ≥6 months, we compared care level changes and deaths within 6 months and complications within 1 month postoperatively between those with and without LTC using Fisher exact test., Results: We identified 3406 eligible women. Of the 447 women with LTC and 2959 women without LTC, 16 (3.6%) and 415 (14.0%), respectively, underwent surgery. Among 393 women with a postsurgical interval ≥6 months, 19 (4.8%) required LTC at surgery. Two of the 19 women with LTC (10.5%) and eight of 374 women without LTC (2.1%) experienced worsening care-needs level. No deaths were recorded. Urinary tract infection (UTI) was significantly more frequent in women with LTC than in women without LTC (36.8% vs 8.6%). Other complications were rare in both groups., Conclusion: The proportion of patients who underwent surgery for POP was lower in women with LTC than in women without LTC. Postoperative UTI was common and 11% had a worsening care-needs level postoperatively, whereas other complications were infrequent. Further detailed studies would contribute to providing optimal treatment to enhance patients' quality of life., (© 2024 International Federation of Gynecology and Obstetrics.)

To characterize utility of atrioventricular block (AVB) dogs as atrial fibrillation (AF) model, we studied remodeling processes occurring in their atria in acute (<2 weeks) and chronic (>4 weeks) phases. Fifty beagle dogs were used. Holter electrocardiogram demonstrated that paroxysmal AF occurred immediately after the production of AVB, of which duration tended to be prolonged in chronic phase. Electrophysiological analysis showed that inter-atrial conduction time and duration of burst pacing-induced AF increased in the chronic phase compared with those in the acute phase, but that atrial effective refractory period was hardly altered. Echocardiographic study revealed that diameters of left atrium, right pulmonary vein and inferior vena cava increased similarly in the acute and chronic phases. Histological evaluation indicated that hypertrophy and fibrosis in atrial tissue increased in the chronic phase. Electropharmacological characterization showed that i.v. pilsicainide effectively suppressed burst pacing-induced AF with increasing atrial conduction time and refractoriness of AVB dogs in chronic phase, but that i.v. amiodarone did not exert such electrophysiological effects. Taken together, AVB dogs in chronic phase appear to possess such pathophysiology as developed in the atria of early-stage AF patients, and therefore they can be used to evaluate drug candidates against early-stage AF., Competing Interests: Declaration of competing interest The authors declare no potential conflicts of interest except for H.S. and Y.A., who were employees of CMIC Pharma Science Co., Ltd., (Copyright © 2024 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

Background: We examined the safety and efficacy of acceleration training (AT) in patients immediately after cardiac surgery., Methods and Results: This randomized controlled study included patients who underwent open-heart surgery using cardiopulmonary bypass. Of these patients, 31 received regular cardiac rehabilitation (CR) and 39 received AT in addition to regular CR (AT group). AT was provided using a vibration platform (Power Plate ® Pro7 TM and Power plate ® personal; Performance Health System, Chicago, IL, USA). The AT group performed 5 static resistance training sessions: squats, wide stance squats, toe stands, banded squats, and front lunges. Each vibration session lasted 30 s. We evaluated the short physical performance battery, anterior mid-thigh thickness, maximum voluntary isometric contraction of the knee extensors, and serum intercellular adhesion molecule (ICAM-1) and vascular cell adhesion molecule (VCAM-1) concentrations as indicators of endothelial function. The observation period was during hospitalization and lasted approximately 20 days. No adverse events occurred during AT. Ultrasound revealed a significantly lower reduction in muscle mass at discharge in the AT group. No significant differences were observed in ICAM-1 and VCAM-1 concentrations between the 2 groups preoperatively, postoperatively, or at discharge., Conclusions: AT is considered safe and effective for patients immediately after open-heart surgery. AT, along with regular CR, may prevent skeletal muscle mass loss, muscle weakness, and physical function loss immediately after open-heart surgery.

Background: Sacubitril/valsartan, being both a neprilysin inhibitor and angiotensin receptor blocker, exhibits a renin-angiotensin-aldosterone system (RAAS) inhibitory effect. However, no study has investigated the administration of sacubitril/valsartan in patients early after surgery using cardiopulmonary bypass., Methods and Results: This was a prospective observational study of 63 patients who underwent open heart surgery and were treated with sacubitril/valsartan. No serious adverse events occurred. Among the 63 patients, sacubitril/valsartan was discontinued in 13 due to hypotension (n=10), renal dysfunction (n=2), and dizziness (n=1). Atrial natriuretic peptide concentrations increased significantly from Day 3 of treatment (P=0.0142 vs. Postoperative Day 1) and remained high thereafter. In contrast, plasma renin activity was significantly suppressed from Day 3 onwards (P=0.00206 vs. Postoperative Day 1). A decrease in creatinine concentrations and an increase in the estimated glomerular filtration rate were observed on Day 3; this improvement in renal function was not observed in the historical control group, in which patients did not receive sacubitril/valsartan. New postoperative atrial fibrillation was less frequent in the study group compared with the historical control (12.7% vs. 38.0%; P=0.0034)., Conclusions: Sacubitril/valsartan administration was safe immediately after open heart surgery in patients without postoperative hypotension. It enhanced serum atrial natriuretic peptide concentrations and suppressed RAAS activation.

ICH established S7B and E14 guidelines in 2005 to prevent drug-induced torsade de pointes (TdP), effectively preventing the development of high-risk drugs. However, those guidelines unfortunately hampered the development of some potentially valuable drug candidates despite not being proven to be proarrhythmic. In response, Comprehensive In Vitro Proarrhythmia Assay (CiPA) and Exposure-Response Modeling were proposed in 2013 to reinforce proarrhythmic risk assessment. In 2022, ICH released E14/S7B Q&As (Stage 1), emphasizing a "double negative" nonclinical scenario for low-risk compounds. For "non-double negative" compounds, new Q&As are expected to be enacted as Stage 2 shortly, in which more detailed recommendations for proarrhythmia models and proarrhythmic surrogate markers will be provided. This review details the onset mechanisms of drug-induced TdP, including I Kr inhibition, pharmacokinetic factors, autonomic regulation and reduced repolarization reserve. It also explores the utility of proarrhythmic surrogate markers (J-T peak , T peak -T end and terminal repolarization period) besides QT interval. Finally, it presents various in silico, in vitro, ex vivo and in vivo models for proarrhythmic risk prediction, such as CiPA in silico model, iPS cell-derived cardiomyocyte sheet, Langendorff perfused heart preparation, chronic atrioventricular block animals (dogs, monkeys, pigs and rabbits), acute atrioventricular block rabbits, methoxamine-sensitized rabbits, and genetically engineered rabbits for specific long QT syndromes. Those models along with the surrogate markers can play important roles in quantifying TdP risk of new compounds, impacting late-phase clinical design and regulatory decision-making, and preventing adverse events on post-marketing clinical use. Significance Statement Since ICH S7B/E14 guidelines unfortunately hampered the development of some potentially valuable compounds with unproven proarrhythmic risk, Comprehensive In Vitro Proarrhythmia Assay and Exposure-Response Modeling were proposed in 2013 to reinforce proarrhythmic risk assessment of new compounds. In 2022, ICH released Q&As (Stage 1) emphasizing "double negative" nonclinical scenario for low-risk compounds, and new Q&As (Stage 2) for "non-double negative" compounds are expected. This review delves into proarrhythmic mechanisms with surrogate markers, and explores various models for proarrhythmic risk prediction., (Copyright © 2024 American Society for Pharmacology and Experimental Therapeutics.)

Fourteen Speech and Language Therapists/Pathologists (SLT/Ps) from 13 countries across 5 continents made up the International Confederation of Cleft Lip and Palate and Related Craniofacial Anomalies (ICCPCA) CLEFT 2022 Speech Taskforce. Following a group consensus activity led by an external facilitator using Lightning Design Thinking principles, "task-shifting" was identified as the topic for this Taskforce. Absence and scarcity of SLT/Ps in many parts of the world have led to non-SLT/Ps delivering speech and language therapy services to individuals with cleft lip +/- palate. This narrative is the first known attempt to develop a framework, describing the different types of providers and their scope of practice., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Despite advances in systemic chemotherapy, patients with gastric cancer (GC) and peritoneal metastases (PMs) continue to have poor prognoses. Intraperitoneal (IP) administration of Paclitaxel (PTX) combined with systemic chemotherapy shows promise in treating PMs from GC. However, methods of drug administration need to be optimized to maximize efficacy. In this study, we utilized a mouse model with PMs derived from a human GC cell line, administering PTX either IP or intravenously (IV), and Carboplatin (CBDCA) IV 0, 1, and 4 days after PTX administration. The PMs were resected 30 min later, and concentrations of PTX and CBDCA in resected tumors were measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Results indicated that PTX concentrations were higher with IP administration than with IV administration, with significant differences observed on days 0 and 1. CBDCA concentrations 4 days post-IP PTX administration were higher than with simultaneous IV PTX administration. These findings suggest that IP PTX administration enhances CBDCA concentration in peritoneal tumors. Therefore, sequential IV administration of anti-cancer drugs appears more effective than simultaneous administration with IP PTX, a strategy that may improve prognoses for patients with PMs.

Blue rubber bleb nevus syndrome (BRBNS) is a rare systemic vascular disorder characterized by multifocal venous malformations (VMs). Little is known about the perinatal management of pregnant women with BRBNS owing to the limited number of reported cases. We present the case of a 36-year-old primigravida with BRBNS who underwent an uneventful cesarean section under spinal anesthesia for breech presentation. A thorough systemic examination revealed VMs in various organs, including the skin, conjunctiva, larynx, gastrointestinal tract, lungs, and vulva. Prior to spinal anesthesia, careful examination using imaging modalities was conducted to assess the spinal and epidural involvement of the VMs to avoid complications, including accidental puncture of the VMs, associated bleeding, and epidural hematoma. In pregnant women with BBNS, it is imperative to scrutinize the localization and distribution of VMs throughout the body to anticipate potential complications and select the appropriate delivery mode and anesthetic management., Competing Interests: The authors declare that they have no conflicts of interest.

Background: Currently, clinical indicators for evaluating endothelial permeability in sepsis are unavailable. Endothelium-derived extracellular vesicles (EDEVs) are emerging as biomarkers of endothelial injury. Platelet endothelial cell adhesion molecule (PECAM) and vascular endothelial (VE)-cadherin are constitutively expressed endothelial intercellular adhesion molecules that regulate intercellular adhesion and permeability. Herein, we investigated the possible association between EDEVs expressing intercellular adhesion molecules (PECAM+ or VE-cadherin+ EDEVs) and endothelial permeability and sepsis severity., Methods: Human umbilical vein endothelial cells (HUVECs) were stimulated with tumor necrosis factor alpha (TNF-α) directly or after pretreatment with permeability-modifying reagents such as angiopoietin-1, prostacyclin, or vascular endothelial growth factor (VEGF) to alter TNF-α-induced endothelial hyperpermeability. Endothelial permeability was measured using the dextran assay or transendothelial electrical resistance. Additionally, a prospective cross-sectional observational study was conducted to analyze circulating EDEV levels in patients with sepsis. EDEVs were examined in HUVEC culture supernatants or patient plasma (nonsepsis, n = 30; sepsis, n = 30; septic shock, n = 42) using flow cytometry. The Wilcoxon rank-sum test was used for comparisons between 2 groups. Comparisons among 3 or more groups were performed using the Steel-Dwass test. Spearman's test was used for correlation analysis. Statistical significance was set at P < .05., Results: TNF-α stimulation of HUVECs significantly increased EDEV release and endothelial permeability. Pretreatment with angiopoietin-1 or prostacyclin suppressed the TNF-α-induced increase in endothelial permeability and inhibited the release of PECAM+ and VE-cadherin+ EDEVs. In contrast, pretreatment with VEGF increased TNF-α-induced endothelial permeability and the release of PECAM+ and VE-cadherin+ EDEVs. However, pretreatment with permeability-modifying reagents did not affect the release of EDEVs expressing inflammatory stimulus-inducible endothelial adhesion molecules such as E-selectin, intracellular adhesion molecule-1, or vascular cell adhesion molecule-1. The number of PECAM+ EDEVs on admission in the septic-shock group (232 [124, 590]/μL) was significantly higher (P = .043) than that in the sepsis group (138 [77,267]/μL), with an average treatment effect of 98/μL (95% confidence interval [CI], 2-270/μL), and the number of VE-cadherin+ EDEVs in the septic-shock group (173 [76,339]/μL) was also significantly higher (P = .004) than that in the sepsis group (81 [42,159]/μL), with an average treatment effect (ATE) of 79/μL (95% CI, 19-171/μL); these EDEV levels remained elevated until day 5., Conclusions: EDEVs expressing intercellular adhesion molecules (PECAM+ or VE-cadherin+ EDEVs) may reflect increased endothelial permeability and could be valuable diagnostic and prognostic markers for sepsis., Competing Interests: Conflicts of Interest: See Disclosures at the end of the article., (Copyright © 2024 International Anesthesia Research Society.)

Objectives: We examined the effects of preoperative Impella treatment on haemodynamic stability, organ recovery and postoperative outcomes in patients with postinfarction ventricular septal rupture (PIVSR) and cardiogenic shock (CS)., Methods: Between April 2018 and February 2024, the data of 10 of 15 patients with PIVSR and CS who underwent Impella therapy were analysed. Emergency surgery was contingent on haemodynamic stability with the Impella/ECpella, except in the presence of organ failure. We utilized a generalized linear mixed model to evaluate organ ischaemia through changes in blood parameters upon admission and at subsequent intervals post-Impella insertion., Results: Preoperative Impella or combined Impella and ECpella (5 patients each) support was provided, with diagnoses and operations occurring at an average of 4 days (interquartile range: 2-5) and 8 days (interquartile range: 2-14) after myocardial infarction, respectively. Treatment significantly reduced lactate, alanine aminotransferase, creatine kinase-MB and troponin I levels (P ≤ 0.05 for all). Conversely, no significant change was noted in the aspartate aminotransferase level or the estimated glomerular filtration rate. Haemoglobin and platelet counts decreased despite transfusions (P < 0.001). No surgical deaths occurred; however, 70% of the patients required prolonged mechanical ventilation, and 80% were transferred to other facilities for rehabilitation., Conclusions: Impella or ECpella treatment can improve haemodynamic and organ failure outcomes in patients with PIVSR and CS. However, the risks of prolonged support, including haemorrhagic events and the need for extended rehabilitation, point to a need for comparative studies to optimize support duration., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery.)

The α-1,3-glucanase Agl-EK14 from Flavobacterium sp. EK-14 comprises a signal peptide (SP), a catalytic domain (CAT), a first immunoglobulin-like domain (Ig1), a second immunoglobulin-like domain (Ig2), a ricin B-like lectin domain (RicinB), and a carboxy-terminal domain (CTD). SP and CTD are predicted to be involved in extracellular secretion, while the roles of Ig1, Ig2, and RicinB are unclear. To clarify their roles, domain deletion enzymes Agl-EK14ΔRicinB, Agl-EK14ΔIg2RicinB, and Agl-EK14ΔIg1Ig2RicinB were constructed. The insoluble α-1,3-glucan hydrolytic, α-1,3-glucan binding, and fungal cell wall hydrolytic activities of the deletion enzymes were almost the same and lower than those of Agl-EK14. Kinetic analysis revealed that the K m values of the deletion enzymes were similar and uniformly higher than those of Agl-EK14. These results suggest that the deletion of RicinB causes a decline in binding and hydrolytic activity and increases the K m value. To confirm the role of RicinB, Ig1, Ig2, and RicinB were fused with green fluorescent protein (GFP). As a result, RicinB-fused GFP (GFP-RicinB) showed binding to insoluble α-1,3-glucan and Aspergillus oryzae cell walls, whereas Ig1- and Ig2-fused GFP did not. These results indicated that RicinB is involved in α-1,3-glucan binding. The fusion protein GFP-Ig1Ig2RicinB was also constructed and GFP-Ig1Ig2RicinB showed strong binding to the cell wall of A. oryzae compared to GFP-RicinB. Gel filtration column chromatography suggested that the strong binding was due to GFP-Ig1Ig2RicinB loosely associated with itself., (Copyright © 2024 The Society for Biotechnology, Japan. Published by Elsevier B.V. All rights reserved.)

Abstract: Information regarding the genetic alterations in extramammary Paget disease (EMPD) is scarce. This study investigated the significance of CDKN2A and MTAP alterations in EMPD progression using immunohistochemistry and panel DNA sequencing. In total, 24 invasive/metastatic EMPD cases were included in this study. The immunoexpression of p16 and MTAP in the primary in situ, primary invasive, and metastatic tumor components was evaluated. Panel DNA sequencing was performed for metastatic tumor components in 5 of the 24 cases. Immunoexpression of p16 in the in situ tumor component was at least partially preserved in all 19 tested cases (100%). By contrast, the invasive tumor component was diffusely or partially lost in 18 (81.8%) of 22 tested cases. Regarding the foci of lymph node metastasis, 13 (81.2%) of the 16 patients showed a significant loss of p16 expression. Loss of MTAP immunoexpression was observed less frequently compared with the loss of p16 expression. CDKN2A homozygous deletions were confirmed in all 5 tested cases by sequencing, whereas MTAP deletions were detected in only 2 cases. In conclusion, p16 expression loss and CDKN2A deletions can be frequently seen in invasive/metastatic cases of EMPD., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Atrial fibrillation (AF) and heart failure with preserved ejection fraction (HFpEF) often coexist; however, clinically available anti-AF drugs can exacerbate symptoms of HFpEF. M201-A suppressed ryanodine receptor-mediated diastolic Ca 2+ leakage, possibly inhibiting common pathological processes toward AF and HFpEF. To bridge the basic information to clinical practice, we assessed its cardiohemodynamic, anti-AF and ventricular proarrhythmic profile using halothane-anesthetized dogs (n = 4). M201-A hydrochloride in doses of 0.03, 0.3 and 3 mg/kg/10 min was intravenously administered, providing peak plasma concentrations of 0.09, 0.81 and 5.70 μg/mL, respectively. The high dose of M201-A showed various cardiovascular actions. Namely, M201-A increased mean blood pressure and tended to enhance isovolumetric ventricular relaxation without suppressing ventricular contraction or decreasing cardiac output. M201-A enhanced atrioventricular conduction, but hardy affected intra-atrial/ventricular conduction. Importantly, M201-A prolonged effective refractory period more potently in the atrium than in the ventricle, indicating that it may become an atrial-selective antiarrhythmic drug. Meanwhile, M201-A prolonged QT interval/QTcV, and showed reverse frequency-dependent delay of ventricular repolarization. M201-A prolonged J-T peak c without prolonging T peak -T end or terminal repolarization period, indicating the risk of causing torsade de pointes is negligible. Thus, M201-A is expected to become a hopeful therapeutic strategy for patients having pathology of both AF and HFpEF., (Copyright © 2024 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

Objective: We evaluated the blood flow within the downstream aortic false lumen after frozen elephant trunk repair for acute aortic dissection and identified hemodynamic predictors of false lumen expansion and negative false lumen remodeling using four-dimensional flow magnetic resonance imaging., Methods: Thirty-one patients (Stanford type A, n = 28; Stanford type B, n = 3) with patent false lumen who underwent frozen elephant trunk procedures for acute aortic dissection were included in this observational study. Each patient underwent computed tomography during the follow-up period and four-dimensional flow magnetic resonance imaging within 3 postoperative months. The false lumen volumetric expansion rate was calculated using computed tomography data. The direction and the rate of flow in the lower descending aortic false lumen were analyzed. Negative false lumen remodeling was defined as a volumetric increase of > 10% from the baseline volume., Results: Negative false lumen remodeling had developed in 6 of the 31 patients during the observation period. Most of the false lumen flows were biphasic during systole. The range between peak and nadir flow rates was associated with the false lumen volumetric expansion rate (β coefficient = 6.77; p < 0.01, R 2  = 0.43)., Conclusions: The range between peak and nadir flow rates may serve as a hemodynamic predictor of negative false lumen remodeling, enabling further treatment for patients at risk of expansion in the downstream aorta., (© 2023. The Author(s).)

A 71-year-old man presented with exertional dyspnea. Chest radiography revealed multiple pulmonary nodules, and contrast-enhanced computed tomography showed findings suspicious of right renal pelvic cancer. Percutaneous lung tumor biopsy revealed a histological diagnosis of urothelial carcinoma, and right renal pelvic cancer cT3N2M1 was diagnosed. Favorable response was shown during primary chemotherapy with gemcitabine and cisplatin but resulted in tumor progression after four cycles. The patient was switched to a second-line treatment, pembrolizumab, which resulted in rapid tumor growth. Hyper-progression was suspected, and the patient was promptly switched to a third-line treatment, enfortumab vedotin. The tumor shrank significantly. After three treatment cycles, an adverse event of enteritis was observed. A biopsy of the intestinal mucosa led to a histopathologic diagnosis of late-onset immune-related adverse event; therefore, enfortumab vedotin could be continued.

Purpose: The present study investigated potential access vessels in patients receiving hemodialysis who underwent surgical aortic valve replacement and determined which approaches were most suitable for performing transcatheter aortic valve implantation., Methods: Consecutive patients undergoing hemodialysis with aortic valve stenosis who underwent surgical aortic valve replacement were included. Preoperative computed tomography data were analyzed to assess the vessel diameter and calcification. Simulations were conducted to determine the feasibility of inserting the 14-F eSheath of Sapien 3 via transfemoral, trans-cervical, trans-subclavian, and direct aorta approaches., Results: A total of 72 patients were included in this study. The access route was characterized by severe calcification of the common iliac artery. The transfemoral approach was feasible in 77.8% of the cases, but the rate decreased to 33% when the calculations were based on the maximum sheath extension diameter. The trans-cervical, trans-subclavian, and direct aortic approaches were suitable for many patients. Lower extremity artery disease was identified as a risk factor for the unsuitability of the transfemoral approach., Conclusions: Common iliac artery calcification in patients undergoing hemodialysis restricts the use of the transfemoral approach. Therefore, some patients require alternative approaches., (© 2023. The Author(s).)

The nucleus is highly organized, such that factors involved in the transcription and processing of distinct classes of RNA are confined within specific nuclear bodies 1,2 . One example is the nuclear speckle, which is defined by high concentrations of protein and noncoding RNA regulators of pre-mRNA splicing 3 . What functional role, if any, speckles might play in the process of mRNA splicing is unclear 4,5 . Here we show that genes localized near nuclear speckles display higher spliceosome concentrations, increased spliceosome binding to their pre-mRNAs and higher co-transcriptional splicing levels than genes that are located farther from nuclear speckles. Gene organization around nuclear speckles is dynamic between cell types, and changes in speckle proximity lead to differences in splicing efficiency. Finally, directed recruitment of a pre-mRNA to nuclear speckles is sufficient to increase mRNA splicing levels. Together, our results integrate the long-standing observations of nuclear speckles with the biochemistry of mRNA splicing and demonstrate a crucial role for dynamic three-dimensional spatial organization of genomic DNA in driving spliceosome concentrations and controlling the efficiency of mRNA splicing., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

The regressive evolution of independent lineages often results in convergent phenotypes. Several teleost groups display secondary loss of the stomach, and four gastric genes, atp4a, atp4b, pgc, and pga2 have been co-deleted in agastric (stomachless) fish. Analyses of genotypic convergence among agastric fishes showed that four genes, slc26a9, kcne2, cldn18a, and vsig1, were co-deleted or pseudogenized in most agastric fishes of the four major groups. kcne2 and vsig1 were also deleted or pseudogenized in the agastric monotreme echidna and platypus, respectively. In the stomachs of sticklebacks, these genes are expressed in gastric gland cells or surface epithelial cells. An ohnolog of cldn18 was retained in some agastric teleosts but exhibited an increased non-synonymous substitution when compared with gastric species. These results revealed novel convergent gene losses at multiple loci among the four major groups of agastric fish, as well as a single gene loss in the echidna and platypus., (© 2024. The Author(s).)

Cardio-stimulatory actions of aciclovir have been considered to primarily depend on the sympathetically-mediated reflex resulting from its hypotensive effect. To further clarify onset mechanisms of the cardio-stimulatory actions, we initially studied them using isoflurane-anesthetized dogs under thorough β 1 -adrenoceptor blockade with atenolol (1 mg/kg, i.v.) (n = 4). Aciclovir (20 mg/kg/10 min, i.v.) decreased mean arterial blood pressure by 10 mmHg, whereas it increased heart rate by 10 bpm and maximum upstroke velocity of ventricular pressure by 928 mmHg/s, and shortened AH interval by 2 ms, indicating that cardio-stimulatory actions were not totally abolished by β 1 -adrenoceptor blockade. Then, unknown mechanisms of cardio-stimulatory action were explored. Since aciclovir has a similar chemical structure to theophylline, in silico molecular docking simulation was performed, indicating aciclovir as well as theophylline possesses strong likelihood of interactions with phosphodiesterase 1A, 1C and 3A. Indeed, aciclovir inhibited phosphodiesterase 1A derived from the bovine heart (n = 4), moreover it exerted positive chronotropic action on the atrial tissue preparation of rats along with an increase of tissue cyclic AMP concentration (n = 4). These results indicate that cardio-stimulatory actions of aciclovir could result from not only hypotension-induced, reflex-mediated increase of sympathetic tone but also its inhibitory effects on phosphodiesterase in the heart., Competing Interests: Declaration of competing interest The authors indicated no potential conflict of interest., (Copyright © 2024 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

Aim: This study aimed to comprehensively compare the characteristics of out-of-hospital cardiac arrest (OHCA) with medical and non-medical origins attributed to traffic accidents and explore the potential association between the cases with a medical origin and neurologically favorable outcomes., Methods: In this retrospective nationwide population-based study, baseline data were collected between January 2018 and December 2020. We analyzed 5091 OHCA associated with traffic accidents on the road scene. Only those encounters involving treatment or transport by prehospital emergency medical technicians were included. The characteristics of OHCA incidents and their outcomes were analyzed by categorizing patients into "medical origin" and "non-medical origin" groups., Results: Medical-origin cases exhibited several distinct characteristics, including higher frequencies of occurrence during the daytime (79.3% [706/890] vs. 68.9% [2895/4201], p < 0.001), a higher prevalence among male (77.8% [692/890] vs. 68.3% [2871/4201], p < 0.001) and younger patients (median [25-75%]: 63 years [42-77] vs. 66 years [50-76], p = 0.003), a higher proportion of shockable initial rhythms(10.5% [93/890] vs. 1.1% [45/4201], p < 0.001), an increased number of cases requiring advanced airway management (33.8% [301/890] vs. 28.5% [1199/4201], p = 0.002) and adrenaline administration by emergency medical teams (26.9% [239/890] vs. 21.7% [910/4201], p < 0.001), and shorter transport times (55.3% [492/890] vs. 60.9% [2558/4201], p = 0.002) compared to non-medical-origin cases. However, medical-origin cases also had lower witness rates (42.8% [381/890] vs. 27.2% [1142/4201], p < 0.001) and were less likely to be transported to higher-level hospitals (55.3% [492/890] vs. 60.9% [2558/4201], p = 0.002). Propensity score matching analysis identified factors associated with favorable neurological outcomes in medical-origin traffic accidents. The adjusted odds ratios were as follows: 8.46 (3.47-20.61) for cases with shockable initial rhythms, 2.36 (1.01-5.52) for cases involving traffic accidents due to medical origin, and 0.09 (0.01-0.67) for cases where advanced airway management was provided., Conclusion: In this retrospective study, the occurrence of OHCAs of medical origin involving traffic accidents were associated with favorable neurological outcomes. These cases more frequently demonstrated favorable factors for survival compared to those classified as of non-medical origin. The findings have important implications for public health and EMS professionals, they will guide future research aimed at optimizing prehospital care strategies and improving survival rates for similar cases., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The importance of temporary mechanical circulatory support for treating acute heart failure with cardiogenic shock is increasingly recognized, and Impella (Abiomed, Danvers, MA, USA) has received particular attention in this regard. Impella is an axial flow left ventricular assist device (LVAD) built into the tip of a catheter. It is inserted via a peripheral artery and implanted into the left ventricle. Although the morphology of Impella is different from a typical LVAD, it has similar actions and effects as an LVAD in terms of left ventricular drainage and aortic blood delivery. Impella increases mean arterial pressure (MAP) and systemic blood flow, thereby improving peripheral organ perfusion and promoting recovery from multiple organ failure. In addition, left ventricular unloading with increased MAP increases coronary perfusion and decreases myocardial oxygen demand, thereby promoting myocardial recovery. Impella is also useful as a mechanical vent of the left ventricle in patients supported with veno-arterial extracorporeal membrane oxygenation. Indications for Impella include emergency use for cardiogenic shock and non-emergent use during high-risk percutaneous coronary intervention and ventricular tachycardia ablation. Its intended uses for cardiogenic shock include bridge to recovery, durable device, heart transplantation, and heart surgery. Prophylactic use of Impella in high-risk patients undergoing open heart surgery to prevent postcardiotomy cardiogenic shock is also gaining attention. While there have been many case reports and retrospective studies on the benefits of Impella, there is little evidence based on sufficiently large randomized controlled trials (RCTs). Currently, several RCTs are now ongoing, which are critical to determine when, for whom, and how these devices should be used. In this review, we summarize the principles, physiology, indications, and complications of the Impella support and discuss current issues and future expectations for the device., Competing Interests: Declaration of competing interest None., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

TNNI3 is a gene that causes hypertrophic cardiomyopathy (HCM). A 14-year-old girl who was diagnosed with nonobstructive HCM presented with cardiopulmonary arrest due to ventricular fibrillation. Genetic testing revealed a novel de novo heterozygous missense variant in TNNI3, NM&#95;000363.5:c.583A>T (p.Ile195Phe), which was determined to be the pathogenic variant. The patient exhibited progressive myocardial fibrosis, left ventricular remodeling, and life-threatening arrhythmias. Genetic testing within families is useful for risk stratification in pediatric HCM patients., (© 2024. The Author(s).)

Increased occupational exposure of radiation workers is a major problem during open reduction and internal fixation (ORIF) of the hip joint, as the surgeon's eye lens is in close proximity to the patient and the X-ray tube. The purposes of this study were to clarify the occupational exposure of radiation workers during ORIF of the hip joint and to examine the need for radiation protection measures. The radiation exposure of radiation workers was evaluated by making an airborne dose distribution map using phantom experiments. The radiation goggles attached with a small optically stimulated luminescence dosimeter were used in clinical practice to measure the lens dose received by the surgeon, and the necessity of radiation goggles was examined. The airborne dose distribution in ORIF of the hip joint showed a wider area of high dose rate during axial fluoroscopy of the femoral neck than during posterior-anterior fluoroscopy. In axial fluoroscopy of the femoral neck, the surgeon was always in the high dose rate range of 10 µGy/min or higher, the nurses were in the dose rate range of 4 to 10 µGy/min, and the radiologic technologists were in the dose rate range of 0.5 µGy/min or lower. The maximum 3 mm dose equivalent to the surgeon per case was 0.38 mSv. In contradiction, radiation goggles were useful in ORIF because they provided approximately 60% shielding. It is advisable to work with radiation goggles to avoid cataracts.

To elucidate the relationship between the interval from cardiopulmonary resuscitation initiation to return of spontaneous circulation (ROSC) and neurologically favourable 1-month survival in order to determine the appropriate duration of basic life support (BLS) without advanced interventions. This population-based cohort study included patients aged ≥ 18 years with 9132 out-of-hospital cardiac arrest of presumed cardiac origin who were bystander-witnessed and had achieved ROSC between 2018 and 2020. Patients were classified into two groups based on the resuscitation methods as the "BLS-only" and the "BLS with administered epinephrine (BLS-AE)" groups. Receiver operating characteristic (ROC) curve analysis indicated that administering BLS for 9 min yielded the best neurologically outcome for patients with a shockable rhythm [sensitivity, 0.42; specificity, 0.27; area under the ROC curve (AUC), 0.60] in the BLS-only group. Contrastingly, for patients with a non-shockable rhythm, performing BLS for 6 min yielded the best neurologically outcome (sensitivity, 0.65; specificity, 0.43; AUC, 0.63). After propensity score matching, multivariate analysis revealed that BLS-only resuscitation [6.44 (5.34-7.77)] was associated with neurologically favourable 1-month survival. This retrospective study revealed that BLS-only intervention had a significant impact in the initial minutes following CPR initiation. Nevertheless, its effectiveness markedly declined thereafter. The optimal duration for effective BLS-only intervention varied depending on the patient's initial rhythm. Consequently, advanced interventions should be administered within the first few minutes to counteract the diminishing effectiveness of BLS-only intervention., (© 2024. The Author(s).)

An injectable anti-influenza drug peramivir has been reported to induce QT-interval prolongation in some phase III studies, although its thorough QT/QTc study was negative. We investigated the discrepancy among those clinical studies using isoflurane-anesthetized beagle dogs (n = 4). Peramivir in doses of 1 mg/kg/10 min (sub-therapeutic dose) followed by 10 mg/kg/10 min (clinically-relevant dose) was intravenously administered. Peramivir prolonged QT interval/QTcV and T peak -T end , and tended to delay ventricular repolarization in a reverse-frequency dependent manner, indicating I Kr inhibition in vivo. Meanwhile, peramivir did not alter P-wave duration, PR interval or QRS width, indicating a lack of impact on cardiac conduction via Na +  or Ca 2+ channel inhibition in vivo. Peramivir prolonged T peak -T end and tended to prolong terminal repolarization period, which would develop substrates for initiating and maintaining spiral reentry, respectively. Meanwhile, peramivir did not prolong J-T peak c, which could not induce early afterdepolarization, a trigger inducing torsade de pointes. Thus, our results support that clinical dose exposure of peramivir can delay the ventricular repolarization in influenza patients. Peramivir has only a small potential to induce torsade de pointes in patients with the intact hearts, but caution should be paid on its use for patients formerly having the trigger for torsade de pointes., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2024 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

Aim: In Japan, Niraparib maintenance therapy for primary and recurrent ovarian cancer was approved in September 2020 and is expected to improve the prognosis of ovarian cancer. However, the safety of niraparib maintenance therapy in Japanese patients has not been fully evaluated., Methods: Patients with ovarian cancer (including fallopian tube and peritoneal cancer) treated with niraparib at Jichi Medical University Hospital from September 2020 to August 2022 were enrolled in this study. Patient background, starting dose, rates of interruption, reduction, or discontinuation, adverse events (AEs) during treatment, and estimated glomerular filtration rate (eGFR) trends were retrospectively analyzed., Results: Twenty-nine patients received niraparib maintenance therapy during the study period, including 21 with primary cancer and 8 patients with recurrent cancer. Seventeen patients (58.6%) required dose interruptions and 16 patients (55.2%) required dose reductions. Only two patients (6.9%) discontinued treatment due to fatigue and nausea. The most frequent AE was creatinine increases in 18 patients (62.1%, all grades). Although eGFR levels decreased significantly after niraparib therapy compared to before niraparib therapy (59.3 vs. 50.3 mL/min/1.73 m 2 , p < 0.001), the levels returned to pre-niraparib initiation levels after discontinuation of niraparib (64.6 vs. 64.6 mL/min/1.73 m 2 , p = 0.96). Multivariate regression analysis showed that diabetes was independently associated with decreased eGFR (p = 0.013)., Conclusions: Niraparib maintenance therapy frequently increased serum creatinine, but the change was reversible. Further studies are needed to determine the effects of niraparib on renal function in Japanese patients., (© 2023 Japan Society of Obstetrics and Gynecology.)

Introduction and Objectives: To compare gonad doses with and without a gonad protector and to optimize the use of gonadal protectors in infants thorax radiography., Materials and Methods: Two pediatric anthropomorphic phantoms are used: an X-ray system for KXO-50SS/DRX-3724HD, and a digital radiography system for CALNEO Smart C12, with and without a gonad protector during infants thorax radiography. A real time skin dosimeter is placed on the X-ray system, and a real time skin dosimeter is inserted on the front side of the mammary gland, the front and back sides of the true pelvis level, and on the ovaries and testes. The X-ray system is irradiated 15 times using phantoms with and without a gonad protector. The measured entrance patient doses values of for the real time skin dosimeter are compared for each phantom, with and without the gonad protector., Results: The medium of measured entrance patient doses values for front side dose of the true pelvis level with and without the protector are 10.00 and 5.00 μGy at newborn, and 10.00 and 0.00μGy at one year, respectively. The medium of measured entrance patient doses values for the back side dose of the true pelvis level with and without the protector are 0.00 and 0.00 μGy at both newborn one year, respectively. The measured entrance patient doses cannot be detected in the ovaries and testes with or without the protector. No significant differences are observed in the measured entrance patient doses values for the front and back side doses of the pelvis, ovaries, and testes at newborn and one year, with and without the protector (p>0.05)., Conclusions: No significant difference was observed in gonad dose measurements with and without the gonad protector during infants chest radiography. We believe that gonadal protector wearing is not necessary., (Copyright © 2022 SERAM. Published by Elsevier España, S.L.U. All rights reserved.)

In a world increasingly confronted by cardiovascular diseases (CVDs) and an aging population, accurate risk assessment prior to cardiac surgery is critical. Although effective, traditional risk calculators such as the Japan SCORE, Society of Thoracic Surgeons score, and EuroSCORE II may not completely capture contemporary risks, particularly due to emerging factors such as frailty and sarcopenia. These calculators often focus on regional and ethnic specificity and rely heavily on evaluations based on age and underlying diseases. Growth differentiation factor-15 (GDF-15) is a stress-responsive cytokine that has been identified as a potential biomarker for sarcopenia and a tool for future cardiac risk assessment. Preoperative plasma GDF-15 levels have been associated with preoperative, intraoperative, and postoperative factors and short- and long-term mortality rates in patients undergoing cardiac surgery. Increased plasma GDF-15 levels have prognostic significance, having been correlated with the use of cardiopulmonary bypass during surgery, amount of bleeding, postoperative acute kidney injury, and intensive care unit stay duration. Notably, the inclusion of preoperative levels of GDF-15 in risk stratification models enhances their predictive value, especially when compared with those of the N-terminal prohormone of brain natriuretic peptide, which does not lead to reclassification. Thus, this review examines traditional risk assessments for cardiac surgery and the role of the novel biomarker GDF-15. This study acknowledges that the relationship between patient outcomes and elevated GDF-15 levels is not limited to CVDs or cardiac surgery but can be associated with variable diseases, including diabetes and cancer. Moreover, the normal range of GDF-15 is not well defined. Given its promise for improving patient care and outcomes in cardiovascular surgery, future research should explore the potential of GDF-15 as a biomarker for postoperative outcomes and target therapeutic intervention., Competing Interests: Declaration of competing interest The authors declare that there is no conflict of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Vertebrates have expanded their habitats during evolution, which accompanies diversified routes for water acquisition. Water is acquired by oral intake and subsequent absorption by the intestine in terrestrial and marine animals which are subjected to constant dehydration, whereas most water is gained osmotically across body surfaces in freshwater animals. In addition, a significant amount of water, called metabolic water, is produced within the body by the oxidation of hydrogen in organic substrates. The importance of metabolic water production as a strategy for water acquisition has been well documented in desert animals, but its role has attracted little attention in marine animals which also live in a dehydrating environment. In this article, the author has attempted to reevaluate the role of metabolic water production in body fluid regulation in animals inhabiting desiccating environments. Because of the exceptional ability of their kidney, marine mammals are thought to typically gain water by drinking environmental seawater and excreting excess NaCl in the urine. On the other hand, it is established that marine teleosts drink seawater to enable intestinal water and ion absorption, and the excess NaCl is excreted by branchial ionocytes. In addition to the oral route, we suggest through experiments using eels that water production by lipid metabolism is an additional route for water acquisition when they encounter seawater. It seems that metabolic water production contributes to counteract dehydration before mechanisms for water regulation are reversed from excretion in freshwater to acquisition in seawater.

Thin and light vibrators that leverage the inverse piezoelectric effect with a diaphragm mechanism are promising vibrotactile actuators owing to their form factors and high temporal and frequency response. However, generating perceptually sufficient displacement in the low-frequency domain is challenging. This study presents a lever mechanism mounted on a diaphragm vibrator to enhance the vibrotactile intensity of low-frequency vibrotactile stimuli. The lever mechanism is inspired by the tactile contact lens consisting of an array of cylinders held against the skin on a sheet that enhances micro-bump tactile detection. We built an experimental apparatus including our previously developed thin-film diaphragm-type vibrator, which reproduced the common characteristic of piezoelectric vibrators: near-threshold displacement (10 to 20 μm) at low frequency. Experiments demonstrated enhanced vibrotactile intensity at frequencies less than 100 Hz with the lever mechanism. Although the arrangement and material of the mechanism can be improved, our findings can help improve the expressiveness of diaphragm-type vibrators.

Although morphine has been used for treatment-resistant dyspnea in end-stage heart failure patients, information on its cardiovascular safety profile remains limited. Morphine was intravenously administered to halothane-anesthetized dogs (n=4) in doses of 0.1, 1 and 10 mg/kg/10 min with 20 min of observation period. The low and middle doses attained therapeutic (0.13 µg/mL) and supratherapeutic (0.97 µg/mL) plasma concentrations, respectively. The low dose hardly altered any of the cardiovascular variables except that the QT interval was prolonged for 10-15 min after its start of infusion. The middle dose reduced the preload and afterload to the left ventricle for 5-15 min, then decreased the left ventricular contractility and mean blood pressure for 10-30 min, and finally suppressed the heart rate for 15-30 min. Moreover, the middle dose gradually but progressively prolonged the atrioventricular conduction time, QT interval/QTcV, ventricular late repolarization period and ventricular effective refractory period without altering the intraventricular conduction time, ventricular early repolarization period or terminal repolarization period. A reverse-frequency-dependent delay of ventricular repolarization was confirmed. The high dose induced cardiohemodynamic collapse mainly due to vasodilation in the initial 2 animals by 1.9 and 3.3 min after its start of infusion, respectively, which needed circulatory support to treat. The high dose was not tested further in the remaining 2 animals. Thus, intravenously administered morphine exerts a rapidly appearing vasodilator action followed by slowly developing cardiosuppressive effects. Morphine can delay the ventricular repolarization possibly through I Kr inhibition in vivo, but its potential to develop torsade de pointes will be small.

This study aims to represent fine texture differences in pencil hardness using intensity segment modulation (ISM), a sensory equivalent conversion method of vibration from high to low frequencies. This method enables the presentation of delicate tactile sensations even with small transducers. We integrated this approach in the world's thinnest ultra-thin PZT-MEMS vibrator with a stylus-type device. The vibration waveforms of four types of pencil hardness were captured under the same conditions, and the differences in the frequency components were confirmed. We compared the fine texture feelings under raw signal, ISM, and ISM below 1 kHz conditions by conducting discrimination tests and subjective similarity evaluations. The results showed that ISM could reproduce similar feelings of the pencil hardness.

Background: Progesterone therapy is a relatively inexpensive treatment option for endometrial and breast cancers, with few side effects. Two signaling pathways usually mediate the physiological effects of progesterone, namely genomic and non-genomic actions. Genomic action occurs slowly via the nuclear progesterone receptor (PR), whereas the membrane progesterone receptor (mPR) induces rapid non-genomic action., Aims: We investigated the effects of progesterone and various PR agonists on ovarian cancer cells., Methods and Results: PR expression of six serous ovarian cancer cell lines was examined by western blotting, and mPR expression was examined by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). PR-negative and mPR-positive ovarian cancer cells were exposed to progesterone and seven types of PR agonists (medroxyprogesterone acetate [MPA], dehydroepiandrosterone, dienogest, levonorgestrel, drospirenone, pregnenolone, and allopregnanolone) at 10-400 μM, and viable cell counts after exposure for 30 min were measured using the water-soluble tetrazolium (WST-1) assay. Ovarian cancer cell lines were exposed to 100 μM progesterone, and the expression of BAX, a pro-apoptotic protein, after 1-5 min was examined by western blotting. Western blotting detected no PR expression in the six serous ovarian cancer cell lines. In contrast, RT-qPCR detected mPR expression in all six serous ovarian cancer cell lines. Progesterone and MPA-induced cell death in all tested ovarian cancer cell lines in a concentration-dependent manner, whereas no effect was observed for other PR agonists. Western blotting revealed that pro-apoptotic protein BAX expression occurred 1 min after exposure to progesterone, suggesting that the cytocidal effects are mediated by rapid non-genomic action., Conclusion: Progesterone and MPA exhibited a rapid cytocidal effect on PR-negative ovarian cancer cells through non-genomic action. Progesterone and MPA could be novel adjuvant therapies for ovarian cancer., (© 2023 The Authors. Cancer Reports published by Wiley Periodicals LLC.)

Multiplexed imaging uncovers precise three-dimensional maps of single nuclei.

Bipolar disorder (BD) is a common psychiatric disorder, but its pathophysiology is not fully elucidated. The current study focused on its electrophysiological characteristics, especially power spectral density (PSD). Resting state with eyes opened magnetoencephalography data were collected from 21 patients with BD and 22 healthy controls. The whole brain's PSD was calculated from source reconstructed waveforms at each frequency band (delta: 1-3 Hz, theta: 4-7 Hz, alpha: 8-12 Hz, low beta: 13-19 Hz, high beta: 20-29 Hz, and gamma: 30-80 Hz). We compared PSD values on the marked vertices at each frequency band between healthy and patient groups using a Mann-Whitney rank test to examine the relationship between significantly different PSD and clinical measures. The PSD in patients with BD was significantly decreased in lower frequency bands, mainly in the default mode network (DMN) areas (bilateral medial prefrontal cortex, bilateral precuneus, left inferior parietal lobe, and right temporal cortex in the alpha band) and salience network areas (SAL; left anterior insula [AI] at the delta band, anterior cingulate cortex at the theta band, and right AI at the alpha band). No significant differences in PSD were observed at low beta and high beta. PSD was not correlated with age or other clinical scales. Altered PSDs of the DMN and SAL were observed in the delta, theta, and alpha bands. These alterations contribute to the vulnerability of BD through the disturbance of self-referential mental activity and switching between the default mode and frontoparietal networks., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

The first prophylactic vaccine against human papillomavirus (HPV) 16 and HPV18 was licensed in Japan in 2009. HPV vaccine effectiveness against high-grade cervical lesions has been demonstrated among young Japanese women, but evidence of its effects on invasive cervical cancer (ICC) is lacking. Using data from two different cancer registries, we compared recent trends of new ICC cases by age group using Poisson regression analysis. We also analyzed time trends in HPV16/18 prevalence among 1414 Japanese women aged <40 years newly diagnosed with ICC in the past decade. Based on the population-based cancer registry, the incidence of ICC among young women aged 20-29 years showed a significant decline from 3.6 to 2.8 per 100 000 women-years during 2016-2019, but no similar decline was observed for older age groups (p < 0.01). Similarly, using data from the gynecological cancer registry of the Japan Society of Obstetrics and Gynecology, the annual number of ICCs among women aged 20-29 years also decreased from 256 cases to 135 cases during 2011-2020 (p < 0.0001). Furthermore, a declining trend in HPV16/18 prevalence in ICC was observed only among women aged 20-29 years during 2017-2022 (90.5%-64.7%, p = 0.05; Cochran-Armitage trend test). This is the first report to suggest population-level effects of HPV vaccination on ICC in Japan. Although the declining trend in HPV16/18 prevalence among young women with ICC supports a causal linkage between vaccination and results from cancer registries, further studies are warranted to confirm that our findings are attributable to vaccination., (© 2023 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

The purpose of this study was to evaluate the effectiveness of a hands-on seminar using a Web conferencing system, based on the post-event questionnaires of the face-to-face and online seminars of the hands-on seminar. For participants to feel realistic training in the online seminars, four educational videos explaining the procedure of the practical skill were created. We compared results of questionnaires acquired from participants after the face-to-face and online seminars. The questions about expectation, comprehension, satisfaction level, and lecture time for the seminars were graded on a 5-point scale. The higher the scores, the higher the rating, except for lecture time. A score of 3 was appropriate for the lecture time, with a higher score indicating that the seminar felt longer and a lower score indicating that the seminar felt shorter. In the evaluation of classroom lectures, such as expectation, comprehension, and satisfaction level for the seminars, there were no significant differences between the face-to-face and online seminars, and both achieved high scores of 4 or more. There was a significant difference in the evaluation of lecture time for classroom lectures, with participants feeling that it was too short in the face-to-face but just right in the online. In all evaluations for hands-on training and discussion, there were no significant differences between the face-to-face and online seminars, and both achieved high scores of 4 or more and time was short. It was concluded that our proposed online seminar approach could achieve a high level of evaluation as face-to-face seminars.

Background: Transcatheter valve replacement is contraindicated in patients with active infective endocarditis. However, few reports suggest that it could be beneficial for high-risk surgical patients with healed infective endocarditis. Here, we report a case of a surgical transcatheter aortic valve in a patient with healed repeated prosthetic valve endocarditis using a stentless valve., Case Presentation: A 79-year-old female who underwent the Bentall procedure using a stentless valve and coronary artery bypass grafting for annuloaortic ectasia 22 years ago was hospitalized for stage II bioprosthetic valve failure. The patient had a history of prosthetic valve endocarditis three times: the first and second prosthetic valve endocarditis occurred 15 years ago, and the third prosthetic valve endocarditis occurred 3 years ago. The causative organisms were Campylobacter fetus and Enterococcus faecalis. With appropriate antibiotic therapy, the lesion was localized and healed completely without valve destruction; however, the patient developed rapid aortic regurgitation. Based on a review of the patient's history of prosthetic valve endocarditis, the absence of signs of infection, and clinical findings of transesophageal echocardiography and computed tomography, a diagnosis of structural valve deterioration with healed infective endocarditis was made. Subsequently, a transcatheter aortic valve in a surgical aortic valve using a balloon-expandable type was performed, because the patient had a high surgical risk of 12.7%. The patient's postoperative course was uneventful. At the 1-year follow-up, there were no signs of infection or valve abnormalities., Conclusions: Transcatheter valve replacement can be a treatment option for high-risk surgical patients with healed limited lesions in infective endocarditis., (© 2023. Japan Surgical Society.)

Background: Recent guidelines state that improving the survival rate of patients with ruptured abdominal aortic aneurysm (rAAA) requires a protocol or algorithm for the emergency management of these patients. We aimed to investigate whether introducing a protocol treatment for rAAA improves clinical outcomes compared with the pre-protocol strategy., Methods: At our institution, 92 patients treated for rAAA between June 2008 and August 2022 were retrospectively analyzed. In 2014, the protocol-based treatment was introduced comprising a transfer algorithm to shorten the time to proximal control, use of an endovascular occlusion balloon, strict indications for endovascular aortic aneurysm repair (EVAR) or open surgical repair, and perioperative care, including for abdominal compartment syndrome (ACS). Clinical outcomes were compared between the protocol and pre-protocol group, including operative status, all-cause mortality, and rAAA-related death at 30-day, in-hospital, and 1-year postoperative follow-ups., Results: Overall, 52 and 40 patients received the protocol-based and pre-protocol treatments, respectively. EVAR was more frequently performed in the protocol group. The rate of achieving time to proximal control was significantly faster, and the transfusion volume was lower in the protocol group. ACS occurred more frequently in the protocol group with a higher EVAR. No difference was found in all-cause mortality between the two groups. The protocol group exhibited fewer rAAA-related deaths than the pre-protocol group during the following time points: 30 days (9.6% vs. 22.5%), during the hospital stay (11.5% vs. 30.0%), and 1 year (14.5% vs. 31.5%)., Conclusions: The protocol-based treatment improved the survival rate of patients with rAAA., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Endothelial dysfunction and increased left ventricular (LV) stiffness are associated with the incidence of heart failure with preserved ejection fraction (HFpEF). This study evaluated the association between endothelial dysfunction and LV diastolic stiffness., Methods and results: Endothelial dysfunction evaluated by flow-medicated vasodilation (FMD) and the reactive hyperemia index (RHI), which reflects endothelial dysfunction in the microvasculature, was measured in 112 subjects with hypertension in the Flow-Mediated Dilation Japan (FMD-J) study. Using transthoracic echocardiography, LV diastolic stiffness was evaluated by measuring diastolic wall strain (DWS) in the LV posterior wall. In this cross-sectional study, associations among FMD, RHI, and DWS were investigated using multiple regression analyses. The mean (±SD) age of the subjects 65±9 years, and 63% were men. DWS was significantly associated with RHI, but not FMD, on multivariate linear regression analysis (β=0.39; P<0.0001). This association was preserved in subjects without LV hypertrophy (β=0.46; P<0.0001). A DWS ≤median, suggesting increased LV diastolic stiffness, was significantly associated with RHI on multivariate logistic regression analysis (odds ratio 20.58; 95% confidence interval 4.83-87.63; P<0.0001). The receiver operating characteristic curve presented a cut-off value of 2.21 for RHI, with a sensitivity of 77% and a specificity of 71%, for DWS ≤median., Conclusions: RHI, rather than FMD, was associated with DWS. Endothelial dysfunction in the microvasculature may be associated with increased LV diastolic stiffness.