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Image-enhanced endoscopy (IEE) has advanced gastrointestinal disease diagnosis and treatment. Traditional white-light imaging has limitations in detecting all gastrointestinal diseases, prompting the development of IEE. In this review, we explore the utility of IEE, including texture and color enhancement imaging and red dichromatic imaging, in pancreatobiliary (PB) diseases. IEE includes methods such as chromoendoscopy, optical-digital, and digital methods. Chromoendoscopy, using dyes such as indigo carmine, aids in delineating lesions and structures, including pancreato-/cholangio-jejunal anastomoses. Optical-digital methods such as narrow-band imaging enhance mucosal details and vessel patterns, aiding in ampullary tumor evaluation and peroral cholangioscopy. Moreover, red dichromatic imaging with its specific color allocation, improves the visibility of thick blood vessels in deeper tissues and enhances bleeding points with different colors and see-through effects, proving beneficial in managing bleeding complications post-endoscopic sphincterotomy. Color enhancement imaging, a novel digital method, enhances tissue texture, brightness, and color, improving visualization of PB structures, such as PB orifices, anastomotic sites, ampullary tumors, and intraductal PB lesions. Advancements in IEE hold substantial potential in improving the accuracy of PB disease diagnosis and treatment. These innovative techniques offer advantages paving the way for enhanced clinical management of PB diseases. Further research is warranted to establish their standard clinical utility and explore new frontiers in PB disease management.

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BACKGROUND: Tryptase, a mast cell protease, has been identified as a potential therapeutic target in managing patients with refractory asthma. We assessed the efficacy, safety, pharmacokinetics, and pharmacodynamics of MTPS9579A, an anti-tryptase antibody, in a phase 2a randomized trial for patients with uncontrolled asthma and a phase 1c trial to understand activity within the lower respiratory tract. METHODS: Phase 2a patients (n = 134) received 1800 mg MTPS9579A or placebo intravenously every 4 weeks for 48 weeks. The primary endpoint was time to the first composite exacerbation event. Phase 1c patients (n = 27) received one intravenous dose of 300 or 1800 mg MTPS9579A or placebo. Both trials measured MTPS9579A concentrations and effects on tryptase in serum and nasal lining fluid; phase 1c also analyzed bronchial lining fluid. RESULTS: MTPS9579A did not meet the primary endpoint (hazard ratio = 0.90; 95% CI: 0.55-1.47; p = 0.6835); exacerbation rates in the placebo group were low. Serum and nasal MTPS9579A pharmacokinetics and tryptase levels were consistent with data from healthy volunteers. However, in phase 1c patients, compared to nasal levels, MTPS9579A bronchial concentrations were 6.8-fold lower, and bronchial active and total tryptase levels were higher (119-fold and 30-fold, respectively). Pharmacokinetic/pharmacodynamic modeling predicted intravenous doses of 3800 mg every 4 weeks would be necessary to achieve 95% active tryptase inhibition from baseline. CONCLUSIONS: The MTPS9579A dose tested in the phase 2a study was insufficient to inhibit tryptase in bronchial lining fluid, likely contributing to the observed lack of efficacy.

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This study aimed to investigate the effect of Japanese dietary patterns on metabolic dysfunction-associated steatotic liver disease (MASLD) and liver fibrosis. After excluding factors affecting the diagnosis of hepatic steatosis, 727 adults were analyzed as part of the Health Promotion Project. The dietary patterns of the participants were classified into rice, vegetable, seafood, and sweet based on their daily food intake. Liver stiffness measurements and controlled attenuation parameters were performed using FibroScan. Energy and nutrient intake were calculated using the Brief-type Self-administered Diet History Questionnaire. Univariate and multivariate analyses were used to identify the risk factors for liver fibrosis within the MASLD population. The vegetable group had significantly lower liver fibrosis indicators in the MASLD population than the rice group. The multivariate analysis identified a body mass index ≥ 25 kg/m2 (odds ratio [OR], 1.83; 95% confidence interval [CI], 1.01-1.83; p = 0.047) and HOMA-IR ≥ 1.6 (OR, 3.18; 95% CI, 1.74-5.78; p < 0.001) as risk factors for liver fibrosis, and vegetable group membership was a significant low-risk factor (OR, 0.38; 95% CI, 0.16-0.88; p = 0.023). The multivariate analysis of nutrients in low-risk foods revealed high intake of α-tocopherol (OR, 0.74; 95% CI, 0.56-0.99; p = 0.039) as a significant low-risk factor for liver fibrosis. This study suggests that a vegetable-based Japanese dietary pattern, through the antioxidant effects of α-tocopherol, may help prevent liver fibrosis in MASLD and the development of MASLD.

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Background: Cardiac resynchronization therapy (CRT) with biventricular pacing is a well-established therapy. Left bundle branch area pacing (LBBAP) is a safe technique providing physiological pacing, and LBBAP-optimized CRT (LOT-CRT) has been shown to provide better electrical resynchronization than traditional CRT. However, there are few reports on shock lead placement in the left bundle branch area (LBBA) during CRT-defibrillator (CRT-D) implantation. Case summary: A 76-year-old woman with heart failure from dilated cardiomyopathy presented with left bundle branch block pattern (QRS duration, 160 ms). Left ventricular ejection fraction was 21%. Cardiac resynchronization therapy-defibrillator implantation was performed due to worsening symptoms. By reshaping the Agilis HisPro catheter and adding a septal curve, the shock lead was placed deep into the ventricular septum, narrowing QRS duration to 114 ms. Left ventricular activation time was 84 ms. A defibrillation threshold test confirmed successful treatment without adverse events. At 6-month follow-up, left ventricular ejection fraction improved from 21 to 63%, with the patient's condition improving from New York Heart Association class III to class I. Discussion: It was reported that QRS narrowing in CRT was related to long-term mortality, and LOT-CRT further decreased QRS duration as compared with LBBP only or biventricular pacing and increased the response rate. Combining LBBAP with coronary sinus pacing can potentially achieve superior electrical resynchronization. Lack of a suitable tool for direct shock lead placement in LBBA necessitated additional LBBAP lead in conventional LOT-CRT. Our successful LOT-CRT-D procedure with minimal number of leads through Agilis HisPro catheter reshaping enabled direct LBBA shock lead placement.

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AIMS: Atrial fibrillation (AF) is frequently associated with heart failure with preserved ejection fraction (HFpEF), but the diagnosis and prediction of the outcomes of HFpEF are difficult. Notably, the Heart Failure Association of the European Society of Cardiology proposed the use of the HFA-PEFF score in the diagnosis of HFpEF. This study aimed to assess the prognostic value of the pre- and post-procedural HFA-PEFF scores in patients with preserved ejection fraction (EF) after catheter ablation (CA) for AF. The primary endpoint was a composite of cardiac hospitalization for cardiovascular events and all-cause mortality. The secondary endpoint was AF recurrence. METHODS AND RESULTS: Overall, 354 patients with AF and preserved EF who underwent CA as well as blood tests and transthoracic echocardiography 2 weeks before and 6 months after CA from January 2018 to December 2019 were retrospectively enrolled in the study. In the 354 participants, univariate analysis showed that the post-procedural HFA-PEFF score was associated with a 3-year risk of the primary endpoint (hazard ratio [HR] = 3.73; 95% confidence interval [CI] = 2.07-6.73; P < 0.001), whereas the pre-procedural HFA-PEFF score was not (HR = 1.24, 95% CI = 0.82-1.86, P = 0.307). Further, the association between the post-procedural HFA-PEFF score and primary endpoint was not modified even after including other relevant variables into the score. Similar to the primary endpoint, the post-procedural HFA-PEFF score was associated with the 3-year risk of AF recurrence (P < 0.001). CONCLUSIONS: In patients with preserved EF undergoing AF ablation, the HFA-PEFF score at 6 months after CA was associated with the primary endpoint and AF recurrence at the 3-year follow-up.

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Key Clinical Message: Atrial fibrillation ablation, including pulmonary vein isolation immediately after left atrial appendage closure (LAAC), is a rare and challenging issue. Intracardiac echocardiography guidance can help identify the LAAC device position for safe atrial fibrillation ablation without LAAC device-related adverse events even immediately after LAAC device implantation. Abstract: Early phase atrial fibrillation (AF) ablation after left atrial appendage closure (LAAC) is a rare and challenging issue. Here, we present a case illustrating the feasibility of AF ablation under intracardiac echocardiography guidance immediately after LAAC device implantation without LAAC device-related adverse events.

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The in situ measurement technique for a metal/metal-oxide mixture at extra-high temperature above 2000 K has been desired in the field of nuclear safety engineering. In the present study, we succeeded in simultaneous XAFS-XRD measurements of the Zr oxidation [Zr + O → Zr(O) + ZrO2] up to 1952 K and ZrO2-Y2O3 reaction from 1952 to 2519 K. The chemical shift during Zr oxidation was observed in the absorption spectra around the Zr K-edge, and the interatomic cation-cation and cation-oxygen distances obtained by the fitting analysis of EXAFS during the Y2O3-ZrO2 reaction are explained. Also, the temperature dependency of the anharmonic effect was investigated by comparing the fitted second- and third-order cumulants with the theoretical ones in which the Morse potential was applied as an interatomic potential, giving a good explanation about the local structure dynamics. Finally, the applicability of the developed system to investigation of nuclear fuel materials, such as UO2-Zr, is discussed.

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Fetal growth restriction (FGR) is a major concern in perinatal care. Various medications have been proposed as potential treatments for this serious condition. Nonetheless, there is still no definitive treatment. We studied tadalafil, a phosphodiesterase-5 inhibitor, as a therapeutic agent for FGR in clinical studies and animal experiments. In this review, we summarize our preclinical and clinical data on the use of tadalafil for FGR. Our studies in mouse models indicated that tadalafil improved FGR and hypertensive disorders of pregnancy. A phase II trial we conducted provided evidence supporting the efficacy of tadalafil in prolonging pregnancy (52.4 vs. 36.8 days; p = 0.03) and indicated a good safety profile for fetuses and neonates. Fetal, neonatal, and infant mortality was significantly lower in mothers receiving tadalafil treatment than that in controls (total number: 1 vs. 7, respectively; p = 0.03), and no severe adverse maternal events associated with tadalafil were observed. Although further studies are needed to establish the usefulness of tadalafil in FGR treatment, our research indicates that the use of tadalafil in FGR treatment may be a paradigm shift in perinatal care.

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Personalized dosing approaches play important roles in clinical practices to improve benefit: risk profiles. Whereas this is also important for drug development, especially in the context of drugs with narrow therapeutic windows, such approaches have not been fully evaluated during clinical development. Fazpilodemab (BFKB8488A) is an agonistic bispecific antibody which was being developed for the treatment of nonalcoholic steatohepatitis. The objective of this study was to characterize the exposure-response relationships of fazpilodemab with the purpose of guiding dose selection for a phase II study, as well as to evaluate various personalized dosing strategies to optimize the treatment benefit. Fazpilodemab exhibited clear exposure-response relationships for a pharmacodynamic (PD) biomarker and gastrointestinal adverse events (GIAEs), such as nausea and vomiting. Static exposure-response analysis, as well as longitudinal adverse event (AE) analysis using discrete-time Markov model, were performed to characterize the observations. Clinical trial simulations were performed based on the developed exposure-response models to evaluate probability of achieving target PD response and the frequency of GIAEs to inform phase II dose selection. Dynamic simulation of personalized dosing strategies demonstrated that the AE-based personalized dosing is the most effective approach for optimizing the benefit-risk profiles. The approach presented here can be a useful framework for quantifying the benefit of personalized dosing for drugs with narrow therapeutic windows.

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STUDY OBJECTIVE: To assess the impact visceral adipose tissue percentage (VAT%) on surgical outcomes during minimally invasive surgery in obese women with endometrial cancer. DESIGN: Retrospective observational cohort study. SETTING: Mie University Hospital, Japan. PATIENTS: Of the 73 women (body mass index [BMI] >30 kg/m2) with obesity and primary endometrial cancer, 52 underwent robotic surgery, while 21 underwent laparoscopic surgery between April 2014 and December 2022. INTERVENTIONS: We investigated the correlation between surgical outcomes (operative time and blood loss) and obesity (BMI and visceral adipose tissue percentage [VAT%]). MEASUREMENTS AND MAIN RESULTS: Abdominal fat-related parameters were measured at the level of the umbilicus using preoperative computed tomography. A weak negative correlation was found between BMI and VAT% (CC = -0.313, p = .001). Multivariate analysis showed that VAT% had a stronger correlation to total and practical operative time than BMI (ß = 0.338 vs 0.267, ß = 0.311 vs 0.209, respectively) and was an independent predictor of blood loss. VAT% was an independent predictive marker prolonged for operative time and increased blood loss during lymphadenectomy. CONCLUSION: VAT% could be an indicator of surgical outcomes for patients with obesity and endometrial cancer.

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Recently, conduction system pacing has been performed in patients with impaired cardiac function. We report a case in which a DF4 implantable cardioverter defibrillator lead was screwed directly into the left bundle branch area with the support of a steerable delivery sheath.

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Although the late cardiac tamponade in leadless pacemaker implantation (LPI) is rare, we encountered such an incident in patient with AVEIR-VR™ system on hemodialysis and warfarinization. When LPI with active fixation system, we should aim for successful single-attempt deployment using electrical premapping to prevent cardiac tamponade including the late phase.

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The effect of membrane transporters on drug disposition, efficacy and safety is now well recognized. Since the initial publication from the International Transporter Consortium, significant progress has been made in understanding the roles and functions of transporters, as well as in the development of tools and models to assess and predict transporter-mediated activity, toxicity and drug-drug interactions (DDIs). Notable advances include an increased understanding of the effects of intrinsic and extrinsic factors on transporter activity, the application of physiologically based pharmacokinetic modelling in predicting transporter-mediated drug disposition, the identification of endogenous biomarkers to assess transporter-mediated DDIs and the determination of the cryogenic electron microscopy structures of SLC and ABC transporters. This article provides an overview of these key developments, highlighting unanswered questions, regulatory considerations and future directions.

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Natural language processing (NLP) is a branch of artificial intelligence, which combines computational linguistics, machine learning, and deep learning models to process human language. Although there is a surge in NLP usage across various industries in recent years, NLP has not been widely evaluated and utilized to support drug development. To demonstrate how advanced NLP can expedite the extraction and analyses of information to help address clinical pharmacology questions, inform clinical trial designs, and support drug development, three use cases are described in this article: (1) dose optimization strategy in oncology, (2) common covariates on pharmacokinetic (PK) parameters in oncology, and (3) physiologically-based PK (PBPK) analyses for regulatory review and product label. The NLP workflow includes (1) preparation of source files, (2) NLP model building, and (3) automation of data extraction. The Clinical Pharmacology and Biopharmaceutics Summary Basis of Approval (SBA) documents, US package inserts (USPI), and approval letters from the US Food and Drug Administration (FDA) were used as our source data. As demonstrated in the three example use cases, advanced NLP can expedite the extraction and analyses of large amounts of information from regulatory review documents to help address important clinical pharmacology questions. Although this has not been adopted widely, integrating advanced NLP into the clinical pharmacology workflow can increase efficiency in extracting impactful information to advance drug development.

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Background: It is unknown whether atrial fibrillation (AF) burden varies by pacing site in patients with reactive atrial antitachycardia pacing (rATP). We aimed to compare AF burden in patients with high atrial septal pacing (HASp) via delivery catheter and right atrial appendage pacing (RAAp) in patients with sick sinus syndrome (SSS). Methods: We retrospectively identified 109 patients with a history of paroxysmal AF and SSS who had received dual-chamber pacemaker implantation between January 2017 and December 2019, of whom 39 and 70 patients had HASp and RAAp, respectively. rATP was initiated after a 1-month post-implantation run-in period. Results: Patients with HASp had a significantly shorter P-wave duration during atrial pacing than those with RAAp (99.3 ± 10.4 vs. 116.0 ± 14.3 ms, p < .001). During the 3-year follow-up period, the incidence of an AF lasting longer than 1 or 7 days was significantly lower (hazard ratio [HR], 0.45; p = .016; HR, 0.24; p = .004) than in those with RAAp. The median time of AF/AT per day in the follow-up periods was significantly shorter in the HASp group than in the RAAp group (10 vs. 18 min/day, p = .018). Atrial lead division did not occur in the HASp group during the follow-up period. Conclusions: HASp via delivery catheter is as safe as RAAp, and HASp combined with rATP is effective for reducing AF burden in patients with SSS and paroxysmal AF.

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Key Clinical Message: Bile duct metastasis of breast cancer is rare. It often causes obstructive jaundice which makes the patient interrupt state of treatment. Endoscopic drainage for obstructive jaundice is effective and less invasive treatment option also in this case. Abstract: A 66-year-old breast ductal carcinoma patient developed obstructive jaundice, presenting with epigastric discomfort and dark-colored urine. Computed tomography and endoscopic retrograde cholangiopancreatography revealed bile duct stenosis. Brushing cytology and tissue biopsy confirmed bile duct metastasis, a self-expandable metallic stent was placed/replaced endoscopically, and chemotherapy was continued, extending the patient's life.