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Hiroaki Hagiwara,1 Yoshinori Kinno,1 Tadashi Ikegami2 1Department of Radiology, Yokohama Minamikyosai Hospital, Yokohama, Japan; 2Department of Diagnostic Imaging, Kanagawa Dental University, Yokosuka, JapanCorrespondence: Hiroaki Hagiwara, Department of Radiology, Yokohama Minamikyosai Hospital, 1-21-1 Mutsuura-higashi Kanazawa-ku, Yokohama, 236-0037, Japan, Tel +81-45-782-2101, Fax +81-45-701-9159, Email hhagi1936@gmail.comPurpose: Spontaneous pneumomediastinum, supposedly attributed to air leakage from the respiratory tract, is a common complication of interstitial lung disease often resulting in mediastinal widening. However, several cases of pneumomediastinum without mediastinal widening have been observed. This study aimed to investigate the cause of pneumomediastinum in patients without mediastinal widening.Patients and Methods: This study included 41 patients diagnosed with pneumomediastinum using computed tomography (CT) between July 2011 and September 2021 at Yokohama Minamikyosai Hospital; patients had undergone previous CT showing no gas density. Based on a comparison with previous CT images, the patients were classified into two groups: without mediastinal widening and with mediastinal widening.Results: Of the 41 patients, 13 and 28 had pneumomediastinum without and with mediastinal widening, respectively. There were no significant differences in the sex, age, body mass index, or pneumomediastinum distribution between the groups. However, the rate of weight loss per month was significantly greater in the group without mediastinal widening than in that with mediastinal widening. No significant differences were observed in the respiratory function test results between the two groups; that said, 10 of the 13 patients without mediastinal widening had restrictive disorders. Pulmonary disease in this group included idiopathic pulmonary fibrosis (n = 6), interstitial lung disease with collagen disease (n = 4), and other disease (n = 1). Pneumomediastinum occurred during periods of weight loss in all patients without widening, excluding two patients without data.Conclusion: Pneumomediastinum without mediastinal widening occurs during rapid weight loss and is often associated with restrictive lung disorders. The negative pressure attributed to the decreased plasticity of the lungs, which complements the space where the mediastinal fat has disappeared, is presumably the cause of pneumomediastinum. This pathophysiology is different from that of conventional pneumomediastinum attributed to increased intrapleural space pressure; thus, we propose to name the abovementioned pathophysiology “negative pressure pneumomediastinum”.Graphical Abstract: Keywords: interstitial lung disease, idiopathic lung fibrosis, restrictive lung disorder

Here, we synthesized Co-based, anion-incorporated‍ ‌R‌u‌d‌d‌l‌e‌s-d‌e‌n‌-‌Popper perovskite electrocatalysts (LaSrCoO 4 -x X y ) and compared their catalytic performances in the oxygen reduction reaction (ORR) and oxygen evolution reaction (OER). The ORR mechanism with the newly synthesized F-doped LaSrCoO 4 catalyst was dominated by a four-electron process, and the number of electrons involved in the reaction increased compared with that for LaSrCoO 4 . The OER activity of the hydride-doped LaSrCoO 4 catalyst was the highest among the LaSrCoO 4 system catalysts. Density functional theory calculations revealed that there is a correlation between the Co 3d unoccupied orbital band centre and the OER activity. The addition of anions and substitution of metal sites improved the ORR and OER activities of the catalysts. Our findings confirmed that the addition of heteroatom anions can improve the activity of perovskite-type electrocatalysts, promoting their application in various fields., Competing Interests: We declare we have no competing interests., (© 2024 The Author(s).)

Competing Interests: Conflict of interest: None declared.

Although 129 I discharge from watersheds is fundamental for assessing long-term radiation effects on aquatic ecosystems, 129 I originating from the Fukushima nuclear accident is yet be evaluated. This study investigated the transport behavior of 129 I by riverbank surveys conducted from 2013 to 2015 in a watershed where the 129 I/ 137 Cs activity ratio is low in the mountainous area and high in the plain as of 2011. Until 2015, the 129 I/ 137 Cs activity ratio of the levee crown in the studied watershed was similar to that of the surrounding area in 2011. However, the 129 I/ 137 Cs ratios of the surface riverbank sediments were all low, indicating that radionuclides transported from the mountainous area were deposited on the riverbank in the plain. The vertical distribution of the 129 I/ 137 Cs ratio in the riverbank sediments indicated that some 129 I and 137 Cs deposited during the accident remained in the lower layers, but most were eroded immediately after the accident. Based on the 129 I/ 137 Cs ratios of sediments deposited on the riverbank, which remained constant until 2015 after the accident, the amount of 129 I discharged to the ocean was determined from the previously evaluated 137 Cs discharge. It was calculated that 1.8 × 10 5 Bq and 1.2 × 10 7 Bq of 129 I were discharged with sediment from the studied watershed and the contaminated river watersheds (Abukuma River and Fukushima coastal rivers, including the study river), respectively. This amount of 129 I was 0.3% of the 129 I released from the Fukushima Dai-ichi Nuclear Power Plant into the ocean immediately after the accident. Furthermore, a comparison of the 129 I/ 137 Cs ratio showed that the continuous 129 I and 137 Cs discharge from the river contribute little to their amount in the seafloor sediments along the Fukushima coast., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Femoral neck fractures are considered exclusion criteria for atypical femoral fractures; however, femoral neck fractures with atypical femoral fractures have also been reported. Here, we report a case of a femoral neck fracture with features of atypical femoral fractures and a review of the related literature. A 76-year-old woman had been treated with denosumab for five years. The patient had no history of trauma, but complained of pain in the right hip. Radiological examination revealed an incomplete fracture of the right femoral neck. Internal fixation was performed, but fusion was delayed. Bipolar hemiarthroplasty was performed four months after surgery. In a patient with long-term bisphosphonate use, complaints of hip pain could indicate the possibility of an atypical fracture. According to the existing literature, as with atypical femoral fractures, this fracture has a high risk of delayed union; therefore, temporary prosthetic replacement should be considered as a treatment option., Competing Interests: None., (© 2024 The Authors. Published by Elsevier Ltd.)

A novel Fe III complex [Fe(Hex-tnal) 2 ]BPh 4 (1) with a tridentate N 2 O ligand having an n -hexyl chain, Hex-Htnal (=1-((((1-hexyl-1 H -1,2,3-triazol-4-yl)methyl)imino)methyl)naphthalen-2-ol), is reported. Temperature-dependent magnetic susceptibility measurements revealed that 1 exhibits a two-step spin crossover (SCO) transition in the 400-10 K temperature range, including an unusual gradual χ M T change above RT (300-345 K) and a hysteretic χ M T jump in a narrow temperature range of 345-357 K. These behaviors were also characterized by differential scanning calorimetry. Variable-temperature single-crystal X-ray diffraction studies revealed that the order-disorder transition and conformational change of the hexyl chains and the symmetry change associated with the re-entrant structural phase transition, namely triclinic P 1̄ (100-275 K) ↔ monoclinic C 2/ c (296-340 K) ↔ triclinic P 1̄ (360 K), are coupled to variations in intermolecular interactions and the N 4 O 2 coordination environment, resulting in the occurrence of the unusual two-step SCO transition of 1. This study demonstrates that the flexible motion of alkyl substituents in the supramolecular lattice influences the occurrence of anomalous magnetic switching properties.

Noonan syndrome-related myeloproliferative disorder (NS/MPD) and juvenile myelomonocytic leukemia (JMML) are rare MPDs that occur in young children. We herein report a case of NS/MPD with neonatal onset. The patient had a characteristic appearance and high monocyte count in the peripheral blood and bone marrow. Genetic testing showed the E139D mutation in PTPN11 ; however, the patient did not meet all the diagnostic criteria for JMML, and we thus diagnosed him with NS/MPD. Eight other cases of NS/MPD with neonatal onset are also summarized. The initial presentation varied, and the prognosis was considered poor compared with previous reports of NS/MPD., Competing Interests: The authors declare no conflict of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Exercise training increases brain-derived neurotrophic factor (BDNF) expression and improves cognitive function. However, the dynamics of BDNF during inactivity and the effects of exercise intervention on BDNF levels have rarely been examined. Therefore, we aimed to examine changes in serum, skeletal muscle, and brain BDNF levels under these conditions. Mice were divided into control (Co), cast immobilization (CI), reloading (RL), and exercise (Ex) groups. Muscle atrophy was induced by cast immobilization for 2 weeks in the CI, RL, and Ex groups. After cast removal, the RL and Ex groups underwent regrounding and treadmill exercise, respectively, for 2 weeks. Serum, skeletal muscle, and brain BDNF levels showed a similar decreasing trend in the CI group, recovery in the RL group, and a further increase in the Ex group compared with those in the Co group. This indicates that BDNF levels change in parallel with the degree of activity. However, the magnitude of variation differed among the tissues in the order of serum > skeletal muscle > brain tissue. These results suggest that different mechanisms in different tissues regulate BDNF expression. BDNF could potentially act as an objective measure of the impact of both inactivity and exercise-based interventions.

Aims: Although frailty assessment is recommended for guiding treatment strategies and outcome prediction in elderly patients with heart failure (HF), most frailty scales are subjective, and the scores vary among raters. We sought to develop a machine learning-based automatic rating method/system/model of the clinical frailty scale (CFS) for patients with HF., Methods and Results: We prospectively examined 417 elderly (≥75 years) with symptomatic chronic HF patients from 7 centres between January 2019 and October 2023. The patients were divided into derivation ( n = 194) and validation ( n = 223) cohorts. We obtained body-tracking motion data using a deep learning-based pose estimation library, on a smartphone camera. Predicted CFS was calculated from 128 key features, including gait parameters, using the light gradient boosting machine (LightGBM) model. To evaluate the performance of this model, we calculated Cohen's weighted kappa (CWK) and intraclass correlation coefficient (ICC) between the predicted and actual CFSs. In the derivation and validation datasets, the LightGBM models showed excellent agreements between the actual and predicted CFSs [CWK 0.866, 95% confidence interval (CI) 0.807-0.911; ICC 0.866, 95% CI 0.827-0.898; CWK 0.812, 95% CI 0.752-0.868; ICC 0.813, 95% CI 0.761-0.854, respectively]. During a median follow-up period of 391 (inter-quartile range 273-617) days, the higher predicted CFS was independently associated with a higher risk of all-cause death (hazard ratio 1.60, 95% CI 1.02-2.50) after adjusting for significant prognostic covariates., Conclusion: Machine learning-based algorithms of automatically CFS rating are feasible, and the predicted CFS is associated with the risk of all-cause death in elderly patients with HF., Competing Interests: Conflict of interest: none declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Competing Interests: H. Isayama is supported by research grants from Boston Scientific Japan and FUJIFILM Corporation. The funding source has no role in the design, practice, or analysis of this study. H. Hagiwara, K. Tomishima, Y. Jimbo, M. Ushio, A. Suzuki, and T. Fujisawa declare that they have no conflict of interest.

Background/aim: Genistein (4', 5, 7-trihydroxyisoflavone) and daidzein (4', 7-dihydroxyisoflavone) are isoflavones derived from soybean and have anti-cancer effects in various cells. However, the effects of genistein and daidzein on the human osteosarcoma cell line Saos-2 has not been investigated before., Materials and Methods: Human osteosarcoma Saos-2 cells were treated with genistein for 24 and 48 hours. Cytotoxicity and apoptosis were measured., Results: Genistein significantly inhibited proliferation of Saos-2 cells stronger than daidzein in a dose-dependent manner (0 to 80 μM). Genistein also significantly suppressed Saos-2 cell viability in a dose-dependent manner (0 to 100 μM). In contrast, daidzein did not affect Saos-2 cell viability. Real-time PCR revealed that genistein caused G1-arrest by increasing the expression of p21 and p27 mRNAs in Saos-2 cells. In addition, genistein induced apoptosis through the up-regulation of effector caspase-3/7 activity in Saos-2 cells. Genistein also enhanced initiator caspase-9 and TNF-α mRNA expression in cells., Conclusion: Genistein may inhibit proliferation through the up-regulation of p21 and p27 and viability by inducing apoptosis in Saos-2 cells., (Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Carfilzomib is a selective proteasome inhibitor approved for treating relapsed or refractory multiple myeloma (RRMM). Carfilzomib improves overall survival (OS) and progression-free survival (PFS); however, treatment with carfilzomib results in a higher incidence of cardiovascular and renal toxicity. More than 70% of patients with RRMM in clinical practice do not meet the eligibility criteria for randomized clinical trials (RCT). OS and PFS are negatively influenced by complications, concomitant medications and prior treatments. Therefore, we assessed the risk factors influencing the OS and time to next treatment (TTNT) in the real world. TTNT has emerged as a relevant alternative clinical endpoint to PFS., Methods: A retrospective analysis of a large claims database prepared during the post-marketing stages in Japan was performed. The patients treated with carfilzomib for the first time were identified. Multivariable Cox proportional hazards regression analysis was performed to evaluate the risk factors influencing OS and TTNT following carfilzomib treatment., Results: A total of 732 patients with RRMM who received carfilzomib-containing chemotherapy between April 2014 and September 2021 were identified. Multivariable Cox regression analysis for OS and TTNT showed a significantly higher hazard ratio (HR) of 1.48 (95% confidence interval [Cl]: 1.10-2.00; p = 0.010) and 1.38 (95% Cl: 1.15-1.65; p < 0.001), respectively, for patients with renal impairment compared to those without renal impairment. Multivariable Cox regression analysis for OS and TTNT showed a significantly higher HR of 1.80 (95% Cl: 1.27-2.55; p = 0.0010) and 1.38 (95% Cl: 1.14-1.66; p < 0.001), respectively, for patients with prior lenalidomide treatment compared to those without prior lenalidomide treatment., Conclusion: Complication of renal impairment and prior lenalidomide treatment could be risk factors influencing OS and TTNT during carfilzomib treatment., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

This study aimed to investigate the bleeding risk associated with percutaneous transhepatic gallbladder interventions in patients with acute cholecystitis receiving antithrombotic therapy. In this retrospective study, 194 consecutive patients who underwent percutaneous transhepatic gallbladder interventions for acute cholecystitis between April 2011 and April 2021 were enrolled. Patients were sorted into four groups: no prior antithrombotic therapy, discontinued antithrombotic drugs, single antithrombotic drug continued perioperatively, and multiple antithrombotic drugs continued perioperatively. The risk of postoperative bleeding after percutaneous transhepatic gallbladder interventions was evaluated via multivariate logistic regression analysis. Of the 116 (59.8%) patients receiving antithrombotic therapy, 32 (16.5%) discontinued antithrombotic drugs before their respective procedure, 50 (25.8%) continued a single antithrombotic drug, and 34 (17.5%) continued multiple antithrombotic drugs during the perioperative period. The rates of significant and severe bleeding were 10.3% (20/194) and 3.1% (6/194), respectively. The rate of significant bleeding was significantly higher in patients who continued multiple antithrombotic drugs than in patients who received no prior antithrombotic therapy (P = 0.006). In the multivariate logistic regression analysis, the continuation of multiple antithrombotic drugs during the perioperative period was a risk factor for significant bleeding after percutaneous transhepatic gallbladder interventions. In conclusion, the perioperative continuation of multiple antithrombotic drugs is a risk factor for postoperative bleeding after percutaneous transhepatic gallbladder interventions., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Iwamoto et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

BACKGROUND Parkinson's disease (PD) is a neurodegenerative disorder that often requires long-term management of motor symptoms. Continuous infusion of levodopa-carbidopa intestinal gel (LCIG) has shown promising results in alleviating motor fluctuations and improving quality of life. This study aimed to evaluate the efficacy and safety of transgastric jejunostomy (PEG-J) as a delivery method for LCIG in a cohort of 43 PD patients. MATERIAL AND METHODS Forty-three PD patients who were candidates for LCIG therapy underwent transgastric jejunostomy to facilitate continuous infusion of LCIG. The primary outcomes assessed were motor symptom improvement, reduction in motor fluctuations, and medication-related adverse events. Secondary outcomes included changes in quality of life, dyskinesia severity, and healthcare resource utilization. RESULTS The results of this study demonstrated significant improvements in motor symptoms, reduction in motor fluctuations, and enhanced quality of life following PEG-J for LCIG infusion. The treatment was generally well-tolerated, with a low incidence of procedure-related complications. Notably, the use of PEG-J allowed for precise and continuous delivery of LCIG, minimizing variations in drug absorption and ensuring consistent therapeutic levels. CONCLUSIONS Transgastric jejunostomy (PEG-J) offers an effective approach for the continuous infusion of LCIG in Parkinson's disease treatment. This method provides a stable and reliable delivery system, leading to improved symptom control and enhanced quality of life for PD patients.

BACKGROUND Intensive care management of patients with morbid obesity has been linked to a higher mortality rate than that of the normal population and can be challenging. Obesity is a recognized risk factor for pulmonary hypertension, but it can prevent cardiac imaging. This report presents the case of a 28-year-old man with class III (morbid) obesity, a body mass index (BMI) of 70.1 kg/m², and heart failure, requiring pulmonary artery catheterization (PAC) to confirm the diagnosis of pulmonary hypertension. CASE REPORT A 28-year-old male patient with a a body mass index (BMI) of 70.1 kg/m² was admitted to the Intensive Care Unit (ICU) for the management of respiratory and cardiac failure. The patient had class III obesity (BMI >50 kg/m²) and heart failure. Due to the difficulties in evaluating hemodynamic status via echocardiography, a pulmonary artery catheter (PAC) was placed, revealing a mean pulmonary artery pressure of 49 mmHg, and a diagnosis of pulmonary hypertension was made. The alveolar partial pressures of oxygen and carbon dioxide were optimized by ventilatory management to reduce pulmonary vascular resistance. The patient was extubated on day 23 and was discharged from the ICU on day 28. CONCLUSIONS Pulmonary hypertension should be considered in the evaluation of obese patients. Using a PAC during the intensive care management of a patient with obesity could aid in the diagnosis of pulmonary hypertension as well as cardiac dysfunction, determine treatment strategies, and evaluate hemodynamic responses to various therapies.

Fragmented QRS (fQRS) on a 12-lead electrocardiogram is a known marker of fatal arrhythmias or cardiac adverse events in ischemic and non-ischemic cardiomyopathy patients. Nonetheless, the association between fQRS and clinical outcomes in patients with cardiac sarcoidosis (CS) remains unclear. Herein, we investigated whether fQRS is associated with long-term clinical outcomes in CS patients. A total of 78 patients who received immunosuppressive therapy (IST) for clinically diagnosed CS were retrospectively examined. Patients were classified into two groups according to the presence (n = 19) or absence (n = 59) of fQRS on electrocardiogram before IST. The primary outcome was the composite event of all-cause death, ventricular tachyarrhythmias (VTs), and hospitalization for heart failure. Results of late gadolinium enhancement on cardiac magnetic resonance imaging were also analyzed. During a median follow-up period of 3.7 years (interquartile range: 1.6-6.2 years), the primary outcome occurred more frequently in patients with fQRS than in those without (47% vs. 13%, log-rank p = 0.002). Multivariable Cox regression analyses showed that fQRS was an independent determinant of the primary outcome. The incidence of VTs, within 12 months of IST initiation, was comparable between the two groups; however, late-onset VTs, defined as those occurring ≥ 12 months after IST initiation, occurred more frequently in the fQRS group (21% vs. 2%, log-rank p = 0.002). The scar zone and scar border zone were greater in patients with fQRS than in those without it. In conclusion, our analysis suggests that fQRS is an independent predictor of adverse events, particularly late-onset VTs, in patients with CS., (© 2023. Springer Japan KK, part of Springer Nature.)

Competing Interests: Conflict of interest: None declared.

Background and Aim: Liver function can be improved in patients with chronic hepatitis C virus (HCV) infection who achieved sustained virologic response (SVR) with direct-acting antiviral (DAA) treatment. However, to our knowledge, the impact of liver function improvement after SVR on prognosis has not been investigated., Methods: A total of 716 patients with chronic HCV infection and compensated advanced liver fibrosis who began receiving DAA treatment between September 2014 and August 2018 in 25 Japanese hospitals and achieved SVR were enrolled., Results: The median age was 73 years, and 336 (47%) and 380 (53%) patients had albumin-bilirubin (ALBI) grade 1 and grade 2, respectively. Improvement to ALBI grade 1 at 1 year after the end of treatment (EOT) was observed in 76% of the patients with baseline ALBI grade 2. Among 380 patients with baseline ALBI grade 2, alanine aminotransferase (ALT) levels ≥ 40 U/L (p < 0.001) and modified ALBI (mALBI) grade 2a (p < 0.001) were significantly associated with improvement to ALBI grade 1 at 1 year after EOT in multivariate analysis. During the median observation period of 51.8 months, 4 and 10 patients with baseline ALBI grade 1 and 2, respectively, died. In patients with baseline ALBI grade 2, only the absence of improvement to ALBI grade 1 at 1 year after EOT was significantly associated with all-cause mortality in univariate analysis., Conclusions: Baseline ALT levels and mALBI grade were significantly associated with improvement in liver function after SVR. Patients whose liver function improved after SVR could have better prognosis., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Aims: The most efficient way to acutely restore sinus rhythm from atrial fibrillation (AF) is electrical cardioversion, which is painful without adequate sedation. Recent studies in various experimental models have indicated that optogenetic termination of AF using light-gated ion channels may provide a myocardium-specific and potentially painless alternative future therapy. However, its underlying mechanism(s) remain(s) incompletely understood. As brief pulsed light stimulation, even without global illumination, can achieve optogenetic AF termination, besides direct conduction block also modulation of action potential (AP) properties may be involved in the termination mechanism. We studied the relationship between optogenetic AP duration (APD) and effective refractory period (ERP) prolongation by brief pulsed light stimulation and termination of atrial tachyarrhythmia (AT)., Methods and Results: Hearts from transgenic mice expressing the H134R variant of channelrhodopsin-2 in atrial myocytes were explanted and perfused retrogradely. AT induced by electrical stimulation was terminated by brief pulsed blue light stimulation (470 nm, 10 ms, 16 mW/mm 2 ) with 68% efficacy. The termination rate was dependent on pulse duration and light intensity. Optogenetically imposed APD and ERP changes were systematically examined and optically monitored. Brief pulsed light stimulation (10 ms, 6 mW/mm 2 ) consistently prolonged APD and ERP when light was applied at different phases of the cardiac action potential. Optical tracing showed light-induced APD prolongation during the termination of AT., Conclusion: Our results directly demonstrate that cationic channelrhodopsin activation by brief pulsed light stimulation prolongs the atrial refractory period suggesting that this is one of the key mechanisms of optogenetic termination of AT., Competing Interests: Declaration of Competing Interest None declared., (Copyright © 2023. Published by Elsevier Ltd.)

α-Klotho is a longevity-related protein. Its deficiency shortens lifespan with prominent senescent phenotypes, including muscle atrophy and weakness in mice. α-Klotho has two forms: membrane α-Klotho and circulating α-Klotho (c-α-Klotho). Loss of membrane α-Klotho impairs a phosphaturic effect, thereby accelerating phosphate-induced aging. However, the mechanisms of senescence on c-α-Klotho loss remain largely unknown. Herein, with the aging of wild-type mice, c-α-Klotho declined, whereas Smad2, an intracellular transforming growth factor (TGF)-β effector, became activated in skeletal muscle. Moreover, c-α-Klotho suppressed muscle-wasting TGF-β molecules, including myostatin, growth and differentiation factor 11, activin, and TGF-β1, through binding to ligands as well as type I and type II serine/threonine kinase receptors. Indeed, c-α-Klotho reversed impaired in vitro myogenesis caused by these TGF-βs. Oral administration of Ki26894, a small-molecule inhibitor of type I receptors for these TGF-βs, restored muscle atrophy and weakness in α-Klotho (-/-) mice and in elderly wild-type mice by suppression of activated Smad2 and up-regulated Cdkn1a (p21) transcript, a target of phosphorylated Smad2. Ki26894 also induced the slow to fast myofiber switch. These findings show c-α-Klotho's potential as a circulating inhibitor counteracting TGF-β-induced sarcopenia. These data highlight the potential of a novel therapy involving TGF-β blockade to prevent sarcopenia., (Copyright © 2023 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Purpose: Sheath-type tunnelers are frequently used to create vascular access using vascular grafts. However, during vascular access creation, tunnelers damage the surrounding tissues, consequently causing problems, such as swelling, failure to heal, and infection. This study evaluated a novel rod-type tunneler that was designed to prevent tunneler-related tissue damage and its sequelae., Methods: We developed a small-diameter rod-type tunneler that reduces injuries during subcutaneous tunnel creation. The rod diameter of this tunneler is smaller than the vascular graft diameter being implanted. It has a structure in which a vascular graft is implanted at a target site by grasping and pulling the vascular graft. Three dogs were used in the experiment, and arteriovenous grafts were created using a rod-type and a sheath-type tunneler on the left and right thighs, respectively, with a different type of commercially available graft used in each dog. The edema of the tissues surrounding the vascular graft was measured at 11 sites by ultrasonography at prespecified intervals., Results: Compared with implantation using a sheath-type tunneler, when the self-sealing Rapidax II was implanted using the small-diameter rod-type tunneler, the postimplantation edema (degree of change) decreased by 28-53% and 80-247% in the peri-vascular-graft area and within the loop, respectively. The MAXIFLO and SEALPTFE did not significantly reduce postoperative edema but exhibited a tendency for improved postimplantation tissue healing., Conclusions: The reduced-diameter rod-type tunneler may be a useful device for vascular graft implantation., (© 2022. The Japanese Society for Artificial Organs.)

Diabetic cardiomyopathy has been reported to increase the risk of fatal ventricular arrhythmia. The beneficial effects of the selective sodium-glucose cotransporter-2 inhibitor have not been fully examined in the context of antiarrhythmic therapy, especially its direct cardioprotective effects despite the negligible SGLT2 expression in cardiomyocytes. We aimed to examine the antiarrhythmic effects of empagliflozin (EMPA) treatment on diabetic cardiomyocytes, with a special focus on Ca 2+ handling. We conducted echocardiography and hemodynamic studies and studied electrophysiology, Ca 2+ handling, and protein expression in C57BLKS/J-lepr db/db mice ( db/db mice) and their nondiabetic lean heterozygous Lepr db/+ littermates ( db / + mice). Preserved systolic function with diastolic dysfunction was observed in 16-wk-old db/db mice. During arrhythmia induction, db/db mice had significantly increased premature ventricular complexes (PVCs) than controls, which was attenuated by EMPA. In protein expression analyses, calmodulin-dependent protein kinase II (CaMKII) Thr287 autophosphorylation and CaMKII-dependent RyR2 phosphorylation (S2814) were significantly increased in diabetic hearts, which were inhibited by EMPA. In addition, global O -GlcNAcylation significantly decreased with EMPA treatment. Furthermore, EMPA significantly inhibited ventricular cardiomyocyte glucose uptake. Diabetic cardiomyocytes exhibited increased spontaneous Ca 2+ events and decreased sarcoplasmic reticulum (SR) Ca 2+ content, along with impaired Ca 2+ transient, all of which normalized with EMPA treatment. Notably, most EMPA-induced improvements in Ca 2+ handling were abolished by the addition of an O -GlcNAcase (OGA) inhibitor. In conclusion, EMPA attenuated ventricular arrhythmia inducibility by normalizing the intracellular Ca 2+ handling, and we speculated that this effect was, at least partly, due to the inhibition of O -GlcNAcylation via the suppression of glucose uptake into cardiomyocytes. NEW & NOTEWORTHY SGLT2is are known to improve cardiovascular outcomes regardless of the presence of diabetes and decrease traditional cardiovascular risk factors. We demonstrated, for the first time, that EMPA inhibited PVCs by normalizing Ca 2+ handling in diabetic mice. Our data suggest that the effects of SGLT2is on calcium handling may occur because of suppression of O -GlcNAcylation through inhibition of glucose uptake and not because of NHE inhibition, as previously suggested.

The influenza A(H1N1)pdm09 virus that emerged in 2009 causes seasonal epidemic worldwide. The virus acquired several amino acid substitutions that were responsible for antigenic drift until the 2018-2019 influenza season. Viruses possessing mutations in the NA and PA proteins that cause reduced susceptibility to NA inhibitors and baloxavir marboxil, respectively, have been detected after antiviral treatment, albeit infrequently. Here, we analyzed HA, NA, and PA sequences derived from A(H1N1)pdm09 viruses that were isolated during the 2018-2019 and 2019-2020 influenza seasons in Japan. We found that A(H1N1)pdm09 viruses possessing the D187A and Q189E substitutions in HA emerged and dominated during the 2019-2020 season; these substitutions in the antigenic site Sb, a high potency neutralizing antibody-eliciting site for humans, changed the antigenicity of A(H1N1)pdm09 viruses. Furthermore, we found that isolates possessing the N156K substitution, which was predicted to affect the antigenicity of A(H1N1)pdm09 virus at the laboratory level, were detected at a frequency of 1.0% in the 2018-2019 season but 10.1% in the 2019-2020 season. These findings indicate that two kinds of antigenically drifted viruses-N156K and D187A/Q189E viruses-co-circulated during the 2019-2020 influenza season in Japan., Competing Interests: Y.K. has received speaker’s honoraria from Toyama Chemical and Astellas Inc., grant support from Chugai Pharmaceuticals, Daiichi Sankyo Pharmaceutical, Toyama Chemical, Tauns Laboratories, Inc., Otsuka Pharmaceutical Co., Ltd., Denka Seiken Co., Ltd., and Shionogi & Co., Ltd. Y.K. and is a co-founder of FluGen. The other authors have no conflict of interest.

Introduction: Recent studies have demonstrated that sodium-glucose co-transporter-2 inhibitors (SGLT2-i) reduce the risk of atrial fibrillation (AF) in patients with diabetes mellitus (DM), in which oxidative stress due to increased reactive oxygen species (ROS) contributes to the pathogenesis of AF. We aimed to further investigate this, and examine whether the SGLT2-i empagliflozin suppresses mitochondrial-ROS generation and mitigates fibrosis., Methods: A high-fat diet and low-dose streptozotocin treatment were used to induce type-2 DM (T2DM) in Sprague-Dawley rats. The rats were randomly divided into three groups: control, DM, and DM treated with empagliflozin (30 mg/kg/day) for 8 weeks. The mitochondrial respiratory capacity and ROS generation in the atrial myocardium were measured using a high-resolution respirometer. Oxidative stress markers and protein expression related to mitochondrial biogenesis and dynamics as well as the mitochondrial morphology were examined in the atrial tissue. Additionally, mitochondrial function was examined in H9c2 cardiomyoblasts. Atrial tachyarrhythmia (ATA) inducibility, interatrial conduction time (IACT), and fibrosis were also measured., Results: Inducibility of ATA, fibrosis, and IACT were increased in rats with DM when compared to controls, all of which were restored by empagliflozin treatment. In addition, the rats with DM had increased mitochondrial-ROS with an impaired complex I-linked oxidative phosphorylation capacity. Importantly, empagliflozin seemed to ameliorate these impairments in mitochondrial function. Furthermore, empagliflozin reversed the decrease in phosphorylated AMPK expression and altered protein levels related to mitochondrial biogenesis and dynamics, and increased mitochondrial content. Empagliflozin also improved mitochondrial function in H9c2 cells cultured with high glucose medium., Discussion: These data suggest that empagliflozin has a cardioprotective effect, at least in part, by reducing mitochondrial ROS generation through AMPK signaling pathways in the atrium of diabetic rats. This suggests that empagliflozin might suppress the development of AF in T2DM., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Koizumi, Watanabe, Yokota, Tsuda, Handa, Koya, Nishino, Tatsuta, Natsui, Kadosaka, Koya, Nakao, Hagiwara, Kamada, Temma, Tanaka and Anzai.)

Disulfide bonds of 2-isocyanatophenyl methyl disulfide and 2- endo -isocyanato-6- endo -(methyldisulfanyl)bicyclo[2.2.1]heptane showed neighboring group participation in the formation of thiocarbamates. Natural Bond Orbital (NBO) analyses revealed that the unusual nucleophilicity requires a rigid through-space interaction between a lone pair of the disulfide bond and an antibonding orbital of isocyanate.

Background: Intrahepatic hepatocellular carcinoma (HCC) has a high recurrence rate after radiofrequency ablation (RFA). However, to date, no standalone predictive factors for intrahepatic distant recurrence after curative ablation have been reported., Aims: The aim of this study was to investigate predictive factors for intrahepatic distant recurrence after curative treatment with RFA for HCCs., Methods: This multicenter study consisted of 17 institutions that registered 821 patients. The risk factors for intrahepatic distant recurrence after complete ablation by RFA for primary HCC ≤ 2 cm in diameter were identified in a retrospectively collected training set (n = 636) and then validated in a prospectively collected validation set (n = 185)., Results: The cumulative intrahepatic distant and local recurrence rates (i.e., entire recurrence rate) in the training set were 23.6% and 53.7% at 1 and 3 years, respectively. The cumulative intrahepatic distant recurrence rates in the training set were 17.0% and 43.8% at 1 and 3 years, respectively. Multivariate analysis of the training set showed that tumor number and serum levels of α-fetoprotein (AFP) and des-γ-carboxy prothrombin (DCP) were independent risk factors for both entire recurrence and intrahepatic distant recurrence. Intrahepatic distant recurrence risk in both the training and validation cohorts was stratified using a scoring system with three factors: tumor number (single or multiple), AFP (< 10 ng/ml or ≥ 10 ng/ml), and DCP (< 50 mAU/ml or ≥ 50 mAU/ml)., Conclusion: The scoring system composed of tumor number, AFP, and DCP is useful for classifying the risk of intrahepatic distant recurrence after curative ablation for HCC., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Mutations of the caveolin 3 gene cause autosomal dominant limb-girdle muscular dystrophy (LGMD)1C. In mice, overexpression of mutant caveolin 3 leads to loss of caveolin 3 and results in myofiber hypotrophy in association with activation of neuronal nitric oxide synthase (nNOS) at the sarcolemma. Here, we show that caveolin 3 directly bound to nNOS and suppressed its phosphorylation-dependent activation at a specific residue, Ser1412 in the nicotinamide adenine dinucleotide phosphate (NADPH)-flavin adenine dinucleotide (FAD) module near the C-terminus of the reduction domain, in vitro. Constitutively active nNOS enhanced myoblast fusion, but not myogenesis, in vitro. Phosphorylation-dependent activation of nNOS occurred in muscles from caveolin 3-mutant mice and LGMD1C patients. Mating with nNOS-mutant mice exacerbated myofiber hypotrophy in the caveolin 3-mutant mice. In nNOS-mutant mice, regenerating myofibers after cardiotoxin injury became hypotrophic with reduced myoblast fusion. Administration of NO donor increased myofiber size and the number of myonuclei in the caveolin 3-mutant mice. Exercise also increased myofiber size accompanied by phosphorylation-dependent activation of nNOS in wild-type and caveolin 3-mutant mice. These data indicate that caveolin 3 inhibits phosphorylation-dependent activation of nNOS, which leads to myofiber hypertrophy via enhancing myoblast fusion. Hypertrophic signaling by nNOS phosphorylation could act in a compensatory manner in caveolin 3-deficient muscles., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Atrial fibrillation (AF) is associated with electrical remodeling processes that promote a substrate for the maintenance of AF. Although the small-conductance Ca 2+ -activated K + (SK) channel is a key factor in atrial electrical remodeling, the mechanism of its activation remains unclear. Regional nitric oxide (NO) production by neuronal nitric oxide synthase (nNOS) is involved in atrial electrical remodeling. In this study, atrial tachyarrhythmia (ATA) induction and optical mapping were performed on perfused rat hearts. nNOS is pharmacologically inhibited by S -methylthiocitrulline (SMTC). The influence of the SK channel was examined using a specific channel inhibitor, apamin (APA). Parameters such as action potential duration (APD), conduction velocity, and calcium transient (CaT) were evaluated using voltage and calcium optical mapping. The dominant frequency was examined in the analysis of AF dynamics. SMTC (100 nM) increased the inducibility of ATA and apamin (100 nM) mitigated nNOS inhibition-induced arrhythmogenicity. SMTC caused abbreviations and enhanced the spatial dispersion of APD, which was reversed by apamin. By contrast, conduction velocity and other parameters associated with CaT were not affected by SMTC or apamin administration. Apamin reduced the frequency of SMTC-induced ATA. In summary, nNOS inhibition abbreviates APD by modifying the SK channels. A specific SK channel blocker, apamin, mitigated APD abbreviation without alteration of CaT, implying an underlying mechanism of posttranslational modification of SK channels. NEW & NOTEWORTHY We demonstrated that pharmacological nNOS inhibition increased the atrial arrhythmia inducibility and a specific small-conductance Ca 2+ -activated K + channel blocker, apamin, reversed the enhanced atrial arrhythmia inducibility. Apamin mitigated APD abbreviation without alteration of Ca 2+ transient, implying an underlying mechanism of posttranslational modification of SK channels.

Heart failure (HF) is a leading cause of death and repeated hospitalizations and often involves cardiac mitochondrial dysfunction. However, the underlying mechanisms largely remain elusive. Here, using a mouse model in which myocardial infarction (MI) was induced by coronary artery ligation, we show the metabolic basis of mitochondrial dysfunction in chronic HF. Four weeks after ligation, MI mice showed a significant decrease in myocardial succinyl-CoA levels, and this decrease impaired the mitochondrial oxidative phosphorylation (OXPHOS) capacity. Heme synthesis and ketolysis, and protein levels of several enzymes consuming succinyl-CoA in these events, were increased in MI mice, while enzymes synthesizing succinyl-CoA from α-ketoglutarate and glutamate were also increased. Furthermore, the ADP-specific subunit of succinyl-CoA synthase was reduced, while its GDP-specific subunit was almost unchanged. Administration of 5-aminolevulinic acid, an intermediate in the pathway from succinyl-CoA to heme synthesis, appreciably restored succinyl-CoA levels and OXPHOS capacity and prevented HF progression in MI mice. Previous reports also suggested the presence of succinyl-CoA metabolism abnormalities in cardiac muscles of HF patients. Our results identified that changes in succinyl-CoA usage in different metabolisms of the mitochondrial energy production system is characteristic to chronic HF, and although similar alterations are known to occur in healthy conditions, such as during strenuous exercise, they may often occur irreversibly in chronic HF leading to a decrease in succinyl-CoA. Consequently, nutritional interventions compensating the succinyl-CoA consumption are expected to be promising strategies to treat HF.

Background: An aberrant increase in the diastolic calcium concentration ([Ca 2+ ] i ) level is a hallmark of heart failure (HF) and the cause of delayed afterdepolarization and ventricular arrhythmia (VA). Although mitochondria play a role in regulating [Ca 2+ ] i , whether they can compensate for the [Ca 2+ ] i abnormality in ventricular myocytes is unknown., Objective: The purpose of this study was to investigate whether enhanced Ca 2+ uptake of mitochondria may compensate for an abnormal increase in the [Ca 2+ ] i of ventricular myocytes in HF to effectively mitigate VA., Methods: We used a HF mouse model in which myocardial infarction was induced by permanent left anterior descending coronary artery ligation. The mitochondrial Ca 2+ uniporter was stimulated by kaempferol. Ca 2+ dynamics and membrane potential were measured using an epifluorescence microscope, a confocal microscope, and the perforated patch-clamp technique. VA was induced in Langendorff-perfused hearts, and hemodynamic parameters were measured using a microtip transducer catheter., Results: Protein expression of the mitochondrial Ca 2+ uniporter, as assessed by its subunit expression, did not change between HF and sham mice. Treatment of cardiomyocytes with kaempferol, isolated from HF mice 28 days after coronary ligation, reduced the appearance of aberrant diastolic [Ca 2+ ] i waves and sparks and spontaneous action potentials. Kaempferol effectively reduced VA occurring in Langendorff-perfused hearts. Intravenous administration of kaempferol did not markedly affect left ventricular hemodynamic parameters., Conclusion: The effects of kaempferol in HF of mice implied that mitochondria may have the potential to compensate for abnormal [Ca 2+ ] i . Mechanisms involved in mitochondrial Ca 2+ uptake may provide novel targets for treatment of HF-associated VA., (Copyright © 2022 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: Anemia is common in heart failure (HF) patients with chronic kidney disease (CKD) and is associated with worse outcomes. Iron supplementation improves symptoms and is associated with reduced risk of hospitalization for HF in iron-deficiency HF patients. However, iron deficiency is present in <30% of anemic HF patients. Erythropoiesis stimulating agents (ESAs) improve symptoms but are associated with increased risk of thromboembolic events in anemic HF patients with CKD. Hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitors are a new class of agents for the treatment of anemia. These agents work by stabilizing the HIF complex, thereby stimulating endogenous erythropoietin production. We hypothesized that HIF-PH inhibitors may be associated with reduced risk of cardiovascular outcomes compared with ESAs in anemic HF patients with CKD. Accordingly, we aim to perform the meta-analysis of studies on the efficacy and safety of HIF-PH inhibitors compared with ESAs in anemic HF patients with CKD., Methods: This meta-analysis will include prospective cohort studies and randomized controlled trials on the effect of HIF-PH inhibitors compared with ESAs in anemic HF patients with CKD. Information of studies will be collected from PubMed, Web of Science, Cochrane Library, and ClinicalTrials.gov. The primary outcome will be cardiovascular death. The secondary outcomes will be all-cause death, hospitalization for HF, HF symptoms, exercise capacity, health-related quality of life, and hemoglobin levels., Discussion: This meta-analysis will evaluate the effect of HIF-PH inhibitors in anemic HF patients with CKD, providing evidence regarding the use of HIF-PH inhibitors in these patients., Systematic Review Registration: INPLASY202230103., Competing Interests: The authors have declared that no competing interests exist.

An 86-year-old man, with a medical history of coronary artery bypass grafting with the right gastroepiploic artery 20 years prior, was admitted to our hospital for right-sided heart failure. Computed tomography findings revealed an intrapericardial diaphragmatic hernia of the transverse colon compressing the right ventricle. The hernia was successfully repaired, and the patient recovered without any complications. Diaphragmatic hernia is rare but may be a lethal complication following coronary artery bypass grafting. We should be aware of the possibility of this condition.

Purpose: Opening the ventricular system during glioblastoma surgery is often necessary, but the consequent effect on the tumor microenvironment of glioblastoma remains unknown. Implantation of carmustine wafer enables direct drug delivery to the tumor site; however, the exact mechanism of the wafer's biodegradation process is unclear, and the available data is limited to in vivo non-human mammalian studies. We hypothesized that the ventricular opening affects the degradation process of the wafer and the glioblastoma tumor microenvironment., Methods: This study included 30 glioblastoma patients. 21 patients underwent carmustine wafer implantation during initial surgery. All patients underwent repeated surgical resection upon recurrence, allowing for pathological comparison of changes associated with wafer implantation. Immunohistochemical analyses were performed using CD68, TMEM119, CD163, IBA1, BIN1, and CD31 antibodies to highlight microglia, macrophages, and tumor vascularity, and the quantitative scoring results were correlated with clinical, molecular, and surgical variables, including the effect of the ventricular opening., Results: The carmustine wafer implanted group presented significantly less TMEM119-positive microglia within the tumor (P = 0.0002). Simple and multiple regression analyses revealed that the decrease in TMEM119-positive microglia was correlated with longer intervals between surgeries and opened ventricular systems. No correlation was observed between age, methylated O6-methylguanine DNA methyltransferase promoter expression, and the extent of surgical resection., Conclusions: Our study findings strongly suggest that biomaterials may possess immunomodulation capacity, which is significantly impacted by the ventricular opening procedure. Furthermore, our data highlights the pathophysiological effects of the ventricular opening within the surrounding human brain, especially after the wafer implantation., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Nearly half of patients with heart failure (HF) have preserved ejection fraction (EF) and the mortality and morbidity of patients with HF with preserved EF (HFpEF) are high. Patients with HFpEF are often elderly and their primary chronic symptom is severe exercise intolerance that results in a reduced quality of life. Thus, improvement of exercise capacity and quality of life presents another important clinical outcome in HFpEF patients. Recent randomized controlled trials (RCTs) and meta-analyses of RCTs reported that sodium-glucose cotransporter 2 (SGLT-2) inhibitors improved cardiovascular (CV) outcomes in patients with HF with reduced EF. Although the effects of SGLT-2 inhibitors in HFpEF patients have been examined in multiple RCTs, results are inconsistent due partly to limited power. We aimed to conduct a meta-analysis of RCTs on the effects of SGLT-2 inhibitors in HFpEF patients., Methods and Results: The search of electronic databases identified 11 RCTs including 10,845 patients. In pooled analyses, SGLT-2 inhibitors reduced the risk of a composite of hospitalization for HF and CV death (hazard ratio [95 % CI] = 0.78 [0.70, 0.87], P fix  < 0.001). SGLT-2 inhibitors significantly increased 6-minute walk distance (weighted mean difference [95 % CI] = 18.0 [6.8, 29.3] m; P fix  = 0.002) and the Kansas City Cardiomyopathy Questionnaire Total Symptom Score (weighted mean difference [95 % CI] = 2.57 [0.19, 4.96] points; P random  = 0.035) and reduced plasma NT-pro B-type natriuretic peptide levels (weighted mean difference [95 % CI] = -60.16 [-82.99, -37.33] pg/ml; P fix  < 0.001) compared with control., Conclusion: The present meta-analysis suggests that SGLT-2 inhibitors may be beneficial for HFpEF patients, especially in diabetic patients., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)

Background: Electrical storms (ESs) in patients with structural heart disease (SHD) have been reported to be associated with a poor prognosis. However, the detailed cause of death and influence of implantable cardioverter defibrillator (ICD) therapy in ES patients have not been fully investigated. Therefore, we sought to explore the detailed clinical course after an ES and the impact of the ICD therapy in patients with SHDs., Methods: We retrospectively analyzed 31 consecutive patients with ESs who had undergone an ICD implantation. ESs were defined as three or more ventricular arrhythmias within 24 h., Results: During a mean follow up of 4.5 years, 13 patients died. Among them, cardiovascular death (CVD) was observed in 11/13 (85%), and the leading cause of the CVD was end-stage heart failure. A New York Heart Association class ≥III at the time of the ES occurrence (HR 6.51 95% CI 1.94-25.1, p = 0.003) and any shock therapy (HR 5.94 95% CI 1.06-112.2, p = 0.04) were associated with CVD., Conclusion: In the current single center study, the major cause of death in ES patients with SHDs was end-stage heart failure. Any shock therapy was associated with CVD. Arrhythmia management to avoid ICD shocks might reduce the mortality in ES patients., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Combination immunotherapy with anti-programmed cell death1-ligand1 (PD-L1) and anti-vascular endothelial growth factor (VEGF) antibodies has become the standard treatment for patients with unresectable HCC (u-HCC). However, limited patients obtain clinical benefits. Cell-free DNA (cfDNA) in peripheral blood contains circulating tumor DNA (ctDNA) that reflects molecular abnormalities in tumor tissue. We investigated the potential of cfDNA/ctDNA as biomarkers for predicting the therapeutic outcome in u-HCC patients treated with anti-PD-L1/VEGF therapy. We enrolled a multicenter cohort of 85 HCC patients treated with atezolizumab and bevacizumab (Atezo/Bev) between 2020 and 2021. Pretreatment plasma was collected, and cfDNA levels were quantified. Ultradeep sequencing of cfDNA was performed with a custom-made panel for detecting mutations in 25 HCC-related cancer genes. We evaluated the association of cfDNA/ctDNA profiles and clinical outcomes. Patients with high plasma cfDNA levels showed a significantly lower response rate and shorter progression-free survival and overall survival (OS) than those with low cfDNA levels. ctDNA detected in 55% of HCC patients included the telomerase reverse transcriptase (TERT) promoter in 31% of these patients, tumor protein 53 (TP53) in 21%, catenin beta 1 (CTNNB1) in 13% and phosphatase and tensin homolog (PTEN) in 7%. The presence or absence of ctDNA did not predict the efficacy of Atezo/Bev therapy. Twenty-six patients with a TERT mutation had significantly shorter OS than those without. The presence of a TERT mutation and alpha-fetoprotein (AFP) ≥ 400 ng/mL were independent predictors of poor OS according to multivariate Cox proportional hazard analysis and could be used to stratify patients treated with Atezo/Bev therapy based on prognosis. In conclusion, pretreatment cfDNA/ctDNA profiling may be useful for predicting the therapeutic outcome in u-HCC patients treated with anti-PD-L1/VEGF therapy.

After the Tokyo Electric Power Company Fukushima Daiichi Nuclear Power Plant accident in Japan, freshwater ecosystems near the site remained contaminated by radiocesium (RCs). Clarifying RCs concentrations in aquatic insects is crucial because fishes consume these insects that transfer RCs into freshwater ecosystems. As aquatic insects are usually measured for radioactivity in bulk samples of several tens of insects, variation in RCs concentration among individuals is not captured. In this study, we investigated the variability in 137Cs activity concentration in individual aquatic insects in detritivorous caddisfly (Stenopsyche marmorata) and carnivorous dobsonfly (Protohermes grandis) larvae from the Ota River, Fukushima. Caddisfly larvae showed sporadically higher radioactivity in 4 of the 46 caddisfly larvae, whereas no such outliers were observed in 45 dobsonfly larvae. Autoradiography and scanning electron microscopy analyses confirmed that these caddisfly larvae samples contained radiocesium-bearing microparticles (CsMPs), which are insoluble Cs-bearing silicate glass particles. CsMPs were also found in potential food sources of caddisfly larvae, such as periphyton and drifting particulate organic matter, indicating that larvae may ingest CsMPs along with food particles of similar size. Although CsMP distribution and uptake by organisms in freshwater ecosystems is relatively unknown, our study demonstrates that CsMPs can be taken up by aquatic insects., Competing Interests: The authors have declared that no competing interests exist.

Background and Aim: The development of hepatocarcinogenesis after a sustained virological response (SVR) remains an important issue affecting the balance between treatment and occupational life of workers with chronic hepatitis C virus (HCV) infection in Japan. Here, we aimed to evaluate the hepatocellular carcinoma (HCC) reducing effect and risk factors for developing HCC after SVR in patients treated with direct-acting antiviral agents (DAAs) among the working population., Methods: We studied 2579 working patients with chronic HCV infection who achieved SVR after antiviral treatment. We compared the difference in the cumulative incidence of post-SVR HCC between the interferon (IFN)-based n  = 1615 and DAA ( n  = 964) groups. The risk factors for post-SVR HCC development were determined in the DAA group., Results: After propensity score matching ( n  = 644 in each group), the HCC development rates were not significantly different between the groups ( P  = 0.186). Multivariate Cox regression and the cutoff values determined by the receiver operating characteristic curve analyses revealed that age ≥61 years, diabetes, lower serum albumin levels <4.0 g/dL at 24 weeks after the end of treatment (EOT), and higher serum α-fetoprotein levels ≥4.1 ng/mL at 24 weeks after the EOT were associated with the development of HCC., Conclusion: The HCC suppressing effect after SVR through DAA treatment is equivalent to that of IFN treatment in patients in the working population. Intensive follow-up is required after SVR with DAA treatment in Japanese workers with these risk factors to ensure the promotion of health and employment support., (© 2022 The Authors. JGH Open: An open access journal of gastroenterology and hepatology published by Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background: Atezolizumab plus bevacizumab was approved for hepatocellular carcinoma (HCC) patients in 2020, but treatment outcomes of atezolizumab plus bevacizumab in real-world settings remain unclear. Hyperprogressive disease (HPD), an acceleration of tumor growth occurring in some types of malignancies treated with immune checkpoint inhibitors, was assessed in HCC patients receiving atezolizumab plus bevacizumab., Methods: Tumor growth kinetics (TGK) and tumor growth rate (TGR) were calculated at pre- and post-treatment in 88 Japanese patients with HCC receiving atezolizumab plus bevacizumab. Hyperprogressive disease was defined as progressive disease (PD) with ≥ two-fold increase in TGK and TGR. The association of baseline characteristics with HPD was analyzed., Results: The best objective responses were partial response, stable disease, and PD in 12 (13.6%), 51 (58.0%), and 25 (28.4%) patients, respectively. The median progression-free survival was 5.0 months. Eleven (12.5%) and 9 (10.2%) patients had a TGK ratio and a TGR ratio of ≥2, respectively. Hyperprogressive disease was observed in nine patients (10.2%) and they showed significantly shorter overall survival than patients without HPD (median, 4.3 months vs. not reached; p < 0.001). Patients with HPD had larger and more intrahepatic tumors, higher levels of α-fetoprotein and lactate dehydrogenase, and higher neutrophil-to-lymphocyte ratio (NLR) at baseline than patients without HPD. NLR of ≥3 at baseline was identified as the only independent factor associated with HPD in multivariate analysis., Conclusions: Hyperprogressive disease was observed in 10.2% of HCC patients receiving atezolizumab plus bevacizumab, and an elevated NLR at baseline had an increased risk of HPD., (© 2021 The Japan Society of Hepatology.)

Background: Heart failure is a major public health problem. Although there have been significant advances in the management of heart failure, the mortality and morbidity in heart failure patients remain high. Heart failure patients are susceptible to influenza-related complications including acute heart failure exacerbations and secondary infections such as pneumonia, both of which lead to significant morbidity and mortality. An earlier meta-analysis of observational cohort studies reported that influenza vaccination was associated with reduced risk of mortality in heart failure patients. Although there are no published randomized controlled trials (RCTs) on the effect of influenza vaccination on clinical outcomes in heart failure patients, there are several on-going RCTs examining the effect in these patients. We aim to conduct a meta-analysis of RCTs to assess the efficacy and safety of influenza vaccination in heart failure patients., Methods: This meta-analysis will include RCTs examining the effect of influenza vaccination in heart failure patients. Information of studies will be collected from electronic databases. The primary outcome of interest will be cardiovascular death. The secondary outcomes of interest will be all-cause death, nonfatal myocardial infarction, nonfatal stroke, hospitalization for heart failure, and hospitalization for any cause., Discussion: This meta-analysis will evaluate the efficacy and safety of influenza vaccination in heart failure patients, providing evidence to the use of influenza vaccine in these patients., Systematic Review Registration: INPLASY202210115., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Atezolizumab/bevacizumab (Atezo/Bev) combination therapy has become a front-line therapy for advanced hepatocellular carcinoma (HCC), but approximately 20% of patients are nonresponders. We investigated circulating biomarkers to predict therapeutic outcomes. We performed simultaneous measurement of 34 proteins using a multiplex bead-based immunoassay in baseline plasma from 34 patients who underwent Atezo/Bev therapy as first- or second-line treatment. Logistic regression analysis showed that plasma IL-6 and interferon alpha (IFNα) levels were significant predictors of non-responders (odds ratio of 13.33 and FDR p = 0.021 for IL-6 and IFNα). The progression-free survival (PFS) and overall survival (OS) of patients with high IL-6 levels were significantly shorter than those of patients with low IL-6 levels. Next, we measured baseline plasma IL-6 levels in 64 HCC patients who underwent Atezo/Bev therapy by ELISA. The IL-6-high group showed higher female ratio, AST levels, tumor markers, Child-Pugh score, and vascular invasion ratio. The PFS and OS of the IL-6-high group were significantly shorter than those of the IL-6-low group. Multivariate Cox proportional hazards analysis showed that IL-6 level and age were independent risk factors for disease progression (hazard ratio of 2.785 and p = 0.015 for IL-6, and hazard ratio 0.306 and p = 0.03 for age). In conclusion, circulating IL-6 levels are a novel prognostic biomarker for advanced HCC patients who undergo combined immunotherapy.

Background: After hepatitis C virus (HCV) elimination, patients should be followed up due to risk of hepatocellular carcinoma (HCC). Growth differentiation factor 15 (GDF15) is a cytokine induced by mitochondrial dysfunction or oxidative stress. Aim To evaluate the prognostic value of GDF15 for HCC occurrence after HCV elimination., Methods: We measured GDF15 levels in stored serum from patients with chronic HCV infection without a history of HCC who had achieved sustained virological response with direct-acting antiviral agents (DAAs). The patients were randomly divided into derivation (n = 964) and validation (n = 642) cohorts., Results: In the derivation cohort, serum GDF15 levels were higher in those with HCC occurrence after DAA treatment than in those without. Multivariate Cox proportional hazards analysis revealed baseline GDF15 (>1350 pg/mL, HR 2.54), AFP (>5 ng/mL, HR 2.00), and the FIB-4 index (>3.25, HR 2.69) to be independent risk factors for HCC. Scoring based on GDF15, AFP and the FIB-4 index stratified HCC occurrence risk. In the validation cohort, the cumulative HCC occurrence rate at 3 years was 0.64%, 3.27% and 15.3% in low-score (N = 171), medium-score (N = 300) and high-score (N = 166) groups, respectively. In the total cohort, scoring divided patients with a FIB-4 index ≤3.25, whose HCC occurrence rate was 2.0% at 3 years, into medium-score and low-score groups with HCC occurrence rates at 3 years of 3.76% and 0.24%, respectively., Conclusions: Serum GDF15 predicts de novo HCC occurrence. Scoring using GDF15, AFP, and the FIB-4 index can predict de novo HCC occurrence risk after HCV elimination., (© 2021 John Wiley & Sons Ltd.)