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Aims: Atrial fibrillation (AF) and heart failure (HF) with preserved ejection fraction (HFpEF) are interlinked and frequently coexisting conditions. To date, patients with AF and HFpEF have limited evidence guiding their management. This study aimed to investigate the predictors of adverse outcomes among patients with AF and HFpEF., Methods: The Fushimi AF Registry is a community-based prospective survey of AF patients in Fushimi-ku, Kyoto, Japan. From the registry, we explored predictors for a composite of cardiac death or HF hospitalization among AF patients with HFpEF (defined as having a prior HF hospitalization or New York Heart Association class ≥2 in association with heart disease and left ventricular ejection fraction ≥50%). Besides, we investigated whether the scoring using the predictors identified by the Fushimi AF Registry could stratify the outcomes in patients with AF and HFpEF registered in another independent Kyoto Congestive Heart Failure Registry., Results: Of 755 patients with AF and HFpEF [mean age: 77.5 ± 9.9 years; female: 391 (52%); paroxysmal AF: 258 (34%); and mean CHA 2 DS 2 -VASc score: 4.5 ± 1.5], cardiac death or HF hospitalization occurred in 246 patients (33%) during the median follow-up period of 4.4 years in the Fushimi AF Registry. Using multivariate Cox regression analysis, age ≥75 years [hazard ratio (HR): 1.72, 95% confidence interval (CI): 1.26-2.36] and non-cardiovascular comorbidities such as anaemia (HR: 1.83, 95% CI: 1.37-2.46), chronic kidney disease (HR: 1.69, 95% CI: 1.27-2.26), diabetes mellitus (HR: 1.55, 95% CI: 1.15-2.09) and chronic obstructive pulmonary disease (HR: 1.87, 95% CI: 1.08-3.22) were independent predictors of adverse outcomes. Meanwhile, cardiovascular comorbidities including coronary artery disease, valvular heart disease or cardiomyopathy were not significantly associated with adverse outcomes. These results were also the case when analysed for patients with AF and HFpEF who registered in the Kyoto Congestive Heart Failure registry (N = 878). The score assigning 1 point for each five predictors (age, anaemia, chronic kidney disease, diabetes mellitus and chronic obstructive pulmonary disease; ranging 0-5 points) stratified the incidence of adverse outcomes among patients with AF and HFpEF registered in the Kyoto Congestive Heart Failure Registry as well as among those in the Fushimi AF Registry (both log-rank; P < 0.001)., Conclusions: Non-cardiovascular comorbidities such as anaemia, diabetes mellitus and kidney or pulmonary disease in addition to advanced age were independent predictors of adverse outcomes in patients with AF and HFpEF. Our study suggests the importance of focusing on these non-cardiovascular comorbidities for individualized risk stratification and optimal management in patients with AF and HFpEF., (© 2024 The Author(s). ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Purpose: The study reviewed a multidisciplinary approach to treating cervicofacial lymphatic malformations (CFLMs) in children., Methods: Between 2007 and 2023, 53 children with CFLMs were treated with the median on-set age of 5 months (0-165) at our institute. For infants, airway management, including possible tracheotomy was prioritized, and a "wait-and-see" policy was adopted to expect spontaneous regression. Once children reached one year of age or diagnosed after infancy, OK-432 sclerotherapy and surgical treatment with/without sirolimus were considered for residual lesions., Results: The median follow-up period was 38 months (0-169). Among 30 infants, tracheostomy was performed in 4 patients, with 3 successfully closed after treatment. Thirteen patients showed excellent improvement without treatment. Sclerotherapy was performed in 15 patients, and partial resection in 5. Six patients were treated with sirolimus and showed moderate shrinkage or cessation of bleeding. Overall, 23 of 30 infants showed moderate to excellent improvement. For the 23 patients diagnosed after infancy, 16 improved without treatment, and 7 showed moderate to excellent improvement with sclerotherapy., Conclusions: The study concluded that early sclerotherapy for infants, particularly around the airway, poses risks, and tracheostomy might be necessary. The comprehensive strategy including "wait-and-see," sclerotherapy, sirolimus treatment, and timely surgery significantly improved the patients' quality of life., Competing Interests: Declarations. Conflict of interest: The authors declare no conflicts of interest in association with the present study., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Context: The mortality rate in thyroid storm (TS) has been reported to be higher than 10%., Objective: We aimed to evaluate the effectiveness of the 2016 guidelines for the management of TS proposed by the Japan Thyroid Association and Japan Endocrine Society., Methods: In this prospective multicenter registry-based study, patients with new-onset TS were registered in the Research Electronic Data Capture (REDCap), a secure web platform. On day 30 after admission, clinical information and prognosis of each patient were added to the platform. On day 180, the prognosis was described., Results: This study included 110 patients with TS. The median of Acute Physiology and Chronic Health Evaluation (APACHE) II score was 13, higher than the score (10) in the previous nationwide epidemiological study (P = .001). Nonetheless, the mortality rate at day 30 was 5.5%, approximately half compared with 10.7% in the previous nationwide survey. Lower body mass index, shock, and lower left ventricular ejection fraction were positively associated with poor prognosis at day 30, while the lack of fever ≥ 38 °C was related to the outcome. The mortality rate in patients with an APACHE II score ≥ 12 for whom the guidelines were not followed was significantly higher than the rate in patients for whom the guidelines were followed (50% vs 4.7%) (P = .01)., Conclusion: Prognosis seemed better than in the previous nationwide survey, even though disease severity was higher. The mortality rate was lower when the guidelines were followed. Thus, the guidelines are useful for managing TS., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

A 75-year-old male, hospitalized with back pain, remained hospitalized for tests for unexplained colitis, which was diagnosed as inflammatory bowel disease unclassified and treated with antibiotics and prednisolone, resulting in Clostridioides difficile colitis. Therefore, antibiotics were discontinued, and oral metronidazole treatment was initiated; however, as the patient's fever persisted, blood cultures were performed. An anaerobic bottle of blood culture turned positive the following day. Initial Gram staining of the positive blood culture fluid showed negative rods, and restaining detected small numbers of Gram-positive rods among the Gram-negative rods. The gray colonies on the subculture medium contained only Gram-negative rods. The bacterium was identified as Flavonifractor plautii using mass spectrometry. We ordered the ATCC 29863 F. plautii strain and compared with the strain of this case. The biochemical test result and the change in colony fluorescence under ultraviolet light of the strain isolated from the patient were identical to those of the ATCC strain, supporting the mass spectrometry results. Bacterial translocation from colonic mucosa was suspected, which improved following levofloxacin and metronidazole therapy. Only eight cases of human F. plautii infection have been reported, and we summarized them as a review. Careful and thorough isolation and identification of bacteria that are rarely isolated clinically, such as F. plautii, is crucial in accumulating evidence on rare infectious diseases., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2024 Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases, and Japanese Society for Infection Prevention and Control. Published by Elsevier Ltd. All rights reserved.)

Background: Anticoagulation therapy for atrial fibrillation (AF) has undergone major changes following the introduction of direct oral anticoagulants (DOAC) in 2011. However, the transition of anticoagulation therapy for AF patients with severe renal dysfunction remains to be elucidated., Methods and Results: Follow-up data, including creatinine clearance (CrCl), were available for 3,706 patients in the Fushimi AF Registry. We divided patients into 3 groups based on CrCl as follows: (1) CrCl ≥50 mL/min; (2) 50 mL/min>CrCl≥30 mL/min; and (3) CrCl <30 mL/min. In patients with CrCl ≥50 mL/min and 50>CrCl≥30 mL/min, prescription of oral anticoagulants increased year-by-year from 2011 to 2021 with a growing proportion of DOAC; however, the prescription of oral anticoagulants remained almost unchanged in those with CrCl <30 mL/min. In patients with CrCl ≥50 mL/min and 50 mL/min>CrCl≥30 mL/min, the incidence of adverse events, including stroke/systemic embolism and major bleeding, was lower among patients enrolled after 2014 than before 2013. However, these trends were not seen in patients with CrCl <30 mL/min., Conclusions: Despite the increased use of DOAC in patients with AF since 2011, anticoagulation therapy for AF patients with severe renal dysfunction has largely remained unchanged, and a reduction in adverse events in those patients has not been observed.

Objectives: Among subepithelial lesions (SELs), gastrointestinal stromal tumors (GISTs) should be identified and surgically treated at an early stage. However, it is difficult to diagnose SELs smaller than 20 mm. In recent years, endoscopic ultrasound (EUS) elastography (EUS-EG) and contrast-enhanced harmonic EUS (CH-EUS) have been reported to be useful for the diagnosis of SELs, although the diagnostic accuracy of a combination of EUS techniques with image enhancement is unknown., Methods: Patients with SELs who underwent EUS-guided tissue acquisition, EUS shear-wave elastography (EUS-SWE), EUS strain elastography (EUS-SE), and CH-EUS from January 2019 to June 2023 were enrolled. To assess the diagnostic accuracy for differentiating GISTs from other SELs, shear-wave velocity on EUS-SWE, the strain ratio on EUS-SE, and vascularity on CH-EUS were determined and their diagnostic accuracies were compared., Results: Forty-three patients were enrolled. When the cut-off value was set at 3.27 m/s, the sensitivity, specificity, and diagnostic accuracy of shear-wave velocity were 28.6%, 86.2%, and 34.9%, respectively. When the cut-off value was set at 3.79, the sensitivity, specificity, and diagnostic accuracy of the strain ratio were 93.1%, 64.3%, and 83.7%, respectively. The sensitivity, specificity, and diagnostic accuracy of CH-EUS were 79.3%, 92.3%, and 83.7%, respectively. When EUS-SE was combined with CH-EUS, the sensitivity and diagnostic accuracy were the highest among binary combinations of image enhancement modalities., Conclusions: EUS-SE and CH-EUS are useful for differentiating GISTs from other SELs. Furthermore, the use of both modalities may further improve the identification of GISTs., Competing Interests: Masayuki Kitano has received honoraria from Olympus Corporation for delivering lectures at conferences and has received research grants from Boston Scientific Corporation and Medico's Hirata Incorporated. The other authors declare no conflict of interest., (© 2024 The Author(s). DEN Open published by John Wiley & Sons Australia, Ltd on behalf of Japan Gastroenterological Endoscopy Society.)

Background: S-588410, a cancer peptide vaccine (CPV), comprises five HLA-A*24:02-restricted peptides from five cancer-testis antigens. In a phase 2 study, S-588410 was well-tolerated and exhibited antitumor efficacy in patients with urothelial cancer. Therefore, we aimed to evaluate the efficacy, immune response, and safety of S-588410 in patients with completely resected esophageal squamous cell carcinoma (ESCC)., Methods: This phase 3 study involved patients with HLA-A*24:02-positive and lymph node metastasis-positive ESCC who received neoadjuvant therapy followed by curative resection. After randomization, patients were administered S-588410 and placebo (both emulsified with Montanide™ ISA 51VG) subcutaneously. The primary endpoint was relapse-free survival (RFS). The secondary endpoints were overall survival (OS), cytotoxic T-lymphocyte (CTL) induction, and safety. Statistical significance was tested using the one-sided weighted log-rank test with the Fleming-Harrington class of weights., Results: A total of 276 patients were randomized (N = 138/group). The median RFS was 84.3 and 84.1 weeks in the S-588410 and placebo groups, respectively (P = 0.8156), whereas the median OS was 236.3 weeks and not reached, respectively (P = 0.6533). CTL induction was observed in 132/134 (98.5%) patients who received S-588410 within 12 weeks. Injection site reactions (137/140 patients [97.9%]) were the most frequent treatment-emergent adverse events in the S-588410 group. Prolonged survival was observed in S-588410-treated patients with upper thoracic ESCC, grade 3 injection-site reactions, or high CTL intensity., Conclusions: S-588410 induced immune response and had acceptable safety but failed to reach the primary endpoint. A high CTL induction rate and intensity may be critical for prolonging survival during future CPV development., (© 2024. The Author(s).)

Aims: In recent years, there has been remarkable development in machine learning (ML) models, showing a trend towards high prediction performance. ML models with high prediction performance often become structurally complex and are frequently perceived as black boxes, hindering intuitive interpretation of the prediction results. We aimed to develop ML models with high prediction performance, interpretability, and superior risk stratification to predict in-hospital mortality and worsening heart failure (WHF) in patients with acute heart failure (AHF)., Methods and Results: Based on the Kyoto Congestive Heart Failure registry, which enrolled 4056 patients with AHF, we developed prediction models for in-hospital mortality and WHF using information obtained on the first day of admission (demographics, physical examination, blood test results, etc.). After excluding 16 patients who died on the first or second day of admission, the original dataset (n = 4040) was split 4:1 into training (n = 3232) and test datasets (n = 808). Based on the training dataset, we developed three types of prediction models: (i) the classification and regression trees (CART) model; (ii) the random forest (RF) model; and (iii) the extreme gradient boosting (XGBoost) model. The performance of each model was evaluated using the test dataset, based on metrics including sensitivity, specificity, area under the receiver operating characteristic curve (AUC), Brier score, and calibration slope. For the complex structure of the XGBoost model, we performed SHapley Additive exPlanations (SHAP) analysis, classifying patients into interpretable clusters. In the original dataset, the proportion of females was 44.8% (1809/4040), and the average age was 77.9 ± 12.0. The in-hospital mortality rate was 6.3% (255/4040) and the WHF rate was 22.3% (900/4040) in the total study population. In the in-hospital mortality prediction, the AUC for the XGBoost model was 0.816 [95% confidence interval (CI): 0.815-0.818], surpassing the AUC values for the CART model (0.683, 95% CI: 0.680-0.685) and the RF model (0.755, 95% CI: 0.753-0.757). Similarly, in the WHF prediction, the AUC for the XGBoost model was 0.766 (95% CI: 0.765-0.768), outperforming the AUC values for the CART model (0.688, 95% CI: 0.686-0.689) and the RF model (0.713, 95% CI: 0.711-0.714). In the XGBoost model, interpretable clusters were formed, and the rates of in-hospital mortality and WHF were similar among each cluster in both the training and test datasets., Conclusions: The XGBoost models with SHAP analysis provide high prediction performance, interpretability, and reproducible risk stratification for in-hospital mortality and WHF for patients with AHF., (© 2024 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: Most patients hospitalized for heart failure (HF) present with signs of congestion. Prognostic significance of clinical congestion may vary depending on left ventricular ejection fraction (LVEF). This study aims to investigate the prognostic impact of congestion across different LVEF categories., Methods and Results: Composite congestion scores (CCSs; 0-9) derived from the severity of edema, jugular venous pressure, and orthopnea, were analyzed on admission and at discharge in 3787 patients hospitalized for HF (LVEF ≥ 40%: n = 2347, LVEF < 40%: n = 1440). The median admission CCS was 4 in both LVEF strata (P = .64). Adjusted hazard ratios (HRs; 95% confidence interval [CI]) of the moderate (CCS 4-6) and severe congestion [7-9] groups relative to the mild congestion [0-3] group on admission for a composite of all-cause death or HF rehospitalization were 1.20 (1.04-1.39, P = .01) and 1.54 (1.27-1.86, P < .001) in the LVEF ≥ 40% stratum, and 1.20 (1.01-1.44, P = .04) and 0.82 (0.61-1.07, P = .14) in the LVEF < 40% stratum, respectively (P interaction < .001). A total of 16% of the patients with LVEF ≥40% and 14% with LVEF <40% had residual congestion (CCS ≥ 1) at discharge, which was associated with a respective adjusted HR of 1.40 (1.18-1.65, P < .001) and 1.25 (0.98-1.58, P = .07) for postdischarge death or HF rehospitalization (P interaction  = 0.63)., Conclusion: The severity of clinical congestion on admission was associated with adverse clinical outcomes in patients with LVEF ≥ 40%, but not in those with LVEF < 40%. These findings warrant further studies to better understand the detailed profile of congestion across the LVEF spectrum., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Some patients with atrial fibrillation (AF), albeit less frequently, may regress from sustained to paroxysmal type. We sought to investigate how the regression of AF is associated with outcomes. Among the AF patients enrolled in the Fushimi AF Registry who were identified as having sustained AF at baseline, conversion of sustained to paroxysmal AF during follow-up was defined as AF regression. Major adverse cardiovascular events (MACE) were defined as a composite of cardiac death, myocardial infarction, ischemic stroke, systemic embolism, or hospitalization due to heart failure. Among 2,261 patients with sustained AF at baseline, AF regression was observed in 214 (9.5%) patients over a median follow-up period of 5.8 years (1.78% per patient-year). The annual incidence of MACE in patients with AF regression was significantly lower than those without (3.47% vs. 6.59% per patient-year, P < 0.001; adjusted hazard ratio [HR], 0.53, 95% confidence interval [CI], 0.38-0.72). Furthermore, AF regression was significantly associated with reduced risk of MACE during and after the regression period from sustained to paroxysmal forms (during regression period: adjusted HR, 0.45; 95% CI, 0.22-0.90; after regression period: adjusted HR, 0.43; 95% CI, 0.26-0.67). The incidence of MACE was comparable between spontaneous regression (35/178: 19.7%) and therapy-associated regression (either receiving catheter ablation or antiarrhythmic drugs before the regression) (7/36: 19.4%) (P=0.98). Regression of AF was associated with a lower incidence of adverse cardiovascular events. The risk of adverse events decreased significantly during the regression period and its reduction level persisted after regression. URL: http://www.umin.ac.jp/ctr/index.htm Unique identifier: UMIN000005834., Competing Interests: Declaration of competing interest Dr. Akao received lecture fees from Pfizer, Bristol-Myers Squibb, Boehringer Ingelheim, Bayer Healthcare, and Daiichi Sankyo. All other authors have reported that they have no relationships relevant to the content of this paper to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Patients with type 2 diabetes mellitus are frequently hospitalized for heart failure. The ratio of early diastolic mitral inflow velocity to early diastolic mitral annulus velocity (E/e'), measured by echocardiography, is a simple and convenient indicator of diastolic dysfunction. Various large clinical trials have reported that sodium glucose transporter-2 inhibitor therapy reduced cardiovascular events and hospitalizations in heart failure patients. We examined the effect of tofogliflozin on various physiological and cardiac function. A retrospective analysis was performed on elderly patients aged 65 years or older with type 2 diabetes mellitus attending Himi Municipal Hospital who were taking oral tofogliflozin 20 mg/day. Measurement of physiological and hormonal variables, blood sampling, and echocardiographic evaluations at 0, 1, 3, and 6 months were performed on those with ejection fraction (EF) of 40% or greater at the time of treatment. Statistical analysis was performed using t-tests and mixed-effects models, with brain natriuretic peptide less than or not less than 100 pg/mL, estimated glomerular filtration rate (eGFR) less than or not less than 50 mL/min/1.73 m2, and diuretics administered or not. Hypoglycemic effects were observed at 0, 1, 3, and 6 months. At each time point, EF was retained and E/e' was significantly reduced. On the other hand, most physiological parameters and laboratory results showed no clinical abnormalities. Mixed-effects models showed time-dependent reduction of E/e' in high/low brain natriuretic peptide, high/low eGFR, with or without diuretics between baseline and at 6 months. The interaction with time was significant in high/low eGFR. Tofogliflozin was shown to improve E/e', a measure of diastolic function, while maintaining EF, with hypoglycemic effects and no clinical side effects., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Myasthenia gravis (MG) is an autoimmune disease that targets neuromuscular junctions. While immunotherapy remains the cornerstone of treatment, the effects of Janus kinase (JAK) inhibitors on MG remain underexplored. In this report, we describe the case of a 58-year-old woman with ocular myasthenia gravis who received treatment with the JAK inhibitor, baricitinib for alopecia areata. The patient presented with left eyelid ptosis and an inadequate response to steroids and pyridostigmine, along with symptoms of alopecia areata. Following diagnosis, we initiated a treatment regimen consisting of baricitinib for six months. After initiation of baricitinib, we observed a complete resolution of the patient's MG symptoms, accompanied by hair regrowth, even when steroids were tapered and pyridostigmine was discontinued. Furthermore, the titer of the anti-acetylcholine receptor antibody was decreased. This report represents the first reported case of anti-acetylcholine receptor antibody-positive MG that was successfully treated through the inhibition of JAK activity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background and Aims: To overcome the technical difficulties associated with gastric endoscopic submucosal dissection (ESD), a novel traction device that can alter the direction of traction was developed. This study compared the efficacy and safety of conventional ESD versus those of traction-assisted gastric ESD., Methods: Patients with a single gastric epithelial neoplasm were randomized to receive conventional (n = 75) or traction-assisted (n = 73) gastric ESD. The primary outcome was ESD procedure time., Results: There were no differences between the conventional and traction-assisted groups with respect to treatment results or adverse events. The mean procedure time was similar for both groups (78.9 vs 88.3 minutes, respectively; P = .3); however, times for the traction device tended to be shorter for lesions in the lesser curvature of the upper or middle stomach (84.6 vs 123.2 minutes; P = .057)., Conclusions: Traction-assisted ESD for lesions in the lesser curvature of the upper or middle stomach were shorter, thereby reducing the procedure time of conventional ESD. (Clinical trial registration: University Hospital Medial Information Network Clinical Trials Registry, identifier 000044450.)., Competing Interests: Disclosure The following author disclosed financial relationships: M. Kitano: honoraria from Olympus Corporation (for delivering lectures at conferences). All other authors disclosed no financial relationships., (Copyright © 2024 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.)

Background: Treatment of advanced non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) has a higher response rate than with conventional chemotherapy in patients positive for EGFR mutations. However, the efficacy of EGFR-TKI therapy may be reduced in patients positive for the EGFR exon 21 L858R point mutation., Objective: To determine the clinical characteristics of patients with EGFR exon 21 L858R point mutation-positive NSCLC who are non-responders to EGFR-TKI therapy and the factors that predict response to EGFR-TKI therapy., Methods: Patients with NSCLC treated with EGFR-TKIs were evaluated for response after treatment, and those who responded were compared with those who did not respond., Results: Of 31 patients, 21 (67.7%) responded to EGFR-TKI therapy (the response group). There were significantly more programmed death ligand 1 (PDL1)-negative patients in the response group than in the non-response group. A significantly higher number of patients in the PDL1-positive group developed interstitial lung disease (ILD) after EGFR-TKI therapy than those in the PDL1-negative group., Conclusion: EGFR-TKI therapy is likely to be non-responsive in PDL1-positive patients with EGFR exon 21 L858R point mutation-positive NSCLC. The PDL1-positive group is at a high risk of developing ILD., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Institutional Review Board of Kanazawa Medical University issued approval C057. This study was approved by the Institutional Review Board of Kanazawa Medical University (approval number: C057). Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Takahara et al.)

Background: We previously showed that total tumor resection enhances metastatic growth in a syngeneic metastatic mouse model of neuroblastoma. In this study, we further investigated which surgical factors contributed most to metastatic growth., Methods: Tumor cells derived from MYCN transgenic mice were subcutaneously injected into wild-type mice. Mice were randomly assigned to receive partial resection (PR group), subcutaneous implantation of a sponge (Sp group), or observation (Obs group). The lymph node metastasis volume and the frequency of lung metastasis were compared 14 days after assignment by measuring C-reactive protein (CRP) and interleukin-6 (IL-6) levels., Results: The lymph node metastasis volume in the Sp group was larger than in the Obs group (148.4 [standard deviation {SD}: 209.5] vs. 10.2 [SD 12.8] mm 3 ). The frequency of lung metastasis was greater in the Sp group than in the PR group (11.9 [SD 12.2] vs. 6.6 [SD 4.0] counts/slide). The CRP level in the Sp group was higher than in the PR group (2.3 [SD 0.5] vs. 1.5 [SD 0.4] μg/mL), and the IL-6 level in the Sp group was higher than in the PR or Obs groups (28.4 [SD 34.5] vs. 12.4 [SD 19.0] vs. 5.4 [SD 8.1] pg/mL)., Conclusion: Metastatic growth may be enhanced by systemic inflammation., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: This study aimed to clarify whether the range of motion (ROM), anterior and posterior (AP) stability and other clinical measures changed in patients who underwent tibia-first total knee arthroplasty (TF-TKA) using navigation with a computer-aided system after surgery., Methods: This is a retrospective study and we conducted a matched cohort analysis of 60 measured resection (MR)-TKAs and 52 TF-TKAs performed by a single surgeon. All the surgeries used the same implant and approach. Baseline differences between the groups were adjusted using propensity score matching. We compared each patient's measured ROM and Oxford Knee Score (OKS) and performed knee AP laxity measurements by using a device during routine follow-ups., Results: A total of 40 MR-TKAs with a mean age of 73.5 ± 5.6 years and sex (male 10, female 30) were compared to 40 TF-TKAs with a mean age of 74.0 ± 5.7 years and sex (male 13, female 27) at 2-year follow-ups. Two years postoperatively, there was a significant difference in the AP laxity at 30° of knee flexion between both groups (7.0 ± 3.4 mm vs. 5.2 ± 2.3 mm, p  < 0.01). In contrast, no differences were found between both groups for knee flexion (120.8 ± 9° vs. 116.7 ± 9.8°, p  = 0.07) and OKS score (41.8 ± 6.9 vs. 41.0 ± 5.9, p  = 0.61)., Conclusion: The AP stability in the midflexion obtained using the tibia-first technique remained consistent even after 2 years. However, OKS and ROM were not significantly different from those of the MR-TKA group., Level of Evidence: Retrospective comparative LEVEL III study., Competing Interests: The authors declare no conflict of interest., (© 2024 The Author(s). Journal of Experimental Orthopaedics published by John Wiley & Sons Ltd on behalf of European Society of Sports Traumatology, Knee Surgery and Arthroscopy.)

The lysosomal degradation of macromolecules produces diverse small metabolites exported by specific transporters for reuse in biosynthetic pathways. Here we deorphanized the major facilitator superfamily domain containing 1 (MFSD1) protein, which forms a tight complex with the glycosylated lysosomal membrane protein (GLMP) in the lysosomal membrane. Untargeted metabolomics analysis of MFSD1-deficient mouse lysosomes revealed an increase in cationic dipeptides. Purified MFSD1 selectively bound diverse dipeptides, while electrophysiological, isotope tracer and fluorescence-based studies in Xenopus oocytes and proteoliposomes showed that MFSD1-GLMP acts as a uniporter for cationic, neutral and anionic dipeptides. Cryoelectron microscopy structure of the dipeptide-bound MFSD1-GLMP complex in outward-open conformation characterized the heterodimer interface and, in combination with molecular dynamics simulations, provided a structural basis for its selectivity towards diverse dipeptides. Together, our data identify MFSD1 as a general lysosomal dipeptide uniporter, providing an alternative route to recycle lysosomal proteolysis products when lysosomal amino acid exporters are overloaded., (© 2024. The Author(s).)

Catheter-related bloodstream infections (CRBSIs) caused by Lactobacillus spp. and Lacticaseibacillus spp. are rare, and their clinical course and optimal treatment remain uncertain. In this report, we present a 46-year-old male patient who experienced clinically diagnosed Lacticaseibacillus paracasei CRBSI on four separate occasions, despite receiving systemic administration of antibiotics and antimicrobial lock therapy. The patient did not develop L. paracasei bacteremia after catheter removal. This case report furthers our knowledge of CRBSI caused by Lactobacillus and related genera and highlights the need for further research., 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 Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases, and Japanese Society for Infection Prevention and Control. Published by Elsevier Ltd. All rights reserved.)

Factor XIa (FXIa) may be involved in thrombus formation, but only to a lesser extent involved in haemostasis. Several novel FXIa inhibitors are under investigation, and Phase II trials demonstrated marked reduction of bleeding compared with standard treatment by factor Xa inhibitors. Asundexian is a small molecule that selectively inhibits FXIa. A large-scale Phase III clinical trial, OCEANIC-AF, has been initiated to compare the efficacy and safety between asundexian and apixaban. However, the OCEANIC-AF study was recently halted due to the inferior efficacy of asundexian versus the apixaban control arm. The present report describes up-to-date evidence of FXIa inhibitors and discusses the future position of FXIa inhibitors for patients with AF., Competing Interests: Disclosure: TI has received lecture honoraria from Bayer, Daiichi Sankyo and Pfizer. GAD and KH are on the European Cardiology Review editorial board; this did not influence peer review. All other authors have no conflicts of interest to declare. Funding: Grant-in-aid for clinical research from the National Hospital Organisation, Japan., (Copyright © The Author(s), 2024. Published by Radcliffe Group Ltd.)

The Drosophila downstream receptor kinase (Drk), a homologue of human GRB2, participates in the signal transduction from the extracellular to the intracellular environment. Drk receives signals through the interaction of its Src homology 2 (SH2) domain with the phosphorylated tyrosine residue in the receptor tyrosine kinases (RTKs). Here, we present the solution NMR structure of the SH2 domain of Drk (Drk-SH2), which was determined in the presence of a phosphotyrosine (pY)-containing peptide derived from a receptor tyrosine kinase, Sevenless (Sev). The solution structure of Drk-SH2 possess a common SH2 domain architecture, consisting of three β strands imposed between two α helices. Additionally, we interpret the site-specific interactions of the Drk-SH2 domain with the pY-containing peptide through NMR titration experiments. The dynamics of Drk-SH2 were also analysed through NMR-relaxation experiments as well as the molecular dynamic simulation. The docking simulations of the pY-containing peptide onto the protein surface of Drk-SH2 provided the orientation of the peptide, which showed a good agreement with the analysis of the SH2 domain of GRB2.

Aim: Whether serum concentration of procalcitonin (PCT), brain natriuretic peptide (BNP) and albumin (Alb) have an association with the outcome of hospitalized older patients is unclear. We investigated clinical outcomes and any predictive factors in hospitalized Japanese older patients with a risk of infection., Methods: In the retrospective study, 820 Japanese patients were followed up for 30 days or until death. During the observation period, 656 patients survived and 164 patients died. The predictive factors of death were analyzed according to demographic and clinical variables., Results: The survival rate was decreased as the serum PCT increased from <0.5 to ≥10 ng/mL, as was also the case with BNP from <300 to ≥300 pg./mL, whereas low Alb (<2.5 g/dL) showed a lower survival rate than high Alb (≥2.5 g/dL; P < 0.01). Using the Cox regression model, the multivariable-adjusted hazard ratios (95% confidence interval) were as follows: PCT 0.5-2 versus <0.5 ng/mL: 1.61(1.04-2.49), PCT 2-10 versus <0.5 ng/mL: 1.91(1.15-3.16), PCT ≥10 versus <0.5 ng/mL: 2.90(1.84-4.59), high BNP 1.26 (0.89-1.76) and low Alb 0.68 (0.52-0.87). The mortality rate increased as the number of scores (PCT + BNP + Alb) increased., Conclusions: Concentration-dependent high PCT, high BNP and low Alb were positive risk factors associated with poor prognosis in hospitalized older patients with a risk of infection. Geriatr Gerontol Int 2024; 24: 571-576., (© 2024 Japan Geriatrics Society.)

Aims: Atrial fibrillation (AF) type (paroxysmal, persistent, or permanent) is important in determining therapeutic management; however, clinical outcomes by AF type are largely unknown for hospitalized patients with heart failure (HF)., Methods and Results: The Japanese Registry Of Acute Decompensated Heart Failure is a retrospective, multicenter, and nationwide registry of patients hospitalized for acute HF in Japan. Follow-up data were collected up to 5 years after hospitalization. Patients were divided based on diagnosis and AF type into 3 groups [without AF, paroxysmal AF, and sustained AF (defined as a composite of persistent and permanent AF)], and compared the backgrounds and outcomes between the groups. Of 12 895 hospitalized HF patients [mean age: 78 ± 13 years, female: 6077 (47%), and mean left ventricular ejection fraction: 47 ± 17%], 1725 had paroxysmal AF, and 3672 had sustained AF. Compared with patients without AF, sustained AF had a higher risk of the primary composite endpoint of cardiovascular (CV) death or HF hospitalization [hazard ratio (HR): 1.09, 95% confidence interval (CI): 1.01-1.17; P = 0.03], mainly driven by HF hospitalization [HR: 1.16, 95% CI: 1.06-1.26; P < 0.001], whereas the corresponding risk for the primary endpoint in patients with paroxysmal AF was not elevated (HR: 1.03, 95% CI: 0.94-1.13; P = 0.53) after adjustment by multivariable Cox regression analysis. These results were consistent among the subgroups of patients with reduced or preserved ejection fraction (interaction P = 0.74)., Conclusion: Among hospitalized patients with HF, sustained AF, but not paroxysmal AF, was significantly associated with a higher risk for CV death or HF hospitalization, indicating the importance of accounting for AF type in HF patients., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Palliative care, including symptom alleviation and advance-care planning, is relevant for patients with heart failure (HF). The Supportive and Palliative Care Indicator Tool (SPICT) is a tool for identifying patients who may benefit from palliative-care assistance but has not been validated in patients hospitalized due to HF., Methods and Results: Clinical backgrounds, symptom burdens and outcomes were evaluated using the SPICT as assessed on admission in consecutive hospitalized patients with HF. SPICT-positive was defined when 2 or more general indicators and a New York Heart Association class ≥ III were present. Of 601 patients hospitalized due to HF (mean age: 79 ± 12 years; male, 314 [52%]; and mean left ventricular ejection fraction: 44 ± 18%), 100 (17%) patients were SPICT-positive. SPICT-positive patients were older (85 ± 9 vs 78 ± 12 years; P < 0.001) and had higher clinical frailty scales (6 ± 1 vs 4 ± 1 points; P < 0.001), whereas symptom burdens assessed by the Integrated Palliative care Outcome Scale were not different (17 [13, 28] vs 20 [11, 26] points; P = 0.97) when compared with patients who were SPICT-negative. During the median follow-up period of 518 days, 178 patients (30%) died. Being SPICT-positive was independently associated with higher all-cause mortality (hazard ratio: 3.49, 95% confidence interval: 2.41-5.05; P < 0.001) after adjusting for age, sex, New York Heart Association class IV, Get-With-The-Guideline risk score, N-terminal pro B-type natriuretic peptide levels, and left ventricular ejection fractions., Conclusions: In patients admitted for HF, being SPICT-positive was significantly associated with higher all-cause mortality rates, suggesting the utility of the SPICT as an indicator to initiate advance-care planning for end-of-life care among patients hospitalized due to HF., Competing Interests: Disclosures None., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The sodium glucose transporter 2 (SGLT2) inhibitor tofogliflozin is a glucose-lowering drug that causes the excretion of surplus glucose by inhibiting SGLT2. Because of tofogliflozin's osmotic diuresis mechanism, patients' serum electrolytes, body fluid levels, and cardiac function must be monitored. We retrospectively analyzed the cases of 64 elderly Japanese patients with type 2 diabetes mellitus (T2DM) who received tofogliflozin for 3 months. Their HbA1c, serum electrolytes (sodium, potassium, chloride), hematocrit, brain natriuretic peptide (cardiac volume load marker) and renin and aldosterone (RAA; an index of regulatory hormones involved in body fluid retention) were continuously monitored during the investigation period. Renal function and cardiac function (by echocardiography) were assessed throughout the period. HbA1c significantly decreased (β1=-0.341, p<0.0001, linear regression analysis [LRA]). Most of the hormonal, electrolyte, and physiological parameters were maintained throughout the study period. In these circumstances, E/e' tended to decrease (β1=-0.382, p=0.13, LRA). Compared to the baseline, E/e' was significantly decreased at 1 and 3 months (p<0.01, p<0.05). In the higher E/e' group (E/e'≥10, n=34), E/e' decreased significantly (β1=-0.63, p<0.05, LRA). ΔE/e' was correlated with body-weight change during treatment (r=0.64, p<0.01). The 3-month tofogliflozin treatment improved glycemic control and diastolic function represented by E/e' in T2DM patients, without affecting serum electrolytes, renal function, or RAA. No negative impacts on the patients were observed. Three-month tofogliflozin treatment lowered glucose and improved cardiac diastolic function., Competing Interests: No potential conflict of interest relevant to this article was reported.

There are currently no abstract classifiers, which can be used for new diagnostic test accuracy (DTA) systematic reviews to select primary DTA study abstracts from database searches. Our goal was to develop machine-learning-based abstract classifiers for new DTA systematic reviews through an open competition. We prepared a dataset of abstracts obtained through database searches from 11 reviews in different clinical areas. As the reference standard, we used the abstract lists that required manual full-text review. We randomly splitted the datasets into a train set, a public test set, and a private test set. Competition participants used the training set to develop classifiers and validated their classifiers using the public test set. The classifiers were refined based on the performance of the public test set. They could submit as many times as they wanted during the competition. Finally, we used the private test set to rank the submitted classifiers. To reduce false exclusions, we used the Fbeta measure with a beta set to seven for evaluating classifiers. After the competition, we conducted the external validation using a dataset from a cardiology DTA review. We received 13,774 submissions from 1429 teams or persons over 4 months. The top-honored classifier achieved a Fbeta score of 0.4036 and a recall of 0.2352 in the external validation. In conclusion, we were unable to develop an abstract classifier with sufficient recall for immediate application to new DTA systematic reviews. Further studies are needed to update and validate classifiers with datasets from other clinical areas., (© 2023 John Wiley & Sons, Ltd.)

Background: Long-term urinary outcomes after anorectal malformation (ARM) repair are affected by surgical approach and sacral anomalies. This study aimed to compare laparoscopic-assisted anorectoplasty (LAARP) and posterior sagittal anorectoplasty (PSARP) in terms of urinary complications., Methods: Between 2001 and 2022, 45 patients were treated with LAARP or PSARP. The rectourethral fistula and inflow angle between the fistula and rectum was confirmed by preoperative colonography. The incidence of urinary complications and treatment were compared between the two groups., Results: Four patients (14%) had remnant fistula and five patients (17%) had neurogenic bladder dysfunction in LAARP group, while three patients (18%) had urethral injury in PSARP group. All patients with remnant fistula were asymptomatic and followed without treatment. The incidence of remnant fistula improved between earlier decade and later decade. In all cases with urethral injury, suture repair was performed and no postoperative leakage was noted. All five patients with neurogenic bladder dysfunction had spine abnormalities that required clean intermittent catheterization (CIC) and two were free from CIC finally., Conclusions: It is important to check inflow angle preoperatively to prevent remnant fistula. For PSARP, meticulous dissection is required when separating fistula from urethra because they create common wall. The most contributing factor to neurogenic bladder is sacral anomalies. Preoperative evaluation and postoperative urinary drainage are important., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Streptococcus mitis/oralis group isolates with reduced carbapenem susceptibility have been reported, but its isolation rate in Japan is unknown. We collected 356 clinical α-hemolytic streptococcal isolates and identified 142 of them as S. mitis/oralis using partial sodA sequencing. The rate of meropenem non-susceptibility was 17.6% (25/142). All 25 carbapenem-non-susceptible isolates harbored amino acid substitutions in/near the conserved motifs in PBP1A, PBP2B, and PBP2X. Carbapenem non-susceptibility is common among S. mitis/oralis group isolates in Japan., Competing Interests: The authors declare no conflict of interest.

Aims: Atrial fibrillation (AF) increases the risk of heart failure (HF); however, little is known regarding the risk stratification for incident HF in AF patients, especially with preserved left ventricular ejection fraction (LVEF)., Methods and Results: The Fushimi AF Registry is a community-based prospective survey of AF patients. From the registry, 3002 non-valvular AF patients with preserved LVEF and with the data of antero-posterior left atrial diameter (LAD) at enrolment were investigated. Patients were stratified by LAD (<40, 40-44, 45-49, and ≥50 mm) with backgrounds and HF hospitalization incidences compared between groups. Of 3002 patients [mean age, 73.5 ± 10.7 years; women, 1226 (41%); paroxysmal AF, 1579 (53%); and mean CHA 2 DS 2 -VASc score, 3.3 ± 1.7], the mean LAD was 43 ± 8 mm. Patients with larger LAD were older and less often paroxysmal AF, with a higher CHA 2 DS 2 -VASc score (all P < 0.001). Heart failure hospitalization occurred in 412 patients during the median follow-up period of 6.0 years. Larger LAD was independently associated with a higher HF hospitalization risk [LAD ≥ 50 mm: hazard ratio (HR), 2.36; 95% confidence interval (CI), 1.75-3.18; LAD 45-49 mm: HR, 1.84; 95% CI, 1.37-2.46; and LAD 40-44 mm: HR, 1.34; 95% CI, 1.01-1.78, compared with LAD < 40 mm) after adjustment by age, sex, AF type, and CHA 2 DS 2 -VASc score. These results were also consistent across major subgroups, showing no significant interaction., Conclusion: Left atrial diameter is significantly associated with the risk of incident HF in AF patients with preserved LVEF, suggesting the utility of LAD regarding HF risk stratification for these patients., Competing Interests: Conflict of interest: Ma.A. received lecture fees from Pfizer, Bristol Myers Squibb, Boehringer Ingelheim, Bayer Healthcare, and Daiichi Sankyo. All other authors have reported that they have no relationships relevant to the content of this paper to disclose., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: The superiority of thoracoscopic repair (TR) over conventional open repair (COR) for esophageal atresia, especially in terms of long-term outcomes, remains to be investigated. The aim of this study was to compare short- and long-term results between TR and COR group., Methods: Patients who underwent TR or COR for esophageal atresia without other predispositions to musculoskeletal deformities (2003-2016) and had been followed up for a minimum of 5 years were retrospectively reviewed. Musculoskeletal deformities (e.g., scoliosis, chest wall asymmetry, and rib deformities) were mainly evaluated based on the most recent chest radiographs., Results: Nine and eight patients were included in the TR and COR groups, respectively; the mean follow-up period was 8.7 and 11.5 years, respectively (p = 0.14). These groups had similar epidemiological characteristics and rates of postoperative complications. Musculoskeletal deformities developed significantly less frequently in the TR group versus the COR group (11 % vs. 88 %, p < 0.05; scoliosis: 0 % vs. 38 %, p = 0.08; chest wall asymmetry: 11 % vs. 50 %, p = 0.14; and rib deformities: 11 % vs. 88 %, p < 0.05, respectively)., Conclusion: TR was associated with a decreased incidence of musculoskeletal deformities and comparable complication rates versus COR for esophageal atresia repair. TR may achieve better long-term outcomes in this setting., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2024 Asian Surgical Association and Taiwan Robotic Surgery Association. Published by Elsevier B.V. All rights reserved.)

Background & Aims: Reported rates of delayed bleeding (DB) after endoscopic resection using direct oral anticoagulants (DOACs) are high and heterogeneous. This large-scale multicenter study analyzed cases of DB after colorectal endoscopic submucosal dissection related to various types of DOACs in Japan (the ABCD-J study) with those associated with warfarin., Methods: We retrospectively reviewed 1019 lesions in patients treated with DOACs and 459 lesions in patients treated with warfarin among 34,455 endoscopic submucosal dissection cases from 47 Japanese institutions between 2012 and 2021. The DB rate (DBR) with each DOAC was compared with that with warfarin. Risk factors for DB in patients treated with DOACs or warfarin were also investigated., Results: The mean tumor sizes in the DOAC and warfarin groups were 29.6 ± 14.0 and 30.3 ± 16.4 mm, respectively. In the DOAC group, the DBR with dabigatran (18.26%) was significantly higher than that with apixaban (10.08%, P = .029), edoxaban (7.73%, P = .001), and rivaroxaban (7.21%, P < .001). Only rivaroxaban showed a significantly lower DBR than warfarin (11.76%, P = .033). In the multivariate analysis, heparin bridging therapy (odds ratio [OR], 2.18; 95% confidence interval [CI], 1.27-3.73, P = .005), rectal location (2.01, 1.28-3.16, P = .002), and procedure time ≥55 minutes (2.43, 1.49-3.95, P < .001) were significant risk factors for DB in the DOAC group. The DB risk in the DOAC group (OR, (95% CI)) was 2.13 (1.30-3.50) and 4.53 (2.52-8.15) for 1 and 2 significant risk factors, respectively., Conclusions: Dabigatran was associated with a higher DBR than other DOACs, and only rivaroxaban was associated with a significantly lower DBR than warfarin., (Copyright © 2024 AGA Institute. Published by Elsevier Inc. All rights reserved.)