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Abstract Aim Laparoscopic segmentectomy (LS) using indocyanine green (ICG) fluorescence navigation with negative staining method has potential for performing accurate and safe anatomical excision. This study aimed to evaluate the significance of LS using ICG fluorescence navigation compared with open segmentectomy (OS). Methods Eighty‐seven patients who underwent anatomical segmentectomies were evaluated for OS (n = 44) and LS (n = 43). The Glissonean pedicle approach was performed using either extra‐ or intrahepatic method, depending on the location of segment in LS. After clamping pedicle, negative staining method was performed. Liver transection was done along intersegmental plane visualizing by overlay mode of ICG camera. Surgical outcomes were compared between two groups. Correlation between predicted resecting liver volume (PRLV) calculated using volumetry and actual resected liver volume (ARLV) was assessed in two groups. Results Patients who underwent LS showed better outcomes in operative time, blood loss, and length of hospital stay. There were significantly fewer Grade II and Grade III or higher postoperative complications in LS group. Both values of AST (p

Purpose: We evaluated associations between outcomes and time to achieving temperature targets during targeted temperature management of out-of-hospital cardiac arrest. Methods: Using Comprehensive Registry of Intensive Care for out-of-hospital cardiac arrest Survival (CRITICAL) study, we enrolled all patients transported to participating hospitals from 1 July 2012 through 31 December 2017 aged ≥ 18 years with out-of-hospital cardiac arrest of cardiac aetiology and who received targeted temperature management in Osaka, Japan. Primary outcome was Cerebral Performance Category scale of 1 or 2 one month after cardiac arrest, designated as “one-month favourable neurological outcome”. Non-linear multivariable logistic regression analyses assessed the primary outcome based on time to reaching temperature targets. In patients subdivided into quintiles based on time to achieving temperature targets, multivariable logistic regression calculated adjusted odds ratios and 95% confidence intervals. Results: We analysed 473 patients. In non-linear multivariable logistic regression analysis, p value for non-linearity was < 0.01. In the first quintile (< 26.7 minutes), second quintile (26.8–89.9 minutes), third quintile (90.0–175.1 minutes), fourth quintile (175.2–352.1 minutes), and fifth quintile (≥ 352.2 minutes), one-month favourable neurological outcome was 32.6% (31/95), 40.0% (36/90), 53.5% (53/99), 57.4% (54/94), and 37.9% (36/95), respectively. Adjusted odds ratios with 95% confidence intervals for one-month favourable neurological outcome in the first, second, third, and fifth quintiles compared with the fourth quintile were 0.38 (0.20 to 0.72), 0.43 (0.23 to 0.81), 0.77 (0.41 to 1.44), and 0.46 (0.25 to 0.87), respectively. Conclusion: Non-linear multivariable logistic regression analysis could clearly describe the association between neurological outcome in patients with out-of-hospital cardiac arrest and the time from the introduction of targeted temperature management to reaching the temperature targets.

Abstract Aims The guideline‐directed medical therapy (GDMT) has been recommended for heart failure (HF) with reduced ejection fraction (HFrEF) based on the accumulating clinical evidence. However, it is difficult to implement all the trial‐proven medications for every patient in the real world. Methods and results A simple GDMT score was created, according to the combination of GDMT drugs (renin–angiotensin system inhibitors, beta‐blockers, mineralocorticoid receptor antagonists, and sodium–glucose transporter 2 inhibitors) administration and their dosage (0–9 points). Its impact on the prognosis of HF patients was investigated. Admitted HF patients [HFrEF and HF with mildly reduced ejection fraction (HFmrEF), n = 1054] were retrospectively analysed (excluding those with in‐hospital death and dialysis). A simple GDMT score ≥5, but not the number of medications, was significantly associated with a reduction of all‐cause death, HF readmission, and composite outcome (HF readmission and all‐cause death) (P

Background Few prediction models for individuals with early‐stage out‐of‐hospital cardiac arrest (OHCA) have undergone external validation. This study aimed to externally validate updated prediction models for OHCA outcomes using a large nationwide dataset. Methods and Results We performed a secondary analysis of the JAAM‐OHCA (Comprehensive Registry of In‐Hospital Intensive Care for Out‐of‐Hospital Cardiac Arrest Survival and the Japanese Association for Acute Medicine Out‐of‐Hospital Cardiac Arrest) registry. Previously developed prediction models for patients with cardiac arrest who achieved the return of spontaneous circulation were updated. External validation was conducted using data from 56 institutions from the JAAM–OHCA registry. The primary outcome was a dichotomized 90‐day cerebral performance category score. Two models were updated using the derivation set (n=3337). Model 1 included patient demographics, prehospital information, and the initial rhythm upon hospital admission; Model 2 included information obtained in the hospital immediately after the return of spontaneous circulation. In the validation set (n=4250), Models 1 and 2 exhibited a C‐statistic of 0.945 (95% CI, 0.935–0.955) and 0.958 (95% CI, 0.951–0.960), respectively. Both models were well‐calibrated to the observed outcomes. The decision curve analysis showed that Model 2 demonstrated higher net benefits at all risk thresholds than Model 1. A web‐based calculator was developed to estimate the probability of poor outcomes (https://pcas‐prediction.shinyapps.io/90d_lasso/). Conclusions The updated models offer valuable information to medical professionals in the prediction of long‐term neurological outcomes for patients with OHCA, potentially playing a vital role in clinical decision‐making processes.

Abstract Although the formation of bone-like nodules is regarded as the differentiation process from stem cells to osteogenic cells, including osteoblasts and osteocytes, the precise biological events during nodule formation are unknown. Here we performed the osteogenic induction of human induced pluripotent stem cells using a three-dimensional (3D) culture system using type I collagen gel and a rapid induction method with retinoic acid. Confocal and time-lapse imaging revealed the osteogenic differentiation was initiated with vigorous focal proliferation followed by aggregation, from which cells invaded the gel. Invading cells changed their morphology and expressed osteocyte marker genes, suggesting the transition from osteoblasts to osteocytes. Single-cell RNA sequencing analysis revealed that 3D culture-induced cells with features of periosteal skeletal stem cells, some of which expressed TGFβ-regulated osteoblast-related molecules. The role of TGFβ signal was further analyzed in the transition from osteoblasts to osteocytes, which revealed that modulation of the TGFβ signal changed the morphology and motility of cells isolated from the 3D culture, suggesting that the TGFβ signal maintains the osteoblastic phenotype and the transition into osteocytes requires down-regulation of the TGFβ signal.

Abstract Background Focal Purkinje ventricular arrhythmias (VAs) might originate from the vicinity of the proximal portion of the cardiac conducting system. This study aimed to clarify the features associated with focal Purkinje VAs originating from the proximal conduction system. Methods A total of 18 patients with focal Purkinje VAs undergoing radiofrequency catheter ablation (RFCA) were retrospectively examined and divided into the proximal type or the non‐proximal type. The proximal type was defined as having the origin at the proximal half of the interventricular septum, or the proximal half and the septal side of the anterior wall. The 12‐lead electrocardiogram and electrophysiological findings were investigated. Results Seven patients met criteria for proximal type of focal Purkinje VA. Out of the 7, 4 patients with proximal VAs had multiple QRS morphologies of VAs clinically, whereas out of 11 patients with non‐proximal VAs, only 1 had multiple morphologies (p = .047). VA QRS duration was shorter in the proximal type than in the non‐proximal type (111.2 ± 19.8 ms vs. 135.7 ± 17.7 ms; p = .003). The absolute axis difference between sinus rhythm and VA was smaller in the proximal type (80.4 ± 46.1°vs. 138.8 ± 59.6°; p = .014). The absolute axis difference ≤134° was useful in distinguishing the two types. Recurrence of VA was recorded in 3 proximal type patients and 3 non‐proximal type patients. No procedure‐related conduction block was observed. Conclusion A VA of absolute axis difference ≤134°, and multiple QRS morphologies of clinical VAs indicate a proximal origin. Focal Purkinje VAs from proximal origins can be suppressed by RFCA without severe conduction disturbance.

Abstract Background Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disease characterized by progressive heterotopic ossification (HO) in soft tissues due to a heterozygous mutation of the ACVR1A gene (FOP-ACVR1A), which erroneously transduces the BMP signal by Activin-A. Although inflammation is known to trigger HO in FOP, the role of FOP-ACVR1A on inflammatory cells remains to be elucidated. Results We generated immortalized monocytic cell lines from FOP-iPSCs (FOP-ML) and mutation rescued iPSCs (resFOP-ML). Cell morphology was evaluated during the monocyte induction and after immortalization. Fluorescence-activated cell sorting (FACS) was performed to evaluate the cell surface markers CD14 and CD16 on MLs. MLs were stimulated with lipopolysaccharide or Activin-A and the gene expression was evaluated by quantitative PCR and microarray analysis. Histological analysis was performed for HO tissue obtained from wild type mice and FOP-ACVR1A mice which conditionally express human mutant ACVR1A gene by doxycycline administration. Without any stimulation, FOP-ML showed the pro-inflammatory signature of CD16+ monocytes with an upregulation of INHBA gene, and treatment of resFOP-ML with Activin-A induced an expression profile mimicking that of FOP-ML at baseline. Treatment of FOP-ML with Activin-A further induced the inflammatory profile with an up-regulation of inflammation-associated genes, of which some, but not all, of which were suppressed by corticosteroid. Experiments using an inhibitor for TGFβ or BMP signal demonstrated that Activin-A-induced genes such as CD16 and CCL7, were regulated by both signals, indicating Activin-A transduced dual signals in FOP-ML. A comparison with resFOP-ML identified several down-regulated genes in FOP-ML including LYVE-1, which is known to suppress matrix-formation in vivo. The down-regulation of LYVE-1 in HO tissues was confirmed in FOP model mice, verifying the significance of the in vitro experiments. Conclusion These results indicate that FOP-ML faithfully recapitulated the phenotype of primary monocytes of FOP and the combination with resFOP-ML is a useful tool to investigate molecular events at the initial inflammation stage of HO in FOP.

Abstract Background The association between spontaneous initial body temperature on hospital arrival and neurological outcomes has not been sufficiently studied in patients after out-of-hospital cardiac arrest (OHCA). Methods From the prospective database of the Comprehensive Registry of Intensive Care for OHCA Survival (CRITICAL) study in Osaka, Japan, we enrolled all patients with OHCA of medical origin aged > 18 years for whom resuscitation was attempted and who were transported to participating hospitals between 2012 and 2019. We excluded patients who were not witnessed by bystanders and treated by a doctor car or helicopter, which is a car/helicopter with a physician. The patients were categorized into three groups according to their temperature on hospital arrival: ≤35.9 °C, 36.0–36.9 °C (normothermia), and ≥ 37.0 °C. The primary outcome was 1-month survival, with a cerebral performance category of 1 or 2. Multivariable logistic regression analyses were performed to evaluate the association between temperature and outcomes (normothermia was used as the reference). We also assessed this association using cubic spline regression analysis. Results Of the 18,379 patients in our database, 5014 witnessed adult OHCA patients of medical origin from 16 hospitals were included. When analyzing 3318 patients, OHCA patients with an initial body temperature of ≥37.0 °C upon hospital arrival were associated with decreased favorable neurological outcomes (6.6% [19/286] odds ratio, 0.51; 95% confidence interval, 0.27–0.95) compared to patients with normothermia (16.4% [180/1100]), whereas those with an initial body temperature of ≤35.9 °C were not associated with decreased favorable neurological outcomes (11.1% [214/1932]; odds ratio, 0.78; 95% confidence interval, 0.56–1.07). The cubic regression splines demonstrated that a higher body temperature on arrival was associated with decreased favorable neurological outcomes, and a lower body temperature was not associated with decreased favorable neurological outcomes. Conclusions In adult patients with OHCA of medical origin, a higher body temperature on arrival was associated with decreased favorable neurologic outcomes.

ABSTRACT Collagen X is a non‐fibril collagen produced by hypertrophic chondrocytes and was believed to associate with the calcification process of growth plate cartilage. The homozygous loss of Col10a1 gene in mice, however, demonstrated no remarkable effects on growth plate formation or skeletal development. To investigate the role of collagen X in human chondrocytes, we established human induced pluripotent stem cells (hiPSCs) with heterozygous (COL10A1+/−) or homozygous (COL10A1−/−) deletions of COL10A1 gene using the dual sgRNA CRISPR/Cas9 system. Several mutant clones were established and differentiated into hypertrophic chondrocytes by a previously reported 3D induction method. No remarkable differences were observed during the differentiation process between parental and mutant cell lines, which differentiated into cells with features of hypertrophic chondrocytes, indicating that collagen X is dispensable for the hypertrophic differentiation of human chondrocytes in vitro. To investigate the effects of collagen X deficiency in vivo, chondrocyte pellets at the proliferating or prehypertrophic stage were transplanted into immunodeficient mice. Proliferating pellet‐derived tissues demonstrated the zonal distribution of chondrocytes with the transition to bone tissues mimicking growth plates, and the proportion of bone tended to be larger in COL10A1−/− tissues. Prehypertrophic pellet‐derived tissues produced trabecular bone structures with features of endochondral ossification, and there was no clear difference between parental‐ and mutant‐derived tissues. A transcriptome analysis of chondrocyte pellets at the hypertrophic phase showed a lower expression of proliferating‐phase genes and a higher expression of calcification‐phase genes in COL10A1−/− pellets compared with parental cell pellets. These in vitro and in vivo data suggested that collagen X is dispensable for the hypertrophic differentiation and endochondral ossification of human iPSC‐derived chondrocytes, though it may facilitate the differentiation process. Thus, COL10A1−/− iPSC lines are useful for investigating the physiological role of collagen X in chondrocyte differentiation. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Abstract Aims It has been reported that congestive heart failure (CHF) readmission has not decreased in the last decade. It is also reported that CHF readmission is likely to occur shortly after discharge. We investigated whether an early follow‐up at outpatient care within 2 weeks after discharge affects the long‐term readmission rate and prognosis. Methods and results We reviewed consecutive 1002 patients admitted to our hospital due to CHF. Two‐hundred and fifty‐nine patients who died in‐hospital or were transferred to another hospital or readmitted within 2 weeks were excluded and 743 of discharged patients were analysed. We extracted contributing variables associated with heart failure (HF) readmission and the composite adverse outcome (all cause death or HF readmissions) by univariate and multivariate analysis. Multivariate analysis showed that the early follow‐up was independently associated with freedom from HF readmission and the composite outcome. We divided these patients into two groups, with/without early follow‐up and performed a propensity score‐matching analysis (n = 259 each). HF readmission during 2 year follow‐up was significantly less in the early follow‐up group [P = 0.02, hazard ratio (HR) = 0.647, 95% confidence interval (CI) = 0.447–0.935] as well as the composite outcome was less in the early follow‐up group (P = 0.01, HR = 0.643, 95% CI = 0.456–0.908). Medication adjustments were done in only 33.2% of the patients. Rates of HF readmissions were comparable regardless of whether or not medication adjustment was done at the early follow‐up (P = 0.505, HR = 1.208, 95% CI = 0.692–2.106). Conclusions The present study demonstrates that an early follow‐up approach after discharge in CHF patients may improve the long‐term prognosis. These results may not depend on medication adjustment but rather on modifying patient factors early after discharge.

Abstract Background The pulmonary veins (PVs) have unique electrophysiological properties triggering and maintaining atrial fibrillation (AF). Bigeminal PV electrical activity (PV bigeminy) during sinus rhythm has been reported; however, its mechanisms and clinical implication remain unclear. We hypothesized that PV bigeminy indicates arrhythmogenic activities and influences clinical outcome. Methods and Results We retrospectively analyzed electrophysiological studies in 465 patients with AF who underwent first session PV isolation (PVI). PV bigeminy was observed in 30 PVs of 23 patients (4.9% of patients). PV bigeminy was observed in left inferior PV (LIPV) in 15 patients, which was the most prevalent, followed by left superior in seven and right superior in seven and right inferior in one. In response to atrial extra stimulus, the second PV potentials (PV2) showed decremental conduction properties, suggesting reentrant mechanisms involved (n = 5). Interestingly, AF was initiated from the 23 PVs with bigeminy in 21 patients (76.7% of 30 PVs with bigeminy), spontaneously or in response to drugs, which was significantly more prevalent from the AF initiation rate from each PV in the control 442 patients (182 firings in 1290 PVs, 14.1%, P

Summary: Background: Postoperative pancreatic fistula (POPF) after pancreatoduodenectomy greatly influences patients' postoperative course. Several evaluation methods have been used to assess the risk of clinically relevant POPF (CR-POPF) after pancreatoduodenectomy namely, the original, alternative, and updated alternative fistula risk scores (o-FRS, a-FRS, and ua-FRS, respectively). Methods: We enrolled 106/179 patients who underwent pancreatoduodenectomy in our institution between April 2013 and Mar 2018. CR-POPF was defined as grade B and C POPF according to the 2016 definitions of the International Study Group on Pancreatic Surgery. Results: Pancreatic gland texture was the only significant risk factor for CR-POPF (p = 0.007). The CR-POPF incidence increased significantly according to the risk groups defined by both o-FRS (p = 0.004) and a-FRS (p = 0.004). The area under the curve for o-FRS, a-FRS, and ua-FRS was 0.693, 0.693, and 0.671, respectively. Conclusion: o-FRS, a-FRS, and ua-FRS were almost equally useful for risk evaluation for CR-POPF after pancreatoduodenectomy. Further studies, especially for preoperative objective evaluation of pancreatic gland texture, are needed for more useful and accurate risk evaluation.

Abstract Background Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal-dominant disease characterized by heterotopic ossification (HO) in soft tissues and caused by a mutation of the ACVR1A/ALK2 gene. Activin-A is a key molecule for initiating the process of HO via the activation of mTOR, while rapamycin, an mTOR inhibitor, effectively inhibits the Activin-A-induced HO. However, few reports have verified the effect of rapamycin on FOP in clinical perspectives. Methods We investigated the effect of rapamycin for different clinical situations by using mice conditionally expressing human mutant ACVR1A/ALK2 gene. We also compared the effect of rapamycin between early and episode-initiated treatments for each situation. Results Continuous, episode-independent administration of rapamycin reduced the incidence and severity of HO in the natural course of FOP mice. Pinch-injury induced HO not only at the injured sites, but also in the contralateral limbs and provoked a prolonged production of Activin-A in inflammatory cells. Although both early and injury-initiated treatment of rapamycin suppressed HO in the injured sites, the former was more effective at preventing HO in the contralateral limbs. Rapamycin was also effective at reducing the volume of recurrent HO after the surgical resection of injury-induced HO, for which the early treatment was more effective. Conclusion Our study suggested that prophylactic treatment will be a choice of method for the clinical application of rapamycin for FOP.

Background Pulmonary vein isolation (PVI) is an established ablation procedure for atrial fibrillation (AF), however, PVI alone is insufficient to suppress AF recurrence. Non-pulmonary vein (non-PV) trigger ablation is one of the promising strategies beyond PVI and has been shown to be effective in refractory/persistent AF cases. To make non-PV trigger ablation more standardized, it is essential to develop a simple method to localize the origin of non-PV triggers. Methods We retrospectively analyzed 37 non-PV triggers in 751 ablation sessions for symptomatic AF from January 2017 to December 2020. Regarding non-PV triggers, intra-atrial activation interval from the earliest in right atrium (RA) to proximal coronary sinus (CS) (RA-CSp) and that from the earliest in RA to distal CS (RA-CSd) obtained by a basically-positioned duodecapolar RA-CS catheter were compared among 3 originating non-PV areas [RA, atrial septum (SEP) and left atrium (LA)]. Results RA-CSp of RA non-PV trigger (56.4 ± 23.4 ms) was significantly longer than that of SEP non-PV (14.8 ± 25.6 ms, p = 0.019) and LA non-PV (-24.9 ± 27.9 ms, p = 0.0004). RA-CSd of RA non-PV (75.9 ± 32.1 ms) was significantly longer than that of SEP non-PV (34.2 ± 32.6 ms, p = 0.040) and LA non-PV (-13.3 ± 41.2 ms, p = 0.0008). RA-CSp and RA-CSd of SEP non-PV were significantly longer than those of LA non-PV (p = 0.022 and p = 0.016, respectively). Sensitivity and specificity of an algorithm to differentiate the area of non-PV trigger using RA-CSp (cut-off value: 50 ms) and RA-CSd (cut-off value: 0 ms) were 88% and 97% for RA non-PV, 81% and 73% for SEP non-PV, 65% and 95% for LA non-PV, respectively. Conclusions The analysis of intra-atrial activation sequences was useful to differentiate non-PV trigger areas. A simple algorithm to localize the area of non-PV trigger would be helpful to identify non-PV trigger sites in AF ablation.

Abstract Background Induction test of atrial fibrillation (AF) is one of endpoint measures in catheter ablation (CA). However, its predictive value in long‐term outcome remains controversial. Methods Ninety‐eight patients (61 years, 77 males) with persistent AF who underwent pulmonary vein antrum isolation‐based CA were retrospectively analyzed. We determined whether inducibility of AF/atrial tachyarrhythmias (AT) by atrial burst pacing at the end of CA and other characteristics were associated with the recurrence of AF/AT. Atrial burst pacing was performed with 30‐beat from the coronary sinus; increasing from 240 to 320 ppm. Inducibility was defined as AF/AT lasting ≥5 minutes following atrial burst pacing. Results AF/AT was induced in 50 patients (51%). During 1 year of follow‐up, 71 patients (72.4%) had no recurrence of AF/AT. A logistic regression analysis showed that female gender (OR 3.8; P = 0.02), multiple sessions (OR 3.5; P = 0.02), and early recurrence of AF/AT (OR 5.3; P = 0.004) were associated with clinical recurrence. AF/AT Inducibility was not associated with clinical recurrence (P = 0.65). A subanalysis in patients with enlarged LA (LA diameter ≥45 mm, n = 40) showed that AF/AT inducibility was associated with recurrence (OR 8.1; P = 0.04). The positive and negative predictive values of AF/AT inducibility for AF/AT recurrence were 41 and 89%, respectively. Negative predictive value was increased to 92.3% when the inducibility was defined as AF/AT of ≥30 seconds following atrial burst pacing. Conclusions AF/AT inducibility cannot predict long‐term clinical recurrence in patients with persistent AF. However, it may have a prognostic value especially in patients with enlarged LA.

Cases: We report 2 cases of missing condylar region associated with severe elbow trauma treated with our new surgical technique and present the outcomes at the 9- and 10-year follow-ups. Our method focused on anatomical isometric point reconstruction, which consisted of the reconstruction of the missing condylar region with the iliac bone and the collateral ligament with the palmaris longus tendon. Conclusions: This injury is rare, and treatment is challenging because of the difficulty in identifying the isometric point. Both patients achieved good elbow function. The bone defect region was almost remodeled with minimal bone tunnel enlargement. Overall, our technique can provide positive results. [ABSTRACT FROM AUTHOR]