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Dienogest has been proven effective as long-term therapeutic option for pelvic pain caused by endometriosis. However, in Taiwan, there is a lack of a well-tailored consensus on its long-term administration. To address this gap, Taiwanese experts in collaboration with the Taiwan Endometriosis Society (TES), convened to provide structured recommendations on dienogest treatment and monitoring strategies. Drawing from clinical evidence and collective expertise, the experts formulated individualized treatment strategies based on treatment objectives and the patient's demographics. The experts recommend long-term dienogest administration for endometriosis patients for appropriate symptom control while reducing the risk of disease recurrence. Specifically, they recommend regular ultrasound examinations and relevant blood tests to monitor disease progression and therapeutic response with additional breast screening for patients at high risk for breast cancer. These recommendations aim to provide physicians with comprehensive guidance on the long-term administration of dienogest for endometriosis, ensuring patient safety and optimizing treatment outcomes.

Abstract Background Early detection of T790M mutation in exon 20 of epidermal growth factor receptor (EGFR) in non-small cell lung cancer (NSCLC) patients with brain metastasis is crucial for optimizing treatment strategies. In this study, we developed radiomics models to distinguish NSCLC patients with T790M-positive mutations from those with T790M-negative mutations using multisequence MR images of brain metastasis despite an imbalanced dataset. Various resampling techniques and classifiers were employed to identify the most effective strategy. Methods Radiomic analyses were conducted on a dataset comprising 125 patients, consisting of 18 with EGFR T790M-positive mutations and 107 with T790M-negative mutations. Seventeen first- and second-order statistical features were selected from CET1WI, T2WI, T2FLAIR, and DWI images. Four classifiers (logistic regression, support vector machine, random forest [RF], and extreme gradient boosting [XGBoost]) were evaluated under 13 different resampling conditions. Results The area under the curve (AUC) value achieved was 0.89, using the SVM-SMOTE oversampling method in combination with the XGBoost classifier. This performance was measured against the AUC reported in the literature, serving as an upper-bound reference. Additionally, comparable results were observed with other oversampling methods paired with RF or XGBoost classifiers. Conclusions Our study demonstrates that, even when dealing with an imbalanced EGFR T790M dataset, reasonable predictive outcomes can be achieved by employing an appropriate combination of resampling techniques and classifiers. This approach has significant potential for enhancing T790M mutation detection in NSCLC patients with brain metastasis.

Abstract Background Myocarditis substantially increases the risk of ventricular arrhythmia. Approximately 30% of all ventricular arrhythmia cases in patients with myocarditis originate from the right ventricular outflow tract (RVOT). However, the role of NLRP3 signaling in RVOT arrhythmogenesis remains unclear. Methods Rats with myosin peptide–induced myocarditis (experimental group) were treated with an NLRP3 inhibitor (MCC950; 10 mg/kg, daily for 14 days) or left untreated. Then, they were subjected to electrocardiography and echocardiography. Ventricular tissue samples were collected from each rat’s RVOT, right ventricular apex (RVA), and left ventricle (LV) and examined through conventional microelectrode and histopathologic analyses. In addition, whole-cell patch-clamp recording, confocal fluorescence microscopy, and Western blotting were performed to evaluate ionic currents, intracellular Ca2+ transients, and Ca2+-modulated protein expression in individual myocytes isolated from the RVOTs. Results The LV ejection fraction was lower and premature ventricular contraction frequency was higher in the experimental group than in the control group (rats not exposed to myosin peptide). Myocarditis increased the infiltration of inflammatory cells into cardiac tissue and upregulated the expression of NLRP3; these observations were more prominent in the RVOT and RVA than in the LV. Furthermore, experimental rats treated with MCC950 (treatment group) improved their LV ejection fraction and reduced the frequency of premature ventricular contraction. Histopathological analysis revealed higher incidence of abnormal automaticity and pacing-induced ventricular tachycardia in the RVOTs of the experimental group than in those of the control and treatment groups. However, the incidences of these conditions in the RVA and LV were similar across the groups. The RVOT myocytes of the experimental group exhibited lower Ca2+ levels in the sarcoplasmic reticulum, smaller intracellular Ca2+ transients, lower L-type Ca2+ currents, larger late Na+ currents, larger Na+–Ca2+ exchanger currents, higher reactive oxygen species levels, and higher Ca2+/calmodulin-dependent protein kinase II levels than did those of the control and treatment groups. Conclusion Myocarditis may increase the rate of RVOT arrhythmogenesis, possibly through electrical and structural remodeling. These changes may be mitigated by inhibiting NLRP3 signaling.

Objective: Although pulmonary rehabilitation and regular exercise have improved negative emotions and cognitive capacity within cases of chronic obstructive pulmonary disease (COPD), influence by exercise training upon different cognitive and memory functions in COPD is still controversial. This investigation aimed to assess whether cognitive performance and mental health are affected by the benefits of exercise training within cases of COPD. Materials and Methods: This pilot investigation included thirty-three patients with Global Initiative for Chronic Obstructive Lung Disease stage ≥B. Based on the subjects' rights, all included patients could choose to join either the exercise group or the control group, according to their free will. Twelve patients were assigned to receive exercise treatment over a 2-month period, while the remaining 16 patients were assigned to the control group. Cognitive capacity outcomes were measured using the Wechsler Memory Scale-III Word List Test, Stroop task, and psychomotor vigilance task (PVT). Mood states were assessed through the Beck Depression Inventory (BDI) and Beck Anxiety Inventory (BAI). Results: Most cases demonstrated major improvement for BDI and BAI scorings post-60-day therapy. During PVT, the omission rate decreased, while the hit rate increased, indicating an improvement in attention performance. Furthermore, this investigation found a significant increase in immediate verbal and recognition memory for word–list test. However, no major performance shifts were found on Stroop analysis. Conclusion: This investigation demonstrated that a 2-month exercise training program resulted in significant improvement in negative emotions, immediate memory, recognition memory, and attention.

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Trichomonas tenax, an oral commensal parasite commonly found in the human mouth, is associated with periodontitis and poor oral hygiene. However, it has also been identified in the bronchoalveolar lavage fluid (BALF) of individuals with lung diseases. Notably, significant quantities of T. tenax have been isolated following bronchoscopy in cases of empyema and acute respiratory distress syndrome (ARDS). Furthermore, research has demonstrated its ability to induce inflammation in pulmonary epithelial cells. To comprehend the potential role of T. tenax in pneumonia, it is crucial to elucidate the relationship between the parasite and the disease. We investigated the clinical factors associated with T. tenax infection in patients with pneumonia. Employing nested polymerase chain reactions, we amplified nucleic acids from BALF and analyzed the relationships between T. tenax and various clinical factors. Our data revealed a significant association between T. tenax and bacterial infections, high pneumonia severity index (PSI) scores, nasogastric tube feeding, and pulmonary complications. Logistic regression analyses also showed strong associations between T. tenax and these clinical factors in pneumonia patients. These findings suggest that T. tenax infection in pneumonia is accompanied by bacterial infection and severe clinical manifestations.

Summary: The mutated SCN5A gene encoding defective Nav1.5 protein causes arrhythmic ailments and is associated with enhanced cardiac fibrosis. This study investigated whether SCN5A mutation directly affects cardiac fibroblasts and explored how defective SCN5A relates to cardiac fibrosis. SCN5A knockdown (SCN5AKD) human cardiac fibroblasts (HCF) had higher collagen, α-SMA, and fibronectin expressions. Micro-RNA deep sequencing and qPCR analysis revealed the downregulation of miR-452-5p and bioinformatic analysis divulged maladaptive upregulation of transforming growth factor β (TGF-β) signaling in SCN5AKD HCF. Luciferase reporter assays validated miR-452-5p targets SMAD4 in SCN5AKD HCF. Moreover, miR-452-5p mimic transfection in SCN5AKD HCF or AAV9-mediated miR-452-5p delivery in isoproterenol-induced heart failure (HF) rats, resulted in the attenuation of TGF-β signaling and fibrogenesis. The exogenous miR-452-5p significantly improved the poor cardiac function in HF rats. In conclusion, miR-452-5p regulates cardiac fibrosis progression by targeting the TGF-β/SMAD4 axis under the loss of the SCN5A gene.

Atrial fibrillation (AF) is a common phenomenon of sustained arrhythmia leading to heart failure or stroke. Patients with mental disorders (MD), particularly schizophrenia and bipolar disorder, are at a high risk of AF triggered by the dysregulation of the autonomic nervous system, atrial stretch, oxidative stress, inflammation, and electrical or structural remodeling. Moreover, pathophysiological mechanisms underlying MD may also contribute to the genesis of AF. An overactivated hypothalamic–pituitary–adrenal axis, aberrant renin–angiotensin–aldosterone system, abnormal serotonin signaling, disturbed sleep, and genetic/epigenetic factors can adversely alter atrial electrophysiology and structural substrates, leading to the development of AF. In this review, we provide an update of our collective knowledge of the pathophysiological and molecular mechanisms that link MD and AF. Targeting the pathogenic mechanisms of MD-specific AF may facilitate the development of therapeutics that mitigate AF and cardiovascular mortality in this patient population.

Background: The spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is crucial to viral entry and can cause cardiac injuries. Toll-like receptor 4 (TLR4) and NOD-, LPR-, and pyrin-domain-containing 3 (NLRP3) inflammasome are critical immune system components implicated in cardiac fibrosis. The spike protein activates NLRP3 inflammasome through TLR4 or angiotensin-converting enzyme 2 (ACE2) receptors, damaging various organs. However, the role of spike protein in cardiac fibrosis in humans, as well as its interactions with NLRP3 inflammasomes and TLR4, remain poorly understood. Methods: We utilized scratch assays, Western blotting, and immunofluorescence to evaluate the migration, fibrosis signaling, mitochondrial calcium levels, reactive oxygen species (ROS) production, and cell morphology of cultured human cardiac fibroblasts (CFs) treated with spike (S1) protein for 24 h with or without an anti-ACE2 neutralizing antibody, a TLR4 blocker, or an NLRP3 inhibitor. Results: S1 protein enhanced CFs migration and the expressions of collagen 1, α-smooth muscle actin, transforming growth factor β1 (TGF-β1), phosphorylated SMAD2/3, interleukin 1β (IL-1β), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). S1 protein increased ROS production but did not affect mitochondrial calcium content and cell morphology. Treatment with an anti-ACE2 neutralizing antibody attenuated the effects of S1 protein on collagen 1 and TGF-β1 expressions. Moreover, NLRP3 (MCC950) and NF-kB inhibitors, but not the TLR4 inhibitor TAK-242, prevented the S1 protein-enhanced CFs migration and overexpression of collagen 1, TGF-β1, and IL-1β. Conclusion: S1 protein activates human CFs by priming NLRP3 inflammasomes through NF-κB signaling in an ACE2-dependent manner.

Background: Children with ventricular septal defects (VSDs) are considered to have no difference in cardiopulmonary functional capacity with healthy children of the same age; however, studies have shown contradictory findings. The aim of this study was to assess whether Taiwanese children with VSDs exhibited cardiopulmonary deficits. Methods: This is a retrospective cohort study with the data collected from January 2010 to December 2021. All patients and controls (age-, sex-, and body mass index -matched) underwent cardiopulmonary exercise testing (CPET) and pulmonary function test. Results: In total, 157 VSD patients (80 patients with surgically closed VSDs, 77 patients with unrepaired VSDs) and 157 healthy controls were recruited. Pulmonary function test showed significant among-group differences in maximal voluntary ventilation (MVV) (p = 0.015). The surgically closed group had lower MVV compared to the control group. Regarding CPET, we found VSD patients had lower peak oxygen uptake than the controls (surgically closed group: 30.84 ± 6.27 ml/kg/min; unrepaired group: 32.00 ± 5.95 ml/kg/min; control group: 36.76 ± 6.50 ml/kg/min, p

Vitamin D deficiency is associated with hyperlipidemia, but it r emains unclear whether vitamin D supplementation reduces serum lipid levels. The aims of this study were to investigate the associations between increased serum 25-hydroxyvitamin D (25(OH)D) concentrations and lipid levels and identify the characteristics of people with or without lipid reduction associated with increased 25(OH)D levels. The medical records of 118 individuals (53 men; mean age, 54.4 ± 10.6 years) whose serum 25(OH)D levels increased between 2 consecutive measurements were retrospectively reviewed. People with increased 25(OH)D levels (from 22.7 (17.6–29.2) to 32.1 (25.6–36.8) mg/dL; P < 0.01) had a significant reduction in serum levels of triglycerides (TG s) (from 111.0 (80–164) to 104.5 (73–142) mg/dL; P < 0.01) and total cholesterol (TC) (from 187.5 (155–213) to 181.0 (150–210) mg/dL; P < 0.05). The individuals who responded to vitamin D (≥10% reduction in TG or TC levels) exhibited significantly higher baseline TG a nd TC levels than those who did not. Only patients with hyperlipidemia (not those without hyperlipidemia) at baseline exhibited significantly reduced TG and TC levels at fol low-up. However, increasing serum 25(OH)D concentrations were significantly correlated with decreasing lipid levels in individuals with baseline 25(OH)D levels less than 30 ng/mL and in individuals aged 50–65 years (not in patients younger than 50 years or older than 65 years). In conclusion, increasing serum 25(OH)D concentrations may be potentially helpful for the treatment of hyperlipidemia in people with vitamin D deficiency.

Abstract Background The novel sodium-glucose co-transporter 2 inhibitor (SGLT2i) potentially ameliorates heart failure and reduces cardiac arrhythmia. Cardiac fibrosis plays a pivotal role in the pathophysiology of HF and atrial myopathy, but the effect of SGLT2i on fibrogenesis remains to be elucidated. This study investigated whether SGLT2i directly modulates fibroblast activities and its underlying mechanisms. Methods and results Migration, proliferation analyses, intracellular pH assay, intracellular inositol triphosphate (IP3) assay, Ca2+ fluorescence imaging, and Western blotting were applied to human atrial fibroblasts. Empagliflozin (an SGLT2i, 1, or 5 μmol/L) reduced migration capability and collagen type I, and III production. Compared with control cells, empagliflozin (1 μmol/L)- treated atrial fibroblasts exhibited lower endoplasmic reticulum (ER) Ca2+ leakage, Ca2+ entry, inositol trisphosphate (IP3), lower expression of phosphorylated phospholipase C (PLC), and lower intracellular pH. In the presence of cariporide (an Na+-H+ exchanger (NHE) inhibitor, 10 μmol/L), control and empagliflozin (1 μmol/L)-treated atrial fibroblasts revealed similar intracellular pH, ER Ca2+ leakage, Ca2+ entry, phosphorylated PLC, pro-collagen type I, type III protein expression, and migration capability. Moreover, empagliflozin (10 mg/kg/day orally for 28 consecutive days) significantly increased left ventricle systolic function, ß-hydroxybutyrate and decreased atrial fibrosis, in isoproterenol (100 mg/kg, subcutaneous injection)-induced HF rats. Conclusions By inhibiting NHE, empagliflozin decreases the expression of phosphorylated PLC and IP3 production, thereby reducing ER Ca2+ release, extracellular Ca2+ entry and the profibrotic activities of atrial fibroblasts.

Motor-based brain-computer interfaces (BCIs) were developed from the brain signals during motor imagery (MI), motor preparation (MP), and motor execution (ME). Motor-based BCIs provide an active rehabilitation scheme for post-stroke patients. However, BCI based solely on MP was rarely investigated. Since MP is the precedence phase before MI or ME, MP-BCI could potentially detect brain commands at an earlier state. This study proposes a bipedal MP-BCI system, which is actuated by the reduction in frontoparietal connectivity strength. Three substudies, including bipedal classification, neurofeedback, and post-stroke analysis, were performed to validate the performance of our proposed model. In bipedal classification, functional connectivity was extracted by Pearson’s correlation model from electroencephalogram (EEG) signals recorded while the subjects were performing MP and MI. The binary classification of MP achieved short-lived peak accuracy of 73.73(±7.99)% around 200-400 ms post-cue. The peak accuracy was found synchronized to the MP-related potential and the decrement in frontoparietal connection strength. The connection strengths of the right frontal and left parietal lobes in the alpha range were found negatively correlated to the classification accuracy. In the subjective neurofeedback study, the majority of subjects reported that motor preparation instead of the motor imagery activated the frontoparietal dysconnection. Post-stroke study also showed that patients exhibit lower frontoparietal connections compared to healthy subjects during both MP and ME phases. These findings suggest that MP reduced alpha band functional frontoparietal connectivity and the EEG signatures of left and right foot MP could be discriminated more effectively during this phase. A neurofeedback paradigm based on the frontoparietal network could also be utilized to evaluate post-stroke rehabilitation training.

Purpose: Limited data exist on asthma medication patterns in Taiwan. The objectives of the SABINA III cross-sectional study in Taiwan were thus, to describe patient demographics and clinical features and estimate short-acting β2-agonist (SABA) and inhaled corticosteroids (ICS) prescriptions per patient. Methods: Patients (≥18 years) with asthma were classified by investigator-defined asthma severity per the 2017 Global Initiative for Asthma (GINA) recommendations. Data on asthma symptom control (per GINA 2017 recommendations), severe exacerbation history, and prescribed treatments in the 12 months before study visit were collected using electronic case-report forms. Analyses were descriptive. Results: Overall, all 294 analyzed patients (mean [SD] age, 57.9 [15.6] years; female, 69%) were enrolled by specialists and had fully reimbursed healthcare. Most patients were classified with moderate-to-severe asthma (93.2%; GINA steps 3–5), were obese (53.4%) and nonsmokers (79.6%), reported high school or university and/or postgraduate education (61.9%), and had ≤2 comorbidities (89.1%). Mean (SD) asthma duration was 8.3 (10.0) years, with 37.8% of patients experiencing ≥1 severe exacerbation 12 months before the study visit. Overall, 62.2%, 26.2%, and 11.6% of patients had well-controlled, partly controlled, and uncontrolled asthma, respectively. Crucially, 19.3% of patients were prescribed ≥3 SABA canisters in the preceding 12 months (overprescription). ICS, ICS + long-acting β2-agonist fixed-dose combination, and oral corticosteroid bursts were prescribed to 6.5%, 97.3%, and 31.6% of patients, respectively. Conclusion: Despite treatment by specialists and fully reimbursed healthcare, findings indicate room for improvement in asthma control and SABA prescription practices in Taiwan, emphasizing the need to adhere to latest evidence-based guidelines.

BackgroundAmiodarone is commonly used during therapeutic hypothermia (TH) following cardiac arrest due to ventricular arrhythmias. However, electrophysiological changes and proarrhythmic risk after amiodarone treatment have not yet been explored in TH.MethodsEpicardial high-density bi-ventricular mapping was performed in pigs under baseline temperature (BT), TH (32-34°C), and amiodarone treatment during TH. The total activation time (TAT), conduction velocity (CV), local electrogram (LE) duration, and wavefront propagation from pre-specified segments were analyzed during sinus rhythm (SR) or right ventricular (RV) pacing (RVP), along with tissue expression of connexin 43. The vulnerability to ventricular arrhythmias was assessed.ResultsCompared to BT, TH increased the global TAT, decreased the CV, and generated heterogeneous electrical substrate during SR and RVP. During TH, the CV reduction and LE duration prolongation were greater in the anterior mid RV than in the other areas, which changed the wavefront propagation in all animals. Compared to TH alone, amiodarone treatment during TH further increased the TAT and LE duration and decreased the CV. Heterogeneous conduction was partially attenuated after amiodarone treatment. After TH and amiodarone treatment, the connexin 43 expression in the anterior mid RV was lower than that in the other areas, compatible with the heterogeneous CV reduction. The animals under TH and amiodarone treatment had a higher incidence of inducible ventricular arrhythmias than those under BT or TH without amiodarone.ConclusionElectrical heterogeneity during amiodarone treatment and TH was associated with vulnerability to ventricular arrhythmias.

Abstract Diabetes mellitus is associated with cardiovascular disease and cardiac arrhythmia. Accumulation of advanced glycation end products closely correlates with cardiovascular complications through mitochondrial dysfunction or oxidative stress and evoke proliferative, inflammatory, and fibrotic reactions, which might impair cardiac electrophysiological characteristics and increase the incidence of cardiac arrhythmia. This study examined the mechanisms how advanced glycation end products may contribute to arrhythmogenesis of right ventricular outflow tract—a unique arrhythmogenic substrate. A whole‐cell patch clamp, conventional electrophysiological study, fluorescence imaging, Western blot, and confocal microscope were used to study the electrical activity, and Ca2+ homeostasis or signaling in isolated right ventricular outflow tract myocytes with and without advanced glycation end products (100 μg/ml). The advanced glycation end products treated right ventricular outflow tract myocytes had a similar action potential duration as the controls, but exhibited a lower L‐type Ca2+ current, higher late sodium current and transient outward current. Moreover, the advanced glycation end products treated right ventricular outflow tract myocytes had more intracellular Na+, reverse mode Na+–Ca2+ exchanger currents, intracellular and mitochondrial reactive oxygen species, and less intracellular Ca2+ transient and sarcoplasmic reticulum Ca2+ content with upregulated calcium homeostasis proteins and advanced glycation end products related signaling pathway proteins. In conclusions, advanced glycation end products modulate right ventricular outflow tract electrophysiological characteristics with larger late sodium current, intracellular Na+, reverse mode Na+–Ca2+ exchanger currents, and disturbed Ca2+ homeostasis through increased oxidative stress mediated by the activation of the advanced glycation end products signaling pathway.

Abstract Background Glucose monitoring is vital for glycemic control in patients with diabetes mellitus (DM). Continuous glucose monitoring (CGM) measures whole-day glucose levels. Hemoglobin A1c (HbA1c) is a vital outcome predictor in patients with DM. Methods This study investigated the relationship between HbA1c and CGM, which remained unclear hitherto. Data of patients with DM (n = 91) who received CGM and HbA1c testing (1–3 months before and after CGM) were retrospectively analyzed. Diurnal and nocturnal glucose, highest CGM data (10%, 25%, and 50%), mean amplitude of glycemic excursions (MAGE), percent coefficient of variation (%CV), and continuous overlapping net glycemic action were compared with HbA1c values before and after CGM. Results The CGM results were significantly correlated with HbA1c values measured 1 (r = 0.69) and 2 (r = 0.39) months after CGM and 1 month (r = 0.35) before CGM. However, glucose levels recorded in CGM did not correlate with the HbA1c values 3 months after and 2–3 months before CGM. MAGE and %CV were strongly correlated with HbA1c values 1 and 2 months after CGM, respectively. Diurnal blood glucose levels were significantly correlated with HbA1c values 1–2 months before and 1 month after CGM. The nocturnal blood glucose levels were significantly correlated with HbA1c values 1–3 months before and 1–2 months after CGM. Conclusions CGM can predict HbA1c values within 1 month after CGM in patients with DM.

Type 2 diabetes mellitus (T2DM) is a global burden, with an increasing number of people affected and increasing treatment costs. The advances in research and guidelines improve the management of blood glucose and related diseases, but T2DM and its complications are still a big challenge in clinical practice. T2DM is a metabolic disorder in which insulin signaling is impaired from reaching its effectors. Mitochondria are the “powerhouses” that not only generate the energy as adenosine triphosphate (ATP) using pyruvate supplied from glucose, free fatty acid (FFA), and amino acids (AA) but also regulate multiple cellular processes such as calcium homeostasis, redox balance, and apoptosis. Mitochondrial dysfunction leads to various diseases, including cardiovascular diseases, metabolic disorders, and cancer. The mitochondria are highly dynamic in adjusting their functions according to cellular conditions. The shape, morphology, distribution, and number of mitochondria reflect their function through various processes, collectively known as mitochondrial dynamics, including mitochondrial fusion, fission, biogenesis, transport, and mitophagy. These processes determine the overall mitochondrial health and vitality. More evidence supports the idea that dysregulated mitochondrial dynamics play essential roles in the pathophysiology of insulin resistance, obesity, and T2DM, as well as imbalanced mitochondrial dynamics found in T2DM. This review updates and discusses mitochondrial dynamics and the complex interactions between it and metabolic disorders.

Purpose: The optimal treatment for gastroesophageal junction adenocarcinoma (GEJA) remains controversial. We evaluated the treatment patterns and outcomes of patients with locally advanced GEJA according to the histological type. Materials and Methods: We conducted a single-institution retrospective cohort study of patients with locally advanced GEJA who underwent curative-intent surgical resection between 2010 and 2020. Perioperative therapies as well as clinicopathologic, surgical, and survival data were collected. The results of endoscopy and histopathological examinations were assessed for Siewert and Lauren classifications. Results: Among the 58 patients included in this study, 44 (76%) were clinical stage III, and all received neoadjuvant therapy (72% chemoradiation, 41% chemotherapy, 14% both chemoradiation and chemotherapy). Tumor locations were evenly distributed by Siewert Classification (33% Siewert-I, 40% Siewert-II, and 28% Siewert-III). Esophagogastrectomy (EG) was performed for 47 (81%) patients and total gastrectomy (TG) for 11 (19%) patients. All TG patients received D2 lymphadenectomy compared to 10 (21%) EG patients. Histopathological examination showed the presence of 64% intestinal-type and 36% diffuse-type histology. The frequencies of diffuse-type histology were similar among Siewert groups (37% Siewert-I, 36% Siewert-II, and 33% Siewert-III). Regardless of Siewert type and compared to intestinal-type, diffuse histology was associated with increased intraabdominal recurrence rates (P=0.03) and decreased overall survival (hazard ratio, 2.33; P=0.02). With a median follow-up of 31.2 months, 29 (50%) patients had a recurrence, and the median overall survival was 50.5 months. Conclusions: Present in equal proportions among Siewert types of esophageal and gastric cancer, a diffuse-type histology was associated with high intraabdominal recurrence rates and poor survival. Histopathological evaluation should be considered in addition to anatomic location in the determination of multimodal GEJA treatment strategies. [ABSTRACT FROM AUTHOR]

The COronaVIrus Disease 2019 (COVID-19), which developed into a pandemic in 2020, has become a major healthcare challenge for governments and healthcare workers worldwide. Despite several medical treatment protocols having been established, a comprehensive rehabilitation program that can promote functional recovery is still frequently ignored. An online consensus meeting of an expert panel comprising members of the Taiwan Academy of Cardiovascular and Pulmonary Rehabilitation was held to provide recommendations for rehabilitation protocols in each of the five COVID-19 stages, namely (1) outpatients with mild disease and no risk factors, (2) outpatients with mild disease and epidemiological risk factors, (3) hospitalized patients with moderate to severe disease, (4) ventilator-supported patients with clear cognitive function, and (5) ventilator-supported patients with impaired cognitive function. Apart from medications and life support care, a proper rehabilitation protocol that facilitates recovery from COVID-19 needs to be established and emphasized in clinical practice.

Abstract To determine whether genetic predisposition to endometriosis varies depending on ethnicity and in association with expression quantitative trait loci (eQTL) in a Taiwanese population. We conducted a genome-wide association study (GWAS) and replicated it in 259 individuals with laparoscopy-confirmed stage III or IV endometriosis (cases) and 171 women without endometriosis (controls). Their genomic DNA was extracted from blood and evaluated by the GWAS of Taiwan Biobank Array. Novel genetic variants that predispose individuals to endometriosis were identified using GWAS and replication, including rs10739199 (P = 6.75 × 10−5) and rs2025392 (P = 8.01 × 10−5) at chromosome 9, rs1998998 (P = 6.5 × 10−6) at chromosome 14, and rs6576560 (P = 9.7 × 10−6) at chromosome 15. After imputation, strong signals were exhibited by rs10822312 (P = 1.80 × 10−7) at chromosome 10, rs58991632 (P = 1.92 × 10−6) and rs2273422 (P = 2.42 × 10−6) at chromosome 20, and rs12566078 (P = 2.5 × 10−6) at chromosome 1. We used the Genotype-Tissue Expression (GTEx) database to observe eQTL. Among these SNPs, the cis-eQTL rs13126673 of inturned planar cell polarity protein (INTU) showed significant association with INTU expression (P = 5.1 × 10–33). Moreover, the eQTL analysis was performed on endometriotic tissues from women with endometriosis. The expression of INTU in 78 endometriotic tissue of women with endometriosis is associated with rs13126673 genotype (P = 0.034). To our knowledge, this is the first GWAS to link endometriosis and eQTL in a Taiwanese population.

Calcific aortic valve disease (CAVD) is linked to high mortality. Melatonin inhibits nuclear factor-kappa B (NF-κB)/cyclic AMP response element-binding protein (CREB), contributing to CAVD progression. This study determined the role of melatonin/MT1/MT2 signaling in valvular interstitial cell (VIC) calcification. Western blotting and Alizarin red staining were used to analyze NF-κB/CREB/runt-related transcription factor 2 (Runx2) signaling in porcine VICs treated with an osteogenic (OST) medium without (control) or with melatonin for 5 days. Chromatin immunoprecipitation (ChIP) assay was used to analyze NF-κB's transcription regulation of NF-κB on the Runx2 promoter. OST medium-treated VICs exhibited a greater expression of NF-κB, CREB, and Runx2 than control VICs. Melatonin treatment downregulated the effects of the OST medium and reduced VIC calcification. The MT1/MT2 antagonist (Luzindole) and MT1 receptor neutralized antibody blocked the anticalcification effect of melatonin, but an MT2-specific inhibitor (4-P-PDOT) did not. Besides, the NF-κB inhibitor (SC75741) reduced OST medium-induced VIC calcification to a similar extent to melatonin at 10 nmol/L. The ChIP assay demonstrated that melatonin attenuated OST media increased NF-κB binding activity to the promoter region of Runx2. Activation of the melatonin/MT1-axis significantly reduced VIC calcification by targeting the NF-κB/CREB/Runx2 pathway. Targeting melatonin/MT1 signaling may be a potential therapeutic strategy for CAVD.

Purpose: Evidence-based models of cancer survivorship care are lacking. Such models should take into account the perspectives of all stakeholders. The purpose of this integrative review is to examine the current state of the literature on cancer survivorship care from the cancer survivor, the oncology care team, and the primary care team perspectives. Methods: Using defined inclusion and exclusion criteria, we conducted a literature search of PubMed, PsycINFO, CINAHL, and Scopus databases to identify relevant articles on the stakeholders’ perspectives on cancer survivorship care published between 2010 and 2021. We reviewed and abstracted eligible articles to synthesize findings. Results: A total of 21 studies were included in the review. Barriers to the receipt and provision of cancer survivorship care quality included challenges with communication, cancer care delivery, and knowledge. Conclusion: Persistent stakeholder-identified barriers continue to hinder the provision of quality cancer survivorship care. Improved communication, delivery of care, knowledge/information, and resources are needed to improve the quality of survivorship care. Novel models of cancer survivorship care that address the needs of survivors, oncology teams, and PCPs are needed.

Abstract Mechanoelectrical feedback is an important factor in the pathophysiology of atrial fibrillation (AF). Ectopic electrical activity originating from pulmonary vein (PV) myocardial sleeves has been found to trigger and maintain paroxysmal AF. Dilated PVs by high stretching force may activate mechanoelectrical feedback, which induces calcium overload and produces afterdepolarization. These results, in turn, increase PV arrhythmogenesis and contribute to initiation of AF. Paracrine factors, effectors of the renin‐angiotensin system, membranous channels, or cytoskeleton of PV myocytes may modulate PV arrhythmogenesis directly through mechanoelectrical feedback or indirectly through endocardial/myocardial cross‐talk. The purpose of this review is to present laboratory and translational relevance of mechanoelectrical feedback in PV arrhythmogenesis. Targeting mechanoelectrical feedback in PV arrhythmogenesis may shed light on potential opportunities and clinical concerns of AF treatment.

Objective(s): Drug-induced atrial fibrillation (AF) is considered an adverse effect of chemotherapeutic drugs. AF is a crucial risk factor for stroke, heart failure, myocardial infarction, and mortality. Pulmonary veins (PVs) are considered triggers inducing AF, and the sinoatrial node (SAN) may modulate PV activity and participate in AF genesis. AF was associated with early discontinuation of trastuzumab in patients with breast cancer. However, whether trastuzumab directly modulates the electrophysiological characteristics of PV and SAN remains unclear. Materials and Methods: ECG and conventional microelectrode system were used to record rabbit heart rhythm in vivo and electrical activities in vitro from isolated SAN, PV, and SAN-PV preparations. Results: Trastuzumab reduced the beating rate in isolated PV and SAN preparations at 1, 10, and 30 μM (particularly in isolated SAN preparations) and induced burst firings in isolated PV preparations at 10 μΜ. In addition, trastuzumab (10 μM) induced SAN-PV conduction block and burst firings, which were blocked by wortmannin (a PI3K inhibitor, 100 nM). Similarly, ECG recordings showed that acute intravenous administration of trastuzumab (10 mg/kg) reduced rabbit heart rates. Conclusion: Trastuzumab increased PV arrhythmogenesis through interfering with PI3K signaling, which may contribute to the genesis of AF.

The objective of this study is to report a case of deep endometriosis of the paralumbar muscles (psoas, multifidus, and erector spinae) and review existing literature on its management. A 34-year-old female with a history of endometriosis was seen for infertility. Paralumbar muscle masses seen on computed tomography (CT) scan were sampled, confirming endometriosis. Gonadotropin-releasing hormone agonist was given for 2 months. The patient was primed for assisted reproduction. A literature review was conducted to provide an understanding of paralumbar muscle endometriosis. To our knowledge, this is the first reported case of multifidus and erector spinae muscle endometriosis and fifth case of psoas muscle endometriosis. Because the available information is scarce, data from the existing literature on deep endometriosis may aid in the diagnosis and management. Magnetic resonance imaging and CT scan are essential imaging techniques to map lesions. Excision seems prudent, but the approach should be individualized depending on the patient's presentation and her preferences.

Purpose: Single agent PD-1 inhibitors have yielded durable responses in a minority of gastroesophageal cancers. Radiation therapy has been recognized to promote antitumor immune responses and may synergize with anti-PD-1 agents. We sought to evaluate if combining palliative radiation therapy with pembrolizumab can augment antitumor immune responses in gastroesophageal cancer. Methods and Materials: Patients had metastatic gastroesophageal cancer with indication for palliative radiation therapy with ≥2 disease sites outside of the radiation field assessable for abscopal response and biopsies for laboratory correlative analyses. Palliative radiation was delivered to a dose of 30 Gy over 10 fractions. Pembrolizumab, 200 mg, was administered concurrently intravenously every 3 weeks until disease progression, unacceptable toxicity, or study withdrawal, for up to 2 years. Endpoints included PD-L1 expression in pre- and posttreatment biopsies and abscopal objective response rate per Response Evaluation Criteria in Solid Tumors. Results: Of 14 enrolled patients, the objective response rate was 28.6% (95% confidence interval, 8.4%-58.1%), and the median duration of response was not reached (95% confidence interval, 6.9-NR months). Overall, 2 patients had treatment-related grade 3 to 4 adverse events with no grade 5 events. One patient discontinued therapy due to grade 4 colitis. We did not observe an association between radiation and abscopal changes in PD-L1 expression via assessment of an analogous PD-L1 Combined Positive Score, Tumor Proportion Score, Mononuclear Immune Cell Density Score, or proportion of PD-L1-expressing immune cells between pre- and posttreatment tumor biopsies. Conclusions: Combining palliative radiation therapy and pembrolizumab provided promising durable responses in this patient population but we were unable to definitively distinguish abscopal biologic changes. Biomarker analyses beyond PD-L1 expression are needed to better understand putative mechanisms and identify patients who will benefit from this approach.

RationaleAtrial fibrillation is a critical health burden. Targeting calcium (Ca2+) dysregulation and oxidative stress are potential upstream therapeutic strategies. Fibroblast growth factor (FGF) 1 can modulate Ca2+ homeostasis and has antioxidant activity. The aim of this study was to investigate whether FGF1 has anti-arrhythmic potential through modulating Ca2+ homeostasis and antioxidant activity of pulmonary vein (PV) and left atrium (LA) myocytes.MethodsPatch clamp, western blotting, confocal microscopy, cellular and mitochondrial oxidative stress studies were performed in isolated rabbit PV and LA myocytes treated with or without FGF1 (1 and 10 ng/mL). Conventional microelectrodes were used to record electrical activity in isolated rabbit PV and LA tissue preparations with and without FGF1 (3 μg/kg, i.v.).ResultsFGF1-treated rabbits had a slower heart rate than that observed in controls. PV and LA tissues in FGF1-treated rabbits had slower beating rates and longer action potential duration than those observed in controls. Isoproterenol (1 μM)-treated PV and LA tissues in the FGF1-treated rabbits showed less changes in the increased beating rate and a lower incidence of tachypacing (20 Hz)-induced burst firing than those observed in controls. FGF1 (10 ng/mL)-treated PV and LA myocytes had less oxidative stress and Ca2+ transient than those observed in controls. Compared to controls, FGF1 (10 ng/mL) decreased INa−L in PV myocytes and lowered Ito, IKr−tail in LA myocytes. Protein kinase C (PKC)ε inhibition abolished the effects of FGF1 on the ionic currents of LA and PV myocytes.ConclusionFGF1 changes PV and LA electrophysiological characteristics possibly via modulating oxidative stress, Na+/Ca2+ homeostasis, and the PKCε pathway.

Background: COVID-19 has a major impact on cardiovascular diseases and may lead to myocarditis or cardiac failure. The clove-like spike (S) protein of SARS-CoV-2 facilitates its transmission and pathogenesis. Cardiac mitochondria produce energy for key heart functions. We hypothesized that S1 would directly impair the functions of cardiomyocyte mitochondria, thus causing cardiac dysfunction. Methods: Through the Seahorse Mito Stress Test and real-time ATP rate assays, we explored the mitochondrial bioenergetics in human cardiomyocytes (AC16). The cells were treated without (control) or with S1 (1 nM) for 24, 48, and 72 h and we observed the mitochondrial morphology using transmission electron microscopy and confocal fluorescence microscopy. Western blotting, XRhod-1, and MitoSOX Red staining were performed to evaluate the expression of proteins related to energetic metabolism and relevant signaling cascades, mitochondrial Ca2+ levels, and ROS production. Results: The 24 h S1 treatment increased ATP production and mitochondrial respiration by increasing the expression of fatty-acid-transporting regulators and inducing more negative mitochondrial membrane potential (Δψm). The 72 h S1 treatment decreased mitochondrial respiration rates and Δψm, but increased levels of reactive oxygen species (ROS), mCa2+, and intracellular Ca2+. Electron microscopy revealed increased mitochondrial fragmentation/fission in AC16 cells treated for 72 h. The effects of S1 on ATP production were completely blocked by neutralizing ACE2 but not CD147 antibodies, and were partly attenuated by Mitotempo (1 µM). Conclusion: S1 might impair mitochondrial function in human cardiomyocytes by altering Δψm, mCa2+ overload, ROS accumulation, and mitochondrial dynamics via ACE2.

Lithium intoxication induces Brugada-pattern ECG, ventricular arrhythmia, and sudden death with the predominant preference for the male over the female gender. This study investigated the mechanisms of gender difference in lithium-induced arrhythmogenesis. The ECG parameters were recorded in male and female rabbits before and after the intravenous administration of lithium chloride (LiCl) (1, 3, 10 mmol/kg). Patch clamps were used to study the sodium current (INa) and late sodium current (INa-late) in the isolated single male and female right ventricular outflow tract (RVOT) cardiomyocytes before and after LiCl. Male rabbits (n = 9) were more prone to developing lithium-induced Brugada-pattern ECG changes (incomplete right bundle branch block, ST elevation and QRS widening) with fatal arrhythmia (66.7% vs. 0%, p = 0.002) than in female (n = 7) rabbits at 10 mmol/kg (but not 1 or 3 mmol/kg). Compared to those in the female RVOT cardiomyocytes, LiCl (100 μM) reduced INa to a greater extent and increased INa-late in the male RVOT cardiomyocytes. Moreover, in the presence of ranolazine (the INa-late inhibitor, 3.6 mg/kg iv loading, followed by a second iv bolus 6.0 mg/kg administered 30 min later, n = 5), LiCl (10 mmol/kg) did not induce Brugada-pattern ECG changes (p < 0.005). The male gender is much predisposed to lithium-induced Brugada-pattern ECG changes with a greater impact on INa and INa-late in RVOT cardiomyocytes. Targeting INa-late may be a potential therapeutic strategy for Brugada syndrome-related ventricular tachyarrhythmia.

Purpose: Craniospinal irradiation (CSI) using tomotherapy has advantages over standard 3-dimensional techniques. However, there is a paucity of published data on craniospinal setup reproducibility to guide appropriate planning treatment volume (PTV) margins. We sought to evaluate the setup accuracy of patients undergoing CSI to optimize PTV margins. Methods and Materials: We measured residual setup deviation between simulation computed tomography (CT) and daily megavoltage CT after couch shifts made by therapists after megavoltage CT-based image registration for 10 patients who completed CSI at our institution. Translational displacement values were recorded at the sella, top of T1, and top of L5 in the anteroposterior (AP) and lateral planes. Systematic and random error were calculated from displacement values. Using z score analysis, we calculated minimal PTV margins to encompass 90% of recorded fractions at each level. We evaluated whether patient characteristics predict for increased setup error using standard statistical techniques. Results: The mean setup deviation in the AP plane across all treatments was 2.49, 3.40, and 3.83 mm at the sella, T1, and L5, respectively. Mean lateral setup error was 2.86, 4.02, and 5.46 mm at the sella, T1, and L5, respectively. Systematic error ranged from 0.75 to 1.01 mm at the sella, 1.09 to 1.37 mm at T1, and 1.30 to 1.50 mm at L5. Random error ranged from 1.35 to 1.41 mm at the sella, 1.48 to 1.73 mm at T1, and 2.26 to 2.37 mm at L5. The minimum margin to cover 90% of the treatments was 6.4, 8.2, and 10.5 mm at the sella, T1, and L5, respectively. There appeared to be a correlation between older age and lateral setup error in the L spine approaching statistical significance (R, 0.629; P = .052). Conclusions: Setup error increases in the caudal direction of the spine and is greater in the lateral plane compared with the AP plane. We recommend a PTV margin of 5 to 7 mm in the brain and 10 mm in the spine.

Abstract Low‐level laser therapy (LLLT) applying on knee osteoarthritis (OA) patients has shown positive outcomes in analgesic effect and functional recovery. However, few studies applied such therapy on large area of quadriceps muscle in these patients. The aim of this study was to evaluate immediate effect of multi‐focal LLLT on quadriceps of knee OA patients in pain and functional performance. Fifty‐one participants with knee OA were enrolled and evaluated before (T1) and immediately after intervention (T2) by knee joint pain in numeric rating scale (NRS), walking speed, timed five‐chair stands, and quadriceps strength by isokinetic dynamometer. Intervention with two multi‐focal Gallium‐Aluminum‐Arsenide laser devices, each device with 36 laser diodes (wavelength 808 ± 10 nm, continuous, mean power 50 mW, 30 minutes), applied simultaneously over bilateral quadriceps with a total dose of 180 J for each thigh. The multi‐focal LLLT significantly improved knee joint pain as measured by the NRS (54% reduction), timed five‐chair stands, and walking speed (P

Abstract Purpose The American Society of Clinical Oncology guidelines recommend adjuvant chemoradiation (ACR) for margin‐positive (R1) and/or node‐positive (N+) pancreatic cancers. Our goal was to investigate if there is evidence of superiority of adjuvant chemoradiation (ACR) over adjuvant chemotherapy (AC). Methods We utilized data from the National Cancer Database (NCDB) for N+ and/or R1 pancreatic adenocarcinoma patients diagnosed from 2004 to 2012 who underwent ACR or AC. Patients who received neoadjuvant radiation, no adjuvant treatment, or adjuvant radiation alone were excluded. Propensity score nearest‐neighbor 1:1 matching (PSM) was performed between ACR and AC groups based on age, sex, race, insurance, year of diagnosis, comorbidities, tumor site and size, T‐stage, nodal status, margin status, grade, and treatment facility. Primary outcome was overall survival (OS). Results A total of 8297 patients were eligible. After PSM, two well‐balanced groups of 3244 patients each were analyzed. ACR resulted in superior OS compared with AC alone (Hazard ratio [HR] 0.83, 95% CI 0.79‐0.87; median OS 22 vs 19 months, P

Abstract Background Atrial fibrillation (AF) frequently coexists with congestive heart failure (HF) and arginine vasopressin (AVP) V1 receptor antagonists are used to treat hyponatremia in HF. However, the role of AVP in HF-induced AF still remains unclear. Pulmonary veins (PVs) are central in the genesis of AF. The purpose of this study was to determine if AVP is directly involved in the regulation of PV electrophysiological properties and calcium (Ca2+) homeostasis as well as the identification of the underlying mechanisms. Methods Patch clamp, confocal microscopy with Fluo-3 fluorescence, and Western blot analyses were used to evaluate the electrophysiological characteristics, Ca2+ homeostasis, and Ca2+ regulatory proteins in isolated rabbit single PV cardiomyocytes incubated with and without AVP (1 μM), OPC 21268 (0.1 μM, AVP V1 antagonist), or OPC 41061 (10 nM, AVP V2 antagonist) for 4–6 h. Results AVP (0.1 and 1 μM)-treated PV cardiomyocytes had a faster beating rate (108 to 152%) than the control cells. AVP (1 μM) treated PV cardiomyocytes had higher late sodium (Na+) and Na+/Ca2+ exchanger (NCX) currents than control PV cardiomyocytes. AVP (1 μM) treated PV cardiomyocytes had smaller Ca2+ i transients, and sarcoplasmic reticulum (SR) Ca2+ content as well as higher Ca2+ leak. However, combined AVP (1 μM) and OPC 21268 (0.1 μM) treated PV cardiomyocytes had a slower PV beating rate, larger Ca2+ i transients and SR Ca2+ content, smaller late Na+ and NCX currents than AVP (1 μM)-treated PV cardiomyocytes. Western blot experiments showed that AVP (1 μM) treated PV cardiomyocytes had higher expression of NCX and p-CaMKII, and a higher ratio of p-CaMKII/CaMKII. Conclusions AVP increases PV arrhythmogenesis with dysregulated Ca2+ homeostasis through vasopressin V1 signaling.

Atrial fibrillation (AF) is the most common type of sustained arrhythmia in diabetes mellitus (DM). Its morbidity and mortality rates are high, and its prevalence will increase as the population ages. Despite expanding knowledge on the pathophysiological mechanisms of AF, current pharmacological interventions remain unsatisfactory; therefore, novel findings on the underlying mechanism are required. A growing body of evidence suggests that an altered energy metabolism is closely related to atrial arrhythmogenesis, and this finding engenders novel insights into the pathogenesis of the pathophysiology of AF. In this review, we provide comprehensive information on the mechanistic insights into the cardiac energy metabolic changes, altered substrate oxidation rates, and mitochondrial dysfunctions involved in atrial arrhythmogenesis, and suggest a promising advanced new therapeutic approach to treat patients with AF.

(1) Background: Heart failure is a complex disease leading to functional disability. Cardiopulmonary exercise testing (CPET) is the gold standard in assessing aerobic capacity and formulating function-based prognostic stratification; however, patients with acute heart failure after medical treatment usually remain with markedly reduced exercise capacity, leading to early termination of CPET with submaximal testing results. The current study aimed to assess the cardiorespiratory fitness and characteristics of CPET variables of patients after acute heart failure treatment and determine potential CPET variables with prognostic value. (2) Methods: We recruited patients during hospitalization after management of acute heart failure, and pre-discharge CPET was performed. All enrolled patients were followed for one year for major adverse cardiovascular events (MACE). (3) Results: 85 patients were enrolled, with average left ventricular ejection fraction of 30.52%, and peak oxygen consumption of 10.85 mL/min/kg at baseline. The one-year MACE was 50%. Oxygen uptake efficiency slope (OUES) was a significant event predictor, with lower one-year MACE in those with OUES ≥ 1.25 (p < 0.001). Cox regression analysis showed a 5.421-fold increased risk of MACE in those with OUES < 1.25 (p = 0.004). (4) Conclusions: The current results suggested OUES is a significant prognostic indicator in patients with acute heart failure. This also emphasized the critical role of CPET in patients with heart failure for prognostic stratification.

Background: Atrial fibroblasts activation causes atrial fibrosis, which is one major pathophysiological contributor to atrial fibrillation (AF) genesis. Klotho is a pleiotropic protein with remarkable cardiovascular effects, including anti-inflammatory, anti-oxidative, and anti-apoptotic effects. This study investigated whether Klotho can modulate the activity of human atrial fibroblasts and provides an anti-fibrotic effect. Methods: Cell migration assay and proliferation assay were used to investigate fibrogenesis activities in single human atrial fibroblasts with or without treatment of Klotho (10 and 100 pM, 48 h). Calcium fluorescence imaging, the whole-cell patch-clamp, and Western blotting were performed in human atrial fibroblasts treated with and without Klotho (100 pM, 48 h) to evaluate the store-operated calcium entry (SOCE), transient receptor potential (TRP) currents, and downstream signaling. Results: High dose of Klotho (100 pM, 48 h) significantly reduced the migration of human atrial fibroblasts without alternating their proliferation; in addition, treatment of Klotho (100 pM, 48 h) also decreased SOCE and TRP currents. In the presence of BI-749327 (a selective canonical TRP 6 channel inhibitor, 1 μM, 48 h), Klotho (100 pM, 48 h) could not inhibit fibroblast migration nor suppress the TRP currents. Klotho-treated fibroblasts (100 pM, 48 h) had lower phosphorylated phospholipase C (PLC) (p-PLCβ3 Ser537) expression than the control. The PLC inhibitor, U73122 (1 μM, 48 h), reduced the migration, decreased SOCE and TRP currents, and lowered p-PLCβ3 in atrial fibroblasts, similar to Klotho. In the presence of the U73122 (1 μM, 48 h), Klotho (100 pM, 48 h) could not further modulate the migration and collagen synthesis nor suppress the TRP currents in human atrial fibroblasts. Conclusions: Klotho inhibited pro-fibrotic activities and SOCE by inhibiting the PLC signaling and suppressing the TRP currents, which may provide a novel insight into atrial fibrosis and arrhythmogenesis.

Objective: Studies among Western children have observed that the peak oxygen consumption (peak V˙O2) of boys is higher than that of girls, and this difference increases as children progress through adolescence. However, the maturation process and social expectation toward Eastern boys and girls are much different from their Western counterparts. This study aimed to provide baseline information on cardiopulmonary fitness (CRF) of Taiwanese children and adolescents in relation to age and sex. We also evaluated the correlation between body mass and CRF and compared the CRF between non-obese and overweight/obese children.Methods: We conducted a retrospective study of children and adolescents aged 4–18 years in Taiwan. Participants were classified into four groups based on age (group 1, aged 4–6; group 2, aged 7–9; group 3, aged 10–13; and group 4, aged 14–18 years). All participants completed symptom-limited exercise test by treadmill and anthropometric measurements through bioelectrical impedance method.Results: In total, 897 (448 men, 449 women) participants were analyzed. Boys had higher peak V˙O2 (all p < 0.01) and peak metabolic equivalent (MET, all p < 0.05) than girls in all the four groups. Age significantly (P < 0.001) correlated with peak V˙O2 in all participants, boys, and girls, with coefficients of determination (R2) of 0.9349, 0.9433, and 0.9085, respectively. The peak V˙O2 (all p < 0.001) of all the groups and peak MET (all p < 0.05) of group 2–4 associated with BMI and FMI modestly to moderately. Non-obese children had higher peak MET in group 1 (p = 0.049) and group 2–4 (all p < 0.001) than overweight/obese children significantly.Conclusions: The difference in peak V˙O2 and anthropometry–body composition between sexes was observed earlier in children in Taiwan than those in Western countries. Non-obese children had better CRF than overweight/obese children and the difference presented since preschool age.

Pathogen populations in estuarine areas are dynamic, as they are subject to multiple natural and anthropogenic challenges. Heavy rainfall events bring instability to the aquatic environment in estuaries, causing changes in pathogen populations and increased environmental sanitation and public health concerns. In this study, we investigated the effects of heavy precipitation on the occurrence of pathogens in the Puzi River estuary, which is adjacent to the largest inshore oyster farming area in Taiwan. Our results indicated that Vibrio parahaemolyticus and adenovirus were the most frequently detected pathogens in the area. There was a significant difference (Mann-Whitney U test, p < 0.01) in water quality parameters, including total coliform, Escherichia coli, water temperature, turbidity, salinity, and dissolved oxygen, between groups with and without V. parahaemolyticus. In addition, the detection rate was negatively correlated with the average daily rainfall (r2 > 0.8). There was no significant difference between water quality parameters and the presence/absence of adenovirus, but a positive correlation was observed between the average daily rainfall and the detection rate of adenovirus (r2 ≥ 0.75). We conclude that heavy precipitation changes estuarine water quality, causing variations in microbial composition, including pathogens. As extreme weather events become more frequent due to climate change, the potential impacts of severe weather events on estuarine environments require further investigation.

The incidence of lymph node (LN) involvement and its prognostic value based on radiological imaging in stage IIB cervical cancer (CC) remains unclear, and evidence regarding oncological outcomes of patients with stage IIB CC with LN metastases is limited. In this study we retrospectively reviewed the incidence and prognostic significance of pretreatment radiologic LN status in 72 patients with clinical stage IIB CC (FIGO 2009), with or without radiologic evidence of LN enlargement. An enlarged LN was defined as a diameter > 10 mm on CT/MRI. Progression-free survival (PFS) and overall survival (OS) were assessed. Radiologic LN enlargement of >10 mm was observed in 45.8% of patients with stage IIB CC. PFS (p = 0.0088) and OS rates (p = 0.0032) were significantly poorer in the LN group (n = 33) than in the non-LN group (n = 39). Univariate Cox analysis revealed that LN > 10 mm contributed to a higher rate of recurrence and mortality. In conclusion, nearly half of the patients with clinical stage IIB CC had enlarged LNs (>10 mm) identified during pretreatment radiologic evaluation, which negatively impacted prognosis. Our findings highlight the need to incorporate CT- or MRI-based LN assessment before treatment for stage IIB CC.

Abstract Background Alpha-fetoprotein (AFP) is a useful tumor marker for ovarian germ cell tumors, particularly yolk sac tumor (YST). It is valuable for both diagnosis and further follow-up. Epithelial ovarian carcinoma (EOC) rarely secretes AFP, especially for clear cell type and in the postmenopausal women. Based on the limited knowledge about AFP-producing clear cell type EOC, a case and literature review on this topic is extensively reviewed. Case presentation We report a 55-year-old postmenopausal woman experienced vaginal spotting for one month, and serum level of AFP was 60,721 ng/ml initially. Histological examination was clear cell type EOC. Tumor cells revealed strong immunoreactivity for glypican-3 (GPC3) and AFP and weak for hepatocyte nuclear factor-1 beta (HNF-1 beta), but negative for CD30, making the diagnosis of AFP-producing clear cell type EOC with fetal gut differentiation in focal areas, FIGO (International Federation of Gynecology and Obstetrics) IIIc. Although the patient underwent an intensive treatment, including optimal debulking surgery and multi-agent chemotherapy, the patient died of disease. To provide a better understanding of clinical and molecular characteristics of the AFP-producing clear cell type EOC, we conducted a systematic literature review. Conclusions A total of three papers described the AFP-producing clear cell type EOC are available. The overall survival rate of these cases, including the current case is 50%. Although immunohistochemical examination is not always needed in routine for the diagnosis of clear cell type EOC, to distinguish from other tumors, especially germ cell tumors, or to provide the better way to monitor therapeutic response or to evaluate the disease status, immunostaining, including GPC3, HNF-1 beta, CD30, cytokeratin 7 or 20, and AFP is taken into account. Due to rarity, the appropriate chemotherapy regimen and the biological behavior of AFP-producing clear cell type EOC are still unclear.

Abstract Background Fibroblast growth factor (FGF)-2 plays a crucial role in the pathophysiology of cardiovascular diseases (CVDs). FGF-2 was reported to induce cardiac hypertrophy through activation of FGF receptor 1 (FGFR1). Multiple laboratory findings indicate that calcitriol may be a potential treatment for CVDs. In this study, we attempted to investigate whether calcitriol regulates FGFR1 expression to modulate the effects of FGF-2 signaling in cardiac myocytes and explored the potential regulatory mechanism. Methods Western blot, polymerase chain reaction, small interfering RNA, fluorometric activity assay, and chromatin immunoprecipitation (ChIP) analyses were used to evaluate FGFR1, FGFR2, FGFR3, FGFR4, phosphorylated extracellular signal-regulated kinase (p-ERK), β-myosin heavy chain (β-MHC), phosphorylated phospholipase Cγ (p-PLCγ), nuclear factor of activated T cells (NFAT), and histone deacetylase (HDAC) expressions and enzyme activities in HL-1 atrial myocytes without and with calcitriol (1 and 10 nM) treatment, in the absence and presence of FGF-2 (25 ng/mL) or suberanilohydroxamic acid (SAHA, a pan-HDAC inhibitor, 1 μM). Results We found that calcitriol-treated HL-1 cells had significantly reduced FGFR1 expression compared to control cells. In contrast, expressions of FGFR2, FGFR3, and FGFR4 were similar between calcitriol-treated and control HL-1 cells. FGF-2-treated HL-1 cells had similar PLCγ phosphorylation and nuclear/cytoplasmic NFAT expressions compared to control cells. FGF-2 induced lower expressions of p-ERK and β-MHC in calcitriol-treated HL-1 cells than in control cells. FGFR1-knockdown blocked FGF-2 signaling and reversed the protective effects of calcitriol. Compared to control cells, calcitriol-treated HL-1 cells had higher nuclear HDAC activity. The ChIP analysis demonstrated a significant decrease in acetyl-histone H4, which is associated with an increase in HDAC3 in the FGFR1 promoter. Calcitriol-mediated FGFR1 downregulation was attenuated in the presence of SAHA. Conclusions Calcitriol diminished FGFR1 expression through HDAC activation, which ameliorated the harmful effects of FGF-2 on cardiac myocytes.

Histone deacetylases (HDACs) play vital roles in the pathophysiology of heart failure, which is associated with mitochondrial dysfunction. Tumor necrosis factor-α (TNF-α) contributes to the genesis of heart failure and impairs mitochondria. This study evaluated the role of HDACs in TNF-α-induced mitochondrial dysfunction and investigated their therapeutic potential and underlying mechanisms. We measured mitochondrial oxygen consumption rate (OCR) and ATP production using Seahorse XF24 extracellular flux analyzer and bioluminescent assay in control and TNF-α (10 ng/ml, 24 h)-treated HL-1 cells with or without HDAC inhibition. TNF-α increased Class I and II (but not Class IIa) HDAC activities (assessed by Luminescent) with enhanced expressions of Class I (HDAC1, HDAC2, HDAC3, and HDAC8) but not Class IIb HDAC (HDAC6 and HDAC10) proteins in HL-1 cells. TNF-α induced mitochondrial dysfunction with impaired basal, ATP-linked, and maximal respiration, decreased cellular ATP synthesis, and increased mitochondrial superoxide production (measured by MitoSOX red fluorescence), which were rescued by inhibiting HDACs with MPT0E014 (1 μM, a Class I and IIb inhibitor), or MS-275 (1 μM, a Class I inhibitor). MPT0E014 reduced TNF-α-decreased complex I and II enzyme (but not III or IV) activities (by enzyme activity microplate assays). Our results suggest that Class I HDAC actions contribute to TNF-α-induced mitochondrial dysfunction in cardiomyocytes with altered complex I and II enzyme regulation. HDAC inhibition improves dysfunctional mitochondrial bioenergetics with attenuation of TNF-α-induced oxidative stress, suggesting the therapeutic potential of HDAC inhibition in cardiac dysfunction.