Search

The high percentage of Vermamoeba was found in tap water in Korea. This study investigated whether Vermamoeba induced allergic airway inflammation in mice. We selected 2 free-living amoebas (FLAs) isolated from tap water, which included Korean FLA 5 (KFA5; Vermamoeba vermiformis) and 21 (an homolog of Acanthamoeba lugdunensis KA/ E2). We axenically cultured KFA5 and KFA21. We applied approximately 1 × 106 to mice's nasal passages 6 times and investigated their pathogenicity. The airway resistance value was significantly increased after KFA5 and KFA21 treatments. The eosinophil recruitment and goblet cell hyperplasia were concomitantly observed in bronchial alveolar lavage (BAL) fluid and lung tissue in mice infected with KFA5 and KFA21. These infections also activated the Th2-related interleukin 25, thymic stromal lymphopoietin, and thymus and activation-regulated chemokines gene expression in mouse lung epithelial cells. The CD4+ interleukin 4+ cell population was increased in the lung, and the secretion of Th2-, Th17-, and Th1-associated cytokines were upregulated during KFA5 and KFA21 infection in the spleen, lung-draining lymph nodes, and BAL fluid. The pathogenicity (allergenicity) of KFA5 and KFA21 might not have drastically changed during the long-term in vitro culture. Our results suggested that Vermamoeba could elicit allergic airway inflammation and may be an airway allergen.

Exposure to fine particulate matter increases the risk of cardiovascular morbidity and mortality. Few studies have tested the beneficial effect of indoor air filtration intervention in patients with cardiovascular disease. The aim of this study is to investigate the effect of air filtration on mitigating cardiovascular health in patients with coronary artery disease. This randomized, double-blind, crossover study is conducted with 38 coronary artery disease patients. The intervention consists of the following three periods: two-week active and sham air filtration interventions, with a two-week washout period. The indoor PM 2.5 concentration is continuously monitored during the entire study period. We measure the blood pressure, heart rate variability, baroreflex sensitivity, autonomic function test results, and endothelial function. The two-week active air filtration intervention for two weeks reduces the average indoor concentration of PM 2.5 by 33.9%. The indoor PM 2.5 concentration is significantly correlated to cross-correlation baroreflex sensitivity. Active air filtration is significantly associated with a decrease in the indicator of oxidative stress represented as 8-hydroxy-2'-deoxyguanosine. This study shows that a short-term air filtration intervention improved baroreflex sensitivity and might reduce oxidative stress in coronary artery disease patients. These findings suggest that the use of an air purifier could mitigate the recurrence of cardiovascular disease events in patients with coronary artery disease.

Purpose: The role of endogenous testosterone in de novo prostate cancer pathogenesis in humans remains unclear. The effect of testosterone on the tumor genome is not explored. We sought to explore the correlation between perioperative testosterone level and genomic risk score in a cohort of men who underwent radical prostatectomy., Materials and Methods: We included patients who underwent radical prostatectomy (2013-2018) and had adverse pathological features in their final surgical specimens (positive margin, and/or pT3a or higher). The outcome of interest was the genomic risk score: low (<0.45), intermediate (0.45-0.6) and high (>0.6). The associations between serum testosterone level and 188 gene expression-based signatures were examined. Secondary outcomes of interest included biochemical recurrence and receipt of secondary treatment., Results: The median genomic risk score was lower in the low testosterone group compared to the intermediate and normal testosterone groups (0.38 vs 0.52 vs 0.53, respectively; p=0.049). There was no difference in biochemical recurrence-free survival between the 3 testosterone groups (p=0.9). Patients with low testosterone levels had higher odds of receiving secondary treatment (OR: 2.27; 95% CI: 1.14-4.50; p=0.02) than those with normal levels. A total of 43 (of 188) gene expression signatures were associated with testosterone level (p <0.05). In total, 33 signatures were positively associated with serum testosterone levels, including 12 signatures involved in DNA repair pathways., Conclusions: This is the first study to assess the correlation of preoperative testosterone level on the tumor transcriptome and showed no clinical correlation between pre-defined genomic risk score groups and testosterone groups. This study adds to the notion of the limited role of endogenous testosterone on the development of de novo high-risk localized prostate cancer.

Background: Ischemic strokes (ISs) can appear even in non-gender-related CHA 2 DS 2 -VA scores 0~1 patients with atrial fibrillation (AF). We explored the determinants associated with IS development among the patients with non-gender-related CHA 2 DS 2 -VA score 0~1 AF., Methods and Results: In this single-center retrospective registry data for AF catheter ablation (AFCA), we included 1,353 patients with AF (24.7% female, median age 56 years, and paroxysmal AF 72.6%) who had non-gender-related CHA 2 DS 2 -VA score 0~1, normal left ventricular (LV) systolic function, and available H 2 FPEF score. Among those patients, 113 experienced IS despite a non-gender-related CHA 2 DS 2 -VA score of 0~1. All included patients underwent AFCA, and we evaluated the associated factors with IS in non-gender-related CHA 2 DS 2 -VA score 0~1 AF. Patients with ISs in this study had a lower estimated glomerular filtration rate (eGFR) ( p < 0.001) and LV ejection fraction (LVEF; p = 0.017), larger LA diameter ( p < 0.001), reduced LA appendage peak velocity ( p < 0.001), and a higher baseline H 2 FPEF score ( p = 0.018) relative to those without ISs. Age [odds ratio (OR) 1.11 (1.07-1.17), p < 0.001, Model 1] and H 2 FPEF score as continuous [ OR 1.31 (1.03-1.67), p = 0.028, Model 2] variable were independently associated with ISs by multivariate analysis. Moreover, the eGFR was independently associated with IS at low CHA 2 DS 2 -VA scores in both Models 1 and 2. AF recurrence was significantly higher in patients with IS (log-rank p < 0.001) but not in those with high H 2 FPEF scores (log-rank p = 0.079), respectively., Conclusions: Among the patients with normal LVEF and non-gender-related CHA 2 DS 2 -VA score 0~1 AF, the high H 2 FPEF score, and increasing age were independently associated with IS development (ClinicalTrials.gov Identifier: NCT02138695)., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Kim, Yu, Kim, Lee, Uhm, Kim, Nam, Joung, Lee, Heo and Pak.)

Reducing the time to diagnose COVID-19 helps to manage insufficient isolation-bed resources and adequately accommodate critically ill patients. There is currently no alternative method to real-time reverse transcriptase polymerase chain reaction (RT-PCR), which requires 40 cycles to diagnose COVID-19. We propose a deep learning (DL) model to improve the speed of COVID-19 RT-PCR diagnosis. We developed and tested a DL model using the long short-term memory method with a dataset of fluorescence values measured in each cycle of 5810 RT-PCR tests. Among the DL models developed here, the diagnostic performance of the 21st model showed an area under the receiver operating characteristic (AUROC), sensitivity, and specificity of 84.55%, 93.33%, and 75.72%, respectively. The diagnostic performance of the 24th model showed an AUROC, sensitivity, and specificity of 91.27%, 90.00%, and 92.54%, respectively., (© 2022. The Author(s).)

Atrial fibrosis can present as an arrhythmogenic substrate that is correlated with higher recurrence after catheter ablation for atrial fibrillation. Galectin-3, a beta-galactoside-binding lectin, is highly expressed and secreted from macrophages and is important in inflammation and fibrosis. We assessed the clinical implications of serum galectin-3 in patients with atrial fibrillation. This was a prospective cohort study of consecutive patients who underwent radiofrequency catheter ablation in a tertiary referral center from February 2017 to September 2017. Intracardiac blood sampling, echocardiographic measurements, magnetic resonance imaging with late gadolinium enhancement, electrophysiologic testing, and endocardial voltage mapping were consistently implemented in 75 patients before the ablation. Serum galectin-3 level was higher in patients with diabetes mellitus and was correlated with values that indicated the left atrial size. During a median 14 months of follow-up, atrial tachyarrhythmia recurred in 27% of patients. In multivariable Cox regression analysis, non-paroxysmal atrial fibrillation (hazard ratio 6.8; 95% confidence interval 1.6-28.9) and higher galectin-3 levels (hazard ratio 1.3; 95% confidence interval 1.0-1.7) were associated with increased risk of recurrence. Serum galectin-3 may be a prognostic biomarker for risk stratification in patients with atrial fibrillation planned catheter ablation., (© 2022. The Author(s).)

Cancer risk by environmental exposure is modulated by an individual's genetics and age at exposure. This age-specific period of susceptibility is referred to as the "Window of Susceptibility" (WOS). Rats have a similar WOS for developing breast cancer. A previous study in rat identified an age-specific long-range regulatory interaction for the cancer gene, Pappa , that is associated with breast cancer susceptibility. However, the global role of three-dimensional genome organization and downstream gene expression programs in the WOS is not known. Therefore, we generated Hi-C and RNA-seq data in rat mammary epithelial cells within and outside the WOS. To systematically identify higher-order changes in 3D genome organization, we developed NE-MVNMF that combines network enhancement followed by multitask non-negative matrix factorization. We examined three-dimensional genome organization dynamics at the level of individual loops as well as higher-order domains. Differential chromatin interactions tend to be associated with differentially up-regulated genes with the WOS and recapitulate several human SNP-gene interactions associated with breast cancer susceptibility. Our approach identified genomic blocks of regions with greater overall differences in contact count between the two time points when the cluster assignments change and identified genes and pathways implicated in early carcinogenesis and cancer treatment. Our results suggest that WOS-specific changes in 3D genome organization are linked to transcriptional changes that may influence susceptibility to breast cancer., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Baur, Lee, Haag, Chasman, Gould and Roy.)

Objectives: This study aimed to assess acute physiological response of fire suppression simulation affecting cardiovascular health during repeated bouts of simulation., Methods: Fifteen live-fire instructors were randomly divided into three groups according to fire suppression simulation frequency. Vital signs, biomarkers, and heart rate variability (HRV) were measured before and after simulation., Results: Vital signs increased immediately after fire simulation and returned to the normal range after 2 h. Most biomarker levels were changed within the normal ranges 72 h after the simulation training. However, one of the HRV frequency domains, high frequency power, was severely suppressed after 1 h and tended to recover after 2 h of simulation (P < 0.05)., Conclusions: Vital signs and their biomarkers were changed within the normal range regardless of the number of bouts of fire suppression simulations. HRV could be used to assess the effects of fire suppression simulation on cardiovascular health., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 American College of Occupational and Environmental Medicine.)

Phosphodiesterase 5 inhibition (PDE5i) activates cGMP-dependent protein kinase (PKG) and ameliorates heart failure; however, its impact on cardiac mitochondrial regulation has not been fully determined. Here, we investigated the role of the mitochondrial regulator peroxisome proliferator-activated receptor γ co-activator-1α (PGC1α) in the PDE5i-conferred cardioprotection, utilizing PGC1α null mice. In PGC1α +/+ hearts exposed to 7 weeks of pressure overload by transverse aortic constriction, chronic treatment with the PDE5 inhibitor sildenafil improved cardiac function and remodeling, with improved mitochondrial respiration and upregulation of PGC1α mRNA in the myocardium. By contrast, PDE5i-elicited benefits were abrogated in PGC1α -/- hearts. In cultured cardiomyocytes, PKG overexpression induced PGC1α, while inhibition of the transcription factor CREB abrogated the PGC1α induction. Together, these results suggest that the PKG-PGC1α axis plays a pivotal role in the therapeutic efficacy of PDE5i in heart failure., (© 2021 Federation of European Biochemical Societies.)

This study examined factors associated with willingness to engage in communication behaviors related to climate change advocacy. Data were collected as part of an online, longitudinal US study beginning in March 2020. Outcomes included willingness to post materials online, contact state legislators, and talk with peers about climate change. Covariates included climate change-related social norms, avoidance of climate change information, and perceptions of the future impact of climate change. A minority of the 586 respondents (23%) reported regular conversations about climate change, while approximately half of the respondents reported willingness to discuss climate change with peers (58%), post materials online (47%), and contact state legislators (46%). Strong predictors of willingness to engage in each climate change communications behaviors included climate change social norms, not avoiding climate change information, and believing that climate change will have a negative impact on the future. Findings indicate the importance of designing programs to foster increased climate change communications in order to promote community-level climate change advocacy norms.

Acute myeloid leukemia (AML) is a hematological malignancy caused by clonal expansion of myeloid progenitor cells. Most patients with AML respond to chemotherapy, but relapses often occur and infer a very poor prognosis. Thirty to thirty-five percent of AMLs carry a four base pair insertion in the nucleophosmin 1 gene (NPM1) with a C-terminal alternative reading frame of 11 amino acids. We previously identified various neopeptides from the alternative reading frame of mutant NPM1 (dNPM1) on primary AML and isolated an HLA-A*02:01-restricted T-cell receptor (TCR) that enables human T-cells to kill AML cells upon retroviral gene transfer. Here, we isolated T-cells recognizing the dNPM1 peptide AVEEVSLRK presented in HLA-A*11:01. The TCR cloned from a T-cell clone recognizing HLA-A*11:01+ primary AML cells conferred in vitro recognition and lysis of AML upon transfer to CD8 cells, but failed to induce an anti-tumor effect in immunodeficient NSG mice engrafted with dNPM1 OCI-AML3 cells. In conclusion, our data show that AVEEVSLRK is a dNPM1 neoantigen on HLA-A*11:01+ primary AMLs. CD8 cells transduced with an HLA-A*11:01-restricted TCR for dNPM1 were reactive against AML in vitro. The absence of reactivity in a preclinical mouse model requires further preclinical testing to predict the potential efficacy of this TCR in clinical development.

The cornea is a transparent and avascular tissue that plays a central role in light refraction and provides a physical barrier to the external environment. Corneal avascularity is a unique histological feature that distinguishes it from the other parts of the body. Functionally, corneal immune privilege critically relies on corneal avascularity. Corneal lymphangiogenesis is now recognized as a general pathological feature in many pathologies, including dry eye disease (DED), corneal allograft rejection, ocular allergy, bacterial and viral keratitis, and transient corneal edema. Currently, sizable data from clinical and basic research have accumulated on the pathogenesis and functional role of ocular lymphangiogenesis. However, because of the invisibility of lymphatic vessels, ocular lymphangiogenesis has not been studied as much as hemangiogenesis. We reviewed the basic mechanisms of lymphangiogenesis and summarized recent advances in the pathogenesis of ocular lymphangiogenesis, focusing on corneal allograft rejection and DED. In addition, we discuss future directions for lymphangiogenesis research.

Background: Previous studies have shown that Echinococcus granulosus cystic fluid can alleviate Th2 allergic airway inflammatory responses by increasing the number of CD4 + CD25 + Foxp3 + T (regulatory T; Treg) cells. Parasite-derived extracellular vesicles (EV) are known to not only promote parasite infection by communicating between parasites but also regulate the inflammatory response by acting as an immunomodulatory agent in the host., Methods: To evaluate the effect of EV extracted from the cystic fluid of E. granulosus on allergic airway inflammation, gene expression was investigated after administering EV to mouse lung epithelial cells (MLE-12) following 2 h of pretreatment with Aspergillus proteins. An allergic airway inflammation animal model was used to investigate the regulation of the inflammatory response by EV and induced with ovalbumin., Results: EV treatment significantly reduced airway resistance and the number of eosinophils and other immune cells in the bronchoalveolar lavage fluid and Th2- and Th17-related cytokine levels. EV pretreatment decreased the number of IL-4 + CD4 + T cells and increased the number of Treg cells in the lung-draining lymph nodes and spleen., Conclusions: Echinococcus granulosus cystic fluid derived EV ameliorated Th2 allergic airway inflammatory through Treg cells, similar to whole cystic fluid treatment. Thus, EV may be important immunomodulatory molecules in cystic fluid., (© 2021 John Wiley & Sons Ltd.)

Single-cell RNA sequencing data can unveil the molecular diversity of cell types. Cell type atlases of the mouse spinal cord have been published in recent years but have not been integrated together. Here, we generate an atlas of spinal cell types based on single-cell transcriptomic data, unifying the available datasets into a common reference framework. We report a hierarchical structure of postnatal cell type relationships, with location providing the highest level of organization, then neurotransmitter status, family, and finally, dozens of refined populations. We validate a combinatorial marker code for each neuronal cell type and map their spatial distributions in the adult spinal cord. We also show complex lineage relationships among postnatal cell types. Additionally, we develop an open-source cell type classifier, SeqSeek, to facilitate the standardization of cell type identification. This work provides an integrated view of spinal cell types, their gene expression signatures, and their molecular organization., (© 2021. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background and Study Aims: No standard ultrasonography (US) method exists for visualizing the distal common bile duct (CBD). The supine HD view is usually adopted for CBD evaluation, but duodenal or colonic gas shadowing can affect this view., Patients and Methods: We developed and evaluated an easy-to-perform technique, the supine distal CBD view, applying the US protocol for the distal CBD evaluation. Five reviewers checked the visibility of the distal CBD and cystic duct, as well as each view's image quality and influencing factors., Results: The visibility of the distal CBD was enhanced on the supine distal CBD view (86.0%-94.6%) versus the supine hepatoduodenal view (40.8%-82.1%), with less variability among the reviewers. The image quality of the supine distal CBD view was superior to that of the supine HD view (2.52 ± 0.67 vs. 1.93 ± 0.86, respectively; p < 0.01). The depth of the distal CBD from the surface was significantly larger in the patients with nonvisible distal CBDs., Conclusion: We present a user-friendly, easy-to-perform US view for locating and visualizing the distal CBD. With this technique, the distal CBD can be evaluated without changing a patient's position or increasing the duration of the procedure., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Pan-Arab Association of Gastroenterology. Published by Elsevier B.V. All rights reserved.)

Objective: To externally validate a Genomic Classifier (GC) based risk-stratification nomogram identifying candidates who would benefit from adjuvant radiation (aRT) therapy after radical prostatectomy (RP)., Methods: We identified 350 patients who underwent RP, between 2013 and 2018, and had adverse pathological features (positive margin, and/or pT3a or higher) on final pathology. Genomic profile was available for all these men. The clinical recurrence-free survival was estimated using the Kaplan-Meier method. The external validity of the nomogram was tested using the concordance index (c-index), calibration plot, and decision curve analysis., Results: The median follow-up of the cohort was 26.5 months. Overall, 14% of the patients received aRT. During the follow-up period, 3.4% of the patients developed metastasis. Overall 3-year metastasis-free survival was 95% (95% CI 0.92-0.98). The c-index of the nomogram was 0.84. The calibration of the model was favorable. Decision-curve analysis showed a positive net benefit for probabilities ranging between 0.01 and 0.09, with the highest difference at threshold probability around 0.05. At that threshold, the net benefit is 0.06 for the model and 0 for treating all the patients., Conclusion: Our report is the first to confirm the validity of this genomic-based risk-stratification tool in identifying men who might benefit from aRT after RP. As such, it can be a useful instrument to be incorporated in shared decision making on whether administration of aRT will lead to a clinically meaningful benefit. Such a model can also be useful for patients' classification in future clinical trials., (© 2021. Springer-Verlag GmbH Germany, part of Springer Nature.)

While the majority of the American public believe climate change is occurring and are worried, few are engaged in climate change action. In this study, we assessed factors associated with the level of willingness to engage in climate change actions using an online, longitudinal US study of adults. Climate change action outcomes included the level of willingness to post materials online, take political actions, talk with peers about climate change, and donate to or help an organization. Predictors included climate change attitudes, environmental attitudes, political ideology, political party affiliation, and demographic variables. Most (72%) of the 644 respondents only talked about climate change with peers a few times a year or less, though 65% were very or extremely worried about climate change. Many respondents indicated a willingness to do somewhat or a lot more, from 38% willing to talk to peers to 25% for willing to take political actions. In multinomial regression models, the Climate Change Concern scale was strongly and consistently associated with willingness to engage in climate change action. These findings indicate a need to both identify those who are willing to act and finding activities that fit with their interests and availability.

Objective: Management of prostate cancer in kidney transplant recipients presents a unique surgical challenge due to the risk of direct or indirect injury to the transplanted kidney. Herein, we report the largest single center study of Robot-assisted Radical prostatectomy (RARP) in kidney transplant recipients., Methods: Between Jan 2014-2019, 14 kidney transplant recipients with prostate cancer underwent RARP. Clinical and pathological features, perioperative and postoperative complications were retrospectively evaluated. Continence was defined as by patient utilization of zero urinary pads postoperatively., Results: The median (IQR) age at RARP was 60.2 (57.8-61.3) years, the interval between kidney transplant and RARP was 8.1 ± 7.5 years. The median (IQR) PSA was 6.9 (4-8.6); 10 of 14 patients had intermediate or high-risk prostate cancer. The median ASA score was 3, the mean (SD) operative time was 129.7 (26.3) minutes, and mean (SD) blood loss was 110 (44.6) ml. All cases were completed robotically, there was no graft loss or injury to transplanted ureter, and the mean length of stay was 1 (0.26) day.Final pathology demonstrated that 42.8% (6/14) of the patients had nonorgan confined disease (pT3a/T3b). 50% (7/14) of the patients were upgraded to higher risk Gleason disease on final surgical pathology. Post-RARP continence rate at 3 months, and 12 months were 45.5% (5/11) and 87.5% (7/8), respectively., Conclusion: RARP following kidney transplantation represents a safe and feasible operation which does not appear to compromise oncological or transplant outcomes., (© 2021 by SLS, Society of Laparoscopic & Robotic Surgeons.)

Background: The functional and oncologic outcomes of robot-assisted radical prostatectomy (RARP) in octogenarians are not well studied. We sought to study the perioperative, functional, and oncologic outcomes of RARP in octogenarian men. Methods: Between January 2009 and 2019, 46 patients ≥80 years with localized prostate cancer (PCa) underwent RARP in three high-volume robotic urologic practices in the United States. Clinical and pathologic features, and perioperative and postoperative complications were retrospectively evaluated. Functional outcomes for urinary and sexual function were collected via patient-reported questionnaires. Continence was defined as the use of zero or one safety pad per day. Results: The median (interquartile range) age was 81 (80-82), the mean (standard deviation [SD]) operative time was 116.5 (36.4) minutes, and the mean (SD) blood loss was 132 (35.6) mL. All cases were completed robotically, no intraoperative complications were encountered, and the mean length of stay was 1.21 (0.78) days. Regarding 30- and 90-day complication, nine patients had postoperative complications; seven were Clavien-Dindo grade I-II, and two were Clavien-Dindo grade ≥III. Post-RARP continence rates at 3 and 12 months were 68.4% and 84.8%, respectively. Conclusions: RARP represents a feasible option to treat PCa in well-selected octogenarian men. Careful patient selection and counseling are critical before offering surgical treatment for these men.

Background: Prostate cancer (PCa) represents the most common solid organ malignancy in men. Fortunately, at the time of diagnosis, the majority of cases are staged as localized or regional disease, conferring excellent 5- and 10-year cure rates. There are several first line treatment options including surgical approaches such as robot-assisted radical prostatectomy (RARP) and radiation therapy (RT) available to patients with localized disease that offer similar PCa oncologic outcomes but are associated with potentially significant side effects which may impact health-related quality of life (HRQOL) domains. Recently, clinicians and investigators have sought to better understand these changes in HRQOL metrics with the utilization of patient-reported outcomes (PRO). Given that RARP represents the most common surgical treatment for PCa in the United States, there has been a particular interest in assessing these outcomes derived by patient perspectives to more fully appreciate treatment-related impact on quality of life following RARP., Objective: This narrative review sought to explore the instruments available to measure quality of life after RARP, a review of the PRO data after RARP, and future directions for assessing and improving quality of life outcomes following this surgery., Clinical Use: There are several treatment options for men diagnosed with local and regional prostate cancer with similar oncologic outcomes but differing patterns of side effects affecting post-treatment quality of life. Understanding data reported directly by patients following RARP about their side effects and quality of life gives providers additional information for appropriate preoperative counseling for patients choosing between treatment options for their prostate cancer., Competing Interests: No financial or non-financial competing interests to disclose., (© 2021 Hale et al.)

Background and Objectives : Direct current cardioversion (DCCV) is a safe and useful treatment for atrial tachyarrhythmias. In the past, the energy delivered in DCCV was decided upon empirically, based only on the type of tachyarrhythmia. This conventional method does not consider individual factors and may lead to unnecessary electrical damage. Materials and Methods : We performed DCCV in patients with atrial tachyarrhythmias. The impedance and electrical current at the moment of shock were measured. The human thoracic impedance between both defibrillator patches and the electric current that was used were measured. Results : A total of 683 DCCVs were performed on 466 atrial tachyarrhythmia patients. The average impedance was 64 ± 11 Ω and the average successful current was 23 ± 6 mA. The magnitude of the electrical current that was successful depended upon the human impedance (linear regression, B = -0.266, p < 0.001) and the left atrial diameter (B = 0.092, p < 0.001). Impedance was directly proportional to body mass index (BMI) (B = 1.598, p < 0.001) and was higher in females than in males (77 ± 15 Ω vs. 63 ± 11 Ω, p < 0.001). Notably, the high-impedance (>70 Ω) group had a higher BMI (27 ± 4 kg/m 2 vs. 25 ± 3 kg/m 2 , p < 0.001) and a higher proportion of females (37% vs. 9%, p < 0.001) than the low-impedance group (<70 Ω). However, thoracic impedance was not an independent predictor for successful DCCV. Conclusions : Human thoracic impedance was one of the factors that impacted the level of electrical current required for successful DCCV in patients with atrial arrhythmias. In the future, it will be helpful to consider individual predictors, such as BMI and gender, to minimize electrical damage during DCCV.

Background: Multiple genomic tests are available following radical prostatectomy (RP), however, there is a lack of head-to-head evidence for these tests. We sought to compare the performance of two genomic tests in predicting post-RP oncological outcomes., Methods: A cohort of 16 post-RP patients with adverse pathological features who had obtained both Decipher (D) and Prolaris (P) testing. The Pearson correlation was used to compare scores from D and cell cycle progression (CCP) from P. Then, we derived a microarray CCP (mCCP) from D and correlated with P-CCP. The associations of D and mCCP with biochemical recurrence (BCR) and metastasis (M) was evaluated in multivariable survival analysis (MVA) in a large cohort of RP patients treated at Johns Hopkins University (1992-2010). In addition, we characterized the expression of the 31 P-CCP genes and mCCP scores in a cohort of 17,967 RP samples from Decipher platform., Results: There was significant correlation between the D score and P-CCP (r = 0.67, p = 0.004), and between the 10-year probability of BCR reported by P and 5-year probability of M reported by D (r = 0.69, p = 0.003). In this cohort, mCCP derived from the D platform was highly correlated to the reported P-CCP scores from the P platform (r = 0.88, p = 6.7e-6). In a comparative retrospective RP cohort, both mCCP and D were significantly associated with M outcome (p < 0.01 for both). On MVA, D was a predictor of M (HR 1.3, 95% CI [1.12-1.52], p = 0.0005), while mCCP was not a predictor of M (p = 0.62). In the D platform cohort, the 31 P-CCP genes were correlated to each other, and TOP2A was the most correlated to mCCP (r = 0.7)., Conclusions: We found that P and D scores post-RP were correlated and help in identifying patients who at high risk of BCR in this cohort. In a larger cohort with longer follow-up, D was predictor of M, whereas mCCP was not.

[Figure: see text].

High-throughput chromosome conformation capture assays, such as Hi-C, have shown that the genome is organized into organizational units such as topologically associating domains (TADs), which can impact gene regulatory processes. The sparsity of Hi-C matrices poses a challenge for reliable detection of these units. We present GRiNCH, a constrained matrix-factorization-based approach for simultaneous smoothing and discovery of TADs from sparse contact count matrices. GRiNCH shows superior performance against seven TAD-calling methods and three smoothing methods. GRiNCH is applicable to multiple platforms including SPRITE and HiChIP and can predict novel boundary factors with potential roles in genome organization.

Introduction: Atrial fibrillation (AF) leads to rate-dependent atrial changes collectively defined as atrial remodelling (AR). Shortening of the atrial effective refractory period (AERP) and decreased conduction velocity are among the hallmarks of AR. Pharmacological strategies to inhibit AR, thereby reducing the self-perpetual nature of AF, are of great clinical value. Cannabinoid receptor (CBR) ligands may exert cardioprotective effects; CB13, a dual CBR agonist with limited brain penetration, protects cardiomyocytes from mitochondrial dysfunction induced by endothelin-1. Here, we examined the effects of CB13 on normal physiology of the rat heart and development of tachypacing-induced AR. Methods: Rat hearts were perfused in a Langendorff set-up with CB13 (1 µM) or vehicle. Hemodynamic properties of non-paced hearts were examined conventionally. In a different set of hearts, programmed stimulation protocol was performed before and after atrial tachypacing for 90 min using a mini-hook platinum quadrupole electrode inserted on the right atrium. Atrial samples were further assessed by western blot analysis. Results: CB13 had no effects on basal hemodynamic properties. However, the compound inhibited tachypacing-induced shortening of the AERP. Protein expression of PGC1α was significantly increased by CB13 compared to vehicle in paced and non-paced hearts. Phosphorylation of AMPKα at residue threonine 172 was increased suggesting upregulation of mitochondrial biogenesis. Connexin43 was downregulated by tachypacing. This effect was diminished in the presence of CB13. Conclusion: Our findings support the notion that peripheral activation of CBR may be a new treatment strategy to prevent AR in patients suffering from AF, and therefore warrants further study., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Lee, Murninkas, Elyagon, Etzion and Anderson.)

INTRODUCTION It is unknown whether a family history of prostate cancer confers additional risk among men who are candidates for active surveillance (AS)., Materials and Methods: Using a prospectively maintained database of men who underwent radical prostatectomy (RP) (2010- 2018), candidates for AS were identified according to the expanded criteria. Pathological upgrading was defined as a pathologic Gleason score (pGS) of 3+4 or higher for patients with a biopsy GS of 3+3 and a pGS of 4+3 or higher for patients with a biopsy GS of 3+4. Major upgrading was defined as a pGS of 4+4 or higher. The ₓ2 test was used for comparisons., Results: Of 1,320 men who were candidates for AS, 288 (21.8%) had a family history of prostate cancer. There were no differences in terms of the age, number of positive cores, or number of patients with a GS of 7 between the two groups. Pathological upgrading was observed in 61.1% of the total cohort, with no difference observed between the two groups (60.7% versus 62.5%; p = 0.5)., Conclusion: In men who are eligible for AS according to the expanded criteria, a family history of prostate cancer does not appear to be associated with adverse pathology at RP.

INTRODUCTION During the coronavirus disease 2019 (COVID-19) pandemic, decreased presentations for various emergent conditions have been observed. Our objective was to compare the volume of patients with urologic emergencies presenting to emergency departments (EDs) within a single health system before and after the onset of the COVID-19 pandemic., Materials and Methods: A retrospective chart review was performed for 3 EDs within a single health system in the United States to identify all ED consults to urology from January 1, 2019 to May 31, 2020. For emergent consults, covariates were extracted, including demographic information, insurance status, Charlson Comorbidity Index (CCI) score, travel distance from home to the ED, and whether the patient had seen a provider in the hospital system before. Data were compared between COVID-19 months (March-May 2020) and corresponding months in 2019., Results: The study period encompassed 1,179 consults and 373 urologic emergencies. We observed not only a 22% decrease in urologic presentations to the ED compared to corresponding months in 2019, but also a 54% decrease in the proportion of urologic presentations that were truly emergent. For patients with emergent diagnoses, April 2020 saw an increase in Medicare/Medicaid coverage and a decrease in private insurance, May 2020 saw a decreased travel distance from home to the ED, and March and May 2020 saw an increase in patients who had previously seen a health system provider outside of the ED. No changes were seen in demographic characteristics or CCI., Conclusions: During the early COVID-19 pandemic, urologic emergencies within a single health system decreased by 54% compared to the corresponding months pre-pandemic. Those who do present for care may be influenced by both locality and provider familiarity.

Introduction: Current preoperative evaluation methods fail to detect the difference in frailty among patients with the same chronological age. Hence, we sought to assess the ability of a simple 5-item frailty index (5-iFI) score to predict surgical outcomes post radical prostatectomy (RP). Methods: The American College of Surgeons National Surgical Quality Improvement Program was queried for patients who underwent RP between 2008 and 2017. The 5-iFI score was calculated by assigning a point for each of the following conditions: (1) chronic obstructive pulmonary disease or pneumonia, (2) congestive heart failure, (3) dependent functional status, (4) hypertension, and (5) diabetes. Multivariable regression was performed to assess the association between the 5-iFI score and perioperative outcomes. Results: The cohort included 15,546 (46.2%), 14,541 (46.2%), and 3556 (10.6%) patients with 5-iFI scores of 0, 1, and ≥2, respectively. Patients >65 years, nonwhite, and with an American Society of Anesthesiology ≥3 were more likely to have a 5-iFI score ≥2 ( p  < 0.0001). Similarly, a 5-iFI ≥2 score was associated with higher Clavien-Dindo grades complications ( p -trend <0.0001). In addition, a 5-iFI score ≥2 had 1.66 (1.31-2.11) and 1.85 (1.39-2.46) times the odds of Clavien-Dindo grades ≥3 and ≥4 adverse events, respectively. Moreover, a 5-iFI score ≥2 had 28% increased risk of length of stay >1 day ( p  < 0.0001) and increased incidence of early mortality ( p  = 0.01). Conclusions: Frailty, as measured by a simple 5-point frailty index, is an independent predictor of adverse outcomes and early mortality in patients undergoing RP. Preoperative frailty assessment may improve risk stratification and patient counseling before surgery.

Background: Attention problems and decreased quality of life are frequently accompanied in Cerebral Palsy (CP), which can negatively affect rehabilitation of physical disability. However, the majority of affected children remain untreated in the aspects of attention or psychosocial factors. Equine-Assisted Activities and Therapies (EAAT) use horse as a therapeutic modality including grooming as well as mounted riding activities in which patients exercise and experience mounted stimulation. It is known to help improve attention in children with ADHD, so that it can be an exercise therapy that is expected to improvement of attention as well as rehabilitating effects in CP patients. EAA may be a promising strategy to address the unmet need for CP patients. This study aims to investigate the efficacy of EAA for children with CP, those with both CP and ADHD and confirm the comorbidity between CP and ADHD., Methods: Forty-six children with cerebral palsy participated in this study. For the exercise group, they participated in a 40-min session twice a week for a 16-week period, while the control group engaged in daily life without any special treatments. Each children individually were assessed on attention and psychological wellbeing at baseline and post-treatment. Comorbidity were identified based on the Diagnostic and Statistical Manual of Mental Disorder 5th edition (DSM-5) and confirmed by Korean Kiddie-Schedule for Affective Disorders and Schizophrenia Present and Lifetime Version (K-SADS-PL)., Results: Perseveration rated using the Conner's Performance Test (CPT) showed a significant decrease only in the exercise group (p < .024). However, no significant improvement in children's quality of life was observed after EAA program compared with control group. Among the total participants, fifteen children (31.91%) were diagnosed with ADHD. When conducting an additional analysis with the subsample of CP patients diagnosed with ADHD, the d', commission error and perseveration showed a significant decrease only in the exercise group. Children with CP and ADHD reported an improvement in quality of life both in exercise and control group, but only in the exercise group social functioning exhibited a significant difference., Conclusion: The positive effects of the EAA on attention and quality of life were confirmed. Children with CP in the exercise group were more capable to sustain their attention longer. Those with CP and ADHD showed an increase in attention and perceived to have better social skills after receiving 16 weeks of EAA compared to those in the control group. Considering high comorbidity of CP and ADHD, it seems that the EAA program could be the better alternative treatment for CP with attentional problem. The results of this study will contribute to growing evidence for the efficacy of EAA in children especially with CP and ADHD., Trial Registration: This trial was registered on ClinicalTrials.gov ( NCT03870893 ). Registered 26 July 2017.

Cardiomyocytes undergo significant structural and functional changes after birth, and these fundamental processes are essential for the heart to pump blood to the growing body. However, due to the challenges of isolating single postnatal/adult myocytes, how individual newborn cardiomyocytes acquire multiple aspects of the mature phenotype remains poorly understood. Here we implement large-particle sorting and analyze single myocytes from neonatal to adult hearts. Early myocytes exhibit wide-ranging transcriptomic and size heterogeneity that is maintained until adulthood with a continuous transcriptomic shift. Gene regulatory network analysis followed by mosaic gene deletion reveals that peroxisome proliferator-activated receptor coactivator-1 signaling, which is active in vivo but inactive in pluripotent stem cell-derived cardiomyocytes, mediates the shift. This signaling simultaneously regulates key aspects of cardiomyocyte maturation through previously unrecognized proteins, including YAP1 and SF3B2. Our study provides a single-cell roadmap of heterogeneous transitions coupled to cellular features and identifies a multifaceted regulator controlling cardiomyocyte maturation.

The complex pathophysiology of atrial fibrillation (AF) is governed by multiple risk factors in ways that are still elusive. Basic electrophysiological properties, including atrial effective refractory period (AERP) and conduction velocity, are major factors determining the susceptibility of the atrial myocardium to AF. Although there is a great need for affordable animal models in this field of research, in vivo rodent studies are limited by technical challenges. Recently, we introduced an implantable system for long-term assessment of AF susceptibility in ambulatory rats. However, technical considerations did not allow us to perform concomitant supraventricular electrophysiology measurements. Here, we designed a novel quadripolar electrode specifically adapted for comprehensive atrial studies in ambulatory rats. Electrodes were fabricated from medical-grade silicone, four platinum-iridium poles, and stainless-steel fixating pins. Initial quality validation was performed ex vivo, followed by implantation in adult rats and repeated electrophysiological studies 1, 4, and 8 wk postimplantation. Capture threshold was stable. Baseline AERP values (38.1 ± 2.3 and 39.5 ± 2.0 using 70-ms and 120-ms S1-S1 cycle lengths, respectively) confirmed the expected absence of rate adaptation in the unanesthetized state and validated our prediction that markedly higher values reported under anesthesia are nonphysiological. Evaluation of AF substrate in parallel with electrophysiological parameters validated our recent finding of a gradual increase in AF susceptibility over time and demonstrated that this phenomenon is associated with an electrical remodeling process characterized by AERP shortening. Our findings indicate that the miniature quadripolar electrode is a potent new tool, which opens a window of opportunities for better utilization of rats in AF research. NEW & NOTEWORTHY Rodents are increasingly used in AF research. However, technical challenges restrict long-term supraventricular electrophysiology studies in these species. Here, we developed an implantable electrode adapted for such studies in the rat. Our findings indicate that this new tool is effective for long-term follow-up of critical parameters such as atrial refractoriness. Obtained data shed light on the normal electrophysiology and on the increased AF susceptibility that develops in rats with implanted atrial electrodes over time.

Objective: To assess the association between Genomic Classifier (GC)-risk group and post-radical prostatectomy treatment in clinical practice., Methods: Two prospective observational cohorts of men with prostate cancer (PCa) who underwent RP in two referral centers and had GC testing post-prostatectomy between 2013 and 2018 were included. The primary endpoint of the study was to assess the association between GC-risk group and time to secondary therapy. Univariable (UVA) and multivariable (MVA) Cox proportional hazards models were constructed to assess the association between GC-risk group and time to receipt of secondary therapy after RP, where secondary therapy is defined as receiving either RT or ADT after RP., Results: A total of 398 patients are included in the analysis. Patients with high-GC risk were more likely to receive any secondary therapy (OR: 6.84) compared to patients with low/intermediate-GC risk. The proportion of high-GC risk patients receiving RT at 2 years post-RP was 31.5%, compared to only 6.3% among the low/intermediate-GC risk patients., Conclusion: This study demonstrates that physicians in routine practice used GC to identify high risk patients who might benefit the most from secondary treatment. As such, GC score was independent predictor of receipt of secondary treatment., (© 2021 The Authors. BJUI Compass published by John Wiley & Sons Ltd on behalf of BJU International Company.)

Background: Elevation of soluble suppression of tumorigenicity 2 (sST2) is associated with cardiac fibrosis and hypertrophy. Under investigation herein, was whether sST2 level is associated with major adverse cardiac events (MACE) and left ventricular (LV) remodeling after primary percutaneous coronary intervention (PCI) in patients with acute ST-segment elevation myocardial infarction (STEMI)., Methods: In total, this study included 184 patients who underwent successful primary PCI. A subsequent guideline-based medical follow-up was included (61.4 ± 11.8 years old, 85% male, 21% with Killip class ≥ I). sST2 concentration correlations with echocardiographic, angiographic, laboratory parameters, and clinical outcomes in STEMI patients were evaluated., Results: The median sST2 level was 60.3 ng/mL; 6 (3.2%) deaths occurred within 1 year. The sST2 level correlated with LV ejection fraction (LVEF) changes from baseline to 6 months (r= -0.273; p = 0.006) after adjustment for echocardiographic parameters including wall motions score index (WMSI). Recovery of LVEF at 6 months was highest in the tertile 1 group (Δ6 months - baseline LVEF; tertile 1, p = 0.001; tertile 2, p = 0.319; tertile 3, p = 0.205). The decrease in WMSI at 6 months was greater in the tertiles 1 and 2 groups than in the tertile 3 group (Δ6 months - baseline WMSI; tertile 1, p = 0.001; tertile 2, p = 0.013; tertile 3, p = 0.055). There was no association between sST2 levels and short-term (log rank p = 0.598) and long-term (p = 0.596) MACE., Conclusions: sST2 concentration have predictive value for LV remodeling on echocardiography in patients with STEMI who underwent primary PCI. However, sST2 concentration was not associated with short-term and long-term MACE.

Obesity is an increasingly prevalent disease worldwide, and genetic and environmental factors are known to regulate the development of obesity and associated metabolic diseases. Emerging studies indicate that innate and adaptive immune cell responses in adipose tissue play critical roles in the regulation of metabolic homeostasis. Parasitic helminths are the strongest natural inducers of type 2 inflammatory responses, and several studies have revealed that helminth infections inversely correlate with metabolic syndrome. Hence, this study investigated whether helminth infections could have preventative effects on high fat diet-induced obesity. Female C57BL/6 mice were maintained on either a low fat diet (LFD, 10% fat) or a high fat diet (HFD, 60% fat) for 6 weeks after Trichinella spiralis infection. The mice were randomly divided into four groups and were fed a normal diet, LFD, LFD after T. spiralis infection (Inf + LFD), a high fat diet (HFD), or HFD after T. spiralis infection (HFD + inf). All groups were assayed for body weight, food efficiency ratio (FER), total body weight gain (g)/total food intake amount (g) fat weight, and blood biochemical parameters. Our data indicate that the HFD + inf group significantly reduced body weight gain, fat mass, total cholesterol, and FER. Analysis of immune cell composition by flow cytometry revealed that T. spiralis promoted strong decreases in proinflammatory adipose macrophages (F4/80 + CD11c + ) and T cells. The alterations in microbiota from fecal samples of mice were analyzed, which showed that T. spiralis infection decreased the ratio of Firmicutes to Bacteriodetes, thereby restoring the previously increased ratio of Firmicutes to Bacteriodetes in HFD-fed mice. Moreover, elimination of T. spiralis retained the protective effects in the HFD-fed obese mice whereas flubendazole (FLBZ) treatment increased levels of the families Lachnospiraceae and Ruminococcaceae. In summary, we provided novel data suggesting that helminth infection protects against obesity and the protection was closely related to M2 macrophage proliferation, an inhibiting proinflammatory response. In addition, it alters the microbiota in the gut., (Copyright © 2020 Australian Society for Parasitology. Published by Elsevier Ltd. All rights reserved.)

Background: This study aimed to evaluate acute injuries of the radial artery (RA) using optical coherence tomography (OCT) in patients who underwent coronary intervention via the snuffbox approach., Methods: Forty-six patients, who underwent coronary intervention and assessment of the conventional RA using OCT via the snuffbox approach, were enrolled from two university hospitals between August 2018 and August 2019., Results: The mean age of the patients was 65.1 years. In this study population, 6-French (Fr) sheaths were used. The mean diameter of the conventional RA was 2.89 ± 0.33 mm, and the mean lumen area of the conventional RA was 6.68 ± 1.56 mm2. Acute injuries of the conventional RA, after the snuffbox approach, were observed in 5 (10.9%) patients. Intimal tear was observed in the RA in 1 (2.2%) case. Intraluminal thrombi, without vessel injuries, were detected in the RA in 4 (8.7%) cases. However, medial dissection was not observed in the OCT analysis., Conclusions: This retrospective OCT-based study showed that the diameter of the conventional RA was 2.89 mm and acute vessel injury of the conventional RA was rare in patients who underwent coronary intervention via the snuffbox approach.

Background: This study evaluated the status of single nucleotide polymorphisms (SNPs) in Korean patients with early-onset (< 40 years old) atrial fibrillation (AF) and their effects on the outcome after catheter ablation., Methods: A total of 89 patients (35.7 ± 3.7 years, 81 males) with drug-refractory AF (paroxysmal 64.0%) who underwent catheter ablation were included in this study. Sixteen SNPs, including rs13376333, rs10465885, rs10033464, rs2200733, rs17042171, rs6843082, rs7193343, rs2106261, rs17570669, rs853445, rs11708996, rs6800541, rs251253, rs3807989, rs11047543, and rs3825214, were genotyped. Serial 48-hour Holter monitoring was conducted to detect AF recurrences during long-term follow up., Results: Wild-type genotypes of rs11047543 (GG; 26/69 [37.7%] vs. GA; 13/18 [72.2%] vs. AA; 0/0 [0%], P = 0.009) and rs7193343 (CC; 0/7 [0%] vs. CT; 22/40 [55.0%] vs. TT; 18/41 [43.9%], P = 0.025) and the homozygous variant of rs3825214 (AA; 16/31 [51.6%] vs. AG; 22/43 [51.2%] vs. GG; 2/13 [15.4%], P = 0.056) were significantly associated with a lower rate of late recurrence. When the patients were assigned to four groups according to the number of risk alleles (n = 0-3), there were significant differences in recurrence rate (n = 0; 0/3 vs. n = 1; 2/13 [15.4%] vs. n = 2; 24/52 [46.2%] vs. n = 3; 13/17 [76.5%], P = 0.003). When correcting for multiple variables, rs11047543 (hazard ratio [HR], 2.723; 95% confidence interval [CI], 1.358-5.461; P = 0.005) and the number of risk alleles (HR, 2.901; 95% CI, 1.612-5.219; P < 0.001) were significantly associated with recurrence of AF after catheter ablation., Conclusion: Polymorphisms on rs7193343 closest to ZFHX3 (16q22), rs3825214 near to TBX5 (12q24), and rs11047543 near to SOX5 (12p12) modulate the risk for AF recurrence after catheter ablation. The number of risk alleles of these 3 SNPs was an independent predictor of recurrence during long-term follow up in Korean patients with early-onset AF., Competing Interests: The authors have no potential conflicts of interest to disclose., (© 2020 The Korean Academy of Medical Sciences.)

Objective: The current study seeks to replicate and extend principal findings reported in The World at 7:00, a project that examined the psychological experience of situations in 20 countries., Method: Data were collected from participants in 62 countries (N = 15,318), recruited from universities by local collaborators to complete the study via a custom-built website using 42 languages., Results: Several findings of the previous study were replicated. The average reported situational experience around the world was mildly positive. The same countries tended to be most alike in reported situational experience (r = .60) across the two studies, among the countries included in both. As in the previous study, the homogeneity of reported situational experience was significantly greater within than between countries, although the difference was small. The previously reported exploratory finding that negative aspects of situations varied more across countries than positive aspects did not replicate. Correlations between aspects of reported situational experience and country-level average value scores, personality, and demographic variables were largely similar between the two studies., Conclusion: The findings underscore the importance of cross-cultural situational research and the need to replicate its results, and highlight the complex interplay of culture and situational experience., (© 2020 Wiley Periodicals LLC.)

In the adipose tissue (AT), an increase in the M1 macrophage (M1Ø)/M2 macrophage (M2Ø) polarization ratio can be a risk factor enhancing the inflammatory response during aging, as well as increasing the risk of chronic disease, thereby reducing lifespan, or at least reducing "healthy" lifespan. The purpose of this study was to analyze and compare the AT M1Ø/M2Ø polarization ratio at the final lifespan stage in aged and control animals performing lifelong spontaneous wheel running. Based on flow cytometric analysis, the AT ratio of macrophages revealed M2Ø polarization following lifelong spontaneous exercise (LSE) regardless of age. However, for Icam1 and Tnf, the qPCR analysis showed no difference in gene expressions in young mice; Arg1 expression was higher in Young-EXE (exercising) than in Young-CON (control) mice (p < .0001). In Old-EXE, Icam1 (p < .0001) and Tnf (p < .0001) expression were lower than in Old-CON; for Arg1, gene expression in Old-EXE was higher than in Old-CON (p < .0001). LSE prevents deterioration of physical fitness owing to aging, maintaining high M2Ø polarization levels in the AT. Additionally, LSE does not downregulate Icam1 and Tnf in the AT but appears to suppress the increased M1Ø polarization ratio attributed to aging by upregulating Arg1., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Proteotoxicity from insufficient clearance of misfolded/damaged proteins underlies many diseases. Carboxyl terminus of Hsc70-interacting protein (CHIP) is an important regulator of proteostasis in many cells, having E3-ligase and chaperone functions and often directing damaged proteins towards proteasome recycling. While enhancing CHIP functionality has broad therapeutic potential, prior efforts have all relied on genetic upregulation. Here we report that CHIP-mediated protein turnover is markedly post-translationally enhanced by direct protein kinase G (PKG) phosphorylation at S20 (mouse, S19 human). This increases CHIP binding affinity to Hsc70, CHIP protein half-life, and consequent clearance of stress-induced ubiquitinated-insoluble proteins. PKG-mediated CHIP-pS20 or expressing CHIP-S20E (phosphomimetic) reduces ischemic proteo- and cytotoxicity, whereas a phospho-silenced CHIP-S20A amplifies both. In vivo, depressing PKG activity lowers CHIP-S20 phosphorylation and protein, exacerbating proteotoxicity and heart dysfunction after ischemic injury. CHIP-S20E knock-in mice better clear ubiquitinated proteins and are cardio-protected. PKG activation provides post-translational enhancement of protein quality control via CHIP.

Atrial remodeling with fibrosis has been well-described in patients with atrial fibrillation (AF). We hypothesized that the left atrial (LA)-late gadolinium enhancement (LGE) extent on cardiac magnetic resonance (CMR) imaging is associated with LA pressure and can be a marker for suitable candidates for non-paroxysmal AF ablation. A total of 173 AF patients with an LA-LGE area on CMR imaging were enrolled. The clinical parameters, including invasively measured LA pressure, were compared between the patients with extensive LA-LGE (E-LGE, LGE extent ≥ 20%, n = 78) and those with small LA-LGE (S-LGE, LGE extent < 20%, n = 95). The E-LGE group had higher peak LA pressures than the S-LGE group (23 versus 19 mmHg, p < 0.001). The E-LGE group had more patients with non-paroxysmal AF (non-PAF) (51% vs. 34%), heart failure (9% vs. 0%), and higher NT pro-B-type natriuretic peptide (472 vs. 265 pg/ml) (all p < 0.05). LA pressure ≥ 21 mmHg was an independent predictor of E-LGE (OR = 2.218; p = 0.019). In the paroxysmal AF (PAF) subgroup, freedom from atrial arrhythmia after catheter ablation was not different (81% vs 86%, log-rank p = 0.529). However, in the non-PAF subgroup, it was significantly higher in the S-LGE group than in the E-LGE group (81% vs 55%, log-rank p = 0.014). Increased LA pressure was related to the LA-LGE extent. LA-LGE was a good predictor of outcome after catheter ablation, but only in patients with non-PAF.

Prediction of recurrences after catheter ablation of atrial fibrillation (AF) remains challenging. We sought to investigate the long-term outcomes after AF catheter ablation. A total of 2221 consecutive patients who underwent catheter ablation for symptomatic AF were included in this study (mean age 55 ± 11 years, 20.3% women, and 59.0% paroxysmal AF). Extensive ablation, in addition to circumferential pulmonary vein isolation, was more often accomplished in patients with non-paroxysmal AF than in those with paroxysmal AF (87.4% vs. 25.3%, p < 0.001). During a median follow-up of 54 months, sinus rhythm (SR) was maintained in 67.1% after index procedure. After redo procedures in 418 patients, 83.3% exhibited SR maintenance. Recurrence rates were similar for single and multiple procedures (17.4% vs. 16.7%, p = 0.765). Subanalysis showed that the extent of late gadolinium enhancement (LGE), as assessed by cardiac magnetic resonance, is greater in patients with recurrence than in those without recurrence (36.2 ± 23.9% vs. 21.8 ± 13.7%, p < 0.001). Cox-regression analysis revealed that non-paroxysmal AF (hazard ratio (HR) 2.238, 95% confidence interval (CI) 1.905-2.629, p < 0.001), overweight (HR 1.314, 95% CI 1.107-1.559, p = 0.020), left atrium dimension ≥ 45 mm (HR 1.284, 95% CI 1.085-1.518, p = 0.004), AF duration (HR 1.020 per year, 95% CI 1.006-1.034, p = 0.004), and LGE ≥ 25% (HR 1.726, 95% CI 1.330-2.239, p < 0.001) are significantly associated with AF recurrence after catheter ablation. This study showed that repeated catheter ablation improves the clinical outcomes of patients with non-paroxysmal AF, suggesting that AF substrate based on LGE may underpin the mechanism of recurrence after catheter ablation.

Primitive substitution tilings on {\bb R}^d whose expansion maps are unimodular are considered. It is assumed that all the eigenvalues of the expansion maps are algebraic conjugates with the same multiplicity. In this case, a cut-and-project scheme can be constructed with a Euclidean internal space. Under some additional condition, it is shown that if the substitution tiling has pure discrete spectrum, then the corresponding representative point sets are regular model sets in that cut-and-project scheme.

Objective: To explore the incidence of and potential risk factors for acute urine retention (AUR) after robot-assisted radical prostatectomy (RARP) and its effect on early urine continence., Methods: A retrospective analysis of patients who underwent RARP by a single surgeon between July 2016 and June 2017 was performed to assess the incidence of AUR and its effect on early continence. Continence was assessed through self-reported questionnaires completed approximately three months after surgery. Early urine continence was defined as using zero pads per day at the time of the three-month follow-up. Descriptive statistics and logistic regression analysis were used to assess independent predictor of AUR., Results: Of 379 patients, 19 (5%) developed AUR after RARP. No significant difference in baseline characteristics between those who developed AUR post-RARP and those who did not. There was no statistically significant difference in the reported early continence and number of pads used per day between patients with AUR and patients without AUR (31.6% vs. 23.1%, P  = 0.39), (1.6 vs. 1.4, P  = 0.913), respectively., Conclusion: AUR post-RARP is an infrequent postoperative complication with no impact on early continence rate. No patient-related factors were associated with the development of AUR., Competing Interests: None declared., (© 2020 Asian Pacific Prostate Society. Published by Elsevier B.V.)

Rationale: Stimulated PKG1α (protein kinase G-1α) phosphorylates TSC2 (tuberous sclerosis complex 2) at serine 1365, potently suppressing mTORC1 (mechanistic [mammalian] target of rapamycin complex 1) activation by neurohormonal and hemodynamic stress. This reduces pathological hypertrophy and dysfunction and increases autophagy. PKG1α oxidation at cysteine-42 is also induced by these stressors, which blunts its cardioprotective effects., Objective: We tested the dependence of mTORC1 activation on PKG1α C42 oxidation and its capacity to suppress such activation by soluble GC-1 (guanylyl cyclase 1) activation., Methods and Results: Cardiomyocytes expressing wild-type (WT) PKG1α (PKG1α WT ) or cysteine-42 to serine mutation redox-dead (PKG1α CS/CS ) were exposed to ET-1 (endothelin 1). Cells expressing PKG1α WT exhibited substantial mTORC1 activation (p70 S6K [p70 S6 kinase], 4EBP1 [elF4E binding protein-1], and Ulk1 [Unc-51-like kinase 1] phosphorylation), reduced autophagy/autophagic flux, and abnormal protein aggregation; all were markedly reversed by PKG1α CS/CS expression. Mice with global knock-in of PKG1α CS/CS subjected to pressure overload (PO) also displayed markedly reduced mTORC1 activation, protein aggregation, hypertrophy, and ventricular dysfunction versus PO in PKG1α WT mice. Cardioprotection against PO was equalized between groups by co-treatment with the mTORC1 inhibitor everolimus. TSC2-S1365 phosphorylation increased in PKG1α CS/CS more than PKG1α WT myocardium following PO. TSC2 S1365A/S1365A (TSC2 S1365 phospho-null, created by a serine to alanine mutation) knock-in mice lack TSC2 phosphorylation by PKG1α, and when genetically crossed with PKG1α CS/CS mice, protection against PO-induced mTORC1 activation, cardiodepression, and mortality in PKG1α CS/CS mice was lost. Direct stimulation of GC-1 (BAY-602770) offset disparate mTORC1 activation between PKG1α WT and PKG1α CS/CS after PO and blocked ET-1 stimulated mTORC1 in TSC2 S1365A -expressing myocytes., Conclusions: Oxidation of PKG1α at C42 reduces its phosphorylation of TSC2, resulting in amplified PO-stimulated mTORC1 activity and associated hypertrophy, dysfunction, and depressed autophagy. This is ameliorated by direct GC-1 stimulation.

Purpose: Robot-assisted radical prostatectomy has become the predominant surgical modality to manage localized prostate cancer in the U.S. However, there are few studies focusing on the associations between hospital volume and outcomes of robot-assisted radical prostatectomy., Materials and Methods: We identified robot-assisted radical prostatectomies for clinically localized (cT1-2N0M0) prostate cancer diagnosed between 2010 and 2014 in the National Cancer Database. We categorized annual average hospital robot-assisted radical prostatectomy volume into very low, low, medium, high and very high by most closely sorting the final included patients into 5 equal-sized groups (quintiles). Outcomes included 30-day mortality, 90-day mortality, conversion (to open), prolonged length of stay (more than 2 days), 30-day (unplanned) readmission, positive surgical margin and lymph node dissection rates., Results: A total of 114,957 patients were included in the study, and hospital volume was categorized into very low (3 to 45 cases per year), low (46 to 72), medium (73 to 113), high (114 to 218) and very high (219 or more). Overall 30-day mortality (0.12%), 90-day mortality (0.16%) and conversion rates (0.65%) were low. Multivariable logistic regressions showed that compared with the very low volume group, higher hospital volume was associated with lower odds of conversion to open surgery (OR 0.23, p <0.001 for very high), prolonged length of stay (OR 0.25, p <0.001 for very high), 30-day readmission (OR 0.53, p <0.001 for very high) and positive surgical margins (OR 0.61, p <0.001 for very high). Higher hospital volume was also associated with higher odds of lymph node dissection in the intermediate/high risk cohort (OR 3.23, p <0.001 for very high)., Conclusions: Patients undergoing robot-assisted radical prostatectomy at higher volume hospitals are likely to have improved perioperative and superior oncologic outcomes compared to lower volume hospitals.

Background: Robot-assisted radical prostatectomy (RARP) can generally be performed with 1-2 nights of postoperative monitoring before discharge from the hospital. Little is known about what causes individual patients to remain in hospital beyond the second postoperative day., Methods: Data for RARPs performed between 2013 and 2015 were extracted from the American College of Surgeons National Surgical Quality Improvement Program (NSQIP) database. The fraction of cases with prolonged length of stay (PLOS) that can be reasonably attributed to complications was examined. Logistic regression was performed to identify risk factors for PLOS in the overall population and separately in the population of patients with PLOS without any perioperative complications., Results: Of 11,440 patients, 10,342 (90.4%) were discharged on postoperative days 0-2; 80.6% (887/1101) of patients with PLOS did not experience any perioperative complications. The most common complication was bleeding requiring transfusion, but this was present in only 5.6% (62/1101) of patients with PLOS. Logistic regression identified predictors of PLOS as age, race, wound class, American Society of Anesthesiologists class, smoking, diabetes, dyspnea, dependent functional health status, congestive heart failure, operative time, and pelvic lymph node dissection. Results of this regression were insensitive to the exclusion of patients who experienced no perioperative complications., Conclusions: This study utilizes logistic regression on NSQIP data to identify risk factors for PLOS after RARP and, in particular, to evaluate the role of postoperative complications in PLOS. The analysis shows that postoperative complications account for a small minority of cases of PLOS after RARP.