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Po-Ting Lin1 *, Ming-Li Hsieh1,2 *, Shih-Huan Su,1 Ying-Hsu Chang,2,3 Liang-Kang Huang,1,2 Yuan-Cheng Chu,1,2 Hung-Cheng Kan,1,2 Po-Hung Lin,1,2 Kai-Jie Yu,1,2 Cheng-Keng Chuang,1,2 Chun-Te Wu,1,2,4 See-Tong Pang,1,2 I-Hung Shao1,2,5 1Division of Urology, Department of Surgery, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan, Taiwan; 2Department of Medicine, Chang Gung University, Taoyuan, Taiwan; 3Department of Urology, New Taipei Municipal TuCheng Hospital, Chang Gung Memorial Hospital and Chang Gung University, New Taipei, Taiwan; 4Division of Urology, Department of Surgery, Chang Gung Memorial Hospital, Keelung Branch, Keelung, Taiwan; 5Cancer Genome Research Center, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan, Taiwan*These authors contributed equally to this workCorrespondence: I-Hung Shao, Department of Medicine, Chang Gung University, No. 5, Fusing St., Gueishan Dist, Taoyuan City, Taiwan, Email ehomeshao68@gmail.comObjective: Among intravesical instillation protocol in patients with non-muscle-invasive bladder cancer (NMIBC), chemotherapy agents have been widely used during the bacillus Calmette-Guérin (BCG) shortage era since the patient might under the risk of BCG discontinuation. This study evaluates the efficacy of incomplete BCG instillation compared with pure chemotherapy instillation protocol.Materials and Methods: Patients newly diagnosed with intermediate- and high-risk NMIBC who received incomplete BCG intravesical instillation or chemotherapy instillation were retrospectively included. Patients were divided into three groups according to different intravesical instillation schedules: [BCG only], [BCG + Chemo], and [Chemo only]. Comparisons between these three groups were performed. Bladder recurrence-free survival (RFS) was analyzed as the primary endpoint.Results: A total of 475 patients who received intravesical instillations were enrolled. Compared to the [Chemo only] group, the [BCG + Chemo] group had significantly better bladder RFS (p = 0.027). Multivariate analysis of recurrence revealed the [BCG + Chemo] regimen has a hazard ratio 0.381 (95% CI 0.154– 0.941, p = 0.037). The total instillation number > 12 was associated with better RFS (p = 0.001) compared with other instillation numbers.Conclusion: For NMIBC patients facing the risk of unexpected BCG instillation interruption, instead of starting instillation with chemotherapy agents, receiving BCG first till stoppage then shifting to chemotherapy agents is recommended.Keywords: bladder cancer, NMIBC, intravesical instillation, intravesical chemotherapy, BCG, bladder recurrence

Tzu-Chi Teng,1,2 I-Hung Shao,1,2 Yu-Chao Hsu,1,2 Yu Chen,1,2 Shu-Han Tsao,1,2 Yen-Te Kang,1,2 Ming-Li Hsieh1,2 1Division of Urology, Department of Surgery, Linkou Chang Gung Memorial Hospital, Taoyuan City, 33302, Taiwan; 2College of Medicine, Chang Gung University, Taoyuan City, 33302, TaiwanCorrespondence: Ming-Li Hsieh; I-Hung ShaoDivision of Urology, Department of Surgery, Linkou Chang Gung Memorial Hospital, No. 5, Fuxing Street, Guishan District, Taoyuan City, 333423, TaiwanTel +886 975 365 568; +886 975 361311Fax +886-3-3274541Email h0810@cgmh.org.tw; b8902068@cgmh.org.twPurpose: Transurethral procedures, including transurethral resection of the prostate (TURP) and laser prostatectomy, are often linked to emergency room (ER) visits for postoperative bleeding. Although some studies have been conducted, the risk factors associated with these ER visits are not completely understood. This retrospective cohort study identified potential risk factors associated with ER visits for postoperative bleeding.Patients and Methods: Preoperative assessment data and operational and postoperational parameters recorded at Chang Gung Memorial Hospital, Taiwan between December 2015 and January 2017 for patients who underwent elective transurethral procedures were analyzed to identify potential risk factors. The primary endpoint was ER visits for gross hematuria within three months following operation, and the secondary endpoint was ER visits for blood clot-induced urinary retention (clot retention) within three months following operation.Results: A total of 665 patients who underwent elective transurethral procedures were enrolled. The transurethral procedures included monopolar transurethral resection of the prostate (M-TURP), bipolar TURP (B-TURP), greenlight photoselective vaporization of the prostate (PVP), thulium laser enucleation of the prostate (ThuLEP) and thulium laser transurethral vaporesection of the prostate (ThuVARP). Regarding ER visits for clot retention within three months, multivariable logistic regression revealed significantly lower rates of clot retention in patients who received B-TURP than in those who underwent ThuVARP (AOR, 0.18; 95% confidence interval [CI], 0.04– 0.82, p = 0.027). Moreover, significantly higher clot retention was observed in patients who underwent two or more rounds of manual irrigation (AOR, 9.51; 95% CI, 1.66– 54.43, p = 0.011).Conclusion: Multiple manual irrigations shortly after operation can be considered a novel predictor of postoperative clot retention-related ER visits. Among the transurethral procedures, ThuVARP was associated with a higher risk of clot retention-related ER visits than was B-TURP.Keywords: transurethral resection of prostate, laser prostatectomy, hematuria, clot retention

The signaling molecule cyclic di-GMP (cdG) controls the switch between bacterial motility and biofilm production, and fluctuations in cellular levels of cdG have been implicated in Vibrio cholerae pathogenesis. Intracellular concentrations of cdG are controlled by the interplay of diguanylate cyclase (DGC) enzymes, which synthesize cdG to promote biofilms, and phosphodiesterase (PDE) enzymes, which hydrolyse cdG to drive motility. To track the complete regulatory logic of how V. cholerae responds to changing cdG levels, we followed a timecourse of overexpression of either the V. harveyi diguanylate cyclase QrgB or a variant of QrgB lacking catalytic activity (QrgB*). We find that QrgB increases cdG levels relative to QrgB* for 30 minutes after overexpression, but the effect of QrgB on cdG levels plateaus at 30 minutes, indicating tight adaptive control of cdG levels. In contrast, loss of VpsR, a master regulator activating biofilm formation upon binding to cdG, leads to higher baseline levels of cdG and continuously increasing cdG through 60 minutes after QrgB induction, revealing the existence of a negative feedback loop on cdG levels operating through VpsR. Through a combination of RNA polymerase ChIP-seq, RNA-seq, and genetic approaches, we show that transcription of a gene encoding a PDE, cdgC , is activated by VpsR at high cdG concentrations, mediating this negative feedback on cdG levels. We further identify a transcript encoded within, and antisense to, the cdgC open reading frame which we name sRNA negative regulator of CdgC (SnrC). RNA polymerase ChIP-seq and RNA-seq demonstrate SnrC to be expressed specifically under conditions of high cdG in the absence of VpsR. Ectopic SnrC expression increases cdG levels in a manner dependent on CdgC, demonstrating that its effect on cdG levels is likely through interference with CdgC production. Further, although cells lacking cdgC exhibit enhanced biofilm formation, these mutants are outcompeted by wild type V. cholerae in colonization assays that reward a combination of attachment, dispersal, and motility behaviors. These results underscore the importance of negative feedback regulation of cdG to maintain appropriate homeostatic levels for efficient transitioning between biofilm formation and motility, both of which are necessary over the course of the V. cholerae infection cycle.

Prostate cancer (PCa) is the second most prevalent malignancy in men worldwide. The risk factors for PCa include obesity, age and family history. Increased visceral fat has been associated with high PCa risk, which has prompted previous researchers to investigate the influence of body composition and fat distribution on PCa prognosis. However, there is a lack of studies focusing on the mechanisms and interactions between periprostatic adipose tissue (PPAT) and PCa cells. The present study investigated the association between the composition of pelvic adipose tissue and PCa aggressiveness to understand the role played by this tissue in PCa progression. Moreover, PPAT-conditioned medium (CM) was prepared to assess the influence of the PPAT secretome on the pathophysiology of PCa. The present study included 50 patients with localized PCa who received robot-assisted radical prostatectomy. Medical records were collected, magnetic resonance imaging scans were analyzed and body compositions were calculated to identify the associations between adipose tissue volume and clinical PCa aggressiveness. In addition, CM was prepared from PPAT and perivesical adipose tissue (PVAT) collected from 25 patients during surgery, and its effects on the PCa cell lines C4-2 and LNCaP, and the prostate epithelial cell line PZ-HPV-7, were investigated using a cell proliferation assay and RNA sequencing (RNA-seq). The results revealed that the initial prostate-specific antigen level was significantly correlated with pelvic and periprostatic adipose tissue volumes. In addition, PPAT volume was significantly higher in patients with extracapsular tumor extension. PCa cell proliferation was significantly reduced when the cells were cultured in PPAT-CM compared with when they were cultured in control- and PVAT-CM. RNA-seq revealed that immune responses, and the cell death and apoptosis pathways were enriched in PPAT-CM-cultured cells indicating that the cytokines or other factors secreted from PPAT-CM induced PCa cell apoptosis. These findings revealed that the PPAT secretome may inhibit PCa cell proliferation by activating immune responses and promoting cancer cell apoptosis. This mechanism may act as a first-line defense during the early stages of PCa., Competing Interests: The authors declare that they have no competing interests., (Copyright: © 2024 Shao et al.)

Multisystem inflammatory syndrome in children (MIS-C) is an imperative pediatric inflammatory condition closely linked to COVID-19, which garners substantial attention since the onset of the pandemic. Like Kawasaki illness, this condition is characterized by an overactive immune response, leading to symptoms including pyrexia, cardiac and renal complications. To elucidate the pathogenesis of MIS-C and identify potential biomarkers, we conducted an extensive examination of specific cytokines (IL-6, IL-1β, IL-6R, IL-10, and TNF-α) and microRNA (miRNA) expression profiles at various intervals (ranging from 3 to 20 days) in the peripheral blood sample of a severely affected MIS-C patient. Our investigation revealed a gradual decline in circulating levels of IL-6, IL-1β, IL-10, and TNF-α following intravenous immune globulin (IVIG) therapy. Notably, IL-6 exhibited a significant reduction from 74.30 to 1.49 pg./mL, while IL-6R levels remained consistently stable throughout the disease course. Furthermore, we observed an inverse correlation between the expression of hsa-miR-596 and hsa-miR-224-5p and the aforementioned cytokines. Our findings underscore a robust association between blood cytokine and miRNA concentrations and the severity of MIS-C. These insights enhance our understanding of the genetic regulatory mechanisms implicated in MIS-C pathogenesis, offering potential avenues for early biomarker detection and therapy monitoring through miRNA analysis., Competing Interests: J-JH and M-HC were employed by the Inti Taiwan, Inc. The remaining 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 © 2024 Tsai, Hong, Cheng, Cheng, Chen, Hsieh, Hsieh and Shen.)

Radiation therapy is a clinically proven, localized preventive measure for heterotopic ossification (HO). Despite its efficacy, there is a lack of standardization of radiation prescription dosing and fractionation, and the mechanism of the impact of radiation in HO prevention remains unknown. Here, using an established mouse model of traumatic HO induced by burn and tenotomy, we demonstrate that 7Gy in one fraction delivered to the injury site within 72 hours postoperatively significantly decreases HO formation and improves hindlimb range of motion. In-depth single-cell transcriptomic analyses, in combination with immunofluorescent staining, demonstrate decreased cellular numbers as well as aberrant endochondral differentiation and downregulation of associated upstream signaling pathways in irradiated mesenchymal progenitor cells. Our study provides the framework for future mechanistic and clinically relevant studies exploring radiation efficacy in preventing HO formation., Competing Interests: Conflict of Interest Declaration: The authors declare that they have no affiliations with or involvement in any organization or entity with any financial interest in the subject matter or materials discussed in this manuscript., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Clubfoot, or congenital talipes equinovarus deformity, is a common anomaly affecting the foot in infants. However, clinical equipoise remains between different interventions, especially those based on the Ponseti method. The aim of this study was to examine the clinical outcomes of the various interventions for treating idiopathic clubfoot., Methods: Searches of the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, Scopus, and CINAHL were conducted. Randomized controlled trials comparing different interventions, including the Ponseti method, accelerated Ponseti method, Ponseti method with botulinum toxin type A (Botox) injection, Ponseti method with early tibialis anterior tendon transfer (TATT), Kite method, and surgical treatment, were included. Network meta-analyses (NMAs) were conducted according to the PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) reporting guidelines. The primary outcomes were the change in total Pirani score and maximal ankle dorsiflexion. Secondary outcomes were the number of casts, time in casts, and rates of tenotomy, total complications, relapse, adverse events, and additional required major surgery., Results: Eleven randomized controlled trials involving 740 feet were included. According to the SUCRA (surface under the cumulative ranking curve)-based relative ranking, the Ponseti method was associated with the best outcomes in terms of Pirani score changes, maximal ankle dorsiflexion, number of casts, adverse events, and total complications, whereas the accelerated Ponseti method was associated with the best outcomes in terms of time in casts and tenotomy rate. Early TATT ranked best in terms of relapse rate. The Ponseti method with Botox injection was associated with the best outcomes in terms of the need for additional major surgery., Conclusions: The NMAs suggest that the Ponseti method is the optimal treatment overall, despite potential drawbacks such as longer time in casts and higher rates of tenotomy, relapse, and the need for additional surgery compared with other modified approaches. Therefore, clinicians should consider how treatments can be tailored individually., Level of Evidence: Therapeutic Level I . See Instructions for Authors for a complete description of levels of evidence., Competing Interests: Disclosure: The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article ( http://links.lww.com/JBJS/H784 )., (Copyright © 2023 by The Journal of Bone and Joint Surgery, Incorporated.)

The gut microbiome and its metabolites are increasingly implicated in several cardiovascular diseases, but their role in human myocardial infarction (MI) injury responses have yet to be established. To address this, we examined stool samples from 77 ST-elevation MI (STEMI) patients using 16 S V3-V4 next-generation sequencing, metagenomics and machine learning. Our analysis identified an enriched population of butyrate-producing bacteria. These findings were then validated using a controlled ischemia/reperfusion model using eight nonhuman primates. To elucidate mechanisms, we inoculated gnotobiotic mice with these bacteria and found that they can produce beta-hydroxybutyrate, supporting cardiac function post-MI. This was further confirmed using HMGCS2-deficient mice which lack endogenous ketogenesis and have poor outcomes after MI. Inoculation increased plasma ketone levels and provided significant improvements in cardiac function post-MI. Together, this demonstrates a previously unknown role of gut butyrate-producers in the post-MI response., (© 2023. The Author(s).)

Background: Remuscularization of the mammalian heart can be achieved after cell transplantation of human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (CMs). However, several hurdles remain before implementation into clinical practice. Poor survival of the implanted cells is related to insufficient vascularization, and the potential for fatal arrhythmogenesis is associated with the fetal cell-like nature of immature CMs., Methods: We generated 3 lines of hiPSC-derived endothelial cells (ECs) and hiPSC-CMs from 3 independent donors and tested hiPSC-CM sarcomeric length, gap junction protein, and calcium-handling ability in coculture with ECs. Next, we examined the therapeutic effect of the cotransplantation of hiPSC-ECs and hiPSC-CMs in nonobese diabetic-severe combined immunodeficiency (NOD-SCID) mice undergoing myocardial infarction (n≥4). Cardiac function was assessed by echocardiography, whereas arrhythmic events were recorded using 3-lead ECGs. We further used healthy non-human primates (n=4) with cell injection to study the cell engraftment, maturation, and integration of transplanted hiPSC-CMs, alone or along with hiPSC-ECs, by histological analysis. Last, we tested the cell therapy in ischemic reperfusion injury in non-human primates (n=4, 3, and 4 for EC+CM, CM, and control, respectively). Cardiac function was evaluated by echocardiography and cardiac MRI, whereas arrhythmic events were monitored by telemetric ECG recorders. Cell engraftment, angiogenesis, and host-graft integration of human grafts were also investigated., Results: We demonstrated that human iPSC-ECs promote the maturity and function of hiPSC-CMs in vitro and in vivo. When cocultured with ECs, CMs showed more mature phenotypes in cellular structure and function. In the mouse model, cotransplantation augmented the EC-accompanied vascularization in the grafts, promoted the maturity of CMs at the infarct area, and improved cardiac function after myocardial infarction. Furthermore, in non-human primates, transplantation of ECs and CMs significantly enhanced graft size and vasculature and improved cardiac function after ischemic reperfusion., Conclusions: These results demonstrate the synergistic effect of combining iPSC-derived ECs and CMs for therapy in the postmyocardial infarction heart, enabling a promising strategy toward clinical translation., Competing Interests: Disclosures None.

Background: The superior effects of gastric bypass surgery in preventing cardiovascular diseases compared with sleeve gastrectomy are well-established. However, whether these effects are independent of weight loss is not known., Methods: In this retrospective cohort study, we compared the change in cardiometabolic risks of 1073 diabetic patients undergoing Roux-en-Y gastric bypass (RYGB) (n = 265), one-anastomosis gastric bypass (OAGB) (n = 619), and sleeve gastrectomy (SG) (n = 189) with equivalent weight loss from the Min-Shen General Hospital. Propensity score-weighting, multivariate regression, and matching were performed to adjust for baseline differences., Results: After 12 months, OAGB and, to a lesser extent, RYGB exhibited superior effects on glycemic control compared with SG in patients with equivalent weight loss. The effect was significant in patients with mild-to-modest BMI reduction but diminished in patients with severe BMI reduction. RYGB and OAGB had significantly greater effects in lowering total and low-density lipoprotein cholesterol than SG, regardless of weight loss. The results of matching patients with equivalent weight loss yielded similar results. The longer length of bypassed biliopancreatic (BP) limbs was correlated with a greater decrease in glycemic levels, insulin resistance index, lipids, C-reactive protein (CRP) levels, and creatinine levels in patients receiving RYBG. It was correlated with greater decreases in BMI, fasting insulin, insulin resistance index, and C-reactive protein levels in patients receiving OAGB., Conclusion: Diabetic patients receiving OAGB and RYGB had lower glucose and cholesterol levels compared with SG independent of weight loss. Our results suggest diabetic patients with cardiovascular risk factors such as hypercholesterolemia to receive bypass surgery., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Obesity and type 2 diabetes have reached pandemic proportion. ALDH2 (acetaldehyde dehydrogenase 2, mitochondrial) is the key metabolizing enzyme of acetaldehyde and other toxic aldehydes, such as 4-hydroxynonenal. A missense Glu504Lys mutation of the ALDH2 gene is prevalent in 560 million East Asians, resulting in reduced ALDH2 enzymatic activity. We find that male Aldh2 knock-in mice mimicking human Glu504Lys mutation were prone to develop diet-induced obesity, glucose intolerance, insulin resistance, and fatty liver due to reduced adaptive thermogenesis and energy expenditure. We find reduced activity of ALDH2 of the brown adipose tissue from the male Aldh2 homozygous knock-in mice. Proteomic analyses of the brown adipose tissue from the male Aldh2 knock-in mice identifies increased 4-hydroxynonenal-adducted proteins involved in mitochondrial fatty acid oxidation and electron transport chain, leading to markedly decreased fatty acid oxidation rate and mitochondrial respiration of brown adipose tissue, which is essential for adaptive thermogenesis and energy expenditure. AD-9308 is a water-soluble, potent, and highly selective ALDH2 activator. AD-9308 treatment ameliorates diet-induced obesity and fatty liver, and improves glucose homeostasis in both male Aldh2 wild-type and knock-in mice. Our data highlight the therapeutic potential of reducing toxic aldehyde levels by activating ALDH2 for metabolic diseases., (© 2023. Springer Nature Limited.)

15-keto-PGE 2 is one of the eicosanoids with anti-inflammatory properties. In this study, we demonstrated that 15-keto-PGE 2 post-translationally modified the nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) subunits p105/p50 and p65 at Cys59 and Cys120 sites, respectively, hence inhibiting the activation of NF-κB signaling in macrophages. In mice fed a high-fat and high-sucrose diet (HFHSD), 15-keto-PGE 2 treatment reduced pro-inflammatory cytokines and fasting glucose levels. In mice with non-alcoholic steatohepatitis (NASH) induced by a prolonged HFHSD, 15-keto-PGE 2 treatment significantly decreased liver inflammation, lowered serum levels of alanine transaminase (ALT) and aspartate transferase (AST), and inhibited macrophage infiltration. It also reduced lipid droplet size and downregulated key regulators of lipogenesis. These findings highlight the potential of 15-keto-PGE 2 , through NF-κB modification, in preventing the development and progression of steatohepatitis, emphasizing the significance of endogenous lipid mediators in the inflammatory response., Competing Interests: All authors declared no competing financial interests., (© 2023 The Author(s).)

Introduction: Body status, categorized as sarcopenia or obesity and assessed using body mass index and body composition, affects the outcome of bladder cancer patients. However, studies comparing disease progression, recurrence, or overall survival in patients with non-muscle-invasive bladder cancer (NMIBC) with different body compositions are lacking. Therefore, we conducted a retrospective study to identify the impact of body composition, sarcopenia, and obesity on the oncological prognosis of patients with NMIBC who underwent transurethral resection of bladder tumor (TURBT) with Bacillus Calmette-Guerin (BCG) intravesical instillation (IVI)., Methods: Patients with NMIBC who had undergone TURBT with adjuvant IVI with BCG from March 2005 to April 2021 were included. Body composition parameters were evaluated using computed tomography images of the third lumbar vertebrae and further categorized by sarcopenia and obesity. Oncological outcomes including recurrence-free survival (RFS), progression-free survival, and overall survival (OS) after treatment were analyzed., Results: A total of 269 patients were enrolled. Subcutaneous adipose tissue (SAT) density was a significant predictor of RFS, whereas psoas muscle density was a significant predictor of OS in the multivariate analysis. Patients with sarcopenia but without obesity tolerated significantly fewer BCG IVIs than patients without sarcopenia or obesity. Patients with sarcopenia had poorer RFS and OS than those without sarcopenia. In contrast, patients with obesity had better OS than those without obesity., Discussion: Body composition parameters, including SAT density and psoas muscle density, emerged as significant predictors of OS and RFS, respectively. Hence, our findings indicate that body composition is a helpful measurement to assess the oncological outcomes of patients with NMIBC., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Huang, Lin, Chuang, Chuang, Pang, Wu, Chang, Yu, Lin, Kan, Chu, Hung, Hsieh and Shao.)

Background: Uremic pruritus, one of the most painful symptoms experienced by patients receiving dialysis, seriously affects patient quality of life and health, causes physical and mental damage, and increases hospitalization and mortality rates. Multi-modal therapies with evidence-based healthcare are needed to provide patients receiving dialysis with more convenient and feasible medical resources., Purpose: Relevant domestic and international research on the effectiveness and methods of non-invasive acupoint therapy in improving uremic pruritus in dialysis patients was reviewed. Discussing related knowledge can facilitate the evidence-based use of non-invasive acupoint therapy in clinical practice by clinical medical personnel., Methods: Based on the PRISMA (preferred reporting items for systematic reviews and meta-analyses) systematic literature review and integrated analysis method, a keyword search of related articles published before September 2023 was conducted in the following databases: PubMed, Cochrane Library, Embase, Web of Science, Airiti Library, Taiwan Master and Doctoral Dissertation System, Chinese Journal Full-text Database and Wanfang Data Knowledge Service Platform. In 2019, the second version of the Risk of Bias Tool for Randomized Controlled Trials was used to evaluate research quality, after which RevMan 5.4 and Stata 14.0 suite software were used for meta-analysis., Results: Nine of the 112 articles selected, including 10 sets of data and 597 participants, were included in the meta-analysis. The results indicate non-invasive acupoint therapy significantly reduces the degree of uremic pruritus (synthetic effect size = -1.30, 95% confidence interval [-1.67, -0.93], p < .00001). Because the heterogeneity test I² = 76%, showed a high degree of heterogeneity, a subgroup analysis was performed, showing that acupoint massage combined with traditional Chinese medicine fumigation and washing, a general simple itching assessment scale, and the Chinese region achieved better effect sizes., Conclusions / Implications for Practice: Non-invasive acupoint therapy is easy to implement, inexpensive, non-invasive, and associated with few side effects. The authors hope these findings may increase the awareness and understanding of patients with dialysis regarding the practical operation techniques of itching acupoints. According to the results of this systematic review and meta-analysis, massage of the lung and endocrine acupoints at ST-6, SP-10, and LI-11 as well as the relevant points on the ear may be most effective in achieving urinary itching relief. Also, acupoint massage combined with traditional Chinese medicine fumigation, ST-6 far-infrared irradiation, or LI11 transcutaneous acupoint electrical stimulation can further relieve uremic pruritus in this patient population. Based on the results, acupoint massage combined with traditional Chinese medicine fumigation and washing is a complementary method of treatment for uremic pruritus that may be recommended to patients in the future.

Objective: To compare the efficacy and safety of the sandwich method with GreenLight photoselective vaporization (GLPVP) and bipolar transurethral resection (B-TURP) with those of the enucleation method in patients with BPH and a prostate volume ≥ 80 g., Methods: Patients with BPH who underwent either the sandwich method with GLPVP and B-TURP or the enucleation method between 2014 and 2021 were included in the analysis. The primary outcome was the comparison of uroflowmetry results between the 2 groups. Safety analysis of the complication rates was also compared., Results: The cohort included 55 patients in the sandwich group and 41 patients in the enucleation group. In the efficacy analysis, both groups showed comparable uroflowmetry results, except for a higher postoperative average flow rate in the enucleation group. Regarding perioperative parameters, the sandwich method required a longer operating time, and the enucleation group had a higher incidence of manual Foley irrigation. Both groups demonstrated similar postoperative complications., Conclusion: The sandwich method exhibited comparable efficacy and safety to the enucleation method in patients with BPH with a prostate volume ≥ 80 g. Thus, for surgeons who are familiar with GLPVP and B-TURP, the sandwich method may be an alternative surgical approach for BPH patients with large prostates., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Preoperative renal dysfunction is associated with mortality in patients with acute type A aortic dissection (ATAAD) repair. However, the long-term outcome of chronic kidney dysfunction (CKD) in ATAAD is unclear. The study aimed to evaluate the long-term outcome of CKD in patients with ATAAD repair. We retrospectively studied patients with ATAAD repair using data from the Taiwan's National Health Insurance Research Database between July 1, 2004, and December 31, 2013. The outcomes of interest included all-cause mortality, readmission due to any cause, redo aortic surgery, major adverse cardiac and cerebrovascular events, and liver and renal outcomes. There were 3328 patients who received ATAAD repair. These patients were divided into CKD and non-CKD groups. In-hospital mortality in the CKD group was significantly higher than that in the non-CKD group (32.5% vs 18.8%, respectively, odds ratio 2.14, 95% confidence interval [CI] 1.37-3.36). During long-term follow-up, patients with CKD had higher risks of all-cause mortality including in-hospital death (52.6% vs 32.5%; hazard ratio 1.83, 95% CI 1.32-2.55), mortality after discharge (29.7% vs 16.8%; hazard ratio 2.09, 95% CI 1.02-4.29), and readmission rates (67.1% vs 51.6%; subdistribution hazard ratio 2.00, 95% CI 1.43-2.79). However, no significant difference was observed between the dialysis and non-dialysis groups. On the basis of our results, patients with CKD carry a poor long-term outcome after ATAAD repair. Cardiac surgeons should be aware of this condition when dealing with ATAAD repair., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: Patent ductus arteriosus (PDA) is a common complication among premature infants, which may be responsible for prematurity-related complications such as bronchopulmonary dysplasia (BPD). It is unclear whether different interventional methods contribute to the severity of BPD, given the original National Institute of Child Health and Human Development (NICHD) 2001 definition. To date, surgical ligation and the transcatheter approach have been equally successful in premature infants with hemodynamically significant PDA after medical treatment failure. Immediate improvement in the respiratory condition has been reported after transcatheter closure. However, the short-term pulmonary outcome has not been clarified yet., Methods: This retrospective study investigated infants born with a body weight <1000 g and who underwent either surgical ligation or transcatheter closure of PDA in a single tertiary institution. The infants were divided into groups according to the type of procedure (surgical ligation or transcatheter occlusion). The primary outcome was the severity of BPD at discharge or at a postmenstrual age of 36 weeks. The outcome was analyzed with logistic regression., Results: Forty-four patients met the inclusion criteria, of whom 14 underwent transcatheter occlusion and 30 underwent surgical ligation. The overall birth body weights and gestational age ranges were not different. The univariate model revealed an association between the procedure type and BPD severity. After adjusting for confounders, the multivariate model confirmed associations between BPD severity and procedure type and severe respiratory distress syndrome requiring surfactant., Conclusion: Compared with the transcatheter approach, surgery for PDA in extremely preterm infants is associated with severe BPD at discharge. Further large-scale studies are needed to determine the exact mechanism., (© 2023 Wiley Periodicals LLC.)

Background: To evaluate the efficacy of intravesical chemotherapy replacement in patients with intermediate- and high-risk non-muscle-invasive bladder cancer (NMIBC), who underwent bacillus Calmette-Guérin (BCG) instillation but discontinued due to global shortages or toxicity of BCG., Methods: This retrospective study included patients with intermediate- and high-risk NMIBC who received BCG intravesical instillation. Those who discontinued the treatment were divided into the pure BCG group and chemotherapy replacement group. Comparisons between these groups were performed. The primary endpoint was bladder recurrence-free survival (RFS)., Results: A total of 480 patients were included. Baseline characteristics were similar between groups, but the total instillation times were higher in the chemotherapy replacement group than in the pure BCG group (n = 14.9 vs. 10.5). The chemotherapy replacement group had a better three-year RFS ( p = 0.022). On multivariate analysis, the pure BCG group had significantly increased all-time and 3-year recurrences (hazard ratio 2.015 and 2.148) compared to the chemotherapy replacement group., Conclusions: Chemotherapy replacement has a better three-year RFS than no instillation in patients with intermediate- and high-risk NMIBC who received BCG instillation but facing treatment stoppage.

Background: Genome-wide association studies (GWASs) have linked RRBP1 (ribosomal-binding protein 1) genetic variants to atherosclerotic cardiovascular diseases and serum lipoprotein levels. However, how RRBP1 regulates blood pressure is unknown., Methods: To identify genetic variants associated with blood pressure, we performed a genome-wide linkage analysis with regional fine mapping in the Stanford Asia-Pacific Program for Hypertension and Insulin Resistance (SAPPHIRe) cohort. We further investigated the role of the RRBP1 gene using a transgenic mouse model and a human cell model., Results: In the SAPPHIRe cohort, we discovered that genetic variants of the RRBP1 gene were associated with blood pressure variation, which was confirmed by other GWASs for blood pressure. Rrbp1- knockout (KO) mice had lower blood pressure and were more likely to die suddenly from severe hyperkalemia caused by phenotypically hyporeninemic hypoaldosteronism than wild-type controls. The survival of Rrbp1-KO mice significantly decreased under high potassium intake due to lethal hyperkalemia-induced arrhythmia and persistent hypoaldosteronism, which could be rescued by fludrocortisone. An immunohistochemical study revealed renin accumulation in the juxtaglomerular cells of Rrbp1-KO mice. In the RRBP1-knockdown Calu-6 cells, a human renin-producing cell line, transmission electron and confocal microscopy revealed that renin was primarily retained in the endoplasmic reticulum and was unable to efficiently target the Golgi apparatus for secretion., Conclusions: RRBP1 deficiency in mice caused hyporeninemic hypoaldosteronism, resulting in lower blood pressure, severe hyperkalemia, and sudden cardiac death. In juxtaglomerular cells, deficiency of RRBP1 reduced renin intracellular trafficking from ER to Golgi apparatus. RRBP1 is a brand-new regulator of blood pressure and potassium homeostasis discovered in this study., (© 2023. The Author(s).)

Transcutaneous electrical nerve stimulator (TENS) has been demonstrated to be beneficial in glycemic control in animal models, but its application in humans has not been well studied. We randomly assigned 160 patients with type 2 diabetes on oral antidiabetic drugs 1:1 to the TENS study device (n = 81) and placebo (n = 79). 147 (92%) randomized participants (mean [SD] age 59 [10] years, 92 men [58%], mean [SD] baseline HbA 1c level 8.1% [0.6%]) completed the trial. At week 20, HbA 1c decreased from 8.1% to 7.9% in the TENS group (- 0.2% [95% CI - 0.4% to - 0.1%]) and from 8.1% to 7.8% in the placebo group (- 0.3% [95% CI - 0.5% to - 0.2%]) (P = 0.821). Glycemic variability, measured as mean amplitude of glycemic excursion (MAGE) at week 20 were significantly different in the TENS group vs. the placebo group (66 mg/dL [95% CI 58, 73] vs. 79 mg/dL [95% CI 72, 87]) (P = 0.009). Our study provides the clinical evidence for the first time in humans that TENS does not demonstrate a statistically significant HbA 1c reduction. However, it is a safe complementary therapy to improve MAGE in patients with type 2 diabetes., (© 2023. The Author(s).)

Introduction: Chronic kidney disease, which is defined by a reduced estimated glomerular filtration rate and albuminuria, imposes a large health burden worldwide. Ethnicity-specific associations are frequently observed in genome-wide association studies (GWAS). This study conducts a GWAS of albuminuria in the nondiabetic population of Taiwan., Methods: Nondiabetic individuals aged 30-70 years without a history of cancer were enrolled from the Taiwan Biobank. A total of 6,768 subjects were subjected to a spot urine examination. After quality control using PLINK and imputation using SHAPEIT and IMPUTE2, a total of 3,638,350 single-nucleotide polymorphisms (SNPs) remained for testing. SNPs with a minor allele frequency of less than 0.1% were excluded. Linear regression was used to determine the relationship between SNPs and log urine albumin-to-creatinine ratio., Results: Six suggestive loci are identified in or near the FCRL3 (p = 2.56 × 10-6), TMEM161 (p = 4.43 × 10-6), EFCAB1 (p = 2.03 × 10-6), ELMOD1 (p = 2.97 × 10-6), RYR3 (p = 1.34 × 10-6), and PIEZO2 (p = 2.19 × 10-7). Genetic variants in the FCRL3 gene that encode a secretory IgA receptor are found to be associated with IgA nephropathy, which can manifest as proteinuria. The PIEZO2 gene encodes a sensor for mechanical forces in mesangial cells and renin-producing cells. Five SNPs with a p-value between 5 × 10-6 and 5 × 10-5 are also identified in five genes that may have a biological role in the development of albuminuria., Conclusion: Five new loci and one known suggestive locus for albuminuria are identified in the nondiabetic Taiwanese population., (© 2023 S. Karger AG, Basel.)

With the quickly growing population of patients receiving dialysis treatment in Taiwan in recent years, concerns about whether more incidence of inguinal hernia exists in dialysis patients are increasing. In Taiwan, peritoneal dialysis (PD) and hemodialysis (HD) are the 2 most common dialysis types. Therefore, the relationship between dialysis type and inguinal hernia occurrence needs to be evaluated and compared. Our retrospective cohort study included a study population total of 3891 patients diagnosed with end stage renal disease (ESRD) under the HD or PD procedure from 2001 to 2009 from the Longitudinal Health Insurance Database. Also, International Statistical Classification of Diseases and Related Health Problems 9th Revision codes were used to identify ESRD and hernia occurrence. Cox proportional-hazards regression model was applied to measure the risk factors to the hernia occurrence. During the follow-up periods of 3 years, the number of hernia occurrences was 44 (1.13%), 1 (0.03%), and 8 (0.21%) with inguinal, femoral, and ventral hernias, respectively. Only the dialysis type revealed significantly increased hernia risk because PD would increase hernia risk 7 times (adjusted hazard ratio [aHR] = 6.98, 95% CI = 3.59-13.25) than HD. If the patients received PD and shifted to HD later, the risk of hernia was 5 times (aHR = 4.98, 95% CI = 2.29-10.85) than patients with HD. Patients with ESRD receiving PD or PD-HD shift were risk factors of inguinal hernia occurrence. The results may help clinicians increase the alert of possible risk factors and complications at the beginning of dialysis treatment in patients with ESRD., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Targeted temperature management (TTM) is a complex and sophisticated intensive-care procedure that is included in the American Heart Association guidelines for treating patients who remain unconscious after resuscitation from cardiac arrest. TTM has been demonstrated to reduce brain injury associated with reperfusion after resuscitation and to improve the neurological prognosis in patients with cardiac arrest. The TTM process may be divided into four phases: induction, maintenance, rewarming, and normothermia. The critical element in TTM is the quick lowering and slow raising of body temperature, which should be fine-tuned to maintain temperature stability and minimize variation. Caregivers should monitor the physiological changes caused by core body temperature change closely and manage possible complications such as shivering, hypo- and hyper-glycemia, electrolyte imbalance, skin injury, arrhythmia, and infection. Based on contemporary evidence and clinical experience, this article provides critical care nurses a summary and key points of each stage of TTM when used to take care of resuscitated patients after cardiac arrest. We hope this work may help improve patient safety and quality of care during the TTM procedure.

This study evaluated the effect of body composition and pelvic fat distribution on the aggressiveness and prognosis of localized prostate cancer. This study included patients who underwent robot-assisted radical prostatectomy with positive surgical margins. Clinicodemographic data were collected from patients' medical reports. Pretreatment magnetic resonance images (MRI) obtained for cancer staging were reviewed by a single radiologist to calculate pelvic fat distribution and body composition. We correlated these body composition parameters with initial prostate-specific antigen (iPSA), Gleason score, extracapsular tumor extension, and biochemical recurrence (BCR)-free survival. The iPSA was significantly associated with body mass index (BMI; P = .027), pelvic fat volume (P = .004), and perirectal fat volume (P = .001), whereas the Gleason score was significantly associated with BMI only (P = .011). Tumor extracapsular extension was significantly associated with increased periprostatic fat volume (P = .047). Patients with less subcutaneous fat thickness (<2.4 cm) had significantly poor BCR-free survival (P = .039). Pelvic fat distribution, including pelvic fat volume, perirectal fat volume, and periprostatic fat volume, were significantly correlated with prostate cancer aggressiveness. Patients with less subcutaneous fat had an increased risk of BCR after radical prostatectomy., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Primary squamous cell carcinoma of the thyroid is a very rare malignancy with aggressive growth and poor prognosis. There is currently no consensus for treatment modality, however, most patients with primary squamous cell carcinoma of the thyroid are treated with surgery and adjuvant chemoradiation., Case Presentation: We report a rare case of primary squamous cell carcinoma of the thyroid in a 68-year-old White male who underwent chemoradiation and palliative immunotherapy after declining surgery. He was treated with intensity-modulated radiation therapy to 70 Gy in 35 fractions, with concurrent carboplatin-paclitaxel and palliative pembrolizumab. Local thyroid disease recurrence occurred at 6 months post-chemoradiation, and the patient died at 16 months post-chemoradiation., Conclusions: This is the first case report demonstrating the use of pembrolizumab as palliative therapy for primary squamous cell carcinoma of the thyroid. Our study also highlights the importance of chemoradiation in decreasing primary mass size and immunotherapy in preventing metastatic disease progression., (© 2022. The Author(s).)

Objectives: The mainstay of oral cavity cancer treatment is surgery, often with adjuvant therapies. However, patients often present with locally advanced disease and downstaging would render surgery more feasible. We evaluated hypofractionated radiation therapy (QUAD Shot) prior to definitive surgery for head and neck cancers, with a goal of downstaging., Materials and Methods: Eighteen patients with primary head and neck malignancy, predominantly locally advanced oral cavity cancers, received QUAD Shot radiation therapy from June 2016 to July 2021. External beam radiation therapy was delivered to the primary lesion in four fractions over two days, two fractions/day at least six hours apart with total dose ranging from 1400 cGy to 1500 cGy. Twelve patients proceeded to definitive surgery., Results: Of the twelve patients receiving surgery, one had complete response to radiation therapy with no pathological disease seen at surgery. Four patients had a partial response, defined as downstaging on final pathology. Five patients showed no response, and two had progressive disease defined as upstaging on final pathology. Seven patients had radiographic primary tumor shrinkage ≥ 0.5 cm following Quad Shot. The Quad Shot was tolerated well with no reported adverse effects., Conclusion: Discrepancies between clinical- and pathological-staging are common and expected. However, ∼40 % of our patients experienced downstaging following QUAD Shot. Thus, neoadjuvant radiation therapy may be viable for temporizing tumor growth while awaiting surgery, or for downstaging and thus facilitating more technically feasible and less morbid surgery for locally advanced head and neck cancers., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Objectives: To determine the earliest noticeable manifestation and diagnosis in patients diagnosed with tuberculosis (TB) epididymitis/epididymo-orchitis incidentally and to analyze their responses to surgical and medical treatment., Methods: Patients who underwent surgery for the preliminary impression of chronic epididymitis/epididymo-orchitis or epididymal/testicular tumor from 2000 to 2019 were included in the study. The clinical presentations, laboratory data, radiological examinations, and operative findings were analyzed retrospectively. The outcomes were assessed by the responses to anti-TB chemotherapy and post treatment radiographic evaluations., Results: All of our 25 patients with a mean age of 60.6 years were diagnosed incidentally with TB epididymitis (48.0%) and TB epididymo-orchitis (52.0%) according to the histopathological findings from their surgeries. The presence of a palpable scrotal mass (76.0%), was the major presentation. Nineteen (76.0%) patients had undergone complete chemotherapy after the surgery and 15 (78.9%) patients showed complete recovery. Four (21.1%) patients had unfavorable outcomes, 3 had TB autonephrectomies and 1 required re-surgery years after complete chemotherapy. Of the 3 (12.0%) patients who did not receive chemotherapy after their surgeries, 1 had a TB relapse in the spine and lung and 1 developed bladder cancer years later., Conclusion: Tuberculosis epididymitis/epididymo-orchitis is difficult to diagnose. However, some clinical clues can assist including aged patients, extragenital TB histories, poor responses to antibiotic treatment and scrotal skin lesion. Complete anti-TB chemotherapy is mandatory even after the total removal of TB lesion. Supplemental surgical interventions can be considered when the symptoms are not relieved after chemotherapy. Lifespan follow-up is recommended due to high relapse rate., Competing Interests: Declaration of Competing Interest None., (Copyright © 2022 Elsevier Inc. All rights reserved.)

This study aims to evaluate associations between the immunochromatographic rapid test technique and Trichomonas vaginalis (TV) infection in patients with chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) in Taiwan. All patients received post-prostate massage urine (VB3) Trichomonas rapid tests. The demographic characteristics and urogenital symptoms of CP/CPPS were recorded. Routine urinalysis of VB3 was also performed, and laboratory examination results of semen were recorded if available. A total of 29 patients with TV infection and 109 without TV infection were enrolled, which reflected that the prevalence in patients with TV infection was approximately 21%. Patients with TV infection displayed a significantly higher frequency of suprapubic/lower abdominal pain ( p = 0.034), semen leukocyte > 5/high-power field (HPF) ( p = 0.020), and an inflammatory type (category IIIA) ( p = 0.005) than patients without TV infection. A higher prevalence of TV infection was found in patients with category IIIA (47.37%). No significant difference was found in the symptom duration and other clinical symptoms. In conclusion, the high prevalence of TV infection was revealed in CP/CPPS patients using the VB3 rapid Trichomonas test, especially in CP/CPPS patients with category IIIA. Thus, rapid TV testing might be vital for CP/CPPS patients in the hospital., (© 2022 Po-Chih Chang et al., published by Sciendo.)

Background/aim: The role of nuclear respiratory factor 1 (NRF1) on the prostate cancer progression is controversial. We aimed to investigate the effect of NRF1 overexpression on the metastasis potential of PC3 prostate cancer cells and the associated molecular mechanisms., Materials and Methods: Cell survival, migration capacity, mitochondrial biogenesis, the expression of TGF-β signaling and EMT markers were examined after overexpression and silencing of NRF1 in PC3 cells., Results: We found that NRF1-overexpressing cells exhibited a decreased cell viability and proliferation ability as well as a reduced migration capacity compared to control cells. Moreover, ectopic expression of NRF1 increased the mitochondrial biogenesis and inhibited the EMT characteristics, including a decrease in the mesenchymal marker, α-SMA and an increase in the epithelial cell marker, E-cadherin. We also demonstrated that overexpression of NRF1 suppressed the expression of TGF-β signaling in PC3 cells. As expected, silencing of NRF1 reversed the abovementioned effects., Conclusion: This study demonstrated that upregulation of NRF1 holds the potential to inhibit the metastasis of prostate cancer, possibly through an elevation of mitochondrial biogenesis and the subsequent repression of TGF-β-associated EMT. Therapeutic avenues that increase NRF1 expression may serve as an adjunct to conventional treatments of prostate cancer., (Copyright© 2022, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Purpose: Metastatic castration-resistant prostate cancer (mCRPC) has a poor prognosis. Abiraterone acetate (AA), enzalutamide, and chemotherapy are first-line treatments for patients with mCRPC. This study examined prognostic factors for AA response in the form of prostate-specific antigen (PSA) kinetics throughout androgen-deprivation therapy (ADT) in chemonaïve patients with mCRPC., Materials and Methods: We retrospectively included data from 34 chemonaïve patients with mCRPC who had received AA at some point between January 2017 and December 2018. We separated patients into two study arms according to the decrease in PSA percentages after use of AA for 3 months. We correlated PSA kinetics parameters with response and compared the two study groups with respect to PSA kinetics., Results: The patients' median age was 77 years. In the total group of patients, 64% had a response to AA, whereas 35% did not. The ratio of the PSA level at nadir to the level during ADT was significantly higher in the AA-sensitive group (19.78 vs. 1.03, p=0.019)., Conclusions: Patients who experienced a dramatic change in PSA level during ADT were more likely to be resistant to AA after progression to mCRPC. Chemotherapy rather than AA might be more suitable as a first-line treatment for these patients., Competing Interests: The authors have nothing to disclose., (© The Korean Urological Association.)

Extracellular vesicle (EV) secretion is an important mechanism used by cells to release biomolecules. A common necroptosis effector-mixed lineage kinase domain like (MLKL)-was recently found to participate in the biogenesis of small and large EVs independent of its function in necroptosis. The objective of the current study is to gain mechanistic insights into EV biogenesis during necroptosis. Assessing EV number by nanoparticle tracking analysis revealed an increased number of EVs released during necroptosis. To evaluate the nature of such vesicles, we performed a newly adapted, highly sensitive mass spectrometry-based proteomics on EVs released by healthy or necroptotic cells. Compared to EVs released by healthy cells, EVs released during necroptosis contained a markedly higher number of unique proteins. Receptor interacting protein kinase-3 (RIPK3) and MLKL were among the proteins enriched in EVs released during necroptosis. Further, mouse embryonic fibroblasts (MEFs) derived from mice deficient of Rab27a and Rab27b showed diminished basal EV release but responded to necroptosis with enhanced EV biogenesis as the wildtype MEFs. In contrast, necroptosis-associated EVs were sensitive to Ca 2+ depletion or lysosomal disruption. Neither treatment affected the RIPK3-mediated MLKL phosphorylation. An unbiased screen using RIPK3 immunoprecipitation-mass spectrometry on necroptotic EVs led to the identification of Rab11b in RIPK3 immune-complexes. Our data suggests that necroptosis switches EV biogenesis from a Rab27a/b dependent mechanism to a lysosomal mediated mechanism., (© 2022 The Authors. Journal of Extracellular Vesicles published by Wiley Periodicals, LLC on behalf of the International Society for Extracellular Vesicles.)

Background: To compare the intraoperative and postoperative outcomes of indocyanine green (ICG) administration in robot-assisted partial nephrectomy (RAPN) and report the differences in the results between patients with benign and malignant renal tumors. Methods: From 2017 to 2020, 132 patients underwent RAPN at our institution, including 21 patients with ICG administration. Clinical data obtained from our institution’s RAPN database were retrospectively reviewed. Intraoperative, postoperative, pathological, and functional outcomes of RAPN were assessed. Results: The pathological results indicated that among the 127 patients, 38 and 89 had received diagnoses of benign and malignant tumors, respectively. A longer operative time (311 vs. 271 min; p = 0.006) but superior preservation of estimated glomerular filtration rate (eGFR) at 3-month follow-up (90% vs. 85%; p = 0.031) were observed in the ICG-RAPN group. Less estimated blood loss, shorter warm ischemia time, and superior preservation of eGFR at postoperative day 1 and 6-month follow-up were also noted, despite no significant differences. Among the patients with malignant tumors, less estimated blood loss (30 vs. 100 mL; p < 0.001) was reported in the ICG-RAPN subgroup. Conclusions: Patients with ICG-RAPN exhibited superior short-term renal function outcomes compared with the standard RAPN group. Of the patients with malignant tumors, ICG-RAPN was associated with less blood loss than standard RAPN without a more positive margin rate. Further studies with larger cohorts and prospective designs are necessary to verify the intraoperative and functional advantages of the green dye.

Since December 2019, the novel coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has infected ~435 million people and caused ~6 million related deaths as of March 2022. To combat COVID-19, there have been many attempts to repurpose FDA-approved drugs or revive old drugs. However, many of the current treatment options have been known to cause adverse drug reactions. We employed a population-based drug screening platform using 13 human leukocyte antigen (HLA) homozygous human induced pluripotent cell (iPSC) lines to assess the cardiotoxicity and neurotoxicity of the first line of anti-COVID-19 drugs. We also infected iPSC-derived cells to understand the viral infection of cardiomyocytes and neurons. We found that iPSC-derived cardiomyocytes express the ACE2 receptor which correlated with a higher infection of the SARS-CoV-2 virus (r = 0.86). However, we were unable to detect ACE2 expression in neurons which correlated with a low infection rate. We then assessed the toxicity of anti-COVID-19 drugs and identified two cardiotoxic compounds (remdesivir and arbidol) and four neurotoxic compounds (arbidol, remdesivir, hydroxychloroquine, and chloroquine). These data show that this platform can quickly and easily be employed to further our understanding of cell-specific infection and identify drug toxicity of potential treatment options helping clinicians better decide on treatment options.

Objective: To evaluate medication adherence among patients with hepatitis B-related cirrhosis who developed decompensation and mortality, and to examine the association between medication adherence and patients' disease outcomes., Design: In this retrospective case-control study, patients aged over 20 years old and diagnosed with both chronic hepatitis B and cirrhosis from 2007 to 2016 are identified using a population-based medical claims database. Two prognosis endpoints (decompensation and mortality) are used, respectively, to classify subjects into two different case-control sets. Study groups are propensity-score matched. Medication possession ratio (MPR) is used as a measure of treatment adherence for oral antiviral drugs, and conditional logistic regression models are used to estimate the odds of decompensation and mortality after accounting for MPR and other covariates., Results: Between decompensated and compensated patients, longer term treatment adherence is seen higher in the compensated group versus the decompensated group: 1-year MPR (0.65±0.43 vs 0.57±0.53) and 6-month MPR (0.79±0.52 vs 0.76±0.79). On the contrary, 3-month adherence is higher in the decompensated group (1.00±1.15 vs 0.96±0.79). For patients with and without mortality, drug adherence is ubiquitously higher in the alive group regardless of follow-up length: 1-year MPR (0.62±0.44 vs 0.50±0.51), 6-month MPR (0.78±0.62 vs 0.69±0.72) and 3-month MPR (0.97±0.91 vs 0.96±1.12). After accounting for confounding variables, we find that the likelihood of complicated cirrhosis is significantly lower in more adherent patients and the benefit increases with more persistent adherence (log 1-year MPR OR: 0.75, 95% CI: 0.73 to 0.77). Similar results are observed for the adjusted likelihood of mortality (log 1-year MPR OR: 0.70, 95% CI: 0.68 to 0.72)., Conclusions: Long-term patient adherence to oral antiviral therapy remains inadequate in patients with hepatitis B virus-related cirrhosis. Their adherence to oral antiviral therapy appears to be inversely associated with decompensation and mortality., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

It is known that miRNA-378a-3p (miR-378) could be induced by eicosapentaenoic acid (EPA), an omega-3 fatty acid. Herein, we first demonstrated how miR-378 exerts anti-prostate cancer (PCa) actions by influencing multiple target genes, including KLK2, KLK4, KLK6, and KLK14, which are implicated in PCa development, cell proliferation, and cell survival. Furthermore, these genes also correlate with androgen and mTOR signaling transduction, and are considered pivotal pathways for the onset and progression of PCa. In total, four PCa cell lines and eight pairing tissues (tumor vs. normal) from clinical PCa patients were included in the current study. The results showed high significance after EPA induced tumor cells containing higher expression levels of miR-378, and led the PCa cells having low cell viabilities, and they progressed to apoptosis when compared with normal prostate cells (p < 0.001). The findings indicated that EPA might become a potential therapy for PCa, especially because it is derived from the components of natural fish oil; it may prove to be a great help for solving the problem of castration-resistant prostate cancer (CRPC).

Background: Clooxygenase-2 (COX-2) expression is overexpressed in human prostate cancer, and aberrant methylation of the COX-2 promoter has also been elucidated. However, how the methylation of CpG islands at COX-2 regulates its expression in prostate cancer is still unclear. We will determine the methylated 5' CpG island of the COX-2 gene and its role in the expression of COX-2 in prostate androgen-dependent and androgen-independent cancer cells, LNCaP and DU145., Methods: We used western blotting and quantitative reverse transcription polymerase chain reaction (qRT-PCR) to confirm the COX-2 expression in prostate cancer cell lines, including LNCaP (androgen-dependent) and DU145 (androgen-independent) cells. To investigate whether the COX-2 expression was regulated by the methylation status of the 5' CpG island, we treated LNCaP and DU145 cells with the DNA methylation inhibitor, 5-aza-2'-deoxycytidine, and determined COX-2 expression in the treated/untreated cells by western blotting and qRT-PCR. Subsequently, bisulfite sequencing was performed to study the methylation sites in the treated/untreated cells. The effects of 5-aza-2'-deoxycytidine to cell proliferation, cell migration and cell cycle process in DU145 and LNCaP cells were determined using Cell Counting Kit-8 (CCK-8) assay, transwell assay and flow cytometry, respectively., Results: The results revealed that the expression of COX-2 in androgen-dependent LNCaP cells was 5.44-fold (in protein level) and 2.46-fold (in mRNA level) higher than that in androgen-independent DU145 cells. After 5-aza-2'-deoxycytidine treatment, COX-2 expression in DU145 cells was elevated significantly, but no change was found in LNCaP cells. The A and C regions of the COX-2 CpG island exhibited reduced methylation along with that an increased expression of COX-2 was noted in DU145 cell after 5-aza-2'-deoxycytidine treatment. Also, the treatment with 5-aza-2'-deoxycytidine inhibited cell proliferation, cell migration and influenced the cell cycle progression in both DU145 and LNCaP cells., Conclusions: Our results reveal that androgen receptor (AR)-dependent/independent prostate cancer cell lines exhibit different regulation of methylation in COX-2 that regulate its expression. Additionally, 5-aza-2'-deoxycytidine treatment of DU145 and LNCaP cells inhibits their ability of tumor progression., Competing Interests: The authors declare they have no conflict of interest to declare., (Copyright 2022, Liu et al.)

Melatonin exerts a wide range of effects among various tissues and organs. However, there is currently no study to investigate the genetic determinants of melatonin secretion. Here, we conducted a genome-wide association study (GWAS) for melatonin secretion using morning urine 6-hydroxymelatonin sulfate-to-creatinine ratio (UMCR). We initially enrolled 5000 participants from Taiwan Biobank in this study. After excluding individuals that did not have their urine collected in the morning, those who had history of neurological or psychiatric disorder, and those who failed to pass quality control, association of single nucleotide polymorphisms with log-transformed UMCR adjusted for age, sex and principal components of ancestry were analyzed. A second model additionally adjusted for estimated glomerular filtration rate (eGFR). A total of 2373 participants underwent the genome-wide analysis. Five candidate loci associated with log UMCR (P value ranging from 6.83 × 10 -7 to 3.44 × 10 -6 ) encompassing ZFHX3, GALNT15, GALNT13, LDLRAD3 and intergenic between SEPP1 and FLJ32255 were identified. Similar results were yielded with further adjustment for eGFR. Interestingly, the identified genes are associated with circadian behavior, neuronal differentiation, motor disorders, anxiety, and neurodegenerative diseases. We conducted the first GWAS for melatonin secretion and identified five candidate genetic loci associated with melatonin level. Replication and functional studies are needed in the future., (© 2022. The Author(s).)

Vibrio cholerae biofilm formation/maintenance is controlled by myriad factors; chief among these are the regulator VpsR and cyclic di-guanosine monophosphate (c-di-GMP). VpsR has strong sequence similarity to enhancer binding proteins (EBPs) that activate RNA polymerase containing sigma factor σ54. However, we have previously shown that transcription from promoters within the biofilm biogenesis/maintenance pathways uses VpsR, c-di-GMP and RNA polymerase containing the primary sigma factor (σ70). Previous work suggested that phosphorylation of VpsR at a highly conserved aspartate, which is phosphorylated in other EBPs, might also contribute to activation. Using the biofilm biogenesis promoter PvpsL, we show that in the presence of c-di-GMP, either wild type or the phospho-mimic VpsR D59E activates PvpsL transcription, while the phospho-defective D59A variant does not. Furthermore, when c-di-GMP levels are low, acetyl phosphate (Ac∼P) is required for significant VpsR activity in vivo and in vitro. Although these findings argue that VpsR phosphorylation is needed for activation, we show that VpsR is not phosphorylated or acetylated by Ac∼P and either sodium phosphate or potassium phosphate, which are not phosphate donors, fully substitutes for Ac∼P. We conclude that VpsR is an unusual regulator that senses phosphate directly, rather than through phosphorylation, to aid in the decision to form/maintain biofilm., (Published by Oxford University Press on behalf of Nucleic Acids Research 2022.)

In this study, we establish a population-based human induced pluripotent stem cell (hiPSC) drug screening platform for toxicity assessment. After recruiting 1,000 healthy donors and screening for high-frequency human leukocyte antigen (HLA) haplotypes, we identify 13 HLA-homozygous "super donors" to represent the population. These "super donors" are also expected to represent at least 477,611,135 of the global population. By differentiating these representative hiPSCs into cardiomyocytes and neurons we show their utility in a high-throughput toxicity screen. To validate hit compounds, we demonstrate dose-dependent toxicity of the hit compounds and assess functional modulation. We also show reproducible in vivo drug toxicity results using mouse models with select hit compounds. This study shows the feasibility of using a population-based hiPSC drug screening platform to assess cytotoxicity, which can be used as an innovative tool to study inter-population differences in drug toxicity and adverse drug reactions in drug discovery applications., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Carbon-based nanomaterials hold promise for eco-friendly alternatives to heavy-metal-containing quantum dots (QDs) in optoelectronic applications. Here, boric acid-functionalized graphene quantum dots (B-GQDs) were prepared using bottom-up molecular fusion based on nitrated pyrenes and boric acid. Such B-GQDs with crystalline graphitic structures and hydrogen-bonding functionalities would be suitable model systems for unraveling the photoluminescence (PL) mechanism, while serving as versatile building blocks for supramolecular self-assembly. Unlike conventional GQDs with multiple emissive states, the B-GQDs exhibited excitation-wavelength-independent, vibronic-coupled excitonic emission. Interestingly, their PL spectra can be tuned without largely sacrificing the quantum yield (QY) due to two-dimensional self-assembly. In addition, such B-GQDs in a polystyrene matrix possessed an ultrahigh QY (∼90%) and large exciton binding energy (∼300 meV). Benefiting from broadband absorption, ultrahigh QY, and long-wavelength emission, efficient laminated luminescent solar concentrators (100 × 100 × 6.3 mm 3 ) were fabricated, yielding a high power conversion efficiency (1.4%).

Benign prostate hyperplasia (BPH) refers to the nonmalignant enlargement of the transition zone of the prostate gland. While holmium laser enucleation of the prostate and open simple prostatectomy are effective in the management of patients with large prostates, they have some limitations. Thus, this study aimed to analyze the efficacy and safety of the sandwich method of bipolar transurethral resection of the prostate (B-TURP) and GreenLight photoselective vaporization of the prostate (GLPVP) in patients with large prostates. Patients diagnosed with BPH who underwent the sandwich method with B-TURP and GLPVP from 2015 to 2020 were included. Efficacy analyses included the change in the uroflowmetry results in both group A (prostate volume < 80 g) and group B (prostate volume ≥ 80 g), and complication analyses included perioperative complications, early postoperative complications at three months and late postoperative complications at 12 months. The cohort comprised 188 and 44 patients in groups A and B, respectively. The prostate volume of groups A and B were 50.83 ± 14.14 g and 102.03 ± 19.36 g (p < 0.001), respectively. The peak (Qmax) and average (Qavg) flow rates were comparable between the two groups. The only significant difference noted was in the postoperative post-void residual (PVR) urine. Improvement was seen in all the variables including the Qmax, Qavg and PVR urine in each group. No patient experienced perioperative complications. Analysis of the overall one-year complication rate showed no significant difference between the two groups. The sandwich method of B-TURP and GLPVP may be feasible for the management of patients with large prostate.

Cardiovascular catheterization has been applied in infant treatment for several decades. To date, considerable research attention has been paid to cardiovascular catheterization in small neonates. However, peripheral vascular routes of catheterization are possible obstacles for interventionists. Umbilical vein catheterization has been reported as a route for neonates, although few attempts have been made to investigate this approach. This study aimed to retrospectively review cardiovascular intervention using the umbilical vein approach as applied to infants admitted to a tertiary center from 2017 to 2020. Details including the perinatal variables, indication diagnoses, and procedure devices were collected. The enrollment included a total of 16 cases representing 17 intervention events, with infants born at a gestation age of 22-39 weeks and body weight ranging from 478 to 3685 g at the time of the procedure. The postnatal age ranged from 1 to 27 days. The catheter sizes ranged from 4 to 11 Fr. Indications included being admitted for patent ductus arteriosus occlusion ( n = 15), balloon pulmonary valvuloplasty ( n = 3), balloon atrial septostomy (BAS) ( n = 3), pulmonary valve (PV) perforation ( n = 1), and two interventions for catheter placement for continuous venovenous hemofiltration. The success rate for cardiovascular catheterization was 88.2% (15/17). There were two patients for which cannulation failed due to ductus venosus closure: one intraabdominal hemorrhage complication during continuous venovenous hemofiltration (CVVH), and one cardiac catheterization failure of PV perforation due to failure to insert the guiding catheter into the right ventricular outflow tract. Based on these findings, we conclude that cardiac catheterization and the placement of a large-sized catheter through an umbilical vein in a small infant represents a safe and time-saving method when catheterization is required.

Background: Failure to thrive and poor weight gain are the main problems associated with ventricular septal defects complicated by heart failure in pediatric patients. Recent advances in transcatheter closure have enabled safe and effective interventions in these patients., Objectives: The purpose of this study was to describe our experience with transcatheter closure of ventricular septal defects in young children with low weight., Methods: Pediatric patients weighing < 15 kg who underwent transcatheter closure of ventricular septal defects between January 2018 and December 2019 at our hospital were retrospectively enrolled., Results: Twelve patients were enrolled: one with a muscular defect, two with outlet defects, and nine with perimembranous defects. Their median age was 24 (7-60) months, and their median weight before the procedure was 11.8 kg (4.7-14.9 kg; mean Z-score: -1.3). The median precordial echocardiographic defect diameter was 5.6 (2.0-9.3) mm. Successful transcatheter closure was achieved in 11 cases. The mean weight at 1-month follow-up after defect closure was 13.5 kg (6.2-19.8 kg; mean Z-score: -0.2). The mean length of hospitalization was 2.7 days., Conclusions: This study highlights the potential safety and therapeutic efficacy of transcatheter ventricular septal defect closure in infants with low weight. Considerable weight gain and heart failure symptom attenuation at 1 month after transcatheter closure were observed.

A highly dispersive, diffractive optical element is designed and realized for an extremely high spectral resolution spectroscopy for exoplanet telescope application. Our design uses an annular Fresnel hologram to transform incident starlight directly into a spectrogram. The recording of the hologram is accomplished using two spherical waves of different radius of curvature. The resultant hologram consists of an annular grating structure with a gradually shrinking period as a function of increasing radius. The variable period not only could bring the incoming star-light into focus, but also exhibits a large on-axis chromatic behavior. We demonstrate a dispersion of wavelength 430-700 nm over 190 mm on-axis distance, leading to a super fine spectral resolution 0.0266 nm at wavelength 515 nm for a detector size of 20 µm., (© 2021. The Author(s).)