Naringin activates semaphorin 3A to ameliorate TGF-ß-induced endothelial-to-mesenchymal transition related to atrial fibrillation.

The loss of semaphorin 3A (Sema3A), which is related to endothelial-to-mesenchymal transition (EndMT) in atrial fibrosis, is implicated in the pathogenesis of atrial fibrillation (AF). To explore the mechanisms by which EndMT affects atrial fibrosis and assess the potential of a Sema3A activator (naringin) to prevent atrial fibrosis by targeting transforming growth factor-beta (TGF-ß)-induced EndMT, we used human atria, isolated human atrial endocardial endothelial cells (AEECs), and used transgenic mice expressing TGF-ß specifically in cardiac tissues (TGF-ß transgenic mice). We evaluated an EndMT marker (Twist), a proliferation marker (proliferating cell nuclear antigen; PCNA), and an endothelial cell (EC) marker (CD31) through triple immunohistochemistry and confirmed that both EndMT and EC proliferation contribute to atrial endocardial fibrosis during AF in TGF-ß transgenic mice and AF patient tissue sections. Additionally, we investigated the impact of naringin on EndMT and EC proliferation in AEECs and atrial fibroblasts. Naringin exhibited an antiproliferative effect, to which AEECs were more responsive. Subsequently, we downregulated Sema3A in AEECs using small interfering RNA to clarify a correlation between the reduction in Sema3A and the elevation of EndMT markers. Naringin treatment induced the expression of Sema3A and a concurrent decrease in EndMT markers. Furthermore, naringin administration ameliorated AF and endocardial fibrosis in TGF-ß transgenic mice by stimulating Sema3A expression, inhibiting EndMT markers, reducing atrial fibrosis, and lowering AF vulnerability. This suggests therapeutic potential for naringin in AF treatment.

Mitral Valve Repair vs. Replacement by Different Etiologies　- A Nationwide Population-Based Cohort Study.

BACKGROUND: When mitral valve (MV) surgery is indicated, repair is preferred over replacement; however, this preference is not supported by evidence from clinical trials. Furthermore, the benefits of MV repair may not be universal for all etiologies of MV disease. METHODS AND RESULTS: This study identified a total of 18,428 patients who underwent MV repair (n=4,817) or MV replacement (n=13,611) during 2001-2018 from Taiwan's National Health Insurance Research Database. These patients were classified into 4 etiologies: infective endocarditis (IE, n=2,678), rheumatic heart disease (RHD, n=4,524), ischemic mitral regurgitation (IMR, n=3,893), and degenerative mitral regurgitation (DMR, n=7,333). After propensity matching, all-cause mortality during follow-up was lower among patients receiving MV repair than among patients receiving MV replacement in the IE, IMR, and DMR groups (hazard ratio [HR]=0.72, 95% confidence interval [CI]: 0.55-0.93; HR=0.82, 95% CI: 0.73-0.92; and HR 0.73, 95% CI: 0.64-0.84, respectively). However, in the RHD group, the MV reoperation rate was higher after MV repair than after MV replacement (subdistribution HR=1.91, 95% CI: 1.02-3.55). CONCLUSIONS: In comparison with MV replacement, MV repair was associated with a lower late mortality in patients with IE, IMR, and DMR, and a higher risk of reoperation in patients with RHD.

Outcomes of Endovascular Treatment for Infective Aortic Aneurysms　- A Multicenter Retrospective Study.

BACKGROUND: In Taiwan, infective native aortic aneurysms (INAAs) are relatively common, so the aim of present study was to demonstrate the comparative outcomes of endovascular repair for thoracic and abdominal INAAs.Methods and Results: Patients with naïve thoracic or abdominal INAAs managed with endovascular repair between 2001 and 2018 were included in this multicenter retrospective cohort. The confounding factors were adjusted with propensity score (PS). Of the 39 thoracic and 43 abdominal INAA cases, 41 (50%) presented with aneurysmal rupture, most of which were at the infrarenal abdominal (n=35, 42.7%) or descending thoracic aorta (n=25, 30.5%). Salmonella spp. was the most frequently isolated pathogen. The overall in-hospital mortality rate was 18.3%. The risks of in-hospital death and death due to rupture were significantly lower with thoracic INAAs (12.8% vs. 23.3%; PS-adjusted odds ratio (OR) 0.24, 95% confidence interval (CI) 0.06-0.96; 0.1% vs. 9.3%; PS-adjusted OR 0.11, 95% CI 0.01-0.90). During a mean follow-up of 2.5 years, the risk of all-cause death was significantly higher with thoracic INAAs (35.3% vs. 15.2%; PS-adjusted HR 6.90, 95% CI 1.69-28.19). Chronic kidney disease (CKD) was associated with death. CONCLUSIONS: Compared with thoracic INAAs, endovascular repair of abdominal INAAs was associated with a significantly higher in-hospital mortality rate. However, long-term outcomes were worse for thoracic INAAs, with CKD and infections being the most important predictor and cause of death, respectively.

Early Surgery for Infective Endocarditis Complicated With Neurologic Injury.

OBJECTIVES: To estimate the association between early surgery and the risk of mortality in patients with left-sided infective endocarditis in the context of stroke. DESIGN: Retrospective cohort study. SETTING: This study was a multiinstitution study based on the Chang Gung Research Database, which contains electronic medical records from 7 hospitals in northern and southern Taiwan; these include 2 medical centers, 2 regional hospitals, and 3 district hospitals. PARTICIPANTS: Patients with active left-sided infective endocarditis who underwent valve surgery between September 2002 and December 2018. INTERVENTIONS: The authors divided patients into 2 groups, with versus without preoperative neurologic complications, had undergone early (within 7 d) or later surgery, and with brain ischemia or hemorrhage. MEASUREMENTS AND MAIN RESULTS: Three hundred ninety-two patients with a median time from diagnosis to surgery of 6 days were included. No significant differences in postoperative stroke, in-hospital mortality, or follow-up outcomes were observed between the patients with and without neurologic complications. Among the patients with preoperative neurologic complications, patients who underwent early surgery had a lower 30-day postoperative mortality rate (13.1% v 25.8%; hazard ratio, 0.21; 95% CI 0.07-0.67). In the subgroup analysis of the comparison between brain ischemia and hemorrhage groups, there was no significant between-group difference in the in-hospital outcomes or outcomes after discharge. CONCLUSIONS: Early cardiac surgery may be associated with more favorable clinical outcomes in patients with preoperative neurologic complications. Thus, preoperative neurologic complications should not delay surgical interventions.

Utilizing Raman spectroscopy for urinalysis to diagnose acute kidney injury stages in cardiac surgery patients.

BACKGROUND: The successful treatment and improvement of acute kidney injury (AKI) depend on early-stage diagnosis. However, no study has differentiated between the three stages of AKI and non-AKI patients following heart surgery. This study will fill this gap in the literature and help to improve kidney disease management in the future. METHODS: In this study, we applied Raman spectroscopy (RS) to uncover unique urine biomarkers distinguishing heart surgery patients with and without AKI. Given the amplified risk of renal complications post-cardiac surgery, this approach is of paramount importance. Further, we employed the partial least squares-support vector machine (PLS-SVM) model to distinguish between all three stages of AKI and non-AKI patients. RESULTS: We noted significant metabolic disparities among the groups. Each AKI stage presented a distinct metabolic profile: stage 1 had elevated uric acid and reduced creatinine levels; stage 2 demonstrated increased tryptophan and nitrogenous compounds with diminished uric acid; stage 3 displayed the highest neopterin and the lowest creatinine levels. We utilized the PLS-SVM model for discriminant analysis, achieving over 90% identification rate in distinguishing AKI patients, encompassing all stages, from non-AKI subjects. CONCLUSIONS: This study characterizes the incidence and risk factors for AKI after cardiac surgery. The unique spectral information garnered from this study can also pave the way for developing an in vivo RS method to detect and monitor AKI effectively.

Integrating ATAC-seq and RNA-seq to identify differentially expressed genes with chromatin-accessible changes during photosynthetic establishment in Populus leaves.

Leaves are the primary photosynthetic organs, providing essential substances for tree growth. It is important to obtain an anatomical understanding and regulatory network analysis of leaf development. Here, we studied leaf development in Populus Nanlin895 along a development gradient from the newly emerged leaf from the shoot apex to the sixth leaf (L1 to L6) using anatomical observations and RNA-seq analysis. It indicated that mesophyll cells possess obvious vascular, palisade, and spongy tissue with distinct intercellular spaces after L3. Additionally, vacuoles fuse while epidermal cells expand to form pavement cells. RNA-seq analysis indicated that genes highly expressed in L1 and L2 were related to cell division and differentiation, while those highly expressed in L3 were enriched in photosynthesis. Therefore, we selected L1 and L3 to integrate ATAC-seq and RNA-seq and identified 735 differentially expressed genes (DEGs) with changes in chromatin accessibility regions within their promoters, of which 87 were transcription factors (TFs), such as ABI3VP1, AP-EREBP, MYB, NAC, and GRF. Motif enrichment analysis revealed potential regulatory functions for the DEGs through upstream TFs including TCP, bZIP, HD-ZIP, Dof, BBR-BPC, and MYB. Overall, our research provides a potential molecular foundation for regulatory network exploration in leaf development during photosynthesis establishment.

Osteopontin mediation of disturbed flow-induced endothelial mesenchymal transition through CD44 is a novel mechanism of neointimal hyperplasia in arteriovenous fistulae for hemodialysis access.

In dysfunctional arteriovenous fistulae (AVF) for hemodialysis access, neointimal hyperplasia (NH) is prone to occur in the region exposed to disturbed flow. We hypothesized that disturbed flow contributes to NH in AVF by inducing endothelial mesenchymal transition (EndMT) through activation of the osteopontin/CD44 axis. In rats with aortocaval fistula, a rodent model of AVF, we demonstrated development of EndMT and expression of osteopontin and CD44 specifically in the vicinity of the arteriovenous junction using immunostaining. Duplex scan confirmed this region was exposed to a disturbed flow. A mixed ultrastructural phenotype of endothelium and smooth muscle cells was found in luminal endothelial cells of the arteriovenous junction by electron microscopy ascertaining the presence of EndMT. Endothelial lineage tracing using Cdh5-Cre/ERT2;ROSA26-tdTomato transgenic mice showed that EndMT was involved in NH of AVF since the early stage and that the endothelial-derived cells contributed to 24% of neointimal cells. In human umbilical vein endothelial cells (HUVECs) in culture, osteopontin treatment induced EndMT, which was suppressed by CD44 knockdown. Exposure to low oscillatory wall shear stress using a parallel-plate system induced EndMT in HUVECs, also suppressed by osteopontin or CD44 knockdown. In AVF of CD44 knockout mice, EndMT was mitigated and NH decreased by 35% compared to that in wild-type mice. In dysfunctional AVF of patients with uremia, expressions of osteopontin, CD44, and mesenchymal markers in endothelial cells overlying the neointima was also found by immunostaining. Thus, the osteopontin/CD44 axis regulates disturbed flow-induced EndMT, plays an important role in neointimal hyperplasia of AVF, and may act as a potential therapeutic target to prevent AVF dysfunction.

High Triglyceride Variability Increases the Risk of First Attack of Acute Pancreatitis.

INTRODUCTION: Hypertriglyceridemia is the third most common etiology of acute pancreatitis. Whether triglyceride variability, independent of absolute triglyceride levels, is a predictor of acute pancreatitis is unknown. METHODS: We identified 98,819 patients who were diagnosed with hyperlipidemia between January 1, 2007, and December 31, 2013, and had at least 1 triglyceride measurement annually for 4 consecutive years from the Chang Gung Research Database in Taiwan. Triglyceride variability, defined as variability independent of the mean, was calculated in the 4-year run-in period. The patients were stratified according to the quartiles of triglyceride variability and were followed until December 31, 2019, for first attack of acute pancreatitis. RESULTS: During a mean follow-up of 5.9 years, 825 (0.83%) patients were newly diagnosed with acute pancreatitis (14.1 events per 10,000 person-years; 95% confidence interval 13.2-15.1). Triglyceride variability was significantly associated with an increased risk of acute pancreatitis, independent of baseline triglyceride and mean triglyceride levels (hazard ratio, 1.28 [95% confidence interval 1.05-1.57] for the highest vs the lowest quartiles of triglyceride variability; P for trend = 0.006 over the quartiles of triglyceride variability). Subgroup analysis showed that this association was more pronounced among the patients with a higher neutrophil-to-lymphocyte ratio ( P for trend = 0.022). DISCUSSION: In this multi-institutional cohort study, high triglyceride variability was associated with an increased risk of first attack of acute pancreatitis, independent of baseline and mean triglyceride levels. The association between triglyceride variability and acute pancreatitis may be partly mediated by subclinical inflammation.

Fluoroquinolones and Risk of Aortic Aneurysm or Dissection in Patients With Congenital Aortic Disease and Marfan Syndrome.

BACKGROUND: Fluoroquinolone use can be associated with an increased risk of aortic aneurysm (AA) or aortic dissection (AD). The US Food and Drug Administration recently warned against fluoroquinolone use for high-risk patients, such as those with Marfan syndrome. However, the association between fluoroquinolone use and AA/AD risk was unknown in these high-risk patients and therefore it was studied in this work.Methods and Results: Data were collected from a national database between 2000 and 2017 for 550 patients with AA/AD and any congenital aortic disease (mean age 41.5 years; 415 with Marfan syndrome). A case cross-over study was conducted to compare the risk of aortic events (AA/AD) associated with fluoroquinolone and amoxicillin use between the hazard period (from -60 days to -1 day) and a randomly selected reference period (-180 to -121 days; -240 to -181 days; and -300 to -241 days). Compared to the reference period without fluoroquinolone use, fluoroquinolone use during the hazard period was not associated with a greater risk of AA/AD (1.09% vs. 1.09%; odds ratio [OR] 1.000; 95% confidence interval [CI] 0.32-3.10), AA (OR 0.67; 95% CI 0.11-3.99), or AD (OR 1.33; 95% CI 0.30-5.96) in patients with congenital aortic disease or Marfan syndrome. This lack of association was maintained in subgroup analysis, including Marfan syndrome or not, age (≤50 vs. >50 years) and sex. CONCLUSIONS: Fluoroquinolone use was not associated with an increased risk of AA/AD in patients with congenital aortic disease, including Marfan syndrome. More evidence is required for a fluoroquinolone pharmacovigilance plan in these patients.

PdeHCA2 affects biomass in Populus by regulating plant architecture, the transition from primary to secondary growth, and photosynthesis.

MAIN CONCLUSION: PdeHCA2 regulates the transition from primary to secondary growth, plant architecture, and affects photosynthesis by targeting PdeBRC1 and controlling the anatomy of the mesophyll, and intercellular space, respectively. Branching, secondary growth, and photosynthesis are vital developmental processes of woody plants that determine plant architecture and timber yield. However, the mechanisms underlying these processes are unknown. Here, we report that the Populus transcription factor High Cambium Activity 2 (PdeHCA2) plays a role in the transition from primary to secondary growth, vascular development, and branching. In Populus, PdeHCA2 is expressed in undifferentiated provascular cells during primary growth, in phloem cells during secondary growth, and in leaf veins, which is different from the expression pattern of its homolog in Arabidopsis. Overexpression of PdeHCA2 has pleiotropic effects on shoot and leaf development; overexpression lines showed delayed growth of shoots and leaves, reduced photosynthesis, and abnormal shoot branching. In addition, auxin-, cytokinin-, and photosynthesis-related genes were differentially regulated in these lines. Electrophoretic mobility shift assays and transcriptome analysis indicated that PdeHCA2 directly up-regulates the expression of BRANCHED1 and the MADS-box gene PdeAGL9, which regulate plant architecture, by binding to cis-elements in the promoters of these genes. Taken together, our findings suggest that HCA2 regulates several processes in woody plants including vascular development, photosynthesis, and branching by affecting the proliferation and differentiation of parenchyma cells.

Clinical characteristics and prognostic factors in intracranial hemorrhage patients with hematological diseases.

The clinical characteristics and prognosis of intracranial hemorrhage (ICH) in patients with hematological diseases remain controversial. This study aimed to describe the clinical characteristics and explore the prognostic factors in such patients. A total of 238 ICH patients with a hematological disease were recruited from the Institute of Hematology and Blood Diseases Hospital, China, from January 2015 to April 2020. The Cox proportional hazards model was used to identify the prognostic factors for 30-day mortality in ICH patients with a hematological disease. There were 123 cases of acute leukemia (AL), 20 of myelodysplasia/myeloproliferative neoplasm, 35 of aplastic anemia (AA), 29 of immune thrombocytopenia (ITP), 19 of congenital/acquired coagulation factor deficiency, and 12 of other hematological diseases. Furthermore, 121 patients presented with a multi-site hemorrhage (MSH), 58 with a single-site hemorrhage in the brain parenchyma (PCH), 23 with a subarachnoid hemorrhage, 33 with a subdural hemorrhage (SH), and three with an epidural hemorrhage. The Cox proportional hazards model indicated association of SH (vs PCH, hazard ratio [HR]: 0.230; 95% confidence interval [CI]: 0.053-0.996; P = 0.049), low white blood cells (≤ 100 × 109/L vs > 100 × 109/L, HR: 0.56; 95% CI: 0.348-0.910; P = 0.019), AA (vs AL, HR: 0.408; 95% CI: 0.203-0.821; P = 0.012), and ITP (vs AL, HR: 0.197; 95% CI: 0.061-0.640; P = 0.007) with improved 30-day mortality. However, increased age (HR: 1.012; 95% CI: 1.001-1.022; P = 0.034), MSH (vs PCH, HR: 1.891; 95% CI: 1.147-3.117; P = 0.012), and a disturbance of consciousness (HR: 1.989; 95% CI: 1.269-3.117; P = 0.003) were associated with increased risk of 30-day mortality. In conclusion, in this study, we revealed the clinical characteristics of Chinese ICH patients with a hematological disease. Moreover, we identified risk factors (age, white blood cells, AA, ITP, SH, MSH, and a disturbance of consciousness) that may influence 30-day mortality.

Albicanol modulates oxidative stress and the p53 axis to suppress profenofos induced genotoxicity in grass carp hepatocytes.

The organophosphorus pesticide profenofos (PFF) is widely used as an environmental contaminant, and it can remain in water bodies causing serious harm to aquatic organisms. Albicanol is a sesquiterpenoid with potent antioxidant and antagonistic activities against heavy metal toxicity. However, the mechanism of PFF induced genotoxicity in fish hepatocytes and the role Albicanol can play in this process are unknown. In this study, the model was established by treating grass carp hepatocytes with PFF (150 µM) and/or Albicanol (5 × 10-5 µg mL-1) for 24 h. The results showed that PFF exposure arrested L8824 cells in the G1-S phase. PFF caused the increase of MDA level in L8824 cells, while the decrease of SOD, CAT and T-AOC levels caused oxidative stress. Elevated levels of γH2AX, tail moment, tail length, % DNA and 8-OHdG indicated that PFF caused DNA damage in L8824 cells. PFF inhibited the expression levels of cell cycle related regulatory genes (cyclin A, cyclin D, cyclin E, CDK2 and CDK4) by upregulating p53/p21 genes and activating the p53 signaling pathway. Albicanol was used to significantly reduce the above effects caused by PFF exposure on hepatocytes in grass carp. Albicanol could reduce the increase in the proportion of cells in the G1-S phase caused by PFF. In summary, Albicanol could inhibit the genotoxicity of L8824 cells resulted from PFF exposure by decreasing oxidative stress and the p53 pathway.

Albicanol inhibits the toxicity of profenofos to grass carp hepatocytes cells through the ROS/PTEN/PI3K/AKT axis.

Profenofos (PFF) as an environmental pollutant seriously harms the health of aquatic animals, and even endangers human safety through the food chain. Albicanol, a sesquiterpenoid extraction from the Dryopteris fragrans, has previously been shown to effectively exhibit anti-aging, anti-oxidant, and antagonize the toxicity of heavy metals. However, the mechanism of hepatocyte toxicity caused by PFF and the role that Albicanol plays in this process are still unclear. In this study, a PFF poisoning model was established by treating grass carp hepatocytes cells with PFF (150 µM) for 24 h The results of AO/EB staining, Tunel staining and flow cytometry showed that the proportion of apoptotic liver cells increased significantly after exposure. The results of ROS staining show that compared with the control group, ROS levels and PTEN/PI3K/AKT-related gene expression were up-regulated after PFF exposure. RT-qPCR and Western blotting results showed that the expression of PTEN/PI3K/AKT related genes was up-regulated. These results indicate that PFF can induce oxidative stress in hepatocytes and inhibit the phosphorylation of AKT. We further found that the expressions of Bax, CytC, Caspase-3, Caspase-9, Caspase-8 and TNFR1 after PFF exposure were significantly higher than those of the control group, and Bcl-2/Bax was significantly lower than that of the control group. These results indicate that PFF can induce oxidative stress in hepatocytes and inhibit the phosphorylation of AKT and activate mitochondrial apoptosis. Using Albicanol (5 × 10-5 µg mL-1) can significantly reduce the above-mentioned effects of PFF exposure on grass carp hepatocytes cells. In summary, Albicanol inhibits PFF-induced apoptosis by regulating the ROS/PTEN/PI3K/AKT pathway.

Myeloid Neoplasm with PCM1-PDGFRB Transcript Responded to Low-Dose Imatinib: One Case Report with Literature Review.

Through an RNA-seq analysis of an adult patient with unclassifiable myelodysplastic/myeloproliferative neoplasms (MDS/MPN-U), we identified a rare PDGFRB fusion partner gene, PCM1. Conventional chromosome karyotype analysis showed abnormal clones of t(5;8)(q32;p22), and fluorescence in situ hybridization (FISH) confirmed rearrangement of the PDGFRB gene. Reverse transcription PCR (RT-PCR) and Sanger sequencing further confirmed that exon 30 of the PCM1 gene was fused with exon 11 of PDGFRB in frame, and the fusion event was accompanied by a 14 bp deletion of exon 11 of PDGFRB. After low-dose imatinib treatment, the patient achieved complete molecular remission. This study not only broadens the understanding of myeloid/lymphoid neoplasms with PDGFRB rearrangement but also reflects the vital role of RNA-seq in identifying PDGFRB rearrangements.

Derangements and Reversibility of Energy Metabolism in Failing Hearts Resulting from Volume Overload: Transcriptomics and Metabolomics Analyses.

Derangements in cardiac energy metabolism have been shown to contribute to the development of heart failure (HF). This study combined transcriptomics and metabolomics analyses to characterize the changes and reversibility of cardiac energetics in a rat model of cardiac volume overload (VO) with the creation and subsequent closure of aortocaval fistula. Male Sprague-Dawley rats subjected to an aortocaval fistula surgery for 8 and 16 weeks exhibited characteristics of compensated hypertrophy (CH) and HF, respectively, in echocardiographic and hemodynamic studies. Glycolysis was downregulated and directed to the hexosamine biosynthetic pathway (HBP) and O-linked-N-acetylglucosaminylation in the CH phase and was further suppressed during progression to HF. Derangements in fatty acid oxidation were not prominent until the development of HF, as indicated by the accumulation of acylcarnitines. The gene expression and intermediates of the tricarboxylic acid cycle were not significantly altered in this model. Correction of VO largely reversed the differential expression of genes involved in glycolysis, HBP, and fatty acid oxidation in CH but not in HF. Delayed correction of VO in HF resulted in incomplete recovery of defective glycolysis and fatty acid oxidation. These findings may provide insight into the development of innovative strategies to prevent or reverse metabolic derangements in VO-induced HF.

Diagnosis, treatment and genetic analysis of a case with fibrocalculous pancreatic diabetes.

Fibrocalculous pancreatic diabetes (FCPD) is a rare type of diabetes mellitus with both impaired endocrine and exocrine functions of the pancreas. In this report, we presented a case with FCPD, who had recurrent abdominal pain since early childhood and was diagnosed with diabetes mellitus at the age of 25, with pancreatic calcification on abdominal computed tomography (CT) scan. Genetic testing revealed two homozygous mutations in the SPINK1 gene (c.194+2T>C and -191-24G>A). Both the homozygous variants were shared by his unaffected sibling, and the heterozygous variants had been verified on their unaffected parents. Based on this case and 90 other reported cases in China, we retrospectively analyzed the clinical characteristics of FCPD. It is recommended that unclassified diabetic patients with a lean body type, no ketosis tendency but poor islet function should be considered for the possibility of FCPD. Pancreatic imaging and genetic testing may be beneficial for the differential diagnosis. This study improves our understanding and management of FCPD, and also enriches clinical evidence for subsequent research on pathogenic mechanisms and drug target screening.

Benzodiazepines in Patients with Heart Failure and Reduced Ejection Fraction.

Background: In patients with heart failure (HF), anxiety or insomnia is prevalent and associated with poor clinical outcomes. Benzodiazepines (BZDs) are one of the most commonly prescribed medications for anxiety or insomnia in Taiwan. Evidence regarding the effects of BZDs on patients with heart failure and reduced ejection fraction (HFrEF) is inconclusive. Objectives: To evaluate whether BZDs can mitigate the adverse effects of anxiety or insomnia on the prognosis of patients with HFrEF. Methods: Patients with HFrEF were identified from the Chang Gung Research Database between January 1, 2007 and December 31, 2018. Those who received BZD prescriptions were defined as the BZD group; patients in the BZD group were then paired with those who had never been prescribed BZDs after matching for age, sex, and baseline left ventricular ejection fraction, defined as the no-BZD group. Propensity score matching was used to balance baseline characteristics. Cox proportional hazards model and the Fine-Gray subdistribution hazard model were used to examine the association between BZD prescription and the risks of adverse cardiovascular outcomes. Results: After propensity score matching, there were 1,941 patients in both BZD and no-BZD groups. The composite of cardiovascular (CV) death or HF hospitalization (HFH) occurred in 64.4% and 54.4% of the patients in the BZD and no-BZD groups, respectively [hazard ratio (HR): 1.44; 95% confidence interval (CI): 1.32-1.56], which was mainly driven by HFH (HR: 1.52; 95% CI: 1.39-1.67). Conclusions: In the patients with HFrEF, those who received BZD were at a higher overall risk of CV death and HFH.

Upregulation of Myocardial Neutrophil Gelatinase-Associated Lipocalin during Development of Heart Failure Caused by Volume-Overload and the Effect in Regulating Activity of Matrix Metalloproteinase-9.

Background: In patients with heart failure (HF), circulating neutrophil gelatinase-associated lipocalin (NGAL) level is increased, which is considered to be a predictor of mortality or renal outcomes. The expression of NGAL in the heart and kidney and its role in HF remain unclear. Methods: Aortocaval fistula was created in rats as a model of volume overload (VO)-induced HF. Results: During the development of HF, NGAL expression was upregulated in the heart but not in the kidney at both transcriptional and translational levels in the compensatory and HF phases, with a similar level in both phases. Cardiomyocytes were identified as the cell type responsible for NGAL expression. Consistent with the myocardial NGAL expression pattern, the plasma NGAL level was increased in both phases, and the level was not significantly different between both phases. We demonstrated the presence of a matrix metalloproteinase (MMP)-9/NGAL complex in cultured medium of cardiomyocytes isolated from volume-overloaded hearts by gelatin zymography. Formation of MMP-9/NGAL complex was shown to enhance the enzymatic activity of MMP-9. We found that early growth response (Egr)-1 was upregulated in the heart in both compensatory and HF phases. In neonatal cardiomyocytes, Egr-1 overexpression induced the gene expression of NGAL, which was dose-dependently suppressed by an interleukin-1 receptor antagonist. Conclusions: During the development of HF due to VO, NGAL was upregulated in the heart but not in the kidney in both compensatory and HF phases, with a similar expression level. Myocardial NGAL upregulation enhanced MMP-9 activity through formation of the MMP-9/NGAL complex. The expression of myocardial NGAL was regulated by Egr-1.

A HANC Risk Stratification Score for Antiplatelet Therapy Optimization with Low-Dose Prasugrel in Taiwanese Acute Coronary Syndrome Patients from the Switch Study.

Background: A significant proportion of acute coronary syndrome (ACS) patients experience high on-treatment platelet reactivity (HPR) on clopidogrel-based dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI). Objectives: This study assessed key independent risk factors associated with significant HPR risk on clopidogrel, but not prasugrel, in the Switch Study cohort of 200 Taiwanese ACS patients who switched from clopidogrel to low-dose prasugrel for maintenance DAPT after PCI. Methods: Univariate analysis and stepwise multivariate logistic regression analysis were conducted to identify key independent risk factors for HPR on clopidogrel, but not prasugrel. Results: A HANC [H: low hemoglobin (< 13 g/dL for men and < 12 g/dL for women); A: age ≥ 65 years; N: non-ST elevation myocardial infarction; C: chronic kidney disease as defined by estimated glomerular filtration rate < 60 mL/min] risk stratification score was developed, and demonstrated optimal sensitivity and specificity at a cutoff score of ≥ 2. The HANC score compared favorably against the recently validated ABCD score in the full Switch Study cohort (n = 200), and the ABCD-GENE score in a genotyped cohort (n = 102). Conclusions: The HANC score may serve to alert clinicians to patients at potentially higher HPR risk on clopidogrel, but not prasugrel. Further research to validate this score and assess its correlation with clinical outcomes is warranted.

Side-to-side versus end-to-side ileocolic anastomosis in right-sided colectomies: A cohort control study.

Aims: The three main types of anastomotic configurations following colorectal resection are Side-to-Side Anastomosis (S-S), End-to-Side Anastomosis (E-S) and End-to-End Anastomosis (E-E). This study aims to present results from a local cohort supplemented by a systematic review with meta-analysis of existing literature to compare the post-operative outcomes between E-S and S-S. Methods: A cohort study of patients who underwent right colectomy with E-S or S-S anastomosis, was conducted at the National University Hospital Singapore. Electronic databases Embase and Medline were systematically searched from inception to 21 August 2020, in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analysis guidelines. Studies were included if they compared post-operative outcomes between E-S and S-S. Results: In the cohort study, 40 underwent E-S and 154 underwent S-S. Both post-operative ileus (12.5% vs. 29.2%, P = 0.041) and length of hospital stay (9.35 days vs. 14.04 days, P = 0.024) favoured E-S, but anastomotic bleed favoured S-S (15.0% vs. 3.2%, P = 0.004). Five studies were included in the meta-analysis with 860 E-S and 1126 S-S patients. Similarly, post-operative ileus (odds ratio [OR] =0.302; 95% confidence interval [CI]: 0.122-0.747; P = 0.010) and length of hospital stay (mean differences = ‒1.54 days; CI: ‒3.00 to ‒0.076 days; P = 0.039) favoured E-S. Additional sensitivity analysis including only stapled anastomosis showed a lower rate of anastomotic leak in E-S patients (OR = 0.185; 95% CI: 0.054-0.627; P = 0.007). Conclusions: This is the first systematic review to show that the E-S technique produces superior post-operative outcomes after right colectomy compared to S-S. However, the choice of anastomosis was largely surgeon dependent, but surgeon factors were not reported.