A novel computer-assisted tool for 3D imaging of programmed death-ligand 1 expression in immunofluorescence-stained and optically cleared breast cancer specimens.

BACKGROUND: Programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) are the two most common immune checkpoints targeted in triple-negative breast cancer (BC). Refining patient selection for immunotherapy is non-trivial and finding an appropriate digital pathology framework for spatial analysis of theranostic biomarkers for PD-1/PD-L1 inhibitors remains an unmet clinical need. METHODS: We describe a novel computer-assisted tool for three-dimensional (3D) imaging of PD-L1 expression in immunofluorescence-stained and optically cleared BC specimens (n = 20). The proposed 3D framework appeared to be feasible and showed a high overall agreement with traditional, clinical-grade two-dimensional (2D) staining techniques. Additionally, the results obtained for automated immune cell detection and analysis of PD-L1 expression were satisfactory. RESULTS: The spatial distribution of PD-L1 expression was heterogeneous across various BC tissue layers in the 3D space. Notably, there were six cases (30%) wherein PD-L1 expression levels along different layers crossed the 1% threshold for admitting patients to PD-1/PD-L1 inhibitors. The average PD-L1 expression in 3D space was different from that of traditional immunohistochemistry (IHC) in eight cases (40%). Pending further standardization and optimization, we expect that our technology will become a valuable addition for assessing PD-L1 expression in patients with BC. CONCLUSION: Via a single round of immunofluorescence imaging, our approach may provide a considerable improvement in patient stratification for cancer immunotherapy as compared with standard techniques.

A Family of Fitness Landscapes Modeled through Gene Regulatory Networks.

Fitness landscapes are a powerful metaphor for understanding the evolution of biological systems. These landscapes describe how genotypes are connected to each other through mutation and related through fitness. Empirical studies of fitness landscapes have increasingly revealed conserved topographical features across diverse taxa, e.g., the accessibility of genotypes and "ruggedness". As a result, theoretical studies are needed to investigate how evolution proceeds on fitness landscapes with such conserved features. Here, we develop and study a model of evolution on fitness landscapes using the lens of Gene Regulatory Networks (GRNs), where the regulatory products are computed from multiple genes and collectively treated as phenotypes. With the assumption that regulation is a binary process, we prove the existence of empirically observed, topographical features such as accessibility and connectivity. We further show that these results hold across arbitrary fitness functions and that a trade-off between accessibility and ruggedness need not exist. Then, using graph theory and a coarse-graining approach, we deduce a mesoscopic structure underlying GRN fitness landscapes where the information necessary to predict a population's evolutionary trajectory is retained with minimal complexity. Using this coarse-graining, we develop a bottom-up algorithm to construct such mesoscopic backbones, which does not require computing the genotype network and is therefore far more efficient than brute-force approaches. Altogether, this work provides mathematical results of high-dimensional fitness landscapes and a path toward connecting theory to empirical studies.

Prognostic Value of Apical Sparing of Longitudinal Strain in Patients with Symptomatic Aortic Stenosis.

Background: Older patients with aortic stenosis (AS) have a higher incidence of wild-type transthyretin cardiac amyloidosis (ATTR-CA). This study aimed to determine whether apical sparing of longitudinal strain (LS) could help diagnose ATTR-CA and provide useful prognostic information in symptomatic AS. Methods: We performed vendor-independent two-dimensional speckle-tracking analysis of regional and global left ventricular LS in 16 patients with ATTR-CA and 31 patients with non-obstructive hypertrophic cardiomyopathy to determine the best cutoff value of the apical sparing ratio (APSR) for diagnosing ATTR-CA. We then determined the prevalence in patients who had an APSR higher than the best cutoff value and investigated its prognostic value in 230 patients with symptomatic AS. To determine the natural history of symptomatic AS, patients who had aortic valve replacement were censored at the time of surgery. Results: The best cutoff value of APSR was 0.76. APSR ≥ 0.76 was observed in 108 patients with symptomatic AS (48%). The prevalence was not different among the four AS subgroups. During a median follow-up period of 5.7 months, 47 patients had cardiac events. Cox proportional hazards analysis revealed that neither APSR nor APSR ≥ 0.76 was significantly associated with future cardiac events. Conclusions: Apical sparing was frequently observed in patients with symptomatic AS, and it was not a useful predictor of future adverse outcomes. Our results suggest that the underlying cause of apical sparing in AS may not be related to the presence of ATTR-CA.

Comparison of 9-Month Angiographic Follow-Up and Long-Term Clinical Outcomes of Biodegradable Polymer Drug-Eluting Stents and Second-Generation Durable Polymer Drug-Eluting Stents in Patients Undergoing Single Coronary Artery Stenting.

BACKGROUND: The durable polymers (DP) used in first-generation drug-eluting stents (DESs) were associated with long-term cardiovascular events, and thus biodegradable polymer DESs (BP-DESs) and second-generation DP-DESs were designed to overcome this problem. In this study, we compared angiographic follow-up and long-term clinical outcomes between patients who received BP-DESs or second-generation DP-DESs. METHODS: We enrolled 436 patients with single coronary lesions who received a second-generation DP-DES or BP-DES between June 2009 and October 2012. All patients received follow-up angiography when new clinical events developed or at 9 months after index stenting. All participants received follow-up for 5 years. RESULTS: There were no significant differences in patient and lesion characteristics between the two groups. The 9-month angiographic follow-up showed a lower net gain in the second-generation DP-DES group (2.19 mm vs. 2.41 mm, p = 0.040), but a similar binary restenosis rate between the two groups (5.4% vs. 8.7%, p = 0.276). During the 5-year follow-up period, no significant differences were observed between the two groups in major adverse cardiac events (MACEs), cardiovascular death, nonfatal myocardial infarction (MI), target vessel revascularization (TVR), all revascularization, stent thrombosis (ST), or MACE-free survival. CONCLUSIONS: No significant differences were observed in cardiovascular death, nonfatal MI, TVR, all revascularization, ST, or MACE-free survival between the patients undergoing single coronary artery stenting with BP-DESs and second-generation DP-DESs.

Effects of National Hospital Accreditation in Acute Coronary Syndrome on In-Hospital Mortality and Clinical Outcomes.

BACKGROUND: Acute coronary syndrome (ACS) is a life-threatening medical condition that accounts for an annual expenditure of more than $300 billion in the United States. Hospital accreditation has been shown to improve patient and hospital outcomes for various conditions. OBJECTIVES: This study aimed to determine the benefits of hospital accreditation in patients with ACS. METHODS: This nationwide population-based cohort study used Taiwan's National Health Insurance Research Database from 1997 to 2011 (n = 249,354). Multivariable logistic regression was used to analyze the risk of in-hospital events among those treated in accredited and non-accredited hospitals, and to compare outcomes in hospitals before and after accreditation. The effect of accreditation on these events was also stratified by accreditation grade. RESULTS: A total of 823 hospitals were included, of which 2.4% were medical centers, 13.7% were regional hospitals, and 83.8% were district hospitals. The in-hospital mortality [odds ratio (OR), 0.82; 95% confidence interval (CI), 0.79-0.85; p < 0.001] and recurrent acute myocardial infarction (AMI) admission (OR, 0.81; 95% CI, 0.71-0.93; p = 0.003) rates were significantly lower in the after-accreditation group than in the before-accreditation group. There was a substantial and marked decrease in the in-hospital mortality rate after accreditation in 2008. CONCLUSIONS: This cohort study demonstrated that ACS accreditation was associated with better in-hospital mortality and recurrent AMI admission rates in ACS patients.

A circulating miRNA signature for early diagnosis of acute kidney injury following acute myocardial infarction.

BACKGROUND: Acute kidney injury (AKI) is a common complication of acute myocardial infarction (AMI), and is associated with adverse outcomes. The study aimed to identify a miRNA signature for the early diagnosis of post-AMI AKI. METHODS: A total of 108 patients admitted to a coronary care unit (CCU) were divided into four subgroups: AMI-AKI-, AMI+AKI-, AMI+AKI+, and AMI-AKI+. Thirty-six miRNA candidates were selected based on an extensive literature review. Real-time quantitative RT-PCR analysis was used to determine the expression levels of these miRNAs in the serum collected on the day of CCU admittance. TargetScan 7.1 and miRDB databases were used for target prediction and Metacore 6.13 was used for pathway analysis. RESULTS: Through a stepwise selection based on abundance, hemolytic effect and differential expression between four groups, 9 miRNAs were found to have significantly differential expression levels as potential biomarkers for post-AMI AKI specifically. Noticeably, the expression levels of miR-24, miR-23a and miR-145 were significantly down-regulated in AMI+AKI+ patients compared to those in AMI+AKI- patients. Combination of the three miRNAs as a panel showed the best performance in the early detection of AKI following AMI (AUC = 0.853, sensitivity 95.65%), compared to the analysis of serum neutrophil gelatinase-associated lipocalin (AUC = 0.735, sensitivity 63.16%). Furthermore, bioinformatic analysis indicated that these three miRNAs regulate the transforming growth factor beta signaling pathway and involve in apoptosis and fibrosis in AKI. CONCLUSIONS: For the first time, this study identify a unique circulating miRNA signature (miR-24-3p, miR-23a-3p, miR-145-5p) that can potentially early detect AKI following AMI and may be involved in renal injury and fibrosis in post-AMI AKI pathogenesis.

Complete and incomplete revascularization in non-ST segment myocardial infarction with multivessel disease: long-term outcomes of first- and second-generation drug-eluting stents.

The therapeutic effects of reperfusion strategies with complete revascularization (CR) or incomplete revascularization (IR) in non-ST segment myocardial infarction (NSTEMI) patients with multivessel disease (MVD) are controversial. In such patients, whether utilization of different generations of drug-eluting stents (DES) for IR or CR affect long-term major adverse cardiovascular events (MACE) is unknown. This study included 702 NSTEMI patients with MVD who received first-generation (1G) or second-generation (2G) DES. In multivariable analysis, chronic kidney disease, chronic total, 1G DES and IR were independent predictors of long-term MACE. In patients receiving 1G DES, no significant differences of MACE were observed between the IR and CR groups (39.1% vs. 36.2%, p = 0.854). However, in patients receiving 2G DES, significantly fewer MACE were observed in the CR group than in the IR group (3.7% vs. 10.2%, p = 0.002). Compared with patients receiving 1G DES for IR, those receiving 2G DES for IR and CR exhibited significantly lower risk of MACE (59% and 83% lower, respectively). CR could not provide clinical benefits over IR in NSTEMI patients with MVD receiving 1G DES. However, in patients receiving 2G DES, compared with IR, CR was associated with a lower risk of long-term MACE, which was mainly caused by low rates of non-TLR and any revascularization.

Targeted Next Generation Sequencing for Genetic Mutations of Dilated Cardiomyopathy.

BACKGROUND: Approximately one-third of cases of dilated cardiomyopathy (DCM) are caused by genetic mutations. With new sequencing technologies, numerous variants have been associated with this inherited cardiomyopathy, however the prevalence and genotype-phenotype correlations in different ethnic cohorts remain unclear. This study aimed to investigate the variants in Chinese DCM patients and correlate them with clinical presentations and prognosis. METHODS AND RESULTS: From September 2013 to December 2016, 70 index patients underwent DNA sequencing for 12 common disease-causing genes with next generation sequencing. Using a bioinformatics filtering process, 12 rare truncating variants (7 nonsense variants, 4 frameshift variants, and 1 splice site variant) and 29 rare missense variants were identified. Of these, 3 patients were double heterozygotes and 10 patients were compound heterozygotes. Overall, 47.1% (33/70) of the index patients had the seputatively pathogenic variants. The majority (33/41, 80.4%) of these variants were located in titin (TTN). More than 80% of the TTN variants (27/33, 81.8%) were distributed in the A band region of the sarcomere. Patients carrying these variants did not have a different phenotype in disease severity, clinical outcome and reversibility of ventricular function compared with non-carriers. CONCLUSIONS: Several new rare variants were identified in a Chinese population in this study, indicating that there are ethnic differences in genetic mutations in DCM patients. TTN remains the major disease-causing gene. Our results could be a reference for future genetic tests in Chinese populations. No specific genotype-phenotype correlations were found, however a prospective large cohort study may be needed to confirm our findings.

Excessive irisin increases oxidative stress and apoptosis in murine heart.

Irisin is an exercise-related myokine. The abundance of irisin is associated with many diseases, such as myocardial infarction, chronic kidney disease, metabolic syndrome, obesity, and diabetes mellitus. In cardiomyocytes, irisin modulates the mitochondrial thermogenesis, regulates ischemic responses, and affects calcium signaling. Previous studies suggested that irisin increases cardiomyoblast mitochondrial functions and protects ischemic and reperfusion injury in ex vivo murine heart. In human, clinical studies have shown that acute myocardial infarction patients with more elevated serum irisin abundances are associated with increased major adverse cardiovascular events. However, the mechanisms responsible for this discrepancy between in myocardial infarction patients and ex vivo murine heart is unclear. Based on the clinical observations, we hypothesized that excessive irisin might lead to mitochondrial dysfunctions and cardiomyocyte damages. Our data showed that overexpression of irisin in mice with the adenovirus resulted in enhanced mitochondrial respiration with a higher oxygen consumption rate. Enhanced irisin expression in heart and irisin treatment in cardiomyocytes increased reactive oxygen species production. Furthermore, irisin treatment in cardiomyocytes enhanced the apoptosis and the cleaved caspase 9 levels in hypoxic condition. Pathway analysis in the murine heart with the overexpression of irisin showed that angiopoietin-Tie2, IL-8, IL-13, TGF-ß, and thrombopoietin signaling were affected by irisin. Collectively, these results supported that excessive irisin causes mitochondrial overdrive with a higher reactive oxygen species production, which results in increased apoptosis of cardiomyocytes in a hypoxic environment.

Comparison of the Acute and Long-Term Outcomes of Patients With Multivessel Coronary Artery Disease After Angiographic Complete and Incomplete Revascularization With Drug-Eluting Stents.

BACKGROUND: Data regarding the long-term outcomes of a large patient population with multivessel coronary artery disease (MV-CAD) after complete revascularization (CR) and incomplete revascularization (IR) with drug-eluting stent (DES) implantation are controversial. The objective of this study was to evaluate differences between the clinical outcomes of CR and IR in such patients.Methods and Results:A total of 1,502 patients with MV-CAD who received DES between April 2005 and August 2016 were enrolled in this study after propensity score matching. The CR group had 751 patients with 1,368 stents implanted in 1,215 lesions, and the IR group had 751 patients with 1,077 stents implanted in 948 lesions. The CR group had a similar rate of in-hospital major adverse cardiovascular events to the IR group (1.9% vs. 1.6%, P=0.844). Follow-up angiography at 9 months showed no significant difference between the 2 groups for restenosis. The CR group had a higher cardiovascular event-free survival rate than the IR group during a mean follow-up period of 71±62 months (81.8% vs. 72.0%, P<0.001). Kaplan-Meier survival analysis also showed better results in the CR group than in the IR group. CONCLUSIONS: Angiographic CR was associated with more favorable long-term cardiovascular outcomes than angiographic IR in patients with MV-CAD after DES implantation.

Predictors of Long-Term Outcomes After Drug-Eluting Balloon Angioplasty for Bare-Metal Stent Restenosis.

BACKGROUND: Clinical trials have investigated efficacy of drug-eluting balloon (DEB) angioplasty for bare-metal stent (BMS) in-stent restenosis (ISR). Few studies have investigated predictors of long-term outcomes following BMS-ISR treatment with DEB. METHODS: From June 2011 to April 2015, 105 patients with 125 BMS-ISR lesions were enrolled from the Cardiovascular Atherosclerosis and Percutaneous TrAnsluminal INterventions (CAPTAIN) registry. All these lesions were treated with DEB angioplasty as final therapy. The major adverse cardiac events (MACEs) were recurrent clinically driven target lesion revascularisation (TLR), myocardial infarction, and cardiac death after DEB angioplasty. RESULTS: After DEB angioplasty, the angiographic stenosis decreased from 84.8%±12.4% to 22.6%±10.4%. Over a mean follow-up duration of 21.7±13.4months, the rates of TLR at 1-12 months and 12-48 months were 4.8% and 4.2%, respectively. The rates of MACEs at 1-12 months and 12-48 months were 6.7% and 6.1%, respectively. Chronic haemodialysis, calcified lesion, chronic total occlusion lesion before stenting, stent with metal-to-artery ratio >16.5%, and residual stenosis >25% after DEB angioplasty were potential risk factors for MACEs in univariate analysis. After adjustment in multivariate analysis, independent predictors of long-term MACEs were identified as chronic haemodialysis, chronic total occlusion lesion before stenting, and residual stenosis >25% after DEB angioplasty. CONCLUSIONS: The long-term results of DEB angioplasty for BMS-ISR are acceptable in this real-world registry. Patient (chronic haemodialysis), lesion (chronic total occlusion) and angioplasty (residual stenosis percentage) related factors predicted long-term outcomes following BMS-ISR treatment with DEB angioplasty.

Early Detection of Left Ventricular Diverticulum by Transthoracic Echocardiography.

Left ventricular diverticulum is a very rare entity to be found in adults. Noninvasive echocardiography can offer useful information prior to contrast-enhanced computer tomography or invasive angiography. We evaluated a patient with left ventricular apical diverticulum but complained no symptoms. Transthoracic echocardiography demonstrated a outpouching at left ventricle apex. A 640-slice computed tomography later confirmed the left ventricular diverticulum.

CLOCK modulates survival and acute lung injury in mice with polymicrobial sepsis.

Polymicrobial sepsis is a potentially fatal condition and a significant burden on health care systems. Acute lung injury is the most common complication of sepsis and results in high mortality. However, there has been no recent significant progress in the treatment of sepsis or acute lung injury induced by sepsis. Here we show that mice deficient in the circadian protein CLOCK had better survival than wild-type mice after induction of polymicrobial sepsis by cecal ligation and puncture. Inflammatory cytokine production was attenuated and bacterial clearance was improved in CLOCK-deficient mice. Moreover, acute lung injury after induction of sepsis was significantly decreased in CLOCK-deficient mice. Genome-wide profiling analysis showed that inhibin signaling was reduced in CLOCK-deficient mice. These data establish the importance of circadian CLOCK-inhibin signaling in sepsis, which may have potential therapeutic implications.

Circadian CLOCK Mediates Activation of Transforming Growth Factor-ß Signaling and Renal Fibrosis through Cyclooxygenase 2.

The circadian rhythm regulates blood pressure and maintains fluid and electrolyte homeostasis with central and peripheral clock. However, the role of circadian rhythm in the pathogenesis of tubulointerstitial fibrosis remains unclear. Here, we found that the amplitudes of circadian rhythm oscillation in kidneys significantly increased after unilateral ureteral obstruction. In mice that are deficient in the circadian gene Clock, renal fibrosis and renal parenchymal damage were significantly worse after ureteral obstruction. CLOCK-deficient mice showed increased synthesis of collagen, increased oxidative stress, and greater transforming growth factor-ß (TGF-ß) expression. TGF-ß mRNA expression oscillated with the circadian rhythms under the control of CLOCK-BMAL1 heterodimers. The expression of cyclooxygenase 2 was significantly higher in kidneys from CLOCK-deficient mice with ureteral obstruction. Treatment with a cyclooxygenase 2 inhibitor celecoxib significantly improved renal fibrosis in CLOCK-deficient mice. Taken together, these data establish the importance of the circadian rhythm in tubulointerstitial fibrosis and suggest CLOCK/TGF-ß signaling as a novel therapeutic target of cyclooxygenase inhibition.

Combination of Urinary Biomarkers Improves Early Detection of Acute Kidney Injury in Patients With Heart Failure.

BACKGROUND: Acute kidney injury (AKI) is associated with morality and repeated hospitalization, and is frequently encountered in patients with acute decompensated heart failure (ADHF). However, few effective tools exist for early AKI identification and risk stratification. METHODS AND RESULTS: This was a prospective observational study conducted in the coronary care unit (CCU) of a tertiary care university hospital. Patients with a diagnosis of ADHF and who were using diuretics were enrolled.Samples collected between December 2013 and February 2015 were tested for serum cystatin C (Cys-C), urinary neutrophil gelatinase-associated lipocalin, and kidney injury molecule-1 (KIM-1). Demographic, clinical, and laboratory data were evaluated. A total of 103 adult patients with a mean age of 68 years were investigated. AKI was diagnosed in 49 patients (47.6%). For predicting intrinsic AKI on the first day of CCU admission, a combination of Cys-C and urine KIM-1 yielded an excellent area under the receiver operating characteristic curve of 0.828, a sensitivity of 71.0%, and specificity of 43.0%, for an overall accuracy of 78%. CONCLUSIONS: In this study, we found that combinations of the biomarker (Cys-C and KIM-1) were an effective clinical model for predicting AKI in patients with ADHF. The biomarker was also useful for differentiating subclinical AKI in patients with ADHF.

Optimizing immunofluorescence with high-dynamic-range imaging to enhance PD-L1 expression evaluation for 3D pathology assessment from NSCLC tumor tissue.

Assessing programmed death ligand 1 (PD-L1) expression through immunohistochemistry (IHC) is the golden standard in predicting immunotherapy response of non-small cell lung cancer (NSCLC). However, observation of heterogeneous PD-L1 distribution in tumor space is a challenge using IHC only. Meanwhile, immunofluorescence (IF) could support both planar and three-dimensional (3D) histological analyses by combining tissue optical clearing with confocal microscopy. We optimized clinical tissue preparation for the IF assay focusing on staining, imaging, and post-processing to achieve quality identical to traditional IHC assay. To overcome limited dynamic range of the fluorescence microscope's detection system, we incorporated a high dynamic range (HDR) algorithm to restore the post imaging IF expression pattern and further 3D IF images. Following HDR processing, a noticeable improvement in the accuracy of diagnosis (85.7%) was achieved using IF images by pathologists. Moreover, 3D IF images revealed a 25% change in tumor proportion score for PD-L1 expression at various depths within tumors. We have established an optimal and reproducible process for PD-L1 IF images in NSCLC, yielding high quality data comparable to traditional IHC assays. The ability to discern accurate spatial PD-L1 distribution through 3D pathology analysis could provide more precise evaluation and prediction for immunotherapy targeting advanced NSCLC.

The prognostic significance of SYNTAX score after early percutaneous transluminal coronary angioplasty for acute ST elevation myocardial infarction.

INTRODUCTION: SYNergy between percutaneous coronary intervention (PCI) with TAXUS and Cardiac Surgery (SYNTAX) score, which is based on the characteristics of atherosclerotic lesions and the complexity of coronary artery anatomy, is useful for choosing an intervention strategy, but its prognostic significance for acute ST elevation of myocardial infarction (STEMI) remains unknown. This study aimed to redress this issue. METHODS: Our observational study included 151 consecutive patients admitted for acute STEMI who underwent primary PCI between January 1, 2008 and December 31, 2009. The primary endpoint for analysis was 30-day cardiac death. RESULTS: Among the 151 patients, cardiac death occurred in 10 (7%) within 30 days. After the first month, five patients died of non-cardiac causes, but no cardiac death occurred. Multivariate analysis showed that SYNTAX score (odds ratio [OR], 13.79, 95% confidence interval [CI], 1.24-153.38; p=0.033) and a symptom onset-to-therapy time interval >4 h (OR, 11.13; 95% CI, 1.08-114.42; p=0.043) were independent risk factors for 30-day mortality. The SYNTAX score cut-off for discriminating low and high risk was 22. CONCLUSIONS: SYNTAX score is an independent predictor of short-term cardiac mortality in patients with acute STEMI.

The ensemble of gene regulatory networks at mutation-selection balance.

The evolution of diverse phenotypes both involves and is constrained by molecular interaction networks. When these networks influence patterns of expression, we refer to them as gene regulatory networks (GRNs). Here, we develop a model of GRN evolution analogous to work from quasi-species theory, which is itself essentially the mutation-selection balance model from classical population genetics extended to multiple loci. With this GRN model, we prove that-across a broad spectrum of selection pressures-the dynamics converge to a stationary distribution over GRNs. Next, we show from first principles how the frequency of GRNs at equilibrium is related to the topology of the genotype network, in particular, via a specific network centrality measure termed the eigenvector centrality. Finally, we determine the structural characteristics of GRNs that are favoured in response to a range of selective environments and mutational constraints. Our work connects GRN evolution to quasi-species theory-and thus to classical populations genetics-providing a mechanistic explanation for the observed distribution of GRNs evolving in response to various evolutionary forces, and shows how complex fitness landscapes can emerge from simple evolutionary rules.

Left atrial booster-pump function as a predictive parameter for atrial fibrillation in patients with severely dilated left atrium.

Background: Left atrial (LA) dimension ≥50 mm had approximately four times the risk of developing atrial fibrillation (AF). The aim of this study was to investigate whether the application of clinical and echocardiographic parameters could differentiate between the patients having severely dilated left atrium with and without AF. Methods: This retrospective cross-sectional study enrolled consecutive patients with LA dimension ≥50 mm and divided them into three groups: no AF (no-AF), paroxysmal AF (PAF) and non-paroxysmal AF (non-PAF) groups. For PAF and non-PAF groups, all patients underwent radiofrequency ablation, and the echocardiographic parameters were obtained on the next day after ablation. Results: Our study population comprised 160 patients, including 80, 53, and 27 patients in the non-AF, PAF and non-PAF groups, respectively. The no-AF group had a significantly higher body mass index (kg/m2) (29.31±6.27, 27.58±4.12 and 26.57±2.81, P=0.01), and a higher prevalence of diabetes mellitus (DM) [31 (38.80%), 13 (25.00%) and 4 (14.80%), P=0.01] and hypertension [67 (83.80%), 34 (65.40%), and 19 (70.40%), P=0.04], but a lower prevalence of rheumatic heart disease (RHD) [3 (3.80%), 6 (11.50%) and 5 (18.50%), P=0.02] and sick sinus syndrome [0 (0.00%), 6 (11.50%) and 4 (14.80%), P=0.045]. Echocardiographic studies showed that the non-AF group had significantly smaller LA minimal volume index (24.89±9.74, 34.06±19.38 and 42.83±17.44 mL/m2, P<0.01), higher LA emptying fraction (51.99%±13.97%, 38.40%±15.96% and 33.89%±10.73%, P<0.01), longitudinal strain (23.87%±7.72%, 17.11%±8.52% and 12.38%±4.28%, P<0.01) and strain rate than the AF groups. The multivariate analysis showed that the late diastolic component of LA strain rate was the only independent factor associated with the presence of AF (odds ratio, 21.69; 95% CI, 9.77-48.13, P<0.01). Conclusions: LA function plays an important role in the absence of AF in patients with LA dimension ≥50 mm; the late diastolic component of LA strain rate was the only independent variable on multivariate analysis.

Strategies for post-cardiac surgery acute kidney injury prevention: A network meta-analysis of randomized controlled trials.

Objects: Cardiac surgery is associated with acute kidney injury (AKI). However, the effects of various pharmacological and non-pharmacological strategies for AKI prevention have not been thoroughly investigated, and their effectiveness in preventing AKI-related adverse outcomes has not been systematically evaluated. Methods: Studies from PubMed, Embase, and Medline and registered trials from published through December 2021 that evaluated strategies for preventing post-cardiac surgery AKI were identified. The effectiveness of these strategies was assessed through a network meta-analysis (NMA). The secondary outcomes were prevention of dialysis-requiring AKI, mortality, intensive care unit (ICU) length of stay (LOS), and hospital LOS. The interventions were ranked using the P-score method. Confidence in the results of the NMA was assessed using the Confidence in NMA (CINeMA) framework. Results: A total of 161 trials (involving 46,619 participants) and 53 strategies were identified. Eight pharmacological strategies {natriuretic peptides [odds ratio (OR): 0.30, 95% confidence interval (CI): 0.19-0.47], nitroprusside [OR: 0.29, 95% CI: 0.12-0.68], fenoldopam [OR: 0.36, 95% CI: 0.17-0.76], tolvaptan [OR: 0.35, 95% CI: 0.14-0.90], N-acetyl cysteine with carvedilol [OR: 0.37, 95% CI: 0.16-0.85], dexmedetomidine [OR: 0.49, 95% CI: 0.32-0.76;], levosimendan [OR: 0.56, 95% CI: 0.37-0.84], and erythropoietin [OR: 0.62, 95% CI: 0.41-0.94]} and one non-pharmacological intervention (remote ischemic preconditioning, OR: 0.76, 95% CI: 0.63-0.92) were associated with a lower incidence of post-cardiac surgery AKI with moderate to low confidence. Among these nine strategies, five (fenoldopam, erythropoietin, natriuretic peptides, levosimendan, and remote ischemic preconditioning) were associated with a shorter ICU LOS, and two (natriuretic peptides [OR: 0.30, 95% CI: 0.15-0.60] and levosimendan [OR: 0.68, 95% CI: 0.49-0.95]) were associated with a lower incidence of dialysis-requiring AKI. Natriuretic peptides were also associated with a lower risk of mortality (OR: 0.50, 95% CI: 0.29-0.86). The results of a sensitivity analysis support the robustness and effectiveness of natriuretic peptides and dexmedetomidine. Conclusion: Nine potentially effective strategies were identified. Natriuretic peptide therapy was the most effective pharmacological strategy, and remote ischemic preconditioning was the only effective non-pharmacological strategy. Preventive strategies might also help prevent AKI-related adverse outcomes. Additional studies are required to explore the optimal dosages and protocols for potentially effective AKI prevention strategies.