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Background Participation in cardiac rehabilitation ( CR ) is an essential component of care for patients with coronary artery disease. However, little is known about its benefit on cardiovascular outcomes in patients with diabetes mellitus ( DM ) who have undergone percutaneous coronary intervention. The aim of our study was to evaluate the impact of CR in this high‐risk group of patients. Methods and Results We performed a retrospective analysis of all patients with DM who underwent percutaneous coronary intervention in Olmsted County (Minnesota) between 1994 and 2010, assessing the impact of CR participation on clinical outcomes. CR participation was significantly lower in patients with DM (38%, 263/700) compared with those who did not have DM (45%, 1071/2379; P =0.004). Using propensity score adjustment, we found that in patients with DM , CR participation was associated with significantly reduced all‐cause mortality (hazard ratio, 0.56; 95% confidence interval, 0.39–0.80; P =0.002) and composite end point of mortality, myocardial infarction, or revascularization (hazard ratio, 0.77; 95% confidence interval, 0.60–0.98; P =0.037), during a median follow‐up of 8.1 years. In patients without DM , CR participation was associated with a significant reduction in all‐cause mortality (hazard ratio, 0.67; 95% confidence interval, 0.55–0.82; P <0.001) and cardiac mortality (hazard ratio, 0.67; 95% confidence interval, 0.47–0.95; P =0.024). Conclusions CR participation after percutaneous coronary intervention is associated with lower all‐cause mortality rates in patients with DM , to a similar degree as for those without DM . However, CR participation was lower in patients with DM , suggesting the need to identify and correct the barriers to CR participation for this higher‐risk group of patients.

The peripheral blood lymphocyte-to-monocyte ratio (LMR) has been associated with prognosis in many malignancies including metastatic melanoma. However, it has not been studied in patients treated with immune checkpoint inhibitors. In this study, we analyzed the baseline LMR with progression-free survival (PFS) and overall survival (OS) in metastatic melanoma patients treated with pembrolizumab. A total of 133 patients with metastatic melanoma treated with pembrolizumab were included in this retrospective study. LMR was calculated from pretherapy peripheral blood counts and the optimal cutoff value was determined by a receiver operator characteristic curve. PFS and OS were evaluated using the Kaplan–Meier method and multivariate Cox proportional hazard modeling. Patients with an LMR of at least 1.7 showed improved PFS (hazard ratio=0.55; 95% confidence interval: 0.34–0.92; P=0.024) and OS (hazard ratio=0.29; 95% confidence interval: 0.15–0.59; P=0.0007). The baseline LMR is associated with PFS and OS in metastatic melanoma patients treated with pembrolizumab, and could represent a convenient and cost-effective prognostic biomarker. Validation of these findings in an independent cohort is needed.

AbstractObjectivesTo assess the in‐hospital mortality and complications in female between transcatheter aortic valve replacement (TAVR) and surgical aortic valve replacement (SAVR).BackgroundFemale is one of the risk factors for increased adverse events in cardiac surgery.Methods and resultsNationwide Inpatient Sample database was queried from 2011 to 2014 for patients who underwent TAVR or SAVR in female patients. The primary endpoint was in‐hospital all‐cause mortality and second endpoints were perioperative complications. We performed a propensity score analysis to calculate the adjusted odds ratio (OR) for each outcome. Patients who had concomitant cardiac surgery and those who had TAVR or SAVR mainly for aortic regurgitation were excluded. Our query from 2011 to 2014 resulted in a total of 3,067 TAVR and 18,594 SAVR in female patients. TAVR patients were in general elder and had a higher burden of comorbidities. The primary endpoint was similar between TAVR and SAVR (4.2% vs. 3.9%, OR 1.0, P = 0.89). Compared to SAVR, female TAVR patients had less hemorrhage requiring transfusion (12% vs. 21%, OR 0.41, P < 0.001), perioperative cardiac arrest and nonfatal myocardial infarction (9.8% vs. 17%, OR 0.38, P < 0.001), respiratory complication (1.6% vs. 4.4%, OR 0.28, P < 0.001), post‐op sepsis (1.7% vs. 2.9%, OR 0.65, P = 0.03), acute myocardial infarction (3.0% vs. 4.9%, OR 0.60, P < 0.001), and acute kidney injury (15% vs. 18%, OR 0.62, P < 0.001). Conversely, female TAVR patients had significantly increased risk of new pacemaker implantation (11% vs. 5.9%, OR 1.7, P < 0.001) and use of extracorporeal membrane oxygenation (0.66% vs. 0.24%, OR 2.8, P < 0.001). TAVR patients had less nonroutine discharge. The median hospital cost was significantly higher in TAVR than SAVR (median $51,274 vs. $43,677, P < 0.001) but the length of stay was shorter (mean 7.8 days vs. 10.5 days).ConclusionsTAVR may be a better option for those patients with underlying comorbidities that predispose them at higher risk for complications that was less observed in TAVR group. However, higher cost and increased risk of need for extracorporeal membrane oxygenation, although rare, should be taken into consideration upon deciding the optimal mode for aortic valve replacement.

Purpose Abemaciclib, a cyclin-dependent kinase 4 and 6 inhibitor, demonstrated efficacy as monotherapy and in combination with fulvestrant in women with hormone receptor (HR)–positive, human epidermal growth factor receptor 2 (HER2)–negative advanced breast cancer previously treated with endocrine therapy. Methods MONARCH 3 is a double-blind, randomized phase III study of abemaciclib or placebo plus a nonsteroidal aromatase inhibitor in 493 postmenopausal women with HR-positive, HER2-negative advanced breast cancer who had no prior systemic therapy in the advanced setting. Patients received abemaciclib or placebo (150 mg twice daily continuous schedule) plus either 1 mg anastrozole or 2.5 mg letrozole, daily. The primary objective was investigator-assessed progression-free survival. Secondary objectives included response evaluation and safety. A planned interim analysis occurred after 189 events. Results Median progression-free survival was significantly prolonged in the abemaciclib arm (hazard ratio, 0.54; 95% CI, 0.41 to 0.72; P = .000021; median: not reached in the abemaciclib arm, 14.7 months in the placebo arm). In patients with measurable disease, the objective response rate was 59% in the abemaciclib arm and 44% in the placebo arm ( P = .004). In the abemaciclib arm, diarrhea was the most frequent adverse effect (81.3%) but was mainly grade 1 (44.6%). Comparing abemaciclib and placebo, the most frequent grade 3 or 4 adverse events were neutropenia (21.1% v 1.2%), diarrhea (9.5% v 1.2%), and leukopenia (7.6% v 0.6%). Conclusion Abemaciclib plus a nonsteroidal aromatase inhibitor was effective as initial therapy, significantly improving progression-free survival and objective response rate and demonstrating a tolerable safety profile in women with HR-positive, HER2-negative advanced breast cancer.

AbstractBackgroundTo assess the impact of post transcatheter aortic valve implantation (TAVI) mild paravalvular regurgitation (PVR) on mortality. More than moderate PVR after TAVI has decreased with the advent of new‐generation prosthetic valves. However, mild PVR remains common and its clinical impact has been inconsistent. We aimed to assess the impact of mild PVR through meta‐analysis.Methods and ResultsA systematic literature search was conducted through PUBMED and EMBSE. Manuscripts that reported hazard ratio (HR) with 95% confidence interval (CI) for clinical outcome of interest (all‐cause and cardiac mortality) has been included. Random‐effects model was used for calculation of HR. A total of 25 articles including total of 21,018 patients were finally included for quantitative synthesis (meta‐analysis). Our pooled analysis demonstrated higher all‐cause mortality in patients with mild PVR compared to none/trivial PVR (HR 1.26, 95%CI 1.11–1.43, I2=45%, p < 0.001) (follow up duration range 6 months to 5 years). Significant heterogeneity among studies was observed (p for heterogeneity = 0.005). Egger's test showed no evidence of publication bias. Cardiovascular mortality was increased in patients with mild PVR compared with none/trivial PVR (HR 1.28, 95%CI 1.05–1.57, I2=8%, p = 0.02) (follow up duration range 1–3 years).ConclusionsMild PVR was associated with increased all‐cause and cardiovascular mortality after TAVI. Whether further interventions in mild PVR is of benefit, has yet to be determined.

Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease associated with autoimmune phenomena targeting intrahepatic bile duct cells (cholangiocytes). Although its etiopathogenesis remains obscure, development of antimitochondrial autoantibodies against pyruvate dehydrogenase complex E2 is a common feature. MicroRNA (miR) dysregulation occurs in liver and immune cells of PBC patients, but its functional relevance is largely unknown. We previously reported that miR‐506 is overexpressed in PBC cholangiocytes and directly targets both Cl – / anion exchanger 2 and type III inositol 1,4,5‐trisphosphate receptor, leading to cholestasis. Here, the regulation of miR‐506 gene expression and its role in cholangiocyte pathophysiology and immune activation was studied. Several proinflammatory cytokines overexpressed in PBC livers (such as interleukin‐8 [IL8], IL12, IL17, IL18, and tumor necrosis factor alpha) stimulated miR‐506 promoter activity in human cholangiocytes, as revealed by luciferase reporter assays. Experimental overexpression of miR‐506 in cholangiocytes dysregulated the cell proteomic profile (by mass spectrometry), affecting proteins involved in different biological processes including mitochondrial metabolism. In cholangiocytes, miR‐506 (1) induced dedifferentiation with down‐regulation of biliary and epithelial markers together with up‐regulation of mesenchymal, proinflammatory, and profibrotic markers; (2) impaired cell proliferation and adhesion; (3) increased oxidative and endoplasmic reticulum stress; (4) caused DNA damage; and (5) sensitized to caspase‐3‐dependent apoptosis induced by cytotoxic bile acids. These events were also associated with impaired energy metabolism in mitochondria (proton leak and less adenosine triphosphate production) and pyruvate dehydrogenase complex E2 overexpression. Coculture of miR‐506 overexpressing cholangiocytes with PBC immunocytes induced activation and proliferation of PBC immunocytes. Conclusion : Different proinflammatory cytokines enhance the expression of miR‐506 in biliary epithelial cells; miR‐506 induces PBC‐like features in cholangiocytes and promotes immune activation, representing a potential therapeutic target for PBC patients. (H epatology 2018;67:1420‐1440)