Integration of Functional Imaging, Cytometry, and Unbiased Proteomics Reveals New Features of Endothelial-to-Mesenchymal Transition in Ischemic Mitral Valve Regurgitation in Human Patients.

Background: Following myocardial infarction, mitral regurgitation (MR) is a common complication. Previous animal studies demonstrated the association of endothelial-to-mesenchymal transition (EndMT) with mitral valve (MV) remodeling. Nevertheless, little is known about how MV tissue responds to ischemic heart changes in humans. Methods: MVs were obtained by the Cardiothoracic Surgical Trials Network from 17 patients with ischemic mitral regurgitation (IMR). Echo-doppler imaging assessed MV function at time of resection. Cryosections of MVs were analyzed using a multi-faceted histology and immunofluorescence examination of cell populations. MVs were further analyzed using unbiased label-free proteomics. Echo-Doppler imaging, histo-cytometry measures and proteomic analysis were then integrated. Results: MVs from patients with greater MR exhibited proteomic changes associated with proteolysis-, inflammatory- and oxidative stress-related processes compared to MVs with less MR. Cryosections of MVs from patients with IMR displayed activated valvular interstitial cells (aVICs) and double positive CD31+ αSMA+ cells, a hallmark of EndMT. Univariable and multivariable association with echocardiography measures revealed a positive correlation of MR severity with both cellular and geometric changes (e.g., aVICs, EndMT, leaflet thickness, leaflet tenting). Finally, proteomic changes associated with EndMT showed gene-ontology enrichment in vesicle-, inflammatory- and oxidative stress-related processes. This discovery approach indicated new candidate proteins associated with EndMT regulation in IMR. Conclusion: We describe an atypical cellular composition and distinctive proteome of human MVs from patients with IMR, which highlighted new candidate proteins implicated in EndMT-related processes, associated with maladaptive MV fibrotic remodeling.

Impact of the KCNQ2/3 Channel Opener Ezogabine on Reward Circuit Activity and Clinical Symptoms in Depression: Results From a Randomized Controlled Trial.

OBJECTIVE: Preclinical studies point to the KCNQ2/3 potassium channel as a novel target for the treatment of depression and anhedonia, a reduced ability to experience pleasure. The authors conducted the first randomized placebo-controlled trial testing the effect of the KCNQ2/3 positive modulator ezogabine on reward circuit activity and clinical outcomes in patients with depression. METHODS: Depressed individuals (N=45) with elevated levels of anhedonia were assigned to a 5-week treatment period with ezogabine (900 mg/day; N=21) or placebo (N=24). Participants underwent functional MRI during a reward flanker task at baseline and following treatment. Clinical measures of depression and anhedonia were collected at weekly visits. The primary endpoint was the change from baseline to week 5 in ventral striatum activation during reward anticipation. Secondary endpoints included depression and anhedonia severity as measured using the Montgomery-Åsberg Depression Rating Scale (MADRS) and the Snaith-Hamilton Pleasure Scale (SHAPS), respectively. RESULTS: The study did not meet its primary neuroimaging endpoint. Participants in the ezogabine group showed a numerical increase in ventral striatum response to reward anticipation following treatment compared with participants in the placebo group from baseline to week 5. Compared with placebo, ezogabine was associated with a significantly larger improvement in MADRS and SHAPS scores and other clinical endpoints. Ezogabine was well tolerated, and no serious adverse events occurred. CONCLUSIONS: The study did not meet its primary neuroimaging endpoint, although the effect of treatment was significant on several secondary clinical endpoints. In aggregate, the findings may suggest that future studies of the KCNQ2/3 channel as a novel treatment target for depression and anhedonia are warranted.

Intraoperative MRI versus 5-ALA in high-grade glioma resection: a network meta-analysis.

OBJECTIVE: High-grade gliomas (HGGs) continue to carry poor prognoses, and patient outcomes depend heavily on the extent of resection (EOR). The utility of conventional image-guided surgery is limited by intraoperative brain shift. More recent techniques to maximize EOR, including intraoperative imaging and the use of fluorescent dyes, combat these limitations. However, the relative efficacy of these two techniques has never been systematically compared. Thus, the authors performed an exhaustive systematic review in conjunction with quantitative network meta-analyses to evaluate the comparative effectiveness of 5-aminolevulinic acid (5-ALA) and intraoperative MRI (IMRI) in optimizing EOR in HGG. They secondarily analyzed associated progression-free and overall survival and performed subgroup analyses by level of evidence. METHODS: PubMed, Embase, Cochrane Central, and Web of Science were searched for studies evaluating conventional neuronavigation, IMRI, and 5-ALA in HGG resection. The primary study endpoint was the proportion of patients attaining gross-total resection (GTR), defined as 100% elimination of contrast-enhancing lesion on postoperative MRI. Secondary endpoints included overall and progression-free survival and subgroup analyses for level of evidence. Comparative efficacy analysis of IMRI and 5-ALA was performed using Bayesian network meta-analysis models. RESULTS: This analysis included 11 studies. In a classic meta-analysis, both IMRI (OR 4.99, 95% CI 2.65-9.39, p < 0.001) and 5-ALA (OR 2.866, 95% CI 2.127-3.863, p < 0.001) were superior to conventional navigation in achieving GTR. Bayesian network analysis was employed to indirectly compare IMRI to 5-ALA, and no significant difference in GTR was found between the two (OR 1.9 favoring IMRI, 95% CI 0.905-3.989, p = 0.090). A handful of studies additionally suggested that the use of either IMRI (2 and 4 studies, respectively) or 5-ALA (2 and 2 studies, respectively) improves progression-free and overall survival. CONCLUSIONS: IMRI and 5-ALA are individually superior to conventional neuronavigation for achieving GTR of HGG. Between IMRI and 5-ALA, neither method is clearly more effective. Future studies evaluating the comparative cost and surgical time associated with IMRI and 5-ALA will better inform any cost-benefit analysis.

Analysis of Local Control and Pain Control After Spine Stereotactic Radiosurgery Reveals Inferior Outcomes for Hepatocellular Carcinoma Compared With Other Radioresistant Histologies.

PURPOSE: This study aimed to evaluate the efficacy of stereotactic radiosurgery (SRS) for spinal metastases from hepatocellular carcinoma (HCC) compared with other radioresistant histologies (renal cell carcinoma [RCC], melanoma, and sarcoma) in terms of local control (LC) and pain control. METHODS AND MATERIALS: We performed a retrospective review of patients treated with SRS to the spine for metastatic HCC, RCC, melanoma, and sarcoma between January 2007 and May 2014. Radiographic assessments of LC, overall survival, and patient-reported pain control were analyzed as univariable analyses and with various patient- and treatment-related parameters as multivariable analyses (MVA). RESULTS: Of the 96 patients treated with SRS, 41 patients had radioresistant histologies, including 18 HCC, 1 mixed HCC and cholangiocarcinoma, 15 RCC, 6 melanoma, and 1 leiomyosarcoma. Extraosseous disease was present in 63% of patients (74% in HCC; 55% in non-HCC; P = not significant). Spinal cord compression was present in 29% of patients (32% in HCC; 27% in non-HCC; P = not significant), and 24% of patients had decompressive surgery before SRS (26% in HCC; 23% in non-HCC; P = not significant). With a median follow-up time of 8.7 months, the actuarial 3-, 6-, and 12-month LC rates were 71%, 61%, 41%, respectively, for HCC, and 94%, 94%, and 85%, respectively, for non-HCC. The median time to local failure was 3 months for HCC and 11 months for non-HCC. On MVA, there was a strong trend toward inferior LC with HCC (P = .059). Of the 28 patients with pretreatment pain, pain relief was achieved in 93% of patients, but the 2 patients who did not experience pain relief both had HCC. The actuarial 3-, 6-, and 12-month pain control rates were 68%, 51%, 17%, respectively, for HCC, and 100%, 89%, and 89%, respectively, for non-HCC (P = .023), and remained significant on MVA (P = .034). CONCLUSIONS: Compared with other radioresistant histologies, HCC has inferior LC and pain relief after SRS. Whether HCC may benefit from further dose escalation or combined treatment with new therapies is an area of future research.

Secondary surgical-site infection after coronary artery bypass grafting: A multi-institutional prospective cohort study.

OBJECTIVE: To analyze patient risk factors and processes of care associated with secondary surgical-site infection (SSI) after coronary artery bypass grafting (CABG). METHODS: Data were collected prospectively between February and October 2010 for consenting adult patients undergoing CABG with saphenous vein graft (SVG) conduits. Patients who developed a deep or superficial SSI of the leg or groin within 65 days of CABG were compared with those who did not develop a secondary SSI. RESULTS: Among 2174 patients identified, 65 (3.0%) developed a secondary SSI. Median time to diagnosis was 16 days (interquartile range 11-29) with the majority (86%) diagnosed after discharge. Gram-positive bacteria were most common. Readmission was more common in patients with a secondary SSI (34% vs 17%, P < .01). After adjustment, an open SVG harvest approach was associated with an increased risk of secondary SSI (adjusted hazard ratio [HR], 2.12; 95% confidence interval [CI], 1.28-3.48). Increased body mass index (adjusted HR, 1.08, 95% CI, 1.04-1.12) and packed red blood cell transfusions (adjusted HR, 1.13; 95% CI, 1.05-1.22) were associated with a greater risk of secondary SSI. Antibiotic type, antibiotic duration, and postoperative hyperglycemia were not associated with risk of secondary SSI. CONCLUSIONS: Secondary SSI after CABG continues to be an important source of morbidity. This serious complication often occurs after discharge and is associated with open SVG harvesting, larger body mass, and blood transfusions. Patients with a secondary SSI have longer lengths of stay and are readmitted more frequently.

A Prospective Multi-Institutional Cohort Study of Mediastinal Infections After Cardiac Operations.

BACKGROUND: Mediastinal infections are a potentially devastating complication of cardiac operations. This study analyzed the frequency, risk factors, and perioperative outcomes of mediastinal infections after cardiac operations. METHODS: In 2010, 5,158 patients enrolled in a prospective study evaluating infections after cardiac operations and their effect on readmissions and mortality for up to 65 days after the procedure. Clinical and demographic characteristics, operative variables, management practices, and outcomes were compared for patients with and without mediastinal infections, defined as deep sternal wound infection, myocarditis, pericarditis, or mediastinitis. RESULTS: There were 43 mediastinal infections in 41 patients (cumulative incidence, 0.79%; 95% confidence interval [CI] 0.60% to 1.06%). Median time to infection was 20.0 days, with 65% of infections occurring after the index hospitalization discharge. Higher body mass index (hazard ratio [HR] 1.06; 95% CI, 1.01 to 1.10), higher creatinine (HR, 1.25; 95% CI, 1.13 to 1.38), peripheral vascular disease (HR, 2.47; 95% CI, 1.21 to 5.05), preoperative corticosteroid use (HR, 3.33; 95% CI, 1.27 to 8.76), and ventricular assist device or transplant surgery (HR, 5.81; 95% CI, 2.36 to 14.33) were associated with increased risk of mediastinal infection. Postoperative hyperglycemia (HR, 3.15; 95% CI, 1.32 to 7.51) was associated with increased risk of infection in nondiabetic patients. Additional length of stay attributable to mediastinal infection was 11.5 days (bootstrap 95% CI, 1.88 to 21.11). Readmission rates and mortality were five times higher in patients with mediastinal infection than in patients without mediastinal infection. CONCLUSIONS: Mediastinal infection after a cardiac operation is associated with substantial increases in length of stay, readmissions, and death. Reducing these infections remains a high priority, and improving post-operative glycemic management may reduce their risk in patients without diabetes.

A multi-institutional cohort study confirming the risks of Clostridium difficile infection associated with prolonged antibiotic prophylaxis.

OBJECTIVES: The incidence and severity of Clostridium difficile infection (CDI) have increased rapidly over the past 2 decades, particularly in elderly patients with multiple comorbidities. This study sought to characterize the incidence and risks of these infections in cardiac surgery patients. METHODS: A total of 5158 patients at 10 Cardiothoracic Surgical Trials Network sites in the US and Canada participated in a prospective study of major infections after cardiac surgery. Patients were followed for infection, readmission, reoperation, or death up to 65 days after surgery. We compared clinical and demographic characteristics, surgical data, management practices, and outcomes for patients with CDI and without CDI. RESULTS: C difficile was the third most common infection observed (0.97%) and was more common in patients with preoperative comorbidities and complex operations. Antibiotic prophylaxis for >2 days, intensive care unit stay >2 days, and postoperative hyperglycemia were associated with increased risk of CDI. The median time to onset was 17 days; 48% of infections occurred after discharge. The additional length of stay due to infection was 12 days. The readmission and mortality rates were 3-fold and 5-fold higher, respectively, in patients with CDI compared with uninfected patients. CONCLUSIONS: In this large multicenter prospective study of major infections following cardiac surgery, CDI was encountered in nearly 1% of patients, was frequently diagnosed postdischarge, and was associated with extended length of stay and substantially increased mortality. Patients with comorbidities, longer surgery time, extended antibiotic exposure, and/or hyperglycemic episodes were at increased risk for CDI.

Diabetes Is Associated With Reduced Stress Hyperlactatemia in Cardiac Surgery.

OBJECTIVE: Hyperglycemia and hyperlactatemia are associated with increased morbidity and mortality in critical illness. We evaluated the relationship among hyperlactatemia, glycemic control, and diabetes mellitus (DM) after cardiac surgery. RESEARCH DESIGN AND METHODS: This was a retrospective cohort study of 4,098 cardiac surgery patients treated between 2011 and 2015. Patients were stratified by DM and glucose-lowering medication history. Hyperglycemia (glucose >180 mg/dL), hypoglycemia (<70 mg/dL), and the hyperglycemic index were assessed postoperatively (48 h). The relationship between lactate and glucose levels was modeled using generalized linear regression. Mortality was analyzed using an extended Cox regression model. RESULTS: Hyperglycemia occurred in 26.0% of patients without DM (NODM), 46.5% with DM without prior drug treatment (DMNT), 62.8% on oral medication (DMOM), and 73.8% on insulin therapy (DMIT) (P < 0.0001). Hypoglycemia occurred in 6.3%, 9.1%, 8.8%, and 10.8% of NODM, DMNT, DMOM, and DMIT, respectively (P = 0.0012). The lactate levels of all patients were temporarily increased with surgery. This increase was greater in patients who also had hyperglycemia or hypoglycemia and was markedly attenuated in patients with DM. Peak lactate was 5.8 mmol/L (95% CI 5.6, 6.0) in NODM with hyperglycemia vs. 3.3 (95% CI 3.2, 3.4) without hyperglycemia; in DMNT: 4.8 (95% CI 4.4, 5.2) vs. 3.4 (95% CI 3.1, 3.6); in DMOM: 3.8 (95% CI 3.5, 4.1) vs. 2.9 (95% CI 2.7, 3.1); and in DMIT: 3.3 (95% CI 3.0, 3.5) vs. 2.7 (95% CI 2.3, 3.0). Increasing lactate levels were associated with increasing mortality; increasing glucose reduced this effect in DM but not in NODM (P = 0.0069 for three-way interaction). CONCLUSIONS: Stress hyperlactatemia is markedly attenuated in patients with DM. There is a three-way interaction among DM, stress hyperlactatemia, and stress hyperglycemia associated with mortality after cardiac surgery.

Rate Control versus Rhythm Control for Atrial Fibrillation after Cardiac Surgery.

BACKGROUND: Atrial fibrillation after cardiac surgery is associated with increased rates of death, complications, and hospitalizations. In patients with postoperative atrial fibrillation who are in stable condition, the best initial treatment strategy--heart-rate control or rhythm control--remains controversial. METHODS: Patients with new-onset postoperative atrial fibrillation were randomly assigned to undergo either rate control or rhythm control. The primary end point was the total number of days of hospitalization within 60 days after randomization, as assessed by the Wilcoxon rank-sum test. RESULTS: Postoperative atrial fibrillation occurred in 695 of the 2109 patients (33.0%) who were enrolled preoperatively; of these patients, 523 underwent randomization. The total numbers of hospital days in the rate-control group and the rhythm-control group were similar (median, 5.1 days and 5.0 days, respectively; P=0.76). There were no significant between-group differences in the rates of death (P=0.64) or overall serious adverse events (24.8 per 100 patient-months in the rate-control group and 26.4 per 100 patient-months in the rhythm-control group, P=0.61), including thromboembolic and bleeding events. About 25% of the patients in each group deviated from the assigned therapy, mainly because of drug ineffectiveness (in the rate-control group) or amiodarone side effects or adverse drug reactions (in the rhythm-control group). At 60 days, 93.8% of the patients in the rate-control group and 97.9% of those in the rhythm-control group had had a stable heart rhythm without atrial fibrillation for the previous 30 days (P=0.02), and 84.2% and 86.9%, respectively, had been free from atrial fibrillation from discharge to 60 days (P=0.41). CONCLUSIONS: Strategies for rate control and rhythm control to treat postoperative atrial fibrillation were associated with equal numbers of days of hospitalization, similar complication rates, and similarly low rates of persistent atrial fibrillation 60 days after onset. Neither treatment strategy showed a net clinical advantage over the other. (Funded by the National Institutes of Health and the Canadian Institutes of Health Research; ClinicalTrials.gov number, NCT02132767.).

The VA augmentation and switching treatments for improving depression outcomes (VAST-D) study: Rationale and design considerations.

Because two-thirds of patients with Major Depressive Disorder do not achieve remission with their first antidepressant, we designed a trial of three "next-step" strategies: switching to another antidepressant (bupropion-SR) or augmenting the current antidepressant with either another antidepressant (bupropion-SR) or with an atypical antipsychotic (aripiprazole). The study will compare 12-week remission rates and, among those who have at least a partial response, relapse rates for up to 6 months of additional treatment. We review seven key efficacy/effectiveness design decisions in this mixed "efficacy-effectiveness" trial.

The VACS index accurately predicts mortality and treatment response among multi-drug resistant HIV infected patients participating in the options in management with antiretrovirals (OPTIMA) study.

OBJECTIVES: The VACS Index is highly predictive of all-cause mortality among HIV infected individuals within the first few years of combination antiretroviral therapy (cART). However, its accuracy among highly treatment experienced individuals and its responsiveness to treatment interventions have yet to be evaluated. We compared the accuracy and responsiveness of the VACS Index with a Restricted Index of age and traditional HIV biomarkers among patients enrolled in the OPTIMA study. METHODS: Using data from 324/339 (96%) patients in OPTIMA, we evaluated associations between indices and mortality using Kaplan-Meier estimates, proportional hazards models, Harrel's C-statistic and net reclassification improvement (NRI). We also determined the association between study interventions and risk scores over time, and change in score and mortality. RESULTS: Both the Restricted Index (c = 0.70) and VACS Index (c = 0.74) predicted mortality from baseline, but discrimination was improved with the VACS Index (NRI = 23%). Change in score from baseline to 48 weeks was more strongly associated with survival for the VACS Index than the Restricted Index with respective hazard ratios of 0.26 (95% CI 0.14-0.49) and 0.39(95% CI 0.22-0.70) among the 25% most improved scores, and 2.08 (95% CI 1.27-3.38) and 1.51 (95%CI 0.90-2.53) for the 25% least improved scores. CONCLUSIONS: The VACS Index predicts all-cause mortality more accurately among multi-drug resistant, treatment experienced individuals and is more responsive to changes in risk associated with treatment intervention than an index restricted to age and HIV biomarkers. The VACS Index holds promise as an intermediate outcome for intervention research.