Alexandra Graf

Cardiac Magnetic Resonance Postcontrast T1 Time Is Associated With Outcome in Patients With Heart Failure and Preserved Ejection Fraction

Background—The underlying pathophysiology of heart failure with preserved ejection fraction (HFPEF) is incompletely understood, but myocardial extracellular matrix accumulation is thought to play a major role. Our aims were to estimate myocardial extracellular matrix using cardiac magnetic resonance T1 mapping and to assess the relationship between pathobiology/pathophysiology and prognosis. Methods and Results—Patients with suspected HFPEF (n=100) were enrolled in this prospective, observational study. Confirmatory diagnostic tests, cardiac magnetic resonance imaging including T1 mapping, and invasive hemodynamic assessments were performed at baseline. Sixty-one patients with confirmed HFPEF entered a longitudinal outcome-monitoring phase (mean, 22.9±5.0 months), during which 16 had a cardiac event. Cardiac magnetic resonance T1 time (hazard ratio, 0.99; 95% confidence interval, 0.98–0.99; P=0.046), left atrial area (hazard ratio, 1.08; 95% confidence interval, 1.03–1.13; P<0.01), and pulmonary vascular resistance (hazard ratio, 1.01; 95% confidence interval, 1.00–1.01; P=0.03) were significantly associated with cardiac events. Patients with T1 times below the median (<388.3 ms) were at greater risk of cardiac events than the rest of the group (P<0.01). Extracellular matrix of left ventricular biopsies (n=9), quantified by TissueFAXS technology correlated with T1 time (R=0.98; P<0.01). T1 time also correlated with right ventricular–pulmonary arterial coupling (pulmonary vascular resistance: R=−0.36; P<0.01; right ventricular ejection fraction: R=0.28; P=0.01). Conclusions—In the present preliminary study, cardiac magnetic resonance postcontrast T1 time is associated with prognosis in HFPEF, suggesting postcontrast T1 as possible biomarker for HFPEF.

Impact of tricuspid regurgitation on survival in patients with chronic heart failure: unexpected findings of a long-term observational study

AIMS Tricuspid regurgitation (TR) is common in patients with chronic heart failure (CHF) but its prognostic impact is unclear. METHODS AND RESULTS A total of 576 consecutive patients with CHF were prospectively included. The impact of moderate and severe (significant) TR on the combined endpoint death/heart transplantation/left ventricular-assist device implantation was assessed. Patients were followed for 5.8 ± 4.2 (maximum 14.4) years. Kaplan-Meier analysis showed a worse outcome of patients with significant TR (P < 0.0001). By multivariable analysis, amino terminal pro B-type natriuretic peptide (NT-proBNP) (P = 0.0028), systolic left ventricular function (LVF) (P = 0.0014), serum sodium, NYHA functional class, systolic blood pressure, right atrial size (all P = 0.0001), but not TR were significantly related with the outcome. However, as soon as the strong interaction between TR and LVF was included in the model, significant TR determined outcome as well (P = 0.0059). Therefore, in a second analysis patients were stratified for LVF. In patients with mildly or moderately impaired LVF, TR was significantly related with the outcome (HR: 1.368, CI: 1.070-1.748, P = 0.0125), whereas in patients with severely depressed LVF it was not (P = 0.1401). As a proof of concept, we additionally stratified patients according to serum NT-proBNP concentrations. In patients with NT-proBNP concentrations below the median (≤ 280 fmol/mL), TR was related with the outcome (HR: 2.512, CI: 1.127-5.597, P = 0.0242) but it was not in patients with NT-proBNP concentrations above the median (P = 0.3935). CONCLUSION The prognostic impact of TR depends on the severity of CHF. While TR was significantly related with excess mortality in mild to moderate CHF, it provided no additive value in advanced disease when compared with established risk factors.

The bi-objective stochastic covering tour problem

We formulate a bi-objective covering tour model with stochastic demand where the two objectives are given by (i) cost (opening cost for distribution centers plus routing cost for a fleet of vehicles) and (ii) expected uncovered demand. In the model, it is assumed that depending on the distance, a certain percentage of clients go from their homes to the nearest distribution center. An application in humanitarian logistics is envisaged. For the computational solution of the resulting bi-objective two-stage stochastic program with recourse, a branch-and-cut technique, applied to a sample-average version of the problem obtained from a fixed random sample of demand vectors, is used within an epsilon-constraint algorithm. Computational results on real-world data for rural communities in Senegal show the viability of the approach.

Right Ventricular Dysfunction, But Not Tricuspid Regurgitation, Is Associated With Outcome Late After Left Heart Valve Procedure

BACKGROUND Significant tricuspid regurgitation (TR) late after left heart valve procedure is frequent and associated with increased morbidity. Surgical correction carries a significant mortality risk, whereas the impact of TR on survival in these patients is unclear. OBJECTIVES This study sought to assess the impact of significant TR late after left heart valve procedure. METHODS A total of 539 consecutive patients with previous left heart valve procedure (time interval from valve procedure to enrollment 50 ± 30 months) were prospectively followed for 53 ± 15 months. RESULTS Significant TR (defined as moderate or greater severity by echocardiography) was present in 91 (17%) patients (65% female). Patients with TR presented with more symptoms (New York Heart Association functional class ≥II 55% vs. 31%), lower glomerular filtration rates (61 ± 19 ml/min vs. 68 ± 18 ml/min), and a higher likelihood of atrial fibrillation (41% vs. 20%), all statistically significant. Right ventricular (RV) systolic function was worse in patients with significant TR (RV fractional area change 43 ± 11% vs. 47 ± 9%, p < 0.001). A total of 117 (22%) patients died during follow-up. By Kaplan-Meier analysis, overall survival was significantly worse in patients with significant TR (log-rank p < 0.001). However, by multivariable Cox analysis, only RV fractional area change, age, left atrial size, diabetes, and previous coronary artery bypass graft procedure were significantly associated with mortality, but not tricuspid regurgitation. CONCLUSIONS RV dysfunction, but not significant TR, is independently associated with survival late after left heart valve procedure.

Neuromuscular electrical stimulation reduces skeletal muscle protein degradation and stimulates insulin-like growth factors in an age- and current-dependent manner: A randomized, controlled clinical trial in major abdominal surgical patients

Objective:To investigate the effect of neuromuscular electrical stimulation (NMES) on skeletal muscle metabolism after major abdominal surgery. Summary Background Data:Protein catabolism associated with surgical interventions leads to reduced muscle strength, increased clinical complications and prolonged convalescence. Immobilization is suggested as a major stimulus for muscle wasting. This study investigates the potency of NMES on skeletal muscle growth factors and degradation processes in surgical patients. Methods:This observer blind study included 26 patients after major abdominal surgery mainly due to cancer aged 60 ± 10 years. Starting on the first postoperative day, 1 randomly assigned thigh of each patient was treated on 4 consecutive days with NMES, whereas the other leg was used as sham-stimulated control. Thereafter, muscle biopsies from both legs were performed. Differences in mRNA level, protein expression, and enzyme activity between legs were analyzed by cross-over analysis of variance (Clinical Trial Registration Number: NCT00635440). Results:NMES significantly increased total RNA content and total sarcoplasmatic protein content. NMES significantly reduced ubiquitin-conjugated sarcoplasmatic proteins and proteasome activity. The mechano growth factor mRNA level correlated positively with the applied current and negatively with the body mass index of the patients. The increase in insulin like growth factor-1Ea mRNA after NMES correlated negatively with the age of the patients. Conclusions:This study shows that NMES significantly increases total RNA content and reduces protein degradation in postoperative patients. Moreover, the induction of growth factors by NMES reveals dependency on body mass index, age, and applied current. We conclude that NMES is a useful clinical tool to reduce protein catabolism in postoperative patients.

Trends in primary retinal detachment surgery: Results of a bicenter study

Purpose: To assess trends and outcomes in retinal detachment (RD) surgery based on a retrospective, interventional, bicenter study. Methods: Baseline demographic data, surgical procedures, and outcomes from 230 patients with a diagnosis of primary rhegmatogenous RD, who underwent surgery between January 2007 and December 2008 at the Rudolf Foundation Clinic, Vienna (Center 1) and the Weill Cornell Medical College, New York, (Center 2) were analyzed using a regression model. Results: Besides the baseline parameters, lens status (P = 0.01), refraction (P = 0.01), retinal tears (P < 0.02), proliferative vitreoretinopathy (P = 0.02), and previous treatment (P < 0.02), the primary RD procedure (P < 0.0001) was significantly different between the 2 centers. In Center 1, scleral buckling was the most common primary RD procedure (66.19%) compared with vitrectomy (82.42%) in Center 2. Primary retinal reattachment (88.49% Center 1 vs. 84.62% Center 2, P = 0.43) and best-corrected visual acuity at the final follow-up (best-corrected visual acuity ≥ 0.3 logarithm of minimum angle of resolution 48.92% Center 1 vs. 47.25% Center 2, P = 0.78) were not significantly different between the 2 centers. Conclusion: Although there is a trend toward primary vitrectomy, scleral buckling was preferred in the center in Vienna and primary vitrectomy in the center in New York. Despite the different primary RD procedures, anatomical and visual outcomes were comparable.

Combined medial and lateral anatomic ligament reconstruction for chronic rotational instability of the ankle.

Background: This study aimed to extend knowledge on the arthroscopic evaluation of the unstable ankle joint and the outcome of ligament reconstruction on rotational instability. In contrast to previous studies, we investigated the combined repair of lateral and medial ligaments. Methods: Ninety-six patients underwent medial and lateral ligament reconstruction between 2006 and 2008, 81 of whom, with a mean age of 31.9 (range, 14 to 44) years, completed the 12-month followup and were therefore included in this study (Table 1). Clinical, radiographic, and concomitant arthroscopic examination was performed prior to the ligament stabilization. Postoperative followup included clinical and radiographic evaluation after 3, 6, and 12 months. Results: Arthroscopy showed a lesion of the anterior fibulotalar ligament (AFTL), calcaneofibular ligament (CFL), and tibiocalcanear ligament (TCL) (Deep part of deltoid ligament complex) in 67 patients. An avulsion of the proximal insertion point of the ATTL was additionally found in 14 cases. Clinical results 3 months after surgery showed a significant increase in the AOFAS-Hindfoot Score as well as a significant decrease of the Visual Analogue-Scale for pain (VAS) (p < 0.0001). This outcome persisted at the 12-month examination. Conclusion: Rotational instability of the ankle joint in most cases has an injury of the lateral ligaments and a component of the deltoid, the TCL, but rarely with a combined lesion of the TCL and the anterior tibiotalar ligament (ATTL) (Superficial part of deltoid ligament complex). The combined lateral and medial ligament reconstruction with an anchor technique had a good clinical outcome with high patient satisfaction with few complications. Level of Evidence: IV, Retrospective Case Series

Survival of direct resin restorations in posterior teeth within a 19-year period (1996–2015): A meta-analysis of prospective studies

OBJECTIVES The aim of this study is to analyze the survival of posterior composite restorations published within the last 19 years (1996-2015). METHODS In this study only prospective, clinical trials with specification of the failure rate according to Class I/II composite fillings were included. Studies were analyzed according to the observation period (all studies vs. short-term vs. long-term studies). Retrospective studies and/or open laminate studies, tunnel restorations and Class V restorations were excluded. The following variables possibly influencing the failure rate were extracted from the studies: observation period, recall rate, average age of patients, number of patients, ratio of Class I/II fillings, number of restorations, ratio of premolars/molars, operator, method of isolation, bonding generation and filler size. RESULTS A total of 88 studies were included for statistical analysis. The observation period of the studies varied between 1 and 17 years, while most of the studies did not last longer than 5 years. Fracture of the restorations, secondary caries and marginal gap are the main causes for failure in the first 5 years (in descending order), while fracture and secondary caries are similarly distributed in long-term studies. Variables of investigation differed greatly in significance according to the respective observation period. The observation period, the recall rate, the ratio of Class I/II fillings and the number of restorations and patients had a significant influence on the overall failure rate when including all studies (short- and long-term). A linear correlation between the observation period and the failure rate was observed. In long-term studies these variables were not significant any longer. No significant difference in the failure rates between the materials per study was observed. The most common commercial composites investigated were: Tetric Ceram, Surefil, Filtek Supreme (incl. XT), Filtek Z250. The mean annual failure rate was 1.46% (±1.74%) for short-term studies and 1.97% (±1.53) for long-term studies. There is still a big need for clinical studies lasting longer than 5 years, as failure rates of composite restorations in posterior teeth increases with longer observation periods. SIGNIFICANCE A decreasing failure rate with an increasing recall rate as observed in our study suggests a patient selection in regard to availability and dental awareness. Internationally standardized evaluation criteria are mandatory in order to allow comparisons of the outcomes of clinical studies.

Preventive sublingual immunotherapy in preschool children: first evidence for safety and pro-tolerogenic effects.

Prevention of new IgE sensitizations has been described during allergen‐specific immunotherapy. However, prospective data using a preventive approach in very young children who would benefit most are missing. We initiated a prospective pilot study investigating the safety, immunomodulatory, and sensitization‐preventive effect of sublingual immunotherapy (SLIT) in mono/oligoclonally sensitized, clinically asymptomatic children 2–5 yr of age.

Methods for identification and confirmation of targeted subgroups in clinical trials: A systematic review

ABSTRACT Important objectives in the development of stratified medicines include the identification and confirmation of subgroups of patients with a beneficial treatment effect and a positive benefit-risk balance. We report the results of a literature review on methodological approaches to the design and analysis of clinical trials investigating a potential heterogeneity of treatment effects across subgroups. The identified approaches are classified based on certain characteristics of the proposed trial designs and analysis methods. We distinguish between exploratory and confirmatory subgroup analysis, frequentist, Bayesian and decision-theoretic approaches and, last, fixed-sample, group-sequential, and adaptive designs and illustrate the available trial designs and analysis strategies with published case studies.