Adin Cristian Andrei

Sensitivity of hepatitis C virus to cyclosporine A depends on nonstructural proteins NS5A and NS5B

HCV reoccurs after liver transplantation and increases mortality. Cyclosporine, but not tacrolimus, has potent antiviral effects against HCV replication in cell culture. To determine the conditions, if any, under which HCV is susceptible to cyclosporine in vivo, we selected for cyclosporine‐resistant mutant HCV in vitro. The resulting mutations were mapped to x‐ray crystallographic structures and sequence databases. Mutations selected by cyclosporine were clustered in the nonstructural (NS) proteins NS5A and NS5B. Different sets of mutations in NS5A, paired with the same 2 NS5B mutations, conferred different levels of cyclosporine resistance when engineered back into the HCV replicon. Mutations in NS5B are structurally consistent with a proposed model of regulation of RNA binding by cyclophilin B (CyPB). These mutations also highlight a natural polymorphism between different HCV genotypes that correlates with the variation in response to cyclosporine A (CsA) noted in some clinical trials. Replicons engineered to have mutations in only NS5A (P ≤ 0.0001) or only NS5B (P = 0.002) suggest that while both NS5A or NS5B variants alter cyclosporine susceptibility, NS5A has the largest effect. Conclusion: Preexisting sequence variation could alter the effect of cyclosporine on HCV in vivo. (HEPATOLOGY 2007.)

Longitudinal change in the BODE index predicts mortality in severe emphysema.

RATIONALE The predictive value of longitudinal change in BODE (Body mass index, airflow Obstruction, Dyspnea, and Exercise capacity) index has received limited attention. We hypothesized that decrease in a modified BODE (mBODE) would predict survival in National Emphysema Treatment Trial (NETT) patients. OBJECTIVES To determine how the mBODE score changes in patients with lung volume reduction surgery versus medical therapy and correlations with survival. METHODS Clinical data were recorded using standardized instruments. The mBODE was calculated and patient-specific mBODE trajectories during 6, 12, and 24 months of follow-up were estimated using separate regressions for each patient. Patients were classified as having decreasing, stable, increasing, or missing mBODE based on their absolute change from baseline. The predictive ability of mBODE change on survival was assessed using multivariate Cox regression models. The index of concordance was used to directly compare the predictive ability of mBODE and its separate components. MEASUREMENTS AND MAIN RESULTS The entire cohort (610 treated medically and 608 treated surgically) was characterized by severe airflow obstruction, moderate breathlessness, and increased mBODE at baseline. A wide distribution of change in mBODE was seen at follow-up. An increase in mBODE of more than 1 point was associated with increased mortality in surgically and medically treated patients. Surgically treated patients were less likely to experience death or an increase greater than 1 in mBODE. Indices of concordance showed that mBODE change predicted survival better than its separate components. CONCLUSIONS The mBODE demonstrates short- and intermediate-term responsiveness to intervention in severe chronic obstructive pulmonary disease. Increase in mBODE of more than 1 point from baseline to 6, 12, and 24 months of follow-up was predictive of subsequent mortality. Change in mBODE may prove a good surrogate measure of survival in therapeutic trials in severe chronic obstructive pulmonary disease. Clinical trial registered with www.clinicaltrials.gov (NCT 00000606).

Targeted Anticoagulation for Atrial Fibrillation Guided by Continuous Rhythm Assessment With an Insertable Cardiac Monitor: The Rhythm Evaluation for Anticoagulation With Continuous Monitoring (REACT.COM) Pilot Study

Chronic anticoagulation is recommended for patients with AF and additional stroke risk factors, even during long periods of sinus rhythm. Continuous rhythm assessment with an insertable cardiac monitor (ICM) and use of rapid onset novel oral anticoagulants (NOACs) allow for targeted anticoagulation only around an AF episode, potentially reducing bleeding complications without compromising stroke risk.

Designated Liver Transplant Anesthesia Team Reduces Blood Transfusion, Need For Mechanical Ventilation, and Duration of Intensive Care

It was the area of manufacturing in which the idea of continuous quality improvement (CQI) originated and developed to what we consider a highly efficient model for all industries today. Since the 1980s, when the cost of healthcare began rising faster in the United States than the cost of living, quality issues have gradually gained importance for the medical industry and the government. Furthermore, a systematic assessment of healthcare by the Institute of Medicine in 1999 revealed shocking discrepancies between outcomes. One of the main findings suggested that, despite having one of the best acute care services in the world, the United States fails to deliver consistent quality. A growing body of research has confirmed the existence of wide variations that are attributable to differences in medical practices and are unrelated to patients’ preexisting medical conditions. Healthcare leaders recognized long ago that education and continuous systematic development are essential to improving outcome. To build on the strengths of the current system and address the weakness of inconsistent quality, healthcare organizations have initiated CQI processes with various degrees of success over the last few years. Our institution, the University of Wisconsin (UW), is a large transplant center with over 8000 organs transplanted to date, and it is regarded as a pioneer of organ preservation. This article describes the decision process, implementation, and results of a newly established dedicated liver transplant anesthesia team since 2003.

Diastolic Electromechanical Coupling Association of the ECG T-Peak to T-End Interval With Echocardiographic Markers of Diastolic Dysfunction

Background— Electromechanical coupling, a well-described phenomenon in systolic dysfunction, has not been well studied in diastole. We hypothesized that the ECG T-peak to T-end (TpTe) interval, representing transmural dispersion of repolarization, is associated with echocardiographic markers of diastolic dysfunction (DD). Methods and Results— We performed a prospective, cross-sectional study of the association between TpTe and markers of DD in 84 consecutive, unselected patients referred for exercise echocardiography. We systematically measured TpTe on the resting ECG, and we performed comprehensive assessment of DD at rest and at peak stress. ECGs and echocardiograms were analyzed independently, blinded to each other and to all clinical data. By univariable analysis, increased TpTe was associated with older age, increased E/e’ ratio, and DD ( P <0.05 for all associations after correcting for multiple comparisons). Increased TpTe was inversely associated with reduced tissue Doppler e’ velocity, a marker of DD ( R = −0.66, P <0.0001). This association persisted after adjusting for age, QTc, exercise-induced wall motion abnormalities, and left ventricular mass index (β= −0.41 [95% confidence interval, −0.70 to −0.12] cm/s per 10-ms increase in TpTe; P =0.006). Baseline TpTe was also independently associated with resting DD (adjusted odds ratio, 3.9 [95% confidence interval, 1.4–10.7]; P =0.009) and peak exercise E/e’ ratio ( P <0.0001). Conclusions— Increased TpTe is associated with both resting and exercise-induced DD. Electromechanical coupling may represent a pathophysiologic link between electrical transmural dispersion of repolarization and abnormal myocardial relaxation, and may be a novel therapeutic target.Background—Electromechanical coupling, a well-described phenomenon in systolic dysfunction, has not been well studied in diastole. We hypothesized that the ECG T-peak to T-end (TpTe) interval, representing transmural dispersion of repolarization, is associated with echocardiographic markers of diastolic dysfunction (DD). Methods and Results—We performed a prospective, cross-sectional study of the association between TpTe and markers of DD in 84 consecutive, unselected patients referred for exercise echocardiography. We systematically measured TpTe on the resting ECG, and we performed comprehensive assessment of DD at rest and at peak stress. ECGs and echocardiograms were analyzed independently, blinded to each other and to all clinical data. By univariable analysis, increased TpTe was associated with older age, increased E/e’ ratio, and DD (P<0.05 for all associations after correcting for multiple comparisons). Increased TpTe was inversely associated with reduced tissue Doppler e’ velocity, a marker of DD (R= −0.66, P<0.0001). This association persisted after adjusting for age, QTc, exercise-induced wall motion abnormalities, and left ventricular mass index (&bgr;= −0.41 [95% confidence interval, −0.70 to −0.12] cm/s per 10-ms increase in TpTe; P=0.006). Baseline TpTe was also independently associated with resting DD (adjusted odds ratio, 3.9 [95% confidence interval, 1.4–10.7]; P=0.009) and peak exercise E/e’ ratio (P<0.0001). Conclusions—Increased TpTe is associated with both resting and exercise-induced DD. Electromechanical coupling may represent a pathophysiologic link between electrical transmural dispersion of repolarization and abnormal myocardial relaxation, and may be a novel therapeutic target.

Diastolic Electromechanical Coupling: Association of the Electrocardiographic T-peak to T-end Interval with Echocardiographic Markers of Diastolic Dysfunction

Background— Electromechanical coupling, a well-described phenomenon in systolic dysfunction, has not been well studied in diastole. We hypothesized that the ECG T-peak to T-end (TpTe) interval, representing transmural dispersion of repolarization, is associated with echocardiographic markers of diastolic dysfunction (DD). Methods and Results— We performed a prospective, cross-sectional study of the association between TpTe and markers of DD in 84 consecutive, unselected patients referred for exercise echocardiography. We systematically measured TpTe on the resting ECG, and we performed comprehensive assessment of DD at rest and at peak stress. ECGs and echocardiograms were analyzed independently, blinded to each other and to all clinical data. By univariable analysis, increased TpTe was associated with older age, increased E/e’ ratio, and DD ( P <0.05 for all associations after correcting for multiple comparisons). Increased TpTe was inversely associated with reduced tissue Doppler e’ velocity, a marker of DD ( R = −0.66, P <0.0001). This association persisted after adjusting for age, QTc, exercise-induced wall motion abnormalities, and left ventricular mass index (β= −0.41 [95% confidence interval, −0.70 to −0.12] cm/s per 10-ms increase in TpTe; P =0.006). Baseline TpTe was also independently associated with resting DD (adjusted odds ratio, 3.9 [95% confidence interval, 1.4–10.7]; P =0.009) and peak exercise E/e’ ratio ( P <0.0001). Conclusions— Increased TpTe is associated with both resting and exercise-induced DD. Electromechanical coupling may represent a pathophysiologic link between electrical transmural dispersion of repolarization and abnormal myocardial relaxation, and may be a novel therapeutic target.Background—Electromechanical coupling, a well-described phenomenon in systolic dysfunction, has not been well studied in diastole. We hypothesized that the ECG T-peak to T-end (TpTe) interval, representing transmural dispersion of repolarization, is associated with echocardiographic markers of diastolic dysfunction (DD). Methods and Results—We performed a prospective, cross-sectional study of the association between TpTe and markers of DD in 84 consecutive, unselected patients referred for exercise echocardiography. We systematically measured TpTe on the resting ECG, and we performed comprehensive assessment of DD at rest and at peak stress. ECGs and echocardiograms were analyzed independently, blinded to each other and to all clinical data. By univariable analysis, increased TpTe was associated with older age, increased E/e’ ratio, and DD (P<0.05 for all associations after correcting for multiple comparisons). Increased TpTe was inversely associated with reduced tissue Doppler e’ velocity, a marker of DD (R= −0.66, P<0.0001). This association persisted after adjusting for age, QTc, exercise-induced wall motion abnormalities, and left ventricular mass index (&bgr;= −0.41 [95% confidence interval, −0.70 to −0.12] cm/s per 10-ms increase in TpTe; P=0.006). Baseline TpTe was also independently associated with resting DD (adjusted odds ratio, 3.9 [95% confidence interval, 1.4–10.7]; P=0.009) and peak exercise E/e’ ratio (P<0.0001). Conclusions—Increased TpTe is associated with both resting and exercise-induced DD. Electromechanical coupling may represent a pathophysiologic link between electrical transmural dispersion of repolarization and abnormal myocardial relaxation, and may be a novel therapeutic target.

Mortality While Waiting for Aortic Valve Replacement

BACKGROUND Severe symptomatic aortic stenosis (AS) is associated with high mortality without intervention. The impact of waiting time for aortic valve replacement (AVR), either surgically or transcatheter, has not been reported. METHODS From January 2008 to December 2012, we identified 1,005 patients with severe symptomatic AS. AVR was recommended for 823 patients (82%). Of these 823 patients, 721 (87.6%) underwent AVR. We modeled overall survival (OS) since AVR recommendation or intervention date using Cox and multistate models. RESULTS Overall, the median (first, third quartiles) waiting time until operation was 2.9 (1.3, 5.1) weeks. Mortality at these times was lower (p<0.001) in the AVR group (1.2%, 0.3%, 1.7%, respectively) than in the group that did not receive AVR (6.9%, 2.9%, 9.8%, respectively). Thirty-day mortality after AVR was 3.9% (3.2% surgical AVR [SAVR] and 7.0% transcatheter AVR [TAVR]). In patients receiving AVR, waiting time was not associated with increased mortality. Mortality while waiting for AVR was 3.7% and 11.6% at 1 and 6 months, respectively. Mortality while waiting for TAVR was higher than that for SAVR (1-, 6-, and 12-month mortality of 3.7%, 8.0%, and 9.6%, respectively, in SAVR group and 3.8%, 23.3%, and 27.5%, respectively, in TAVR group; p<0.001). CONCLUSIONS Some patients do not receive AVR in a timely fashion, and prolonged waiting time for AVR is associated with mortality greater than the AVR operative mortality. Although waiting time was not associated with poor operative outcomes after AVR, many patients may die while waiting for AVR. Patients should receive AVR on a semiurgent, not elective, basis.

The Perioperative Effect of Increased Body Mass Index on Peripheral Nerve Blockade: an Analysis of 528 Ultrasound Guided Interscalene Blocks

BACKGROUND AND OBJECTIVES Obese patients can pose a unique perioperative anesthetic challenge, making regional anesthetic techniques an intriguing means of providing analgesia for this population. Ultrasound guidance has been touted recently as being beneficial for this population in which surface landmarks can become obscured. In this study, the effect of increased Body Mass Index (BMI) on ultrasound guided interscalene peripheral nerve blockade is investigated. MATERIAL AND METHODS This study is a retrospective review of 528 consecutive patients who received preoperative ultrasound-guided interscalene nerve blocks at the University of Wisconsin Hospital and Clinics. We examined the association between BMI and the following parameters: time required for block placement; presence of Postoperative Nausea and Vomiting (PONV); postoperative Post Anesthesia Care Unit (PACU) pain scores; volume of local anesthetic injected; acute complications; and opioid administration preoperatively, intraoperatively, and postoperatively. Univariate and multivariate least squares and logistic regression models were used. RESULTS An elevated BMI was associated with an increased: time required for block placement (p-value=0.025), intraoperative fentanyl administration (p-value<0.001), peak PACU pain scores (p-value<0.001), PACU opioid administration (p-value<0.001), PACU oral opioid administration (p-value<0.001), total PACU opioid administration (p-value<0.001) and incidence of PACU nausea (p-value=0.025) CONCLUSIONS Ultrasound guided interscalene nerve blocks for perioperative analgesia can be safely and effectively performed in the obese patient but they may be more difficult to perform and analgesia may not be as complete.

Comparison of outcomes and presentation in men-versus-women with bicuspid aortic valves undergoing aortic valve replacement.

Gender disparities in short- and long-term outcomes have been documented in cardiac and valvular heart surgery. However, there is a paucity of data regarding these differences in the bicuspid aortic valve (BAV) population. The aim of this study was to examine gender-specific differences in short- and long-term outcomes after surgical aortic valve (AV) replacement in patients with BAV. A retrospective analysis was performed in 628 consecutive patients with BAV who underwent AV surgery from April 2004 to December 2013. To reduce bias when comparing outcomes by gender, propensity score matching obtained on the basis of potential confounders was used. Women with BAV who underwent AV surgery presented with more advanced age (mean 60.7 ± 13.8 vs 56.3 ± 13.6 years, p <0.001) and less aortic regurgitation (29% vs 44%, p <0.001) and had a higher risk for in-hospital mortality (mean Ambler score 3.4 ± 4.4 vs 2.5 ± 4.0, p = 0.015). After propensity score matching, women received more blood products postoperatively (48% vs 34%, p = 0.028) and had more prolonged postoperative lengths of stay (median 5 days [interquartile range 5 to 7] vs 5 days [interquartile range 4 to 6], p = 0.027). Operative, discharge, and 30-day mortality and overall survival were not significantly different. In conclusion, women with BAV who underwent AV surgery were older, presented with less aortic regurgitation, and had increased co-morbidities, lending higher operative risk. Although women received more blood products and had significantly longer lengths of stay, short- and long-term outcomes were similar.

The air-Q(®) intubating laryngeal airway vs the LMA-ProSeal(TM) : a prospective, randomised trial of airway seal pressure.

We performed a prospective, open‐label, randomised controlled trial comparing the air‐Q® against the LMA‐ProSeal™ in adults undergoing general anaesthesia. One hundred subjects (American Society of Anesthesiologists physical status 1–3) presenting for elective, outpatient surgery were randomly assigned to 52 air‐Q® and 48 ProSeal devices. The primary study endpoint was airway seal pressure. Oropharyngolaryngeal morbidity was assessed secondarily. Mean (SD) airway seal pressures for the air‐Q® and ProSeal were 30 (7) cmH2O and 30 (6) cmH2O, respectively (p = 0.47). Postoperative sore throat was more common with the air‐Q® (46% vs 38%, p = 0.03) as was pain on swallowing (30% vs 5%, p = 0.01). In conclusion, the air‐Q® performs well as a primary airway during the maintenance of general anaesthesia with an airway seal pressure similar to that of the ProSeal, but with a higher incidence of postoperative oropharyngolaryngeal complaints.