Remote Follow-up in a Heart Failure Pragmatic Trial: Insights From the CONNECT-HF.

BACKGROUND: Randomized controlled trials typically require study-specific visits, which can burden participants and sites. Remote follow-up, such as centralized call centers for participant-reported or site-reported, holds promise for reducing costs and enhancing the pragmatism of trials. In this secondary analysis of the CONNECT-HF (Care Optimization Through Patient and Hospital Engagement For HF) trial, we aimed to evaluate the completeness and validity of the remote follow-up process. METHODS AND RESULTS: The CONNECT-HF trial evaluated the effect of a post-discharge quality-improvement intervention for heart failure compared to usual care for up to 1 year. Suspected events were reported either by participants or by health care proxies through a centralized call center or by sites through medical-record queries. When potential hospitalization events were suspected, additional medical records were collected and adjudicated. Among 5942 potential hospitalizations, 18% were only participant-reported, 28% were reported by both participants and sites, and 50% were only site-reported. Concordance rates between the participant/site reports and adjudication for hospitalization were high: 87% participant-reported, 86% both, and 86% site-reported. Rates of adjudicated heart failure hospitalization events among adjudicated all-cause hospitalization were lower but also consistent: 45% participant-reported, 50% both, and 50% site-reported. CONCLUSIONS: Participant-only and site-only reports missed a substantial number of hospitalization events. We observed similar concordance between participant/site reports and adjudication for hospitalizations. Combining participant-reported and site-reported outcomes data is important to capture and validate hospitalizations effectively in pragmatic heart failure trials.

Trajectories of Palliative Care Needs in the ICU and Long-Term Psychological Distress Symptoms.

OBJECTIVES: While palliative care needs are assumed to improve during ICU care, few empiric data exist on need trajectories or their impact on long-term outcomes. We aimed to describe trajectories of palliative care needs during ICU care and to determine if changes in needs over 1 week was associated with similar changes in psychological distress symptoms at 3 months. DESIGN: Prospective cohort study. SETTING: Six adult medical and surgical ICUs. PARTICIPANTS: Patients receiving mechanical ventilation for greater than or equal to 2 days and their family members. MEASUREMENTS AND MAIN RESULTS: The primary outcome was the 13-item Needs at the End-of-Life Screening Tool (NEST; total score range 0-130) completed by family members at baseline, 3, and 7 days. The Patient Health Questionnaire-9 (PHQ-9), Generalized Anxiety Disorder-7 (GAD-7), and Post-Traumatic Stress Scale (PTSS) were completed at baseline and 3 months. General linear models were used to estimate differences in distress symptoms by change in need (NEST improvement ≥ 10 points or not). One-hundred fifty-nine family members participated (median age, 54.0 yr [interquartile range (IQR), 44.0-63.0 yr], 125 [78.6%] female, 54 [34.0%] African American). At 7 days, 53 (33%) a serious level of overall need and 35 (22%) ranked greater than or equal to 1 individual need at the highest severity level. NEST scores improved greater than or equal to 10 points in only 47 (30%). Median NEST scores were 22 (IQR, 12-40) at baseline and 19 (IQR, 9-37) at 7 days (change, -2.0; IQR, -11.0 to 5.0; p = 0.12). There were no differences in PHQ-9, GAD-7, or PTSS change scores by change in NEST score (all p > 0.15). CONCLUSIONS: Serious palliative care needs were common and persistent among families during ICU care. Improvement in needs was not associated with less psychological distress at 3 months. Serious needs may be commonly underrecognized in current practice.

Effect of a Hospital and Postdischarge Quality Improvement Intervention on Clinical Outcomes and Quality of Care for Patients With Heart Failure With Reduced Ejection Fraction: The CONNECT-HF Randomized Clinical Trial.

Importance: Adoption of guideline-directed medical therapy for patients with heart failure is variable. Interventions to improve guideline-directed medical therapy have failed to consistently achieve target metrics, and limited data exist to inform efforts to improve heart failure quality of care. Objective: To evaluate the effect of a hospital and postdischarge quality improvement intervention compared with usual care on heart failure outcomes and care. Design, Setting, and Participants: This cluster randomized clinical trial was conducted at 161 US hospitals and included 5647 patients (2675 intervention vs 2972 usual care) followed up after a hospital discharge for acute heart failure with reduced ejection fraction (HFrEF). The trial was performed from 2017 to 2020, and the date of final follow-up was August 31, 2020. Interventions: Hospitals (n = 82) randomized to a hospital and postdischarge quality improvement intervention received regular education of clinicians by a trained group of heart failure and quality improvement experts and audit and feedback on heart failure process measures (eg, use of guideline-directed medical therapy for HFrEF) and outcomes. Hospitals (n = 79) randomized to usual care received access to a generalized heart failure education website. Main Outcomes and Measures: The coprimary outcomes were a composite of first heart failure rehospitalization or all-cause mortality and change in an opportunity-based composite score for heart failure quality (percentage of recommendations followed). Results: Among 5647 patients (mean age, 63 years; 33% women; 38% Black; 87% chronic heart failure; 49% recent heart failure hospitalization), vital status was known for 5636 (99.8%). Heart failure rehospitalization or all-cause mortality occurred in 38.6% in the intervention group vs 39.2% in usual care (adjusted hazard ratio, 0.92 [95% CI, 0.81 to 1.05). The baseline quality-of-care score was 42.1% vs 45.5%, respectively, and the change from baseline to follow-up was 2.3% vs -1.0% (difference, 3.3% [95% CI, -0.8% to 7.3%]), with no significant difference between the 2 groups in the odds of achieving a higher composite quality score at last follow-up (adjusted odds ratio, 1.06 [95% CI, 0.93 to 1.21]). Conclusions and Relevance: Among patients with HFrEF in hospitals randomized to a hospital and postdischarge quality improvement intervention vs usual care, there was no significant difference in time to first heart failure rehospitalization or death, or in change in a composite heart failure quality-of-care score. Trial Registration: ClinicalTrials.gov Identifier: NCT03035474.

Evolution of drug resistance in HIV protease.

BACKGROUND: Drug resistance is a critical problem limiting effective antiviral therapy for HIV/AIDS. Computational techniques for predicting drug resistance profiles from genomic data can accelerate the appropriate choice of therapy. These techniques can also be used to identify protease mutants for experimental studies of resistance and thereby assist in the development of next-generation therapies. Few studies, however, have assessed the evolution of resistance from genotype-phenotype data. RESULTS: The machine learning produced highly accurate and robust classification of resistance to HIV protease inhibitors. Genotype data were mapped to the enzyme structure and encoded using Delaunay triangulation. Estimates of evolutionary relationships, based on this encoding, and using Minimum Spanning Trees, showed clusters of mutations that closely resemble the wild type. These clusters appear to evolve uniquely to more resistant phenotypes. CONCLUSIONS: Using the triangulation metric and spanning trees results in paths that are consistent with evolutionary theory. The majority of the paths show bifurcation, namely they switch once from non-resistant to resistant or from resistant to non-resistant. Paths that lose resistance almost uniformly have far lower levels of resistance than those which either gain resistance or are stable. This strongly suggests that selection for stability in the face of a rapid rate of mutation is as important as selection for resistance in retroviral systems.

Frequency, Regional Variation, and Predictors of Undetermined Cause of Death in Cardiometabolic Clinical Trials: A Pooled Analysis of 9259 Deaths in 9 Trials.

BACKGROUND: Modern cardiometabolic clinical trials often include cardiovascular death as a component of a composite primary outcome, requiring central adjudication by a clinical events committee to classify cause of death. However, sometimes the cause of death cannot be determined from available data. The US Food and Drug Administration has indicated that this circumstance should occur only rarely, but its prevalence has not been formally assessed. METHODS: Data from 9 global clinical trials (2009-2017) with long-term follow-up and blinded, centrally adjudicated cause of death were used to calculate the proportion of deaths attributed to cardiovascular, noncardiovascular, or undetermined causes by therapeutic area (diabetes mellitus/pre-diabetes mellitus, stable atherosclerosis, atrial fibrillation, and acute coronary syndrome), region of patient enrollment, and year of trial manuscript publication. Patient- and trial-level variables associated with undetermined cause of death were identified using a logistic model. RESULTS: Across 127 049 enrolled participants from 9 trials, there were 9259 centrally adjudicated deaths: 5012 (54.1%) attributable to cardiovascular causes, 2800 (30.2%) attributable to noncardiovascular causes, and 1447 (15.6%) attributable to undetermined causes. There was variability in the proportion of deaths ascribed to undetermined causes by trial therapeutic area, region of enrollment, and year of trial manuscript publication. On multivariable analysis, acute coronary syndrome or atrial fibrillation trial (versus atherosclerotic vascular disease or diabetes mellitus/pre-diabetes mellitus), longer time from enrollment to death, more recent trial manuscript publication year, enrollment in North America (versus Western Europe), female sex, and older age were associated with greater likelihood of death of undetermined cause. CONCLUSIONS: In 9 cardiometabolic clinical trials with long-term follow-up, approximately 16% of deaths had undetermined causes. This provides a baseline for quality assessment of clinical trials and informs operational efforts to potentially reduce the frequency of undetermined deaths in future clinical research.

Levosimendan in Patients with Left Ventricular Dysfunction Undergoing Cardiac Surgery.

BACKGROUND: Levosimendan is an inotropic agent that has been shown in small studies to prevent or treat the low cardiac output syndrome after cardiac surgery. METHODS: In a multicenter, randomized, placebo-controlled, phase 3 trial, we evaluated the efficacy and safety of levosimendan in patients with a left ventricular ejection fraction of 35% or less who were undergoing cardiac surgery with the use of cardiopulmonary bypass. Patients were randomly assigned to receive either intravenous levosimendan (at a dose of 0.2 µg per kilogram of body weight per minute for 1 hour, followed by a dose of 0.1 µg per kilogram per minute for 23 hours) or placebo, with the infusion started before surgery. The two primary end points were a four-component composite of death through day 30, renal-replacement therapy through day 30, perioperative myocardial infarction through day 5, or use of a mechanical cardiac assist device through day 5; and a two-component composite of death through day 30 or use of a mechanical cardiac assist device through day 5. RESULTS: A total of 882 patients underwent randomization, 849 of whom received levosimendan or placebo and were included in the modified intention-to-treat population. The four-component primary end point occurred in 105 of 428 patients (24.5%) assigned to receive levosimendan and in 103 of 421 (24.5%) assigned to receive placebo (adjusted odds ratio, 1.00; 99% confidence interval [CI], 0.66 to 1.54; P=0.98). The two-component primary end point occurred in 56 patients (13.1%) assigned to receive levosimendan and in 48 (11.4%) assigned to receive placebo (adjusted odds ratio, 1.18; 96% CI, 0.76 to 1.82; P=0.45). The rate of adverse events did not differ significantly between the two groups. CONCLUSIONS: Prophylactic levosimendan did not result in a rate of the short-term composite end point of death, renal-replacement therapy, perioperative myocardial infarction, or use of a mechanical cardiac assist device that was lower than the rate with placebo among patients with a reduced left ventricular ejection fraction who were undergoing cardiac surgery with the use of cardiopulmonary bypass. (Funded by Tenax Therapeutics; LEVO-CTS ClinicalTrials.gov number, NCT02025621 .).

Machine learning methods accurately predict host specificity of coronaviruses based on spike sequences alone.

Coronaviruses infect many animals, including humans, due to interspecies transmission. Three of the known human coronaviruses: MERS, SARS-CoV-1, and SARS-CoV-2, the pathogen for the COVID-19 pandemic, cause severe disease. Improved methods to predict host specificity of coronaviruses will be valuable for identifying and controlling future outbreaks. The coronavirus S protein plays a key role in host specificity by attaching the virus to receptors on the cell membrane. We analyzed 1238 spike sequences for their host specificity. Spike sequences readily segregate in t-SNE embeddings into clusters of similar hosts and/or virus species. Machine learning with SVM, Logistic Regression, Decision Tree, Random Forest gave high average accuracies, F1 scores, sensitivities and specificities of 0.95-0.99. Importantly, sites identified by Decision Tree correspond to protein regions with known biological importance. These results demonstrate that spike sequences alone can be used to predict host specificity.

Care Optimization Through Patient and Hospital Engagement Clinical Trial for Heart Failure: Rationale and design of CONNECT-HF.

Many therapies have been shown to improve outcomes for patients with heart failure (HF) in controlled settings, but there are limited data available to inform best practices for hospital and post-discharge quality improvement initiatives. The CONNECT-HF study is a prospective, cluster-randomized trial of 161 hospitals in the United States with a 2×2 factorial design. The study is designed to assess the effect of a hospital and post-discharge quality improvement intervention compared with usual care (primary objective) on HF outcomes and quality-of-care, as well as to evaluate the effect of hospitals implementing a patient-level digital intervention compared with usual care (secondary objective). The hospital and post-discharge intervention includes audit and feedback on HF clinical process measures and outcomes for patients with HF with reduced ejection fraction (HFrEF) paired with education to sites and clinicians by a trained, nationally representative group of HF and quality improvement experts. The patient-level digital intervention is an optional ancillary study and includes a mobile application and behavioral tools that are intended to facilitate improved use of guideline-directed recommendations for self-monitoring and self-management of activity and medications for HFrEF. The effects of the interventions will be measured through an opportunity-based composite score on quality and time-to-first HF readmission or death among patients with HFrEF who present to study hospitals with acute HF and who consent to participate. The CONNECT-HF study is evaluating approaches for implementing HF guideline recommendations into practice and is one of the largest HF implementation science trials performed to date.

Structural studies of antiviral inhibitor with HIV-1 protease bearing drug resistant substitutions of V32I, I47V and V82I.

HIV-1 protease inhibitors are effective in HIV/AIDS therapy, although drug resistance is a severe problem. This study examines the effects of four investigational inhibitors against HIV-1 protease with drug resistant mutations of V32I, I47V and V82I (PRTri) that model the inhibitor-binding site of HIV-2 protease. These inhibitors contain diverse chemical modifications on the darunavir scaffold and form new interactions with wild type protease, however, the measured inhibition constants for PRTri mutant range from 17 to 40 nM or significantly worse than picomolar values reported for wild type enzyme. The X-ray crystal structure of PRTri mutant in complex with inhibitor 1 at 1.5 Šresolution shows minor changes in interactions with inhibitor compared with the corresponding wild type PR complex. Instead, the basic amine at P2 of inhibitor together with mutation V82I induces two alternate conformations for the side chain of Arg8 with new interactions with inhibitor and Leu10. Hence, inhibition is influenced by small coordinated changes in hydrophobic interactions.

Analysis of drug resistance in HIV protease.

BACKGROUND: Drug resistance in HIV is the major problem limiting effective antiviral therapy. Computational techniques for predicting drug resistance profiles from genomic data can accelerate the appropriate choice of therapy. These techniques can also be used to select protease mutants for experimental studies of resistance and thereby assist in the development of next-generation therapies. RESULTS: The machine learning produced highly accurate and robust classification of HIV protease resistance. Genotype data were mapped to the enzyme structure and encoded using Delaunay triangulation. Generative machine learning models trained on one inhibitor could classify resistance from other inhibitors with varying levels of accuracy. Generally, the accuracy was best when the inhibitors were chemically similar. CONCLUSIONS: Restricted Boltzmann Machines are an effective machine learning tool for classification of genomic and structural data. They can also be used to compare resistance profiles of different protease inhibitors.

The East-West late lumen loss study: Comparison of angiographic late lumen loss between Eastern and Western drug-eluting stent study cohorts.

BACKGROUND: Regulatory decisions approving new coronary drug-eluting stent (DES) require mechanistic observations of angiographic late lumen loss (LLL). Patient safety and device approval times could be enhanced if angiographic follow-up data were found to be generalizable across jurisdictions and geographies. The objectives were to assess the comparability of in-segment LLL in Eastern and Western DES populations using the world's largest compilation of follow-up quantitative coronary angiography data. METHODS: Data from 4 manufacturers involving 29 DES clinical trials in Eastern and Western hemispheres were compiled. "East" and "West" cohorts were defined by trial location. Independent core laboratories quantified in-segment LLL for all studies. East and West were compared before and after adjustment for clinical and anatomic covariates known to correlate with LLL via conditioning on propensity score quintiles. An international panel of experts and regulators prospectively established a clinically meaningful difference between East and West mean in-segment LLL of ±0.40 mm. RESULTS: The data set comprised 2,047 East and 4,456 West patients. Unadjusted mean ± SD for West and East in-segment LLL (mm) was 0.25 ± 0.46 and 0.12 ± 0.42, respectively (difference 0.13 mm; 95% CI 0.11-0.16). Propensity score-adjusted in-segment LLL East and West least squares means were 0.11 and 0.26 mm, respectively (difference 0.15 mm; 95% CI 0.13-0.18). CONCLUSIONS: In the world's largest compilation of DES protocol 8- to 13-month angiographic follow-up data, clinically meaningful comparability of in-segment LLL by independent core laboratory quantitative coronary angiography in East and West cohorts was demonstrated in both unadjusted and adjusted comparisons. These findings suggest that DES LLL, once characterized, could be generalized across regulatory jurisdictions over the course of global registration efforts.

Ion-beam-induced bending of semiconductor nanowires.

The miniaturisation of technology increasingly requires the development of both new structures as well as novel techniques for their manufacture and modification. Semiconductor nanowires (NWs) are a prime example of this and as such have been the subject of intense scientific research for applications ranging from microelectronics to nano-electromechanical devices. Ion irradiation has long been a key processing step for semiconductors and the natural extension of this technique to the modification of semiconductor NWs has led to the discovery of ion beam-induced deformation effects. In this work, transmission electron microscopy with in situ ion bombardment has been used to directly observe the evolution of individual silicon and germanium NWs under irradiation. Silicon NWs were irradiated with either 6 keV neon ions or xenon ions at 5, 7 or 9.5 keV with a flux of 3 × 1013 ions cm-2 s-1. Germanium NWs were irradiated with 30 or 70 keV xenon ions with a flux of 1013 ions cm-2 s-1. These new results are combined with those reported in the literature in a systematic analysis using a custom implementation of the transport of ions in matter Monte Carlo computer code to facilitate a direct comparison with experimental results taking into account the wide range of experimental conditions. Across the various studies this has revealed underlying trends and forms the basis of a critical review of the various mechanisms which have been proposed to explain the deformation of semiconductor NWs under ion irradiation.

Automated prediction of HIV drug resistance from genotype data.

BACKGROUND: HIV/AIDS is a serious threat to public health. The emergence of drug resistance mutations diminishes the effectiveness of drug therapy for HIV/AIDS. Developing a computational prediction of drug resistance phenotype will enable efficient and timely selection of the best treatment regimens. RESULTS: A unified encoding of protein sequence and structure was used as the feature vector for predicting phenotypic resistance from genotype data. Two machine learning algorithms, Random Forest and K-nearest neighbor, were used. The prediction accuracies were examined by five-fold cross-validation on the genotype-phenotype datasets. A supervised machine learning approach for automatic prediction of drug resistance was developed to handle genotype-phenotype datasets of HIV protease (PR) and reverse transcriptase (RT). It predicts the drug resistance phenotype and its relative severity from a query sequence. The accuracy of the classification was higher than 0.973 for eight PR inhibitors and 0.986 for ten RT inhibitors, respectively. The overall cross-validated regression R(2)-values for the severity of drug resistance were 0.772-0.953 for 8 PR inhibitors and 0.773-0.995 for 10 RT inhibitors. CONCLUSIONS: Machine learning using a unified encoding of sequence and protein structure as a feature vector provides an accurate prediction of drug resistance from genotype data. A practical webserver for clinicians has been implemented.

Binding of Clinical Inhibitors to a Model Precursor of a Rationally Selected Multidrug Resistant HIV-1 Protease Is Significantly Weaker Than That to the Released Mature Enzyme.

We have systematically validated the activity and inhibition of a HIV-1 protease (PR) variant bearing 17 mutations (PR(S17)), selected to represent high resistance by machine learning on genotype-phenotype data. Three of five mutations in PR(S17) correlating with major drug resistance, M46L, G48V, and V82S, and five of 11 natural variations differ from the mutations in two clinically derived extreme mutants, PR20 and PR22 bearing 19 and 22 mutations, respectively. PR(S17), which forms a stable dimer (<10 nM), is ∼10- and 2-fold less efficient in processing the Gag polyprotein than the wild type and PR20, respectively, but maintains the same cleavage order. Isolation of a model precursor of PR(S17) flanked by the 56-amino acid transframe region (TFP-p6pol) at its N-terminus, which is impossible upon expression of an analogous PR20 precursor, allowed systematic comparison of inhibition of TFP-p6pol-PR(S17) and mature PR(S17). Resistance of PR(S17) to eight protease inhibitors (PIs) relative to PR (Ki) increases by 1.5-5 orders of magnitude from 0.01 to 8.4 µM. Amprenavir, darunavir, atazanavir, and lopinavir, the most effective of the eight PIs, inhibit precursor autoprocessing at the p6pol/PR site with IC50 values ranging from ∼7.5 to 60 µM. Thus, this process, crucial for stable dimer formation, shows inhibition ∼200-800-fold weaker than that of the mature PR(S17). TFP/p6pol cleavage, which occurs faster, is inhibited even more weakly by all PIs except darunavir (IC50 = 15 µM); amprenavir shows a 2-fold increase in IC50 (∼15 µM), and atazanavir and lopinavir show increased IC50 values of >42 and >70 µM, respectively.

Association of hospital myocardial infarction volume with adherence to American College of Cardiology/American Heart Association performance measures: Insights from the National Cardiovascular Data Registry.

BACKGROUND: Adherence to guideline-based therapy improves patient outcomes after acute myocardial infarction (AMI) and hospital AMI volume is associated with reperfusion care, but the extent hospital AMI volume is associated with overall guideline adherence is unclear. METHODS AND RESULTS: We studied 486 hospitals treating 249,877 AMI patients in ACTION Registry-GWTG from January 1, 2007, to March 31, 2011. Hospital adherence to each American College of Cardiology/American Heart Association performance measure was compared between tertiles defined by hospital AMI volume: low (≤108 cases/y), middle (≥109 and ≤227 cases/y), and high (≥228 cases/y). Multivariable logistic regression, adjusting for patient and hospital characteristics, was used to examine the association between annual AMI volume and adherence to each measure. Similar modeling was used to evaluate the relationship between AMI volume and in-hospital mortality. Compared with high-volume hospitals, lower-volume hospitals were less likely to be academically affiliated, or to have cardiac surgery capabilities, electronic health records, or dedicated tobacco treatment services. Higher-volume hospitals had greater adherence to each performance measure, except aspirin use at arrival and reperfusion therapy. The greatest difference was in the rates of referral to cardiac rehabilitation (59%, 76%, and 83% in low-, middle-, and high-volume hospitals, respectively). After multivariable adjustment, higher AMI volume (up to 400 AMI patients/y) remained associated with higher-performance measure adherence. There was no association between AMI volume and in-hospital mortality after adjusting for patient and hospital characteristics. CONCLUSIONS: Higher hospital AMI volume was correlated with better adherence to process of care measures, but not in-hospital mortality.

Rationale and design of the East-West late lumen loss study: Comparison of late lumen loss between Eastern and Western drug-eluting stent study cohorts.

BACKGROUND: The contemporary evaluation of novel drug-eluting stents (DES) includes mechanistic observations that characterize postdeployment stent behavior. Quantification of late lumen loss due to neointimal hyperplasia 8-13 months after stent implantation, via quantitative coronary angiography (QCA), constitutes such an observation and is required by most regulatory authorities. Late lumen loss, as determined by QCA, has been validated as a surrogate for clinical endpoints such as target vessel revascularization. The mechanistic response to DES has not been directly compared across predominantly Asian or Western populations, whereas understanding their comparability across geographic populations could enhance global DES evaluation. OBJECTIVE: The East-West late lumen loss study is designed to demonstrate whether the residual differences in late lumen loss, as assessed by QCA, is different between Eastern and Western DES recipients from studies with protocol angiography at 8-13 months of follow-up. METHODS: Data from independent core laboratories that have characterized angiographic late lumen loss in DES clinical trials with protocol follow-up angiography will be compiled and dichotomized into Eastern and Western populations. A prospectively developed propensity score model incorporating clinical and anatomic variables affecting late lumen loss will be used to adjust comparisons of QCA measurements. CONCLUSION: Documentation of whether there are clinically meaningful differences in mechanistic response to DES implantation across genetically unique geographies could facilitate both the quality and efficiency of global device evaluation requiring invasive follow-up for novel stent designs.

Levosimendan in patients with left ventricular systolic dysfunction undergoing cardiac surgery on cardiopulmonary bypass: Rationale and study design of the Levosimendan in Patients with Left Ventricular Systolic Dysfunction Undergoing Cardiac Surgery Requiring Cardiopulmonary Bypass (LEVO-CTS) trial.

BACKGROUND: Low cardiac output syndrome is associated with increased mortality and occurs in 3% to 14% of patients undergoing cardiac surgery on cardiopulmonary bypass (CPB). Levosimendan, a novel calcium sensitizer and KATP channel activator with inotropic, vasodilatory, and cardioprotective properties, has shown significant promise in reducing the incidence of low cardiac output syndrome and related adverse outcomes in patients undergoing cardiac surgery on CPB. METHODS: LEVO-CTS is a phase 3 randomized, controlled, multicenter study evaluating the efficacy, safety, and cost-effectiveness of levosimendan in reducing morbidity and mortality in high-risk patients with reduced left ventricular ejection fraction (≤35%) undergoing cardiac surgery on CPB. Patients will be randomly assigned to receive either intravenous levosimendan (0.2 µg kg-1 min-1 for the first hour followed by 0.1 µg/kg for 23hours) or matching placebo initiated within 8hours of surgery. The co-primary end points are (1) the composite of death or renal replacement therapy through day 30 or perioperative myocardial infarction, or mechanical assist device use through day 5 (quad end point tested at α<.01), and (2) the composite of death through postoperative day 30 or mechanical assist device use through day 5 (dual end point tested at α<.04). Safety end points include new atrial fibrillation and death through 90days. In addition, an economic analysis will address the cost-effectiveness of levosimendan compared with placebo in high-risk patients undergoing cardiac surgery on CPB. Approximately 880 patients will be enrolled at approximately 60 sites in the United States and Canada between July 2014 and September 2016, with results anticipated in January 2017. CONCLUSION: LEVO-CTS, a large randomized multicenter clinical trial, will evaluate the efficacy, safety, and cost-effectiveness of levosimendan in reducing adverse outcomes in high-risk patients undergoing cardiac surgery on CPB. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov (NCT02025621).

Tackling the problem of HIV drug resistance.

The virally-encoded HIV-1 protease is an effective target for antiviral drugs, however, treatment for HIV infections is limited by the prevalence of drug resistant viral mutants. In this review, we describe our three-pronged approach to analyze and combat drug resistance. Understanding the molecular basis for resistance due to protease inhibitors is a key initial step in this approach. This knowledge is being employed for the design of new, improved inhibitors with high affinity for resistant mutants as well as wild type enzyme. In parallel with experimental studies of diverse mutants and inhibitory compounds, we are developing efficient algorithms to predict drug resistance phenotype from genotype data. This approach has important practical applications in the clinic where genotyping is recommended for individuals with new infections.

Identifying representative drug resistant mutants of HIV.

BACKGROUND: Drug resistance is one of the most important causes for failure of anti-AIDS treatment. During therapy, multiple mutations accumulate in the HIV genome, eventually rendering the drugs ineffective in blocking replication of the mutant virus. The huge number of possible mutants precludes experimental analysis to explore the molecular mechanisms of resistance and develop improved antiviral drugs. RESULTS: In order to solve this problem, we have developed a new algorithm to reveal the most representative mutants from the whole drug resistant mutant database based on our newly proposed unified protein sequence and 3D structure encoding method. Mean shift clustering and multiple regression analysis were applied on genotype-resistance data for mutants of HIV protease and reverse transcriptase. This approach successfully chooses less than 100 mutants with the highest resistance to each drug out of about 10K in the whole database. When considering high level resistance to multiple drugs, the numbers reduce to one or two representative mutants. CONCLUSION: This approach for predicting the most representative mutants for each drug has major importance for experimental verification since the results provide a small number of representative sequences, which will be amenable for in vitro testing and characterization of the expressed mutant proteins.

A randomized, double-blind, placebo-controlled trial to evaluate the safety and effectiveness of intracoronary application of a novel bioabsorbable cardiac matrix for the prevention of ventricular remodeling after large ST-segment elevation myocardial infarction: Rationale and design of the PRESERVATION I trial.

Postinfarction left ventricular (LV) remodeling can result in chronic heart failure and functional impairment. Although pharmacological strategies for established heart failure can be beneficial, preventing remodeling remains a challenge. Injectable bioabsorbable alginate or "bioabsorbable cardiac matrix" (BCM), composed of an aqueous mixture of sodium alginate and calcium gluconate, is a sterile colorless liquid that is a polysaccharide polymer produced from brown seaweed. When exposed to excess ionized calcium present in infarcted myocardium, BCM assembles to form a flexible gel, structurally resembling extracellular matrix, which provides temporary structural support to the infarct zone through and beyond the time needed for mature fibrotic tissue to develop. The PRESERVATION I trial is an early phase randomized, double-blind, placebo-controlled trial comparing intracoronary application of 4 mL of BCM with saline control in patients who develop large infarctions after successful reperfusion of large ST-segment elevation myocardial infarction (MI). Subjects will be randomized 2:1 to either BCM or saline control and will have the study device deployed through an intracoronary microcatheter in the infarct-related artery 2 to 5 days after index ST-segment elevation MI treated with successful primary or rescue percutaneous coronary intervention. The primary effectiveness end point is the absolute change in LV diastolic volume index as measured by 3-dimensional echocardiography from baseline to 6 months after BCM deployment. Secondary effectiveness end points include clinical outcomes, patient-reported quality of life, additional echocardiographic measures, and functional status measures. In summary, the PRESERVATION I trial is a randomized double-blind trial evaluating the effectiveness and safety of the novel device BCM in preventing LV remodeling patients who have large MIs despite undergoing successful primary or rescue percutaneous coronary intervention.