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In trials of oral HIV pre-exposure prophylaxis (PrEP), multiple approaches have been used to measure adherence, including self-report, pill counts, electronic dose monitoring devices, and biological measures such as drug levels in plasma, peripheral blood mononuclear cells, hair, and/or dried blood spots. No one of these measures is ideal and each has strengths and weaknesses. However, accurate estimates of adherence to oral PrEP are important as drug efficacy is closely tied to adherence, and secondary analyses of trial data within identified adherent/non-adherent subgroups may yield important insights into real-world drug effectiveness. We develop a statistical approach to combining multiple measures of adherence and show in simulated data that the proposed method provides a more accurate measure of true adherence than self-report. We then apply the method to estimate adherence in the ADAPT study (HPTN 067) in South African women.

In many applications, it is of interest to assess the relative contribution of features (or subsets of features) toward the goal of predicting a response — in other words, to gauge the variable imp...

There has been increasing interest in physiologic pacing techniques that directly activate the specialized conduction system. We aimed to assess outcomes of conduction system pacing (CSP) in patients with prosthetic heart valves.This systematic review was performed according to PRISMA guidelines. Freeman-Tukey double arcsine transformation with the random-effect model was used to summarize the data. Outcomes studied were 1) implant success (defined as ability to recruit the His-Purkinje system or the distal Purkinje system); (2) lead parameters at implant and follow-up; and (3) procedure-related complications.This systematic review of 7 studies included 267 unique patients in whom CSP was attempted with either HBP or LBBAP for pacing indications after a prosthetic valve. HBP was attempted in 38% (n = 108), while LBBAP in 62% (n = 175) patients. The overall success rate of CSP was 87%, while in patients post-TAVR, the overall success rate was 83.2%. In the subgroup analysis, LBBAP had a significant higher overall success rate compared to HBP (94.3% vs. 76.5%, pCSP is safe and feasible in patients with a prosthetic valve, with a significantly higher success rate and superior lead parameters with LBBAP than HBP, especially in patients post-TAVR.

Background While random forests are one of the most successful machine learning methods, it is necessary to optimize their performance for use with datasets resulting from a two-phase sampling design with a small number of cases—a common situation in biomedical studies, which often have rare outcomes and covariates whose measurement is resource-intensive. Methods Using an immunologic marker dataset from a phase III HIV vaccine efficacy trial, we seek to optimize random forest prediction performance using combinations of variable screening, class balancing, weighting, and hyperparameter tuning. Results Our experiments show that while class balancing helps improve random forest prediction performance when variable screening is not applied, class balancing has a negative impact on performance in the presence of variable screening. The impact of the weighting similarly depends on whether variable screening is applied. Hyperparameter tuning is ineffective in situations with small sample sizes. We further show that random forests under-perform generalized linear models for some subsets of markers, and prediction performance on this dataset can be improved by stacking random forests and generalized linear models trained on different subsets of predictors, and that the extent of improvement depends critically on the dissimilarities between candidate learner predictions. Conclusion In small datasets from two-phase sampling design, variable screening and inverse sampling probability weighting are important for achieving good prediction performance of random forests. In addition, stacking random forests and simple linear models can offer improvements over random forests.

BACKGROUND: Viral load (VL) surrogate endpoints transformed development of HIV and hepatitis C therapeutics. Surrogate endpoints for CMV-related morbidity and mortality could advance development of antiviral treatments. Although observational data support using CMV VL as a trial endpoint, randomized controlled trials (RCTs) demonstrating direct associations between virological markers and clinical endpoints are lacking. METHODS: We performed CMV DNA PCR on frozen serum samples from the only placebo-controlled RCT of ganciclovir for early treatment of CMV after hematopoietic cell transplantation (HCT). We used established criteria to assess VL kinetics as surrogates for CMV disease or death by weeks 8, 24, and 48 after randomization and quantified antiviral effects captured by each marker. We used ensemble-based machine learning to assess the predictive ability of VL kinetics and performed this analysis on a ganciclovir prophylaxis RCT for validation. RESULTS: VL suppression with ganciclovir reduced cumulative incidence of CMV disease and death for 20 years after HCT. Mean VL, peak VL, and change in VL during the first 5 weeks of treatment fulfilled the Prentice definition for surrogacy, capturing more than 95% of ganciclovir’s effect, and yielded highly sensitive and specific predictions by week 48. In the prophylaxis trial, the viral shedding rate satisfied the Prentice definition for CMV disease by week 24. CONCLUSIONS: Our results support using CMV VL kinetics as surrogates for CMV disease, provide a framework for developing CMV preventative and therapeutic agents, and support reductions in VL as the mechanism through which antivirals reduce CMV disease. FUNDING: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.

In a regression setting, it is often of interest to quantify the importance of various features in predicting the response. Commonly, the variable importance measure used is determined by the regression technique employed. For this reason, practitioners often only resort to one of a few regression techniques for which a variable importance measure is naturally defined. Unfortunately, these regression techniques are often suboptimal for predicting the response. Additionally, because the variable importance measures native to different regression techniques generally have a different interpretation, comparisons across techniques can be difficult. In this work, we study a variable importance measure that can be used with any regression technique, and whose interpretation is agnostic to the technique used. This measure is a property of the true data-generating mechanism. Specifically, we discuss a generalization of the analysis of variance variable importance measure and discuss how it facilitates the use of machine learning techniques to flexibly estimate the variable importance of a single feature or group of features. The importance of each feature or group of features in the data can then be described individually, using this measure. We describe how to construct an efficient estimator of this measure as well as a valid confidence interval. Through simulations, we show that our proposal has good practical operating characteristics, and we illustrate its use with data from a study of risk factors for cardiovascular disease in South Africa.

SummarySingle broadly neutralizing antibody (bnAb) regimens are currently being evaluated in randomized trials for prevention efficacy against HIV-1 infection. Subsequent trials will evaluate combination bnAb regimens (e.g., cocktails, multi-specific antibodies), which demonstrate higher potency and breadth in vitro compared to single bnAbs. Given the large number of potential regimens in the research pipeline, methods for down-selecting these regimens into efficacy trials are of great interest. To aid the down-selection process, we developed Super LeArner Prediction of NAb Panels (SLAPNAP), a software tool for training and evaluating machine learning models that predict in vitro neutralization resistance of HIV Envelope pseudoviruses to a given single or combination bnAb regimen, based on Envelope amino acid sequence features. SLAPNAP also provides measures of variable importance of sequence features. These results can rank bnAb regimens by their potential prevention efficacy and aid assessments of how prevention efficacy depends on sequence features.Availability and ImplementationSLAPNAP is a freely available docker image that can be downloaded from DockerHub (https://hub.docker.com/r/slapnap/slapnap). Source code and documentation are available at GitHub (respectively,https://github.com/benkeser/slapnapandhttps://benkeser.github.io/slapnap/).ContactDavid Benkeser,benkeser@emory.edu

A central assumption in the design and conduct of non-inferiority trials is that the active-control therapy will have the same degree of effectiveness in the planned non-inferiority trial as in the prior placebo-controlled trials used to define the non-inferiority margin. This is referred to as the ‘constancy’ assumption. If the constancy assumption fails, decisions based on the chosen non-inferiority margin may be incorrect, and the study runs the risk of approving an inferior product or failing to approve a beneficial product. The constancy assumption cannot be validated in a trial without a placebo arm, and it is unlikely ever to be met completely. When there are strong, observable predictors of constancy, such as dosing and adherence to the active-control product, we can specify conditions where the constancy assumption will likely fail. We propose a method for using measurable predictors of active-control effectiveness to specify non-inferiority margins targeted to the planned study population characteristics. We describe a pre-specified method, using baseline characteristics or post-baseline predictors in the active-control arm, to adapt the non-inferiority margin at the end of the study if constancy is violated. Adaptive margins can help adjust for constancy violations that will inevitably occur in real clinical trials, while maintaining pre-specified levels of Type I error and power.

Objectives This global, multicenter, prospective study, initiated to meet U.S. Food and Drug Administration condition-of-approval requirements, evaluated the safety and efficacy of the Medtronic magnetic resonance imaging (MRI)–conditional pacing system when used in an MRI environment in routine clinical practice. The primary endpoint was MRI-related complications. The secondary endpoint was the cumulative change in pacing capture threshold (PCT) for patients undergoing multiple MRI scans. Background Large-scale, real-world evaluation of MRI in patients implanted with an MRI-conditional pacing system remains limited, with few published data for patients who undergo multiple MRI scans. Methods Patients were enrolled and followed up prospectively from the time of implantation. Evaluation of the pacemaker function was performed before and after MRI. The MRI-related complication-free rate was evaluated. Changes in electrical performance after each scan and cumulative changes over multiple scans were analyzed. Results In 81 centers, 2,629 patients were implanted with a complete SureScan pacing system (41.8% women, age 70.2 ± 12.5 years). A total of 526 patients (28.5%) received 872 clinically indicated MRI scans, including 58 thoracic scans. No MRI-related complications occurred during or after MRI, meeting the primary objective. Six (1%) MRI-related observations (atrial fibrillation, PCT increase, and chest symptoms) were reported. A total of 171 patients (32.5%) underwent 2 or more scans with no cumulative increase in PCT. Conclusions This report constitutes the largest longitudinal MRI experience in patients implanted with an MRI-conditional pacing system. Results support the safety profile of the SureScan system and demonstrate for the first time that patients may safely undergo multiple MRI scans. (SureScan Post-Approval Study; NCT01299675)

Introduction The paradigm for preventing clinically significant cytomegalovirus (CMV) infection and CMV disease after hematopoietic cell transplantation (HCT) has shifted from preemptive treatment to antiviral prophylaxis with the approval of letermovir. Previously, our group validated the use of quantitative CMV DNA viral load as a surrogate endpoint for tissue-invasive CMV disease (ASBMT 2018) in the pre-emptive treatment setting. Objectives To address whether CMV viral load kinetics could serve as valid surrogate endpoints for CMV disease in the prophylactic setting, we performed CMV viral load testing of frozen serum samples collected during a placebo-controlled randomized trial of ganciclovir (GCV) given at engraftment (Goodrich et al. Ann Intern Med 1993). Because this study pre-dated the approval of ganciclovir, CMV disease occurred in an extremely high proportion of patients, allowing us to link viral load kinetics with CMV disease, which would not be possible in the modern treatment environment. Methods We calculated each patient's CMV viral load kinetics (mean, peak, maximum change, percentage of positive viral loads) from samples collected during the first five weeks after randomization and analyzed their value as surrogates for CMV disease by 24 weeks after randomization. First, we tested each marker for fulfillment of the Prentice criteria for valid surrogate endpoints using multivariable logistic regression, including quantifying the degree to which each marker captured the effect of ganciclovir on CMV disease. Secondly, to determine the ability of the viral load markers to predict CMV disease, we developed a ‘SuperLearner' machine learning model and quantified prediction accuracy by cross-validated area under the receiver-operator characteristic curves (cv-AUCs). Results Mean, peak, change, and percentage of positive viral loads were significantly higher in the placebo group than in the ganciclovir group. See viral loads by group in Fig 1. Percentage of positive viral load satisfied Prentice criteria as a valid surrogate endpoint for CMV disease by week 24 after randomization (Fig 2). All kinetics explained greater than 80% of ganciclovir's reduction in CMV disease (mean: 86%, peak: 83%, maximum change: 95%, percent positive: 94%). We found that a SuperLearner model that included all four viral load kinetics, CMV donor serostatus, acute graft-versus-host disease, and baseline viral load predicted CMV disease with 91% cv-AUC in the placebo group, 78% in the ganciclovir group, and 82% in the combined groups (Fig 3). Conclusion We have shown for the first time in a clinical endpoint-rich, placebo-controlled antiviral prophylaxis trial that CMV viral load kinetics fulfill the Prentice criteria as valid surrogate endpoints and have high predictive value for CMV disease after HCT.

The absolute abundance of bacterial taxa in human host-associated environments play a critical role in reproductive and gastrointestinal health. However, obtaining the absolute abundance of many bacterial species is typically prohibitively expensive. In contrast, relative abundance data for many species is comparatively cheap and easy to collect (e.g., with universal primers for the 16S rRNA gene). In this paper, we propose a method to jointly model relative abundance data for many taxa and absolute abundance data for a subset of taxa. Our method provides point and interval estimates for the absolute abundance of all taxa. Crucially, our proposal accounts for differences in the efficiency of taxon detection in the relative and absolute abundance data. We show that modeling taxon-specific efficiencies substantially reduces the estimation error for absolute abundance, and controls the coverage of interval estimators. We demonstrate the performance of our proposed method via a simulation study, a sensitivity study where we jackknife the taxa with observed absolute abundances, and a study of women with bacterial vaginosis.

HVTN 505 is a preventative vaccine efficacy trial testing DNA followed by recombinant adenovirus serotype 5 (rAd5) in circumcised, Ad5-seronegative men and transgendered persons who have sex with men in the United States. Identified immune correlates of lower HIV-1 risk and a virus sieve analysis revealed that, despite lacking overall efficacy, vaccine-elicited responses exerted pressure on infecting HIV-1 viruses. To interrogate the mechanism of the antibody correlate of HIV-1 risk, we examined antigen-specific antibody recruitment of Fcγ receptors (FcγRs), antibody-dependent cellular phagocytosis (ADCP), and the role of anti-envelope (anti-Env) IgG3. In a prespecified immune correlates analysis, antibody-dependent monocyte phagocytosis and antibody binding to FcγRIIa correlated with decreased HIV-1 risk. Follow-up analyses revealed that anti-Env IgG3 breadth correlated with reduced HIV-1 risk, anti-Env IgA negatively modified infection risk by Fc effector functions, and that vaccine recipients with a specific FcγRIIa single-nucleotide polymorphism locus had a stronger correlation with decreased HIV-1 risk when ADCP, Env-FcγRIIa, and IgG3 binding were high. Additionally, FcγRIIa engagement correlated with decreased viral load setpoint in vaccine recipients who acquired HIV-1. These data support a role for vaccine-elicited anti-HIV-1 Env IgG3, antibody engagement of FcRs, and phagocytosis as potential mechanisms for HIV-1 prevention.

The broadly neutralizing antibody (bnAb) VRC01 is being evaluated for its efficacy to prevent HIV-1 infection in the Antibody Mediated Prevention (AMP) trials. A secondary objective of AMP utilizes sieve analysis to investigate how VRC01 prevention efficacy (PE) varies with HIV-1 envelope (Env) amino acid (AA) sequence features. An exhaustive analysis that tests how PE depends on every AA feature with sufficient variation would have low statistical power. To design an adequately powered primary sieve analysis for AMP, we modeled VRC01 neutralization as a function of Env AA sequence features of 611 HIV-1 gp160 pseudoviruses from the CATNAP database, with objectives: (1) to develop models that best predict the neutralization readouts; and (2) to rank AA features by their predictive importance with classification and regression methods. The dataset was split in half, and machine learning algorithms were applied to each half, each analyzed separately using cross-validation and hold-out validation. We selected Super Learner, a nonparametric ensemble-based cross-validated learning method, for advancement to the primary sieve analysis. This method predicted the dichotomous resistance outcome of whether the IC50 neutralization titer of VRC01 for a given Env pseudovirus is right-censored (indicating resistance) with an average validated AUC of 0.868 across the two hold-out datasets. Quantitative log IC50 was predicted with an average validated R2 of 0.355. Features predicting neutralization sensitivity or resistance included 26 surface-accessible residues in the VRC01 and CD4 binding footprints, the length of gp120, the length of Env, the number of cysteines in gp120, the number of cysteines in Env, and 4 potential N-linked glycosylation sites; the top features will be advanced to the primary sieve analysis. This modeling framework may also inform the study of VRC01 in the treatment of HIV-infected persons.

Significance Single-cell high-throughput technologies enable the ability to identify combination cancer therapies that account for intratumoral heterogeneity, a phenomenon that has been shown to influence the effectiveness of cancer treatment. We developed and applied an approach that identifies top-ranking drug combinations based on the single-cell perturbation response when an individual tumor sample is screened against a panel of single drugs. This approach optimizes drug combinations by choosing the minimum number of drugs that produce the maximal intracellular desired effects for an individual sample., An individual malignant tumor is composed of a heterogeneous collection of single cells with distinct molecular and phenotypic features, a phenomenon termed intratumoral heterogeneity. Intratumoral heterogeneity poses challenges for cancer treatment, motivating the need for combination therapies. Single-cell technologies are now available to guide effective drug combinations by accounting for intratumoral heterogeneity through the analysis of the signaling perturbations of an individual tumor sample screened by a drug panel. In particular, Mass Cytometry Time-of-Flight (CyTOF) is a high-throughput single-cell technology that enables the simultaneous measurements of multiple (>40) intracellular and surface markers at the level of single cells for hundreds of thousands of cells in a sample. We developed a computational framework, entitled Drug Nested Effects Models (DRUG-NEM), to analyze CyTOF single-drug perturbation data for the purpose of individualizing drug combinations. DRUG-NEM optimizes drug combinations by choosing the minimum number of drugs that produce the maximal desired intracellular effects based on nested effects modeling. We demonstrate the performance of DRUG-NEM using single-cell drug perturbation data from tumor cell lines and primary leukemia samples.

This global, multicenter, prospective study, initiated to meet U.S. Food and Drug Administration condition-of-approval requirements, evaluated the safety and efficacy of the Medtronic magnetic resonance imaging (MRI)-conditional pacing system when used in an MRI environment in routine clinical practice. The primary endpoint was MRI-related complications. The secondary endpoint was the cumulative change in pacing capture threshold (PCT) for patients undergoing multiple MRI scans.Large-scale, real-world evaluation of MRI in patients implanted with an MRI-conditional pacing system remains limited, with few published data for patients who undergo multiple MRI scans.Patients were enrolled and followed up prospectively from the time of implantation. Evaluation of the pacemaker function was performed before and after MRI. The MRI-related complication-free rate was evaluated. Changes in electrical performance after each scan and cumulative changes over multiple scans were analyzed.In 81 centers, 2,629 patients were implanted with a complete SureScan pacing system (41.8% women, age 70.2 ± 12.5 years). A total of 526 patients (28.5%) received 872 clinically indicated MRI scans, including 58 thoracic scans. No MRI-related complications occurred during or after MRI, meeting the primary objective. Six (1%) MRI-related observations (atrial fibrillation, PCT increase, and chest symptoms) were reported. A total of 171 patients (32.5%) underwent 2 or more scans with no cumulative increase in PCT.This report constitutes the largest longitudinal MRI experience in patients implanted with an MRI-conditional pacing system. Results support the safety profile of the SureScan system and demonstrate for the first time that patients may safely undergo multiple MRI scans. (SureScan Post-Approval Study; NCT01299675).

The United States Food and Drug Administration recently issued guidance that CMV DNAemia (quantitative CMV viral load as measured by PCR) could be used in a composite endpoint along with tissue-invasive CMV disease as the primary endpoint in allogeneic HCT CMV prophylaxis trials. However, the specific time points after antiviral treatment initiation at which to measure viral load and the viral load thresholds that most accurately predict clinical CMV disease have not been identified. In order to estimate the treatment effect of an antiviral agent on CMV clinical outcomes, placebo-controlled, randomized trial data with accompanying viral load measurements are needed. Unfortunately, in the modern era of PCR and early preemptive treatment, ethically, placebo-controlled, randomized trials that allow for the development of CMV disease after HCT can no longer be performed. To overcome this limitation, we performed CMV DNA PCR testing on frozen plasma samples collected during the first 100 days post-HCT in the only placebo-controlled, double-blind RCT of ganciclovir for the early treatment of CMV infection after HCT (Goodrich et al. NEJM 1991). We used three analytic methods (Cox proportional hazards models, machine learning, and a novel non-parametric method) to determine which of 14 viral load markers, measured in the first four weeks of treatment, are the most useful surrogates of antiviral treatment for the prevention of CMV disease. All methods identified peak viral load and percentage of positive samples by week 4 as highly associated with or predictive of tissue-invasive CMV disease by week 8 post-randomization. Cox proportional hazards models (Figure 1) yielded significant associations for peak viral load measured by week 4 (HR 1.4, 95% CI 1.1-1.9) and percentage of positive samples by week 4 (HR 1.6, CI 1.1-2.3). The machine-learning ensemble algorithm SuperLearner implemented in R (Figure 2) demonstrated cross-validated area under the receiver-operator curves of at least 75% for peak viral load (75%, CI 62-87%) and percentage of positive plasma samples (77%, CI 63-90%) measured by week 4. Using a novel statistical technique that allows direct estimation of biomarker surrogacy (Parast et al. Stat Med 2017), we estimated that the percentage of ganciclovir treatment effect explained by peak viral load and percentage of positive samples measured by week 4 was greater than 85%—peak viral load 89%, CI 56-100%; percent positive samples 91%, CI 60-100% (Figure 3). Peak viral load and percentage of positive samples by week 4 are highly predictive of CMV disease and the treatment effect of ganciclovir. Our analysis suggests that these may be the best surrogate markers of ganciclovir treatment and introduces novel methods for identifying optimal candidate biomarkers as surrogates for clinical endpoints.

Objectives Our purpose was to demonstrate that strategically chosen implantable cardioverter-defibrillator (ICD) ventricular tachycardia (VT) or ventricular fibrillation (VF) detection and therapy parameters can reduce the combined incidence of device-delivered shocks, arrhythmic syncope, and untreated sustained symptomatic VT/VF (morbidity index). Background Strategically chosen ICD VT/VF detection and therapy parameters have been shown in previous studies to reduce the number of shocked episodes. In the PREPARE (Primary Prevention Parameters Evaluation) study, these prior strategies were combined with additional strategies specific to primary prevention patients. Methods The PREPARE study was a prospective, cohort-controlled study that analyzed 700 patients (biventricular [Bi-V] ICD and non–Bi-V ICD) with primary prevention indications for an ICD from 38 centers followed for 1 year. VT/VF was detected for rates ≥182 beats/min that were maintained for at least 30 of 40 beats. Antitachycardia pacing was programmed as the first therapy for regular rhythms with rates of 182 to 250 beats/min, and supraventricular tachycardia discriminators were used for rhythms ≤200 beats/min. The control cohort consisted of 689 primary prevention patients from the EMPIRIC (Comparison of Empiric to Physician-Tailored Programming of Implantable Cardioverter Defibrillators Trial) (non–Bi-V ICD, physician arm only) and MIRACLE ICD (Multicenter InSync Implantable Cardioversion Defibrillation Randomized Clinical Evaluation) (Bi-V ICD) trials for whom VT/VF detection and therapy programming were not controlled. Results The PREPARE programming significantly reduced the morbidity index incidence density (0.26 events/patient-year for PREPARE study patients vs. 0.69 control cohort, p = 0.003). The PREPARE study patients were less likely to receive a shock in the first year compared with control patients (9% vs. 17%, p Conclusions Strategically chosen VT/VF detection and therapy parameters can safely reduce shocks and other morbidities associated with ICD therapy in patients receiving an ICD for primary prevention indications. (PREPARE-Primary Prevention Parameters Evaluation; NCT00279279)

OBJECTIVE Sexual liaisons between older men and younger women have been linked to greater risk of HIV acquisition. This study aims to (1) identify psychosocial and behavioral factors associated with age-discordant (partner ≥5 years) versus age-concordant partnerships (-1< partner

We have partially purified the protein and isolated the glcS gene for glycogen synthase in Dictyostelium. glcS mRNA is present throughout development and is the product of a single gene coding for 775 amino acids, with a predicted molecular mass of 87 kD. The sequence is highly similar to glycogen synthase from human muscle, yeast, and rat liver, diverging significantly only at the amino and carboxy termini. Phosphorylation and UDPG binding sites are conserved, with Km values for UDPG being comparable to those determined for other organisms, but in vitro phosphorylation failing to convert between the G6P-dependent (D) and -independent (I) forms. Enzyme activity is relatively constant throughout the life cycle: the I form of the enzyme isolates with the soluble fraction in amoebae, switches to the D form, becomes pellet-associated during early development, and finally reverts during late development to the I form, which again localizes to the soluble fraction. Deletion analysis of the promoter reveals a GC-rich element which, when deleted, abolishes expression of glcS. © 1996 Wiley-Liss, Inc.

Long RP Tachycardia, introduction: The purpose of this study is to describe a simple and reliuhle diagnostic maneuver that allows for the rapid differentiation of atypical AV nodal reentrant tachycardia (AVNRT) from other causes of long KP tachycardia. Lonf^ KP tachycardias may he caused by atypical AVNRT, orthodrnmic reciprocating tachycardia (ORT) involving a .slowly conducting retrograde accessory pathway, or atrial tachycardia. The dilTerentiation of atypical AVNRT from ORT or atrial tachycardia may be difficult, especially when the differential diagnosis includes a posteroseptal accessory pathway or an atrial tachycardia arising in the posteroseptal right atrium. Methods and Results: Twelve patients with atypical AVNRT, 21 with ORT, and 12 with an atrial tachycardia diagnosed using conventiitnal criteria were enrolled In this study. The atrialHis (AH) interval was measured at the His-hundle position during the tachycardia and during atrial pacing from the high right atrium at the tachycardia cycle length in the setting of sinus rhythm. In patients with atypical AVNRT, the mean AH interval was 69 msec ± 50 msec (± SD) longer during high right atrial pacing than during the tachycardia (P < 0.001). In 10 of 12 patients with atypical AVNRT, the AH interval during atrial pacing was more than 40 msec longer than the .\H interval measured during the tachycardia. In contra.st. In patients with ORT or atrial tachycardia, the difYerences in .AH interval hetween atrial pacing and tachycardia were never more than 20 and 10 msec, respectively. Conclusion: The difference in the AH interval between atrial pacing and the tachycardia allows a simple and rapid means of difierentiating atypical AVNRT from other types of long RP tachycardias. (J Cardiovasc Electrophysiol, Vol. 6, pp. 700-710. September 1995)

Background Multicomponent atrial electrograms and “slow pathway potentials” are helpful in identifying target sites for radiofrequency catheter ablation of the slow pathway in patients with atrioventricular (AV) nodal reentrant tachycardia. The purpose of this study was to compare the atrial electrograms recorded at various locations in the right atrium in patients with and without AV nodal reentrant tachycardia to assess the specificity of multicomponent atrial electrograms and possible slow pathway potentials both for the posteroseptal right atrium and for patients with AV nodal reentrant tachycardia. Methods and Results In 25 patients with AV nodal reentrant tachycardia and 23 control patients without AV nodal reentrant tachycardia or dual AV nodal physiology, atrial electrograms with an AV ratio of ≤1:2 were recorded at the posteroseptal right atrium near the coronary sinus ostium and in the right atrium near the posterior, lateral, and anterior aspects of the tricuspid annulus. Attempts were made to identify broad, multicomponent, and double atrial electrograms. There were no significant differences between the patients with and without AV nodal reentrant tachycardia in the mean number of deflections in the atrial electrograms or in the mean duration of the atrial electrograms recorded at any of the atrial sites. In all patients, the number of atrial electrogram deflections and the atrial electrogram duration were significantly greater at the posteroseptal position than at the other three atrial sites. The prevalence of potentials with the appearance of slow pathway potentials in the posterior septum was similar in patients with and without AV nodal reentrant tachycardia (68% and 70%, respectively). The prevalence of these potentials was 6% to 25% at the other three atrial sites ( P Conclusions The atrial electrogram characteristics that have been found to be useful in identifying effective posteroseptal slow pathway ablation sites in patients with AV nodal reentrant tachycardia are equally prevalent in patients without AV nodal reentrant tachycardia or dual AV nodal physiology. Atrial electrograms in the posteroseptal area are broader and contain more deflections than at other areas in the right atrium, possibly because of conduction properties of the posterior transitional zone that are independent of the presence of AV nodal reentrant tachycardia.

BACKGROUND Junctional ectopy may occur during radiofrequency (RF) catheter ablation of the slow pathway in patients with atrioventricular nodal reentrant tachycardia (AVNRT). The purpose of the present study was to characterize this junctional ectopy quantitatively. METHODS AND RESULTS The subjects of this study were 52 consecutive patients with AVNRT who underwent slow pathway ablation and 5 additional patients included retrospectively because they had developed high-degree atrioventricular (AV) block during the procedure. A combined anatomic and electrogram mapping approach was used for slow pathway ablation, and AVNRT was successfully eliminated in all patients. In the group of 52 consecutive patients, the incidence of junctional ectopy was significantly higher during 52 effective applications of RF energy than during 366 ineffective applications (100% versus 65%, P < .001). Compared with ineffective RF energy applications, successful RF energy applications had a significantly longer duration of individual bursts of junctional ectopy (7.1 +/- 7.1 versus 5.0 +/- 7.0 seconds [+/- SD], P < .05), a greater total number of junctional beats during the applications (24 +/- 16 versus 15 +/- 8, P < .01), and a greater total span of time during which junctional ectopy occurred (19 +/- 15 versus 11 +/- 12 seconds, P < .01). Four of the 52 patients plus an additional 5 patients developed transient AV block lasting 34 +/- 37 seconds. In 1 of the 9 patients who had transient AV block, third-degree AV nodal block requiring a permanent pacemaker recurred 2 weeks later. In each of the 9 patients who developed AV block, there was ventriculoatrial (VA) block in association with junctional ectopy during the RF energy application immediately preceding the AV block. Among 48 patients who did not develop AV block, 17 patients had at least one episode of VA block during junctional ectopy. The positive predictive value of VA block during junctional ectopy for the development of AV block was 19% in the consecutive series of 52 patients. Among 31 patients who always had 1:1 VA conduction in association with junctional ectopy, 12 had poor VA conduction in the baseline state, with a VA block cycle length of at least 500 milliseconds during ventricular pacing. CONCLUSIONS In patients with AVNRT undergoing slow pathway ablation, junctional ectopy during the application of RF energy is a sensitive but nonspecific marker of successful ablation. The bursts of junctional ectopy are significantly longer at effective target sites than at ineffective sites. VA conduction should be expected during the junctional ectopy that accompanies slow pathway ablation, even when there is poor VA conduction during baseline ventricular pacing. VA block during junctional ectopy is a harbinger of AV block in patients undergoing RF ablation of the slow pathway. If energy applications are discontinued as soon as VA block occurs, the risk of AV block may be markedly reduced.

No prospective studies have compared sotalol and amiodarone during electropharmacologic testing. The purpose of this prospective, randomized study was to compare the electrophysiologic effects of sotalol and amiodarone in patients with coronary artery disease and sustained monomorphic ventricular tachycardia (VT). Patients with coronary artery disease and sustained monomorphic VT inducible by programmed stimulation were randomly assigned to receive either sotalol (n = 17) or amiodarone (n = 17). The sotalol dose was titrated to 240 mg twice daily over 7 days. Amiodarone dosing consisted of 600 mg 3 times daily for 10 days. An electrophysiologic test was performed in the baseline state and at the end of the loading regimen. An adequate response was defined as the inability to induce VT or the ability to induce only relatively slow hemodynamically stable VT. During the follow-up electrophysiologic test, 24% of patients taking sotalol and 41% of those taking amiodarone had an adequate response to therapy (p = 0.30). Amiodarone lengthened the mean VT cycle length to a greater degree than sotalol (28% vs 12%, p < 0.01). There were no significant differences in the effects of sotalol and amiodarone on the ventricular effective refractory period. In patients with coronary artery disease, amiodarone and sotalol are similar in efficacy in the treatment of VT as assessed by electropharmacologic testing. The effects of the 2 drugs on ventricular refractoriness are similar, but amiodarone slows VT to a greater extent than sotalol.

The purpose of this study was to compare implant charges and convalescence for transvenous and epicardial defibrillation systems. Hospital stay, intensive care utilization, professional fees, and hospital bills were compared in 44 patients who underwent implantation of a cardiac defibrillator between September 1991 and May 1993. Twenty-five consecutive patients received an epicardial lead system, while 19 consecutive patients underwent implantation of the entire transvenous defibrillation system in the electrophysiology laboratory. There were no significant differences between the two groups in mean age or left ventricular ejection fraction. There was a significant reduction in postoperative hospital convalescence from 7.2 ± 2.0 days with epicardial systems to 3.1 ± 1.5 days with transvenous systems (P < 0.001). Postoperative intensive care unit stay was significantly reduced with transvenous systems compared with epicardial systems (0.1 ± 0.2 vs 1.5 ± 0.9 days; P < 0.001). Hospital charges were also significantly reduced with the transvenous lead system implants. Mean implant charges were lower with transvenous systems; $32,090 ±$2,620 vs $38,307 ±$2,701 (P < 0.001); convalescence charges were lower: $5,861 ±$5,010 vs $12,447 ±$4,969 (P < 0.001); the total hospital bill was also significantly lower with transvenous systems: $53,459 ±$12,588 vs $71,981 ±$16,172 (P < 0.001). Professional fees for implantation ($4,131 ±$1,724 vs $6,100 ± 0, P < 0.001), convalescence care ($1,258 ±$960 vs $2,846 ±$1,770; P < 0.001), and total professional fees ($12,925 ±$4,772 vs $15,731 ±$4,055, P < 0.05) were lower in the transvenous defibrillation group. In conclusion, transvenous defibrillation lead systems are associated with significantly shorter postoperative recovery and significantly lower hospital and professional charges.

In some patients with atrial fibrillation, the ventricular rate may be difficult to control with medications. We evaluated a radiofrequency catheter technique to modify atrioventricular conduction in atrial fibrillation in order to control the ventricular rate without creating pathologic atrioventricular block.We studied 19 consecutive patients with atrial fibrillation and uncontrolled ventricular rates refractory to drug therapy. They had had atrial fibrillation for a mean (+/- SD) of 5.5 +/- 4.9 years, had had 4.9 +/- 0.9 unsuccessful drug trials, and were 62 +/- 15 years old. Before the procedure, the maximal ventricular rate during exercise was 180 +/- 39 beats per minute. A total of 11 +/- 5 radiofrequency-energy applications were delivered to the posterior septal or midseptal right atrium, near the ostium of the coronary sinus.Successful control of the ventricular rate without pathologic atrioventricular block was achieved in 14 of the 19 patients (74 percent). Persistent third-degree atrioventricular block requiring a permanent pacemaker occurred inadvertently in four patients (21 percent). Atrioventricular conduction was intentionally ablated in one patient. The 14 patients who had successful modification of conduction had persistent reductions in maximal ventricular rate during exercise (rate at three months, 126 +/- 24 beats per minute; P0.01). These patients had resolution of symptoms related to rapid rates during 8 +/- 2 months of follow-up. One patient had a recurrence of a rapid ventricular rate but was again asymptomatic after a second modification procedure. One patient with dilated cardiomyopathy died suddenly, five months after a successful procedure.A catheter technique to modify atrioventricular conduction without creating pathologic atrioventricular block is feasible in the majority of patients with symptomatic atrial fibrillation and a rapid ventricular rate refractory to drug therapy.

Objectives . The purpose of this study was to prospectively compare in random fashion an anatomic and an electrogram mapping approach for ablation of the slow pathway of atrioventricular (AV) node reentrant tachycardia. Background . Ablation of the slow pathway in patients with AV node reentrant tachycardia can be performed by using either an anatomic or an electrogram mapping approach to identify target sites for ablation. These two approaches have never been compared prospectively. Methods . Fifty consecutive patients with typical AV node reentrant tachycardia were randomly assigned to undergo either an anatomic or an electrogram mapping approach for ablation of the slow AV node pathway. In 25 patients randomly assigned to the anatomic approach, sequential radiofrequency energy applications were delivered along the tricuspid annulus from the level of the coronary sinus ostium to the His bundle position. In 25 patients assigned to the electrogram mapping approach, target sites along the posteromedial tricuspid annulus near the coronary sinus ostium were sought where there was a multicomponent atrial electrogram or evidence of a possible slow pathway potential. If the initial approach was ineffective after 12 radiofrequency energy applications, the alternative approach was then used. Results . The anatomic approach was effective in 21 (84%) of 25 patients, and the electrogram mapping approach was effective in all 25 patients (100%) randomly assigned to this technique (p = 0.1). The four patients with an ineffective anatomic approach had a successful outcome with the electrogram mapping approach. On the basis of intention to treat analysis, there were no significant differences between the electrogram mapping approach and the anatomic approach with respect to the time required for ablation (28 ± 21 and 31 ± 31 min, respectively, mean ± SD, p = 0.7) duration of fluoroscopic exposure (27 ± 20 and 27 ±18 min, respectively, p = 0.9) or mean number of radiofrequency applications delivered (6.3 ± 3.9 vs. 7.2 ± 8.0, p s 0.6). With both the anatomic and electrogram mapping approaches, the atrial electrogram duration and number of peaks in the atrial electrogram were significantly greater at successful target sites than at unsuccessful target sites. Conclusions . The anatomic and electrogram mapping approaches for ablation of the slow AV nodal pathway are comparable in efficacy and duration. If the anatomic approach is initially attempted and fails, the electrogram mapping approach may be successful at sites outside the areas targeted in the anatomic approach. With both the anatomic and electrogram mapping approaches, there are significant differences in the atrial electrogram configuration between successful and unsuccessful target sites.