Abstract Large randomized clinical trials in cardiovascular disease have proliferated over the past 3 decades, with results that have influenced every aspect of cardiology practice. Despite these ...advances, there remains a substantial need for more high-quality evidence to inform cardiovascular clinical practice, given the increasing prevalence of cardiovascular disease around the world. Traditional clinical trials are increasingly challenging due to rising costs, increasing complexity and length, and burdensome institutional and regulatory requirements. This review will examine the current landscape of cardiovascular clinical trials in the United States, highlight recently conducted registry-based clinical trials, and discuss the potential attributes of the recently launched pragmatic clinical trial by the Patient-Centered Outcomes Research Institute’s National Patient-Centered Clinical Research Network, called the ADAPTABLE (Aspirin Dosing: A Patient-centric Trial Assessing the Benefits and Long-term Effectiveness) trial.
Background A gene expression profile (GEP) test able to accurately identify risk of metastasis for patients with cutaneous melanoma has been clinically validated. Objective We aimed for assessment of ...the prognostic accuracy of GEP and sentinel lymph node biopsy (SLNB) tests, independently and in combination, in a multicenter cohort of 217 patients. Methods Reverse transcription polymerase chain reaction (RT-PCR) was performed to assess the expression of 31 genes from primary melanoma tumors, and SLNB outcome was determined from clinical data. Prognostic accuracy of each test was determined using Kaplan-Meier and Cox regression analysis of disease-free, distant metastasis–free, and overall survivals. Results GEP outcome was a more significant and better predictor of each end point in univariate and multivariate regression analysis, compared with SLNB ( P < .0001 for all). In combination with SLNB, GEP improved prognostication. For patients with a GEP high-risk outcome and a negative SLNB result, Kaplan-Meier 5-year disease-free, distant metastasis–free, and overall survivals were 35%, 49%, and 54%, respectively. Limitations Within the SLNB-negative cohort of patients, overall risk of metastatic events was higher (∼30%) than commonly found in the general population of patients with melanoma. Conclusions In this study cohort, GEP was an objective tool that accurately predicted metastatic risk in SLNB-eligible patients.
Angiotensin receptor blockers (ARBs) and/or angiotensin-converting enzyme (ACE) inhibitors could alter mortality from coronavirus disease 2019 (COVID-19), but existing meta-analyses that combined ...crude and adjusted results may be confounded by the fact that comorbidities are more common in ARB/ACE inhibitor users.
We searched PubMed/MEDLINE/Embase for cohort studies and meta-analyses reporting mortality by preexisting ARB/ACE inhibitor treatment in hospitalized COVID-19 patients. Random effects meta-regression was used to compute pooled odds ratios for mortality adjusted for imbalance in age, sex, and prevalence of cardiovascular disease, hypertension, diabetes mellitus, and chronic kidney disease between users and nonusers of ARBs/ACE inhibitors at the study level during data synthesis.
In 30 included studies of 17,281 patients, 22%, 68%, 25%, and 11% had cardiovascular disease, hypertension, diabetes mellitus, and chronic kidney disease. ARB/ACE inhibitor use was associated with significantly lower mortality after controlling for potential confounding factors (odds ratio 0.77 95% confidence interval: 0.62, 0.96). In contrast, meta-analysis of ARB/ACE inhibitor use was not significantly associated with mortality when all studies were combined with no adjustment made for confounders (0.87 95% confidence interval: 0.71, 1.08).
ARB/ACE inhibitor use was associated with decreased mortality in cohorts of COVID-19 patients after adjusting for age, sex, cardiovascular disease, hypertension, diabetes, and chronic kidney disease. Unadjusted meta-analyses may not be appropriate for determining whether ARBs/ACE inhibitors are associated with mortality from COVID-19 because of indication bias.
Les antagonistes des récepteurs de l'angiotensine (ARA) et/ou les inhibiteurs de l'enzyme de conversion de l'angiotensine (IECA) feraient varier la mortalité liée à la COVID-19, mais il est possible que les méta-analyses actuelles qui combinaient les résultats bruts et ajustés soient invalidées du fait que les comorbidités sont plus fréquentes chez les utilisateurs d'ARA/IECA.
Nous avons effectué des recherches dans les bases de données PubMed/MEDLINE/Embase pour trouver des études de cohorte et des méta-analyses qui portent sur la mortalité associée à un traitement préexistant par ARA/IECA chez les patients hospitalisés atteints de la COVID-19. Nous avons utilisé la métarégression à effets aléatoires pour calculer les rapports de cotes regroupés de mortalité ajustés en fonction du déséquilibre de l’âge, du sexe, et de la prévalence des maladies cardiovasculaires, de l'hypertension, du diabète sucré et de l'insuffisance rénale chronique entre les utilisateurs et les non-utilisateurs d'ARA/IECA dans le cadre de l’étude durant la synthèse des données.
Dans les 30 études portant sur 17 281 patients, 22 %, 68 %, 25 % et 11 % avaient respectivement une maladie cardiovasculaire, de l'hypertension, le diabète sucré et de l'insuffisance rénale chronique. L'utilisation des ARA/IECA a été associée à une mortalité significativement plus faible après avoir tenu compte des facteurs confusionnels potentiels (rapport de cotes 0,77 intervalle de confiance à 95 % : 0,62, 0,96). En revanche, la méta-analyse sur l'utilisation des ARA/IECA n'a pas été associée de façon significative à la mortalité lorsque toutes les études ont été combinées sans ajustement sur les facteurs confusionnels (0,87 intervalle de confiance à 95 % : 0,71, 1,08).
L'utilisation des ARA/IECA a été associée à la diminution de la mortalité au sein des cohortes de patients atteints de la COVID-19 après l'ajustement en fonction de l’âge, du sexe, des maladies cardiovasculaires, de l'hypertension, du diabète et de l'insuffisance rénale chronique. Les méta-analyses non ajustées peuvent ne pas permettre de déterminer si les ARA/IECA sont associés à la mortalité liée à la COVID-19 en raison du biais d'indication.
Objective Apolipoprotein E ( APOE ) genotype is a determinant of neurologic recovery after brain ischemia and traumatic brain injury. The APOE ε2 allele has been associated with worse ...neurodevelopmental (ND) outcome after repair of congenital heart defects (CHD) in infancy. Replication of this finding in an independent cohort is essential to validate the observed genotype-phenotype association. Methods The association of APOE genotype with ND outcomes was assessed in a combined cohort of patients with single-ventricle CHD enrolled in the Single Ventricle Reconstruction and Infant Single Ventricle trials. ND outcome was assessed at 14 months using the Psychomotor Development Index (PDI) and Mental Development Index (MDI) of the Bayley Scales of Infant Development-II. Stepwise multivariable regression was performed to develop predictive models for PDI and MDI scores. Results Complete data were available for 298 of 435 patients. After adjustment for preoperative and postoperative covariates, the APOE ε2 allele was associated with a lower PDI score ( P = .038). Patients with the ε2 allele had a PDI score approximately 6 points lower than those without the risk allele, explaining 1.04% of overall PDI variance, because the ε2 allele was present in only 11% of the patients. There was a marginal effect of the ε2 allele on MDI scores ( P = .058). Conclusions These data validate the association of the APOE ε2 allele with adverse early ND outcomes after cardiac surgery in infants, independent of patient and operative factors. Genetic variants that decrease neuroresilience and impair neuronal repair after brain injury are important risk factors for ND dysfunction after surgery for CHD.
Background Eosinophilic esophagitis (EoE) is a chronic antigen-driven allergic inflammatory disease, likely involving the interplay of genetic and environmental factors, yet their respective ...contributions to heritability are unknown. Objective To quantify the risk associated with genes and environment on familial clustering of EoE. Methods Family history was obtained from a hospital-based cohort of 914 EoE probands (n = 2192 first-degree “Nuclear-Family” relatives) and an international registry of monozygotic and dizygotic twins/triplets (n = 63 EoE “Twins” probands). Frequencies, recurrence risk ratios (RRRs), heritability, and twin concordance were estimated. Environmental exposures were preliminarily examined. Results Analysis of the Nuclear-Family–based cohort revealed that the rate of EoE, in first-degree relatives of a proband, was 1.8% (unadjusted) and 2.3% (sex-adjusted). RRRs ranged from 10 to 64, depending on the family relationship, and were higher in brothers (64.0; P = .04), fathers (42.9; P = .004), and males (50.7; P < .001) than in sisters, mothers, and females, respectively. The risk of EoE for other siblings was 2.4%. In the Nuclear-Family cohort, combined gene and common environment heritability was 72.0% ± 2.7% ( P < .001). In the Twins cohort, genetic heritability was 14.5% ± 4.0% ( P < .001), and common family environment contributed 81.0% ± 4% ( P < .001) to phenotypic variance. Probandwise concordance in monozygotic co-twins was 57.9% ± 9.5% compared with 36.4% ± 9.3% in dizygotic co-twins ( P = .11). Greater birth weight difference between twins ( P = .01), breast-feeding ( P = .15), and fall birth season ( P = .02) were associated with twin discordance in disease status. Conclusions EoE RRRs are increased 10- to 64-fold compared with the general population. EoE in relatives is 1.8% to 2.4%, depending on relationship and sex. Nuclear-Family heritability appeared to be high (72.0%). However, the Twins cohort analysis revealed a powerful role for common environment (81.0%) compared with additive genetic heritability (14.5%).
Multiple myeloma is a malignant plasma cell neoplasm that affects more than 20,000 people each year and is the second most common hematologic malignancy. It is part of a spectrum of monoclonal plasma ...cell disorders, many of which do not require active therapy. During the past decade, considerable progress has been made in our understanding of the disease process and factors that influence outcome, along with development of new drugs that are highly effective in controlling the disease and prolonging survival without compromising quality of life. Identification of well-defined and reproducible prognostic factors and introduction of new therapies with unique modes of action and impact on disease outcome have for the first time opened up the opportunity to develop risk-adapted strategies for managing this disease. Although these risk-adapted strategies have not been prospectively validated, enough evidence can be gathered from existing randomized trials, subgroup analyses, and retrospective studies to develop a working framework. This set of recommendations represents such an effort—the development of a set of consensus guidelines by a group of experts to manage patients with newly diagnosed disease based on an interpretation of the best available evidence.
Long-Term Efficacy of Catheter Ablation of Ventricular Tachycardia in Patients With Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy Darshan Dalal, Rahul Jain, Harikrishna Tandri, Jun Dong, ...Shaker M. Eid, Kalpana Prakasa, Crystal Tichnell, Cynthia James, Theodore Abraham, Stuart D. Russell, Sunil Sinha, Daniel P. Judge, David A. Bluemke, Joseph E. Marine, Hugh Calkins Prior studies have reported conflicting results concerning the efficacy of radiofrequency catheter ablation (RFA) of ventricular tachycardia (VT) in arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) patients. We sought to evaluate the efficacy of RFA procedures in ARVD/C. Among 48 RFA procedures performed in 24 patients, 46%, 31%, and 23% resulted in elimination of all inducible VTs, the clinical VT but not all, and none of the inducible VTs, respectively. The cumulative recurrence-free survival was 75%, 50%, and 25% after 1.5, 5, and 14 months, respectively. Long-term VT recurrence did not differ by procedural success, mapping technique, or repetition of the procedure. Our study shows a high rate of VT recurrence in ARVD/C patients undergoing RFA of VT.
We present observations of rapid (sub-second) optical flux variability in V404 Cyg during its 2015 June outburst. Simultaneous three-band observations with the ULTRACAM fast imager on four nights ...show steep power spectra dominated by slow variations on ∼100–1000 s time-scales. Near the peak of the outburst on June 26, a dramatic change occurs and additional, persistent sub-second optical flaring appears close in time to giant radio and X-ray flaring. The flares reach peak optical luminosities of ∼ few × 1036 erg s−1. Some are unresolved down to a time resolution of 24 ms. Whereas the fast flares are stronger in the red, the slow variations are bluer when brighter. The redder slopes, emitted power and characteristic time-scales of the fast flares can be explained as optically thin synchrotron emission from a compact jet arising on size scales ∼140–500 Gravitational radii (with a possible additional contribution by a thermal particle distribution). The origin of the slower variations is unclear. The optical continuum spectral slopes are strongly affected by dereddening uncertainties and contamination by strong Hα emission, but the variations of these slopes follow relatively stable loci as a function of flux. Cross-correlating the slow variations between the different bands shows asymmetries on all nights consistent with a small red skew (i.e. red lag). X-ray reprocessing and non-thermal emission could both contribute to these. These data reveal a complex mix of components over five decades in time-scale during the outburst.
Background Combined immunodeficiency with multiple intestinal atresias (CID-MIA) is a rare hereditary disease characterized by intestinal obstructions and profound immune defects. Objective We sought ...to determine the underlying genetic causes of CID-MIA by analyzing the exomic sequences of 5 patients and their healthy direct relatives from 5 unrelated families. Methods We performed whole-exome sequencing on 5 patients with CID-MIA and 10 healthy direct family members belonging to 5 unrelated families with CID-MIA. We also performed targeted Sanger sequencing for the candidate gene tetratricopeptide repeat domain 7A ( TTC7A ) on 3 additional patients with CID-MIA. Results Through analysis and comparison of the exomic sequence of the subjects from these 5 families, we identified biallelic damaging mutations in the TTC7A gene, for a total of 7 distinct mutations. Targeted TTC7A gene sequencing in 3 additional unrelated patients with CID-MIA revealed biallelic deleterious mutations in 2 of them, as well as an aberrant splice product in the third patient. Staining of normal thymus showed that the TTC7A protein is expressed in thymic epithelial cells, as well as in thymocytes. Moreover, severe lymphoid depletion was observed in the thymus and peripheral lymphoid tissues from 2 patients with CID-MIA. Conclusions We identified deleterious mutations of the TTC7A gene in 8 unrelated patients with CID-MIA and demonstrated that the TTC7A protein is expressed in the thymus. Our results strongly suggest that TTC7A gene defects cause CID-MIA.
OBJECTIVE To examine whether the outcome of patients with primary systemic amyloidosis (AL) has improved over time and to identify predictors of early mortality in patients with AL. PATIENTS AND ...METHODS We studied 2 separate cohorts of patients. The first cohort, consisting of 1998 patients with AL seen at Mayo Clinic between January 1977 and August 2006, was used to examine the trends in overall survival (OS) from diagnosis during this 30-year period. The second cohort, consisting of 313 patients seen between September 2006 and August 2009, was used to validate a model for predicting early mortality. RESULTS The 4-year OS from diagnosis improved during each decade of follow-up: 21%, 24%, and 33%, respectively, for the periods 1977-1986, 1987-1996, and 1997-2006 ( P <.001). Within the last group (1997-2006), 4-year OS during 1997-1999, 2000-2002, and 2003-2006 was 28%, 30%, and 42%, respectively ( P =.02). However, the 1-year mortality remained high during the 30-year period. A risk stratification score using cardiac troponin T, N-terminal probrain natriuretic peptide, and uric acid identified patients at risk of early mortality. The 1-year mortality with 0, 1, 2, or 3 risk factors was 19%, 37%, 61%, and 80%, respectively, in this training cohort of 459 patients. This was confirmed in a validation cohort of 313 patients. CONCLUSION Survival in AL has improved over time, with maximum improvement occurring in the past decade. However, early mortality remains high, and prospective identification of patients at risk of early mortality may allow development of risk-adapted strategies.
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