Objective We evaluated whether percent time in target range (PTTR), risk of over-Anticoagulation [international normalized ratio (INR)>4], and risk of hemorrhage differ by race. As PTTR is a strong predictor of hemorrhage risk, we also determined the influence of PTTR on the risk of hemorrhage by race. Participants and methods Among 1326 warfarin users, PTTR was calculated as the percentage of interpolated INR values within the target range of 2.0-3.0. PTTR was also categorized as poor (PTTR<60%), good (60≤PTTR<70%), or excellent (PTTR≥70%) anticoagulation control. Over-Anticoagulation was defined as INR more than 4 and major hemorrhages included serious, life-Threatening, and fatal bleeding episodes. Logistic regression and survival analyses were carried out to evaluate the association of race with PTTR (≥60 vs. <60) and major hemorrhages, respectively. Results Compared with African Americans, European Americans had higher PTTR (57.6 vs. 49.1%; P<0.0001) and were more likely to attain 60≤PTTR<70% (22.9 vs. 13.1%; P<0.001) or PTTR of at least 70% (26.9 vs. 18.2%; P=0.001). Older (>65 years) patients without venous thromboembolism indication and chronic kidney disease were more likely to attain PTTR of at least 60%. After accounting for clinical and genetic factors, and PTTR, African Americans had a higher risk of hemorrhage [hazard ratio (HR)=1.58; 95% confidence interval (CI): 1.04-2.41; P=0.034]. Patients with 60≤PTTR<70% (HR=0.62; 95% CI: 0.38-1.02; P=0.058) and PTTR of at least 70% (HR=0.27; 95% CI: 0.15-0.49; P<0.001) had a lower risk of hemorrhage compared with those with PTTR less than 60%. Conclusion Despite the provision of warfarin management through anticoagulation clinics, African Americans achieve a lower overall PTTR and have a significantly higher risk of hemorrhage. Personalized medicine interventions tailored to African American warfarin users need to be developed.
Caffeine is one of the most commonly prescribed medications in preterm neonates and is widely used to treat or prevent apnea of prematurity. Caffeine therapy is safe, effectively decreases apnea, and improves short- and long-term outcomes in preterm infants. In this review, the authors summarize the role of caffeine therapy for preterm infants receiving noninvasive respiratory support. As caffeine is already widely used, recent data are summarized that may guide clinicians in optimizing the use of caffeine therapy, with a review of the timing of initiation, dose, and duration of therapy.
by
Gudio Veit;
Radu G. Avramescu;
Annette N. Chiang;
Scott A. Houck;
Zhiwei Cai;
Kathryn W. Peters;
Jeong S. Hong;
Harvey B. Pollard;
William B. Guggino;
William E. Balch;
William R. Skach;
Garry R. Cutting;
Raymond A. Frizzell;
David N. Sheppard;
Douglas M. Cyr;
Eric Sorscher;
Jeffrey L. Brodsky;
Gergely L. Lukacs
More than 2000 mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) have been described that confer a range of molecular cell biological and functional phenotypes. Most of these mutations lead to compromised anion conductance at the apical plasma membrane of secretory epithelia and cause cystic fibrosis (CF) with variable disease severity. Based on the molecular phenotypic complexity of CFTR mutants and their susceptibility to pharmacotherapy, it has been recognized that mutations may impose combinatorial defects in CFTR channel biology. This notion led to the conclusion that the combination of pharmacotherapies addressing single defects (e.g., transcription, translation, folding, and/or gating) may show improved clinical benefit over available low-efficacy monotherapies. Indeed, recent phase 3 clinical trials combining ivacaftor (a gating potentiator) and lumacaftor (a folding corrector) have proven efficacious in CF patients harboring the most common mutation (deletion of residue F508, δF508, or Phe508del). This drug combination was recently approved by the U.S. Food and Drug Administration for patients homozygous for δF508. Emerging studies of the structural, cell biological, and functional defects caused by rare mutations provide a new framework that reveals a mixture of deficiencies in different CFTR alleles. Establishment of a set of combinatorial categories of the previously defined basic defects in CF alleles will aid the design of even more efficacious therapeutic interventions for CF patients.
by
Javed Butler;
Gregg C. Fonarow;
Michael R. Zile;
Carolyn S. Lam;
Lothar Roessig;
Erik B. Schelbert;
Sanjiv J. Shah;
Ali Ahmed;
Robert O. Bonow;
John GF Cleland;
Robert J. Cody;
Ovidiu Chioncel;
Sean P. Collins;
Preston Dunnmon;
Gerasimos Filippatos;
Martin P. Lefkowitz;
Catherine N. Marti;
John J. McMurray;
Frank Misselwitz;
Vasiliki Georgiopoulou
The burden of heart failure with preserved ejection fraction (HFpEF) is considerable and is projected to worsen. To date, there are no approved therapies available for reducing mortality or hospitalizations for these patients. The pathophysiology of HFpEF is complex and includes alterations in cardiac structure and function, systemic and pulmonary vascular abnormalities, end-organ involvement, and comorbidities. There remain major gaps in our understanding of HFpEF pathophysiology. To facilitate a discussion of how to proceed effectively in future with development of therapies for HFpEF, a meeting was facilitated by the Food and Drug Administration and included representatives from academia, industry, and regulatory agencies. This document summarizes the proceedings from this meeting.