BACKGROUND Genetic defects in telomere maintenance and repair cause bone marrow failure, liver cirrhosis, and pulmonary fibrosis, and they increase susceptibility to cancer. Historically, androgens have been useful as treatment for marrow failure syndromes. In tissue culture and animal models, sex hormones regulate expression of the telomerase gene. METHODS In a phase 1–2 prospective study involving patients with telomere diseases, we administered the synthetic sex hormone danazol orally at a dose of 800 mg per day for a total of 24 months. The goal of treatment was the attenuation of accelerated telomere attrition, and the primary efficacy end point was a 20% reduction in the annual rate of telomere attrition measured at 24 months. The occurrence of toxic effects of treatment was the primary safety end point. Hematologic response to treatment at various time points was the secondary efficacy end point. RESULTS After 27 patients were enrolled, the study was halted early, because telomere attrition was reduced in all 12 patients who could be evaluated for the primary end point; in the intention-to-treat analysis, 12 of 27 patients (44%; 95% confidence interval [CI], 26 to 64) met the primary efficacy end point. Unexpectedly, almost all the patients (11 of 12, 92%) had a gain in telomere length at 24 months as compared with baseline (mean increase, 386 bp [95% CI, 178 to 593]); in exploratory analyses, similar increases were observed at 6 months (16 of 21 patients; mean increase, 175 bp [95% CI, 79 to 271]) and 12 months (16 of 18 patients; mean increase, 360 bp [95% CI, 209 to 512]). Hematologic responses occurred in 19 of 24 patients (79%) who could be evaluated at 3 months and in 10 of 12 patients (83%) who could be evaluated at 24 months. Known adverse effects of danazol — elevated liver-enzyme levels and muscle cramps — of grade 2 or less occurred in 41% and 33% of the patients, respectively. CONCLUSIONS In our study, treatment with danazol led to telomere elongation in patients with telomere diseases. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT01441037.)

Administrative claims studies do not adequately distinguish pulmonary arterial hypertension (PAH) from other forms of pulmonary hypertension (PH). Our aim is to develop and validate a set of algorithms using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes and electronic medical records (EMR), to identify patients with PAH. From January 2012 to August 2015, the EMRs of patients with ICD-9-CM codes for PH with an outpatient visit at the University of Texas Medical Branch were reviewed. Patients were divided into PAH or non-PAH groups according to EMR encounter diagnosis. Patient demographics, echocardiography, right heart catheterization (RHC) results, and PAH-specific therapies were assessed. RHC measurements were reviewed to categorize cases as hemodynamically determined PAH or not PAH. Weighted sensitivity, specificity, and positive and negative predictive values were calculated for the developed algorithms. A logistic regression analysis was conducted to determine how well the algorithms performed. External validation was performed at the University of Virginia Health System. The cohort for the development algorithms consisted of 683 patients with PH, PAH group (n = 191) and non-PAH group (n = 492). A hemodynamic diagnosis of PAH determined by RHC was recorded in the PAH (26%) and non-PAH (3%) groups. The positive predictive value for the algorithm that included ICD-9-CM and PAH-specific medications was 66.9% and sensitivity was 28.2% with a c-statistic of 0.66. The positive predictive value for the EMR-based algorithm that included ICD-9-CM, EMR encounter diagnosis, echocardiography, RHC, and PAH-specific medication was 69.4% and a c-statistic of 0.87. A validation cohort of 177 patients with PH examined from August 2015 to August 2016 using EMR-based algorithms yielded a similar positive predictive value of 62.5%. In conclusion, claims-based algorithms that included ICD-9-CM codes, EMR encounter diagnosis, echocardiography, RHC, and PAH-specific medications better-identified patients with PAH than ICD-9-CM codes alone.

Background: Acute pulmonary embolism remains a significant cause of mortality and morbidity worldwide. Benefit of recently developed multidisciplinary PE response teams (PERT) with higher utilization of advanced therapies has not been established. Methods: To evaluate patient-centered outcomes and cost-effectiveness of a multidisciplinary PERT we performed a retrospective analysis of 554 patients with acute PE at the university of Virginia between July 2014 and June 2015 (pre-PERT era) and between April 2017 through October 2018 (PERT era). Six-month survival, hospital length-of-stay (LOS), type of PE therapy, and in-hospital bleeding were assessed upon collected data. Results: 317 consecutive patients were treated for acute PE during an 18-month period following institution of a multidisciplinary PE program; for 120 patients PERT was activated (PA), the remaining 197 patients with acute PE were considered as a separate, contemporary group (NPA). The historical, comparator cohort (PP) was composed of 237 patients. These 3 groups were similar in terms of baseline demographics, comorbidities and risk, as assessed by the Pulmonary Embolism Severity Index (PESI). Patients in the historical cohort demonstrated worsened survival when compared with patients treated during the PERT era. During the PERT era no statistically significant difference in survival was observed in the PA group when compared to the NPA group despite significantly higher severity of illness among PA patients. Hospital LOS was not different in the PA group when compared to either the NPA or PP group. Hospital costs did not differ among the 3 cohorts. 30-day re-admission rates were significantly lower during the PERT era. Rates of advanced therapies were significantly higher during the PERT era (9.1% vs. 2%) and were concentrated in the PA group (21.7% vs. 1.5%) without any significant rise in in-hospital bleeding complications.

Pulmonary artery pulsatility index was independently associated with survival in PAH, highlighting the utility of PAPi in combination with other key measures for risk stratification in this population.

Background The ‘obesity paradox’ refers to the fact that obese patients have better outcomes than normal weight patients. This has been observed in multiple cardiovascular conditions, but evidence for obesity paradox in pulmonary hypertension (PH) remains sparse. Methods We categorized 267 patients from the National Institute of Health-PH registry into five groups based on body mass index (BMI): underweight, normal weight, overweight, obese and morbidly obese. Mortality was compared in BMI groups using the X2 statistic. Five-year probability of death using the PH connection (PHC) risk equation was calculated, and the model was compared with BMI groups using Cox proportional hazards regression and Kaplan-Meier (KM) survival curves. Results Patients had a median age of 39 years (interquartile range 30–50 years), a median BMI of 23.4 kg m −2 (21.0–26.8 kg m−2) and an overall mortality at 5 years of 50.2%. We found a U-shaped relationship between survival and 1-year mortality with the best 1-year survival in overweight patients. KM curves showed the best survival in the overweight, followed by obese and morbidly obese patients, and the worst survival in normal weight and underweight patients (log-rank P = 0.0008). In a Cox proportional hazards analysis, increasing BMI was a highly significant predictor of improved survival even after adjustment for the PHC risk equation with a hazard ratio for death of 0.921 per kg m−2 (95% confidence interval: 0.886–0.954) (P < 0.0001). Conclusion We observed that the best survival was in the overweight patients, making this more of an ‘overweight paradox’ than an ‘obesity paradox’. This has implications for risk stratification and prognosis in group 1 PH patients.