Nintedanib for Systemic Sclerosis-Associated Interstitial Lung Disease

BACKGROUND: Interstitial lung disease (ILD) is a common manifestation of systemic sclerosis and a leading cause of systemic sclerosis-related death. Nintedanib, a tyrosine kinase inhibitor, has been shown to have antifibrotic and antiinflammatory effects in preclinical models of systemic sclerosis and ILD. METHODS: We conducted a randomized, double-blind, placebo-controlled trial to investigate the efficacy and safety of nintedanib in patients with ILD associated with systemic sclerosis. Patients who had systemic sclerosis with an onset of the first non-Raynaud's symptom within the past 7 years and a high-resolution computed tomographic scan that showed fibrosis affecting at least 10% of the lungs were randomly assigned, in a 1:1 ratio, to receive 150 mg of nintedanib, administered orally twice daily, or placebo. The primary end point was the annual rate of decline in forced vital capacity (FVC), assessed over a 52-week period. Key secondary end points were absolute changes from baseline in the modified Rodnan skin score and in the total score on the St. George's Respiratory Questionnaire (SGRQ) at week 52. RESULTS: A total of 576 patients received at least one dose of nintedanib or placebo; 51.9% had diffuse cutaneous systemic sclerosis, and 48.4% were receiving mycophenolate at baseline. In the primary end-point analysis, the adjusted annual rate of change in FVC was 1252.4 ml per year in the nintedanib group and 1293.3 ml per year in the placebo group (difference, 41.0 ml per year; 95% confidence interval [CI], 2.9 to 79.0; P=0.04). Sensitivity analyses based on multiple imputation for missing data yielded P values for the primary end point ranging from 0.06 to 0.10. The change from baseline in the modified Rodnan skin score and the total score on the SGRQ at week 52 did not differ significantly between the trial groups, with differences of 120.21 (95% CI, 120.94 to 0.53; P=0.58) and 1.69 (95% CI, 120.73 to 4.12 [not adjusted for multiple comparisons]), respectively. Diarrhea, the most common adverse event, was reported in 75.7% of the patients in the nintedanib group and in 31.6% of those in the placebo group. CONCLUSIONS: Among patients with ILD associated with systemic sclerosis, the annual rate of decline in FVC was lower with nintedanib than with placebo; no clinical benefit of nintedanib was observed for other manifestations of systemic sclerosis. The adverse-event profile of nintedanib observed in this trial was similar to that observed in patients with idiopathic pulmonary fibrosis; gastrointestinal adverse events, including diarrhea, were more common with nintedanib than with placebo

Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease

BACKGROUND: Patients with atherosclerotic vascular disease remain at high risk for cardiovascular events despite effective statin-based treatment of low-density lipoprotein (LDL) cholesterol levels. The inhibition of cholesteryl ester transfer protein (CETP) by anacetrapib reduces LDL cholesterol levels and increases high-density lipoprotein (HDL) cholesterol levels. However, trials of other CETP inhibitors have shown neutral or adverse effects on cardiovascular outcomes. METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving 30,449 adults with atherosclerotic vascular disease who were receiving intensive atorvastatin therapy and who had a mean LDL cholesterol level of 61 mg per deciliter (1.58 mmol per liter), a mean non-HDL cholesterol level of 92 mg per deciliter (2.38 mmol per liter), and a mean HDL cholesterol level of 40 mg per deciliter (1.03 mmol per liter). The patients were assigned to receive either 100 mg of anacetrapib once daily (15,225 patients) or matching placebo (15,224 patients). The primary outcome was the first major coronary event, a composite of coronary death, myocardial infarction, or coronary revascularization. RESULTS: During the median follow-up period of 4.1 years, the primary outcome occurred in significantly fewer patients in the anacetrapib group than in the placebo group (1640 of 15,225 patients [10.8%] vs. 1803 of 15,224 patients [11.8%]; rate ratio, 0.91; 95% confidence interval, 0.85 to 0.97; P=0.004). The relative difference in risk was similar across multiple prespecified subgroups. At the trial midpoint, the mean level of HDL cholesterol was higher by 43 mg per deciliter (1.12 mmol per liter) in the anacetrapib group than in the placebo group (a relative difference of 104%), and the mean level of non-HDL cholesterol was lower by 17 mg per deciliter (0.44 mmol per liter), a relative difference of -18%. There were no significant between-group differences in the risk of death, cancer, or other serious adverse events. CONCLUSIONS: Among patients with atherosclerotic vascular disease who were receiving intensive statin therapy, the use of anacetrapib resulted in a lower incidence of major coronary events than the use of placebo. (Funded by Merck and others; Current Controlled Trials number, ISRCTN48678192 ; ClinicalTrials.gov number, NCT01252953 ; and EudraCT number, 2010-023467-18 .)

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

Emergency Department Patients with Psychiatric Complaints Return at Higher Rates than Controls

Study objective: At our 35,000 visit/year emergency department (ED), we studied whether patients presenting to the ED with psychiatric complaints were admitted to the hospital at a higher rate than non-psychiatric patients, and whether these patients had a higher rate of reevaluation in the ED within 30 days following the index visit.Methods: We reviewed the electronic records of all ED patients receiving a psychiatric evaluation from January to February 2007 and compared these patients to 300 randomly selected patients presenting during the study period for non-psychiatric complaints. Patients were followed for 30 days, and admission rates and return visits were compared.Results: Two hundred thirty-four patients presented to the ED and were evaluated for psychiatric complaints during the study period. Twenty-four point seven percent of psychiatric patients were admitted upon initial presentation versus 20.7% of non-psychiatric patients (p = 0.258). Twenty-one percent of discharged psychiatric patients returned to the ED within 30 days versus 13.4% of discharged non-psychiatric patients (p=0.041). Patients returning to the ED within 30 days had a 17.1% versus 21.6% admission rate for the psychiatric and non-psychiatric groups, respectively (p=0.485).Conclusion: Patients presenting to this ED with psychiatric complaints were not admitted at a significantly higher rate than non-psychiatric patients. These psychiatric patients did, however, have a significantly higher return rate to the ED when compared to non-psychiatric patients.[West J Emerg Med. 2009;10(4):268-272.

Emergency Department Patients with Psychiatric Complaints Return at Higher Rates than Controls

Study objective: At our 35,000 visit/year emergency department (ED), we studied whether patients presenting to the ED with psychiatric complaints were admitted to the hospital at a higher rate than non-psychiatric patients, and whether these patients had a higher rate of reevaluation in the ED within 30 days following the index visit.Methods: We reviewed the electronic records of all ED patients receiving a psychiatric evaluation from January to February 2007 and compared these patients to 300 randomly selected patients presenting during the study period for non-psychiatric complaints. Patients were followed for 30 days, and admission rates and return visits were compared.Results: Two hundred thirty-four patients presented to the ED and were evaluated for psychiatric complaints during the study period. Twenty-four point seven percent of psychiatric patients were admitted upon initial presentation versus 20.7% of non-psychiatric patients (p = 0.258). Twenty-one percent of discharged psychiatric patients returned to the ED within 30 days versus 13.4% of discharged non-psychiatric patients (p=0.041). Patients returning to the ED within 30 days had a 17.1% versus 21.6% admission rate for the psychiatric and non-psychiatric groups, respectively (p=0.485).Conclusion: Patients presenting to this ED with psychiatric complaints were not admitted at a significantly higher rate than non-psychiatric patients. These psychiatric patients did, however, have a significantly higher return rate to the ED when compared to non-psychiatric patients.[West J Emerg Med. 2009;10(4):268-272.

Emergency Department Patients with Psychiatric Complaints Return at Higher Rates than Controls

Study objective: At our 35,000 visit/year emergency department (ED), we studied whether patients presenting to the ED with psychiatric complaints were admitted to the hospital at a higher rate than non-psychiatric patients, and whether these patients had a higher rate of reevaluation in the ED within 30 days following the index visit.Methods: We reviewed the electronic records of all ED patients receiving a psychiatric evaluation from January to February 2007 and compared these patients to 300 randomly selected patients presenting during the study period for non-psychiatric complaints. Patients were followed for 30 days, and admission rates and return visits were compared.Results: Two hundred thirty-four patients presented to the ED and were evaluated for psychiatric complaints during the study period. Twenty-four point seven percent of psychiatric patients were admitted upon initial presentation versus 20.7% of non-psychiatric patients (p = 0.258). Twenty-one percent of discharged psychiatric patients returned to the ED within 30 days versus 13.4% of discharged non-psychiatric patients (p=0.041). Patients returning to the ED within 30 days had a 17.1% versus 21.6% admission rate for the psychiatric and non-psychiatric groups, respectively (p=0.485).Conclusion: Patients presenting to this ED with psychiatric complaints were not admitted at a significantly higher rate than non-psychiatric patients. These psychiatric patients did, however, have a significantly higher return rate to the ED when compared to non-psychiatric patients.[West J Emerg Med. 2009;10(4):268-272.