Publications

BACKGROUND

Fixed-dose combination of isosorbide dinitrate and hydralazine (FDC-I/H) reduced mortality by 43% and death or first hospitalization for heart failure (HF) by 37% in the African-American Heart Failure Trial (A-HeFT). Reduction in mortality makes it difficult to determine the effect on hospitalizations unless the analysis adjusts for death as a competing risk.

METHODS AND RESULTS

In A-HeFT, 1050 self-identified black patients with moderate to severe HF were randomized to FDC-I/H or placebo. The effects of FDC-I/H on first and all hospitalizations and 30-day readmission rates were analyzed. Deaths as competing risks were adjusted using Fine-Gray regression and joint models of hospitalizations and mortality. There were 558 all-cause and 251 HF hospitalizations in placebo compared with 435 and 173 hospitalizations in the FDC-I/H group. Adjusting for deaths as a competing risk, the effect of FDC-I/H on the first hospitalization for HF, expressed in hazard ratio (95% confidence interval), was 0.61 (0.47-0.80; P<0.001) and 0.88 (0.72-1.06; P=0.18) on the first all-cause hospitalization. The effect of FDC-I/H on all recurrent hospitalizations for HF was 0.66 (0.52-0.83; P=0.0005), similar to the effect on the first hospitalizations for HF, whereas the effect on all hospitalizations for any cause was 0.75 (0.63-0.91; P=0.003). The 30-day all-cause readmission rate after the first hospitalization for HF was 23.6% (29 of 123) in placebo versus 14.8% (12 of 81) in the FDC-I/H group, but the effect (0.59; 0.30-1.16; P=0.12) in this small subgroup was not significant.

CONCLUSIONS

Treatment with FDC-I/H was associated with a substantial reduction in the first and recurrent HF hospitalizations, and in total all-cause hospitalizations, reducing the total burden of costly and distressing hospitalizations.

CLINICAL TRIAL REGISTRATION URL

http://www.clinicaltrials.gov. Unique identifier: NCT00047775.

We evaluated motorcycle taxi ('boda-boda') drivers in Kampala for the prevalence of HIV/sexually transmitted infections. We used respondent-driven sampling to recruit a cross-sectional sample of boda-boda drivers. We collected data through audio computer-assisted self-administered interviews. Men were tested for HIV, syphilis serology using Rapid Plasma Reagin and enzyme immunoassay, and Chlamydia and gonorrhoea using urine polymerase chain reaction. We recruited 683 men. Median age was 26 years; 59.4% were single. The prevalence of HIV was 7.5% (95% CI 5.2-10.0), of positive syphilis serology was 6.1% (95% CI 4.3-8.1), of Chlamydia was 1.1% (95% CI 0.4-2.0), and of gonorrhoea was 1.2% (95% CI 0.1-1.2). Many men (67.8%) had both casual and regular partners, sex with other men (8.7%), and commercial sex (33.1%). Factors associated with having HIV included reporting a genital ulcer (odds ratio [OR] =2.4, 95% CI 1.4-4.4), drinking alcohol during last sex (OR 2.0, 95% CI 1.1-3.7), having 4-6 lifetime partners (OR 2.2, 95% CI 1.0-4.8), and having one's last female partner be >24 years of age (OR 2.8, 95% CI 1.2-6.6). Independent predictors of HIV included age ≥31 (adjusted OR (aOR) 5.8, 95% CI 1.5-48.5), having 4-6 partners (aOR 2.2, 95%CI 1.0-5.1), and self-report of a genital ulcer (OR 2.3, 95% CI 1.2-4.1). Only 39.2% of men were circumcised, and 36.9% had been HIV tested in the past. Male boda-boda drivers have a higher prevalence of HIV than the general population, and low frequency of preventive behaviours, such as circumcision and HIV testing. Targeted and intensified interventions for this group are warranted.

The National Institute of Diabetes and Digestive and Kidney Diseases-supported Kidney Research National Dialogue asked the scientific community to formulate and prioritize research objectives that would enhance understanding of kidney function and disease and improve clinical outcomes. An engaged and growing group of investigators working in type 2 translation (from clinical evidence to implementation in the community) identified barriers to improving patient care in CKD and suggested research priorities to test translational strategies that have been effective for other chronic diseases.

Gene-regulatory enhancers have been identified using various approaches, including evolutionary conservation, regulatory protein binding, chromatin modifications, and DNA sequence motifs. To integrate these different approaches, we developed EnhancerFinder, a two-step method for distinguishing developmental enhancers from the genomic background and then predicting their tissue specificity. EnhancerFinder uses a multiple kernel learning approach to integrate DNA sequence motifs, evolutionary patterns, and diverse functional genomics datasets from a variety of cell types. In contrast with prediction approaches that define enhancers based on histone marks or p300 sites from a single cell line, we trained EnhancerFinder on hundreds of experimentally verified human developmental enhancers from the VISTA Enhancer Browser. We comprehensively evaluated EnhancerFinder using cross validation and found that our integrative method improves the identification of enhancers over approaches that consider a single type of data, such as sequence motifs, evolutionary conservation, or the binding of enhancer-associated proteins. We find that VISTA enhancers active in embryonic heart are easier to identify than enhancers active in several other embryonic tissues, likely due to their uniquely high GC content. We applied EnhancerFinder to the entire human genome and predicted 84,301 developmental enhancers and their tissue specificity. These predictions provide specific functional annotations for large amounts of human non-coding DNA, and are significantly enriched near genes with annotated roles in their predicted tissues and lead SNPs from genome-wide association studies. We demonstrate the utility of EnhancerFinder predictions through in vivo validation of novel embryonic gene regulatory enhancers from three developmental transcription factor loci. Our genome-wide developmental enhancer predictions are freely available as a UCSC Genome Browser track, which we hope will enable researchers to further investigate questions in developmental biology.