Publications

Previous studies demonstrated that the liganded vitamin D receptor (VDR) plays an important role in controlling cardiovascular homeostasis. Both the whole animal VDR gene knockout (VDR) and the myocyte-specific VDR gene deletion result in changes in cardiac structure and function. Clinical states associated with cardiac steatosis (obesity and diabetes mellitus) are also associated with low circulating 25 OH vitamin D levels. We, therefore, examined the effects of VDR deficiency (VDR mouse) in a murine model of cardiac steatosis that expresses the terminal enzyme involved in triglyceride synthesis, diacylglycerol acyltransferase 1 (DGAT1), selectively in the cardiac myocyte. These mice display early cardiac dysfunction and late cardiomyopathy and heart failure. In the present study, we demonstrate that mice harboring both genetic modifications (i.e., MHC-DGAT1 Tg and VDR) exhibit an increase in myocyte size, heart weight/body weight ratio and natriuretic peptide gene expression, all markers of cardiac hypertrophy, that exceed that seen in either VDR or the MHC-DGAT1 Tg mice alone. This was accompanied by a dramatic increase in interstitial fibrosis and increased expression of collagen 1a1 and collagen 3a1, as well as the osteopontin and matrix metalloproteinase 2, genes. At a functional level, this resulted in a 37% reduction in ejection fraction and 55% reduction in fractional shortening in the DGAT1; VDR mice relative to the controls. Collectively, these data demonstrate that deficiency in the vitamin D signaling system enhances the pathological phenotype in this experimental cardiomyopathy and suggest an important role for vitamin D in modulating disease severity in common cardiovascular disorders.

CONTEXT

Patients with advanced illness are prescribed multiple medications in the last year of life, intensifying the risk of negative consequences related to polypharmacy.

OBJECTIVES

To describe the medication burden of patients near the end of life and identify potential areas for improvement in clinician prescribing practices.

METHODS

This was a prespecified secondary analysis of data from a prospective trial. Eligible participants were adults with less than 12 months estimated prognosis taking a statin medication for primary prevention of cardiovascular disease. Participants were enrolled from 15 sites, randomized to continue or discontinue statin medications, and followed for up to a year. Concomitant medications were recorded at least monthly from study enrollment through death. Prescribed medications were categorized by class and subclass. Descriptive statistics were calculated.

RESULTS

On average, participants (n = 244) were 74.3 years old (SD 11.5) and lived 264 days (SD 128); 47.5% of the patients had a primary diagnosis of malignant tumor. This population was exposed to medications across 51 classes, 192 subclasses, and 423 individual medications. Patients took an average of 11.5 (SD 5) medications at the time of enrollment and 10.7 (SD 5) medications at death or study termination. The five most common classes of medications prescribed near the end of life were antihypertensives, broncholytics/bronchodilators, laxatives, antidepressants, and gastric protection agents.

CONCLUSION

There is a significant medication burden placed on patients with advanced illness. Although most medications were prescribed for supportive care, we observed a high prevalence of medications for managing non-life-threatening comorbidities.

We report unbiased metagenomic detection of chikungunya virus (CHIKV), Ebola virus (EBOV), and hepatitis C virus (HCV) from four human blood samples by MinION nanopore sequencing coupled to a newly developed, web-based pipeline for real-time bioinformatics analysis on a computational server or laptop (MetaPORE). At titers ranging from 10(7)-10(8) copies per milliliter, reads to EBOV from two patients with acute hemorrhagic fever and CHIKV from an asymptomatic blood donor were detected within 4 to 10 min of data acquisition, while lower titer HCV virus (1 × 10(5) copies per milliliter) was detected within 40 min. Analysis of mapped nanopore reads alone, despite an average individual error rate of 24 % (range 8-49 %), permitted identification of the correct viral strain in all four isolates, and 90 % of the genome of CHIKV was recovered with 97-99 % accuracy. Using nanopore sequencing, metagenomic detection of viral pathogens directly from clinical samples was performed within an unprecedented <6 hr sample-to-answer turnaround time, and in a timeframe amenable to actionable clinical and public health diagnostics.

Although the demographic revolution has produced hundreds of millions people aged 65 and older, a substantial segment of that population is not enjoying the benefits of extended healthspan. Many live with multiple chronic conditions and disabilities that erode the quality of life. The consequences are also costly for society. In the United States, the most costly 5% of Medicare beneficiaries account for approximately 50% of Medicare's expenditures. This perspective summarizes a recent workshop on biomedical approaches to best extend healthspan as way to reduce age-related dysfunction and disability. We further specify the action items necessary to unite health professionals, scientists, and the society to partner around the exciting and palpable opportunities to extend healthspan.