Faculty Bibliography

Genome-wide association studies (GWAS) have highlighted a large number of genetic variants with potential disease association, but functional analysis remains a challenge. Here we describe an approach to functionally validate identified variants through differentiation of induced pluripotent stem cells (iPSCs) to study cellular pathophysiology. We collected peripheral blood cells from Framingham Heart Study participants and reprogrammed them to iPSCs. We then differentiated 68 iPSC lines into hepatocytes and adipocytes to investigate the effect of the 1p13 rs12740374 variant on cardiometabolic disease phenotypes via transcriptomics and metabolomic signatures. We observed a clear association between rs12740374 and lipid accumulation and gene expression in differentiated hepatocytes, in particular, expression of SORT1, CELSR2, and PSRC1, consistent with previous analyses of this variant using other approaches. Initial investigation of additional SNPs also highlighted correlations with gene expression. These findings suggest that iPSC-based population studies hold promise as tools for the functional validation of GWAS variants.

INTRODUCTION: Psychiatric symptoms are reported to occur frequently in people living with HIV and may be associated with specific antiretrovirals. We analysed psychiatric symptoms observed with dolutegravir and other frequently prescribed anchor drugs. METHODS: Selected psychiatric symptoms (insomnia, anxiety, depression, and suicidality) occurring in HIV-positive patients during dolutegravir treatment across 5 randomized clinical trials (3 double-blind), in the Observational Pharmaco-Epidemiology Research & Analysis (OPERA(R)) cohort, and among cases spontaneously reported to ViiV Healthcare were analysed. RESULTS: In clinical trials, psychiatric symptoms were reported at low and similar rates in patients receiving dolutegravir or comparators (atazanavir, darunavir, efavirenz, or raltegravir). Insomnia was most commonly reported. The highest rates were observed in SINGLE (dolutegravir 17%, efavirenz 12%), with consistently lower rates in the other trials (dolutegravir: 3%-8% versus comparator: 3%-7%). More efavirenz-treated patients withdrew because of psychiatric symptoms than patients treated with other anchor drugs. In OPERA, history of psychiatric symptoms at baseline was lowest in efavirenz-treated patients compared with patients treated with dolutegravir, raltegravir, or darunavir. Despite baseline differences, prevalence and incidence during treatment were similar across the 4 anchor drugs. Withdrawal rates for psychiatric symptoms were lowest for dolutegravir (0%-0.6%) and highest for raltegravir (0%-2.5%). Spontaneously reported events were similar in nature to clinical trial data. CONCLUSIONS: Analysis of 3 different data sources shows that, similar to other frequently prescribed anchor drugs to treat HIV infection, psychiatric symptoms are also reported in DTG-treated patients. These events are reported with low frequency and rarely necessitate DTG discontinuation.

Paclitaxel-coated drug-coated balloons have significantly improved short-term and mid-term clinical outcomes in patients with symptomatic femoropopliteal peripheral artery disease. However, long-term results are awaited. Furthermore, the clinical success of drug-coated balloons in the infrapopliteal peripheral arteries has been more modest and overall similar to traditional balloon angioplasty, and remains an area of unmet clinical need. This article provides an overview of the clinical evidence for paclitaxel-coated balloons in the femoropopliteal and infrapopliteal peripheral artery distributions and future directions in this area.

LEARNING OBJECTIVE #1: Recognize the inciting factors of orthodeoxia with a patent foramen ovale. CASE: An 82 year-old presented with acute onset hypoxia upon extubation after a laparoscopic gastrectomy. She had positional episodes of desaturation to 79% when sitting up, with other vitals signs normal and no dyspnea. Her oxygen saturation was 91% on 2L nasal cannula when supine. Her lungs were clear to auscultation bilaterally. PaO2 was 45mmHg on roomair and increased to only 74 mmHg with 100% O2. Initial transthoracic echocardiogram with bubble study demonstrated a patent foramen ovale (PFO) with normal right atrial and pulmonary artery pressures and function. She had a stable 4.1 cm ascending thoracic aortic aneurysm and multiple, stable hepatic cysts. She was diagnosed with Platypnea-Orthodeoxia Syndrome (POS) due to PFO and underwent successful percutaneous transfemoral closure of the defect. Upon discharge, she was saturating 97% on room air, regardless of position. IMPACT: While PFOs can be seen in up to 29% of the general population, orthodeoxia is much more rare, with less than 200 cases described in the literature. With the elderly population increasing, the incidence of aortic aneurysms and other cardiovascular conditions distorting previously silent PFOs may increase as well, so it is important to maintain a high index of suspicion and perform the gold standard diagnostic test early: echocardiography with bubble study. DISCUSSION: Orthodeoxia, or the arterial deoxygenation that accompanies the positional change from supine to erect, requires two conditions to coexist: an anatomical component (interatrial communication such as a patent foramen ovale [PFO] or atrial septal defect [ASD]) and a functional component that redirects shunted blood flow through the atrial septum. These functional defects can either preferentially direct blood flow through the anatomical defect or cause a transient increase in right atrial pressure, reversing the leftright gradient. The former can be caused by conditions that direct the jet of deoxygenated blood through the interatrial communication by repositioning the atrial septum, such as an ascending aortic aneurysm, intracardiac lipoma, hepatic cyst distorting the right atrium, or aortic valve replacement. Conditions which transiently increase right sided pressures include pulmonary embolism, pulmonary hypertension, pericardial effusion, pneumonectomy, chronic obstructive pulmonary disease and constrictive pericarditis. Measured right sided pressures are typically normal in POS. The pathophysiology in our patient is likely due to her thoracic aortic aneurysm, elongating in the erect position and stretching the interatrial septum and PFO. While a possibility, it is unlikely her hepatic cysts contributed to her presentation as they were small and there has only been one case report of a large liver cyst causing this presentation

Burnout is widespread throughout primary care and is associated with negative consequences for providers and patients. The relationship between the patient-centered medical home model and burnout remains unclear. Using survey data from 8135 and 7510 VA primary care employees in 2012 and 2013, respectively, we assessed whether clinic-level medical home implementation was independently associated with burnout prevalence and estimated whether burnout changed among this workforce from 2012 to 2013. Adjusting for differences in respondent and clinic characteristics, we found that burnout was common among primary care employees, increased by 3.9% from 2012 to 2013, and was not associated with the extent of medical home implementation.

BACKGROUND: Educational and computerized interventions have been shown to reduce red blood cell (RBC) transfusion rates, yet controversy remains surrounding the optimal strategy needed to achieve sustained reductions in liberal transfusions. STUDY DESIGN AND METHODS: The purpose of this study was to assess the impact of clinician decision support (CDS) along with targeted education on liberal RBC utilization to four high-utilizing service lines compared with no education to control service lines across an academic medical center. Clinical data along with associated hemoglobin levels at the time of all transfusion orders between April 2014 and December 2015 were obtained via retrospective chart review. The primary outcome was the change in the rate of liberal RBC transfusion orders (defined as any RBC transfusion when the hemoglobin level is >7.0 g/dL). Secondary outcomes included the annual projected reduction in the number of transfusions and the associated decrease in cost due to these changes as well as length of stay (LOS) and death index. These measures were compared between the 12 months prior to the initiative and the 9-month postintervention period. RESULTS: Liberal RBC utilization decreased from 13.4 to 10.0 units per 100 patient discharges (p = 0.002) across the institution, resulting in a projected 12-month savings of $720,360. The mean LOS and the death index did not differ significantly in the postintervention period. CONCLUSION: Targeted education combined with the incorporation of CDS at the time of order entry resulted in significant reductions in the incidence of liberal RBC utilization without adversely impacting inpatient care, whereas control service lines exposed only to CDS had no change in transfusion habits.