Publications

Medullary thymic epithelial cells (mTECs) facilitate the deletion of developing self-reactive T cells by displaying a diverse repertoire of tissue-specific antigens, a process which largely depends on the expression of the autoimmune regulator (Aire) gene. Mature microRNAs (miRNAs) that regulate gene expression post-transcriptionally are generated in a multistep process. The microprocessor complex, including DGCR8, cleaves canonical miRNAs, but alternative DGCR8-independent miRNA biogenesis pathways exist as well. In order to study the role of canonical miRNAs in thymic epithelial cells (TECs), we ablated Dgcr8 using a FoxN1-Cre transgene. We report that DGCR8-deficient TECs are unable to maintain proper thymic architecture and exhibit a dramatic loss of thymic cellularity. Importantly, DGCR8-deficient TECs develop a severe loss of Aire(+) mTECs. Using a novel immunization approach to amplify and detect self-reactive T cells within a polyclonal TCR repertoire, we demonstrate a link between the loss of Aire expression in DGCR8-deficient TECs and the breakdown of negative selection in the thymus. Thus, DGCR8 and canonical miRNAs are important in TECs for supporting central tolerance.

BACKGROUND

Numerous studies indicate that the use of feeding tubes (FT) in persons with advanced cognitive impairment (CI) does not improve clinical outcomes or survival, and results in higher rates of hospitalization and emergency department (ED) visits. It is not clear, however, whether such risk varies by resident level of CI and whether these ED visits and hospitalizations are potentially preventable. The objective of this study was to determine the rates of ED visits, hospitalizations and potentially preventable ambulatory care sensitive (ACS) ED visits and ACS hospitalizations for long-stay NH residents with FTs at differing levels of CI.

METHODS

We linked Centers for Medicare and Medicaid Services inpatient & outpatient administrative claims and beneficiary eligibility data with Minimum Data Set (MDS) resident assessment data for nursing home residents with feeding tubes in a 5% random sample of Medicare beneficiaries residing in US nursing facilities in 2006 (n = 3479). Severity of CI was measured using the Cognitive Performance Scale (CPS) and categorized into 4 groups: None/Mild (CPS = 0-1, MMSE = 22-25), Moderate (CPS = 2-3, MMSE = 15-19), Severe (CPS = 4-5, MMSE = 5-7) and Very Severe (CPS = 6, MMSE = 0-4). ED visits, hospitalizations, ACS ED visits and ACS hospitalizations were ascertained from inpatient and outpatient administrative claims. We estimated the risk ratio of each outcome by CI level using over-dispersed Poisson models accounting for potential confounding factors.

RESULTS

Twenty-nine percent of our cohort was considered "comatose" and "without any discernible consciousness", suggesting that over 20,000 NH residents in the US with feeding tubes are non-interactive. Approximately 25% of NH residents with FTs required an ED visit or hospitalization, with 44% of hospitalizations and 24% of ED visits being potentially preventable or for an ACS condition. Severity of CI had a significant effect on rates of ACS ED visits, but little effect on ACS hospitalizations.

CONCLUSIONS

ED visits and hospitalizations are common in cognitively impaired tube-fed nursing home residents and a substantial proportion of ED visits and hospitalizations are potentially preventable due to ACS conditions.

BACKGROUND

The new oral anticoagulants (NOAC), dabigatran and rivaroxaban, have been demonstrated to be at least equivalent to warfarin for preventing cardiac thromboembolism (TE) in patients with atrial fibrillation (AF). However, there is limited data regarding use around catheter ablation (CA) procedures.

OBJECTIVE

We evaluated the risk of bleeding and TE complications associated with NOAC use during AF ablation.

METHODS

Consecutive patients undergoing AF ablation between January 2011 and 6 September 2013 were grouped based on peri-procedural anticoagulation regimen: (1) uninterrupted warfarin with therapeutic INR (WARF), n = 114, (2) dabigatran, n = 89, or (3) rivaroxaban, n = 98. NOACs were held for 24 h (dabigatran) or 36 h (rivaroxaban) prior to the procedure. Heparin infusion was initiated 6 h post-procedure for the NOAC groups; NOACs were resumed the morning after the procedure. Antral PVI was performed with activated clotting time (ACT) maintained >300 s. TE or bleeding complications during ablation and through 30 days were compared.

RESULTS

Three hundred and one patients underwent ablation for paroxysmal (71%) or persistent (29%) AF. International Normalization Ratio (INR) for the WARF group was 2.0 ± 0.5. Baseline characteristics were similar among the groups. There were two TE events (asymptomatic cerebral emboli and TIA), and there were 17 bleeding events (large hematoma n = 4; pericardial effusion n = 6; persistent hematuria n = 1; pseudoaneurism/AV fistula n = 6). Of the six pericardial effusions, three required drainage. There was no significant difference in combined TE/bleeding risk among the groups (WARF vs. dabigatran vs. rivaroxaban; 6.2% vs. 6.7% vs. 6.0%; p = 0.82) CONCLUSIONS: In this group of AF patients undergoing CA, use of peri-procedure dabigatran or rivaroxaban compared to uninterrupted warfarin did not lead to an increase in bleeding or TE complications.

INTRODUCTION

Patients with frequent premature ventricular complexes (PVCs) might be at risk for the developing or exacerbation of left ventricular (LV) dysfunction. However, some patients with a high-PVC burden do not develop cardiomyopathy, while other patients with low-PVC burden can develop cardiomyopathy. The purpose of this study was to evaluate the positive predictors of idiopathic PVCs-induced cardiomyopathy.

METHODS AND RESULTS

We investigated 214 patients undergoing successful ablation of PVCs who had no other causes of cardiomyopathy. We divided the study cohort into 2 groups: ejection fraction (EF) ≥ 50% (normal LV) and EF < 50% (LV dysfunction). We analyzed the clinical characteristics, including the electrocardiogram and findings at electrophysiology study. Among these patients, 51 (24%) had reduced LVEF and 163 (76%) had normal LV function. Patients with LV dysfunction had significantly longer coupling interval (CI) dispersion (maximum-CI-minimum-CI) and had significantly higher PVC burden compared to those with normal LV function (CI-dispersion: 115 ± 25 milliseconds vs. 94 ± 19 milliseconds; P < 0.001; PVC burden: 19% vs. 15%; P = 0.04). Furthermore, patients with LV dysfunction had significantly higher body mass index (BMI) compared to those with normal LV function (BMI > 30 kg/m(2) ; 37% vs. 13%; P = 0.001). Logistic regression analysis showed that CI-dispersion, PVC burden, and BMI (>30 kg/m(2) ) are independent predictors of PVC-induced cardiomyopathy.

CONCLUSIONS

In addition to the PVC burden, the CI-dispersion and BMI are associated with PVC-induced cardiomyopathy.

BACKGROUND

The clinical effects and potential benefits of nutrition supplementation interventions for persons living with HIV remain largely unreported, despite awareness of the multifaceted relationship between HIV infection and nutrition. We therefore examined descriptive characteristics and nutritional outcomes of the Food by Prescription (FBP) nutrition supplementation program in Nyanza Province, Kenya.

METHODS

Demographic, health, and anthropometric data were gathered from a retrospective cohort of 1,017 non-pregnant adult patients who enrolled into the FBP program at a Family AIDS Care and Education Services (FACES) site in Nyanza Province between July 2009 and July 2011. Our primary outcome was FBP treatment success defined as attainment of BMI>20, and we used Cox proportional hazards to assess socio-demographic and clinical correlates of FBP treatment success.

RESULTS

Mean body mass index was 16.4 upon enrollment into the FBP program. On average, FBP clients gained 2.01 kg in weight and 0.73 kg/m2 in BMI over follow-up (mean 100 days), with the greatest gains among the most severely undernourished (BMI <16) clients (p<0.001). Only 13.1% of clients attained a BMI>20, though 44.5% achieved a BMI increase ≥0.5. Greater BMI at baseline, younger age, male gender, and not requiring highly active antiretroviral therapy (HAART) were associated with a higher rate of attainment of BMI>20.

CONCLUSION

This study reports significant gains in weight and BMI among patients enrolled in the FBP program, though only a minority of patients achieved stated programmatic goals of BMI>20. Future research should include well-designed prospective studies that examine retention, exit reasons, mortality outcomes, and long-term sustainability of nutrition supplementation programs for persons living with HIV.