Differential regulation of a placental SAM68 and sFLT1 gene pathway and the relevance to maternal vitamin D sufficiency.

OBJECTIVE: The goal of this study was to determine if an axis of placental gene expression associated with early onset and severe preeclampsia (EOSPE) was operative in term pregnancy and correlated with vitamin D sufficiency. METHODS: qPCR analysis of NKX2-5, SAM68, sFLT1 and membrane bound VEGFR1/FLT1 mRNA expression was conducted in placentas from 43 subjects enrolled in a vitamin D3 pregnancy supplementation trial. Pair-wise rank order correlations between patient-specific gene expression levels were calculated, and their relationship to maternal 25(OH)D status was assessed by a two-sample Wilcoxon test. Additionally, we probed the mechanistic link between SAM68 and sFLT1 using siRNA depletion in a human trophoblast cell line model. RESULTS: Positive and highly significant correlations were found between SAM68 vs. sFLT1 and SAM68 vs. FLT1 expression levels, as were significant and differential correlations between the expression of these genes and perinatal 25(OH)D status. The variability when stratified by race/ethnicity was qualitatively distinct from those previously observed in EOSPE. Mechanistic studies confirmed a functional role for SAM68 protein in the regulation of sFLT1 expression. NKX2-5 expression was not significantly correlated with sFLT1 or SAM68 expression in these samples, suggesting that its expression may be significant at earlier stages of pregnancy or be restricted to pathological settings. CONCLUSIONS: These data further support our overarching hypothesis that SAM68 expression is a key determinant of VEGFR1 isoform expression in the placenta, and provide additional insights into how this gene pathway may be differentially deployed or modified in normal and pathological pregnancies.

Physician Confidence in Dental Trauma Treatment and the Introduction of a Dental Trauma Decision-Making Pathway for the Pediatric Emergency Department.

OBJECTIVES: The objectives of this study were to (1) survey and report the awareness and confidence of pediatric emergency medicine physicians in the management of dental trauma and (2) determine the prevalence of dental trauma decision-making pathway utilization in the pediatric emergency department. METHODS: A survey was distributed through e-mail to the pediatric emergency medicine discussion list via Brown University LISTSERV. The survey study included 10 questions and was multiple-choice. The survey contained questions about physician confidence and their use of a dental trauma decision-making pathway. RESULTS: A total of 285 individuals responded to the survey. Somewhat confident was the most common response (61%) followed by not confident (20%) and confident (19%) by respondents in treating dental trauma. Forty-one percent of respondents felt comfortable, 39% somewhat comfortable, 19% not comfortable, and 1% not sure in replanting an avulsed tooth. Only 6% of respondents reported that their pediatric emergency department always or sometimes uses a dental trauma decision-making pathway, whereas 78% of pediatric emergency departments do not. CONCLUSIONS: We believe that the adoption of a decision-making pathway will provide timely management, improve emergency physician comfort, and enhance outcomes for pediatric patients presenting with a dental trauma. A future multicenter review will aim to evaluate these goals based on the utilization of our dental trauma decision-making pathway.

Assessing the Correlation Between Physical Activity and Quality of Life in Advanced Lung Cancer.

BACKGROUND AND OBJECTIVE: Increasing physical activity (PA) is safe and beneficial in lung cancer (LC) patients. Advanced-stage LC patients are under-studied and have worse symptoms and quality of life (QoL). We evaluated the feasibility of monitoring step count in advanced LC as well as potential correlations between PA and QoL. METHODS: This is a prospective, observational study of 39 consecutive patients with advanced-stage LC. Daily step count over 1 week (via Fitbit Zip), QoL, dyspnea, and depression scores were collected. Spearman rank testing was used to assess correlations. Correlation coefficients (ρ) >0.3 or <-0.3 (more and less correlated, respectively) were considered potentially clinically significant. RESULTS: Most (83%) of the patients were interested in participating, and 67% of those enrolled were adherent with the device. Of those using the device (n = 30), the average daily step count was 4877 (range = 504-12 118) steps/d. Higher average daily step count correlated with higher QoL (ρ = 0.46), physical (ρ = 0.61), role (ρ = 0.48), and emotional functioning (ρ = 0.40) scores as well as lower depression (ρ = -0.40), dyspnea (ρ = -0.54), and pain (ρ = -0.37) scores. CONCLUSION: Remote PA monitoring (Fitbit Zip) is feasible in advanced-stage LC patients. Interest in participating in this PA study was high with comparable adherence to other PA studies. In those utilizing the device, higher step count correlates with higher QoL as well as lower dyspnea, pain, and depression scores. PA monitoring with wearable devices in advanced-stage LC deserves further study.

The growing gap in hypertension control between insured and uninsured adults: National Health and Nutrition Examination Survey 1988 to 2010.

Hypertension awareness, treatment, and control are lower among uninsured than insured adults. Time trends in differences and underlying modifiable factors are important for informing strategies to improve health equity. National Health and Nutrition Examination Surveys 1988 to 1994, 1999 to 2004, and 2005 to 2010 data in adults aged 18 to 64 years were analyzed to explore this opportunity. The proportion of adults with hypertension who were uninsured increased from 12.3% in 1988 to 1994 to 17.4% in 2005 to 2010. In 1988 to 1994, hypertension awareness, treatment, and control to <140/<90 mm Hg (30.1% versus 26.5%; P=0.27) were similar in insured and uninsured adults. By 2005 to 2010, the absolute gap in hypertension control between uninsured and insured adults of 21.9% (52.5% versus 30.6%; P<0.001) was explained approximately equally by lower awareness (65.2% versus 80.7%), fewer aware adults treated (75.2% versus 88.5%), and fewer treated adults controlled (63.1% versus 73.5%; all P<0.001). Publicly insured and uninsured adults had similar income. Yet, hypertension control was similar across time periods in publicly and privately insured adults, despite lower income and education in the former. In multivariable analysis, hypertension control in 2005 to 2010 was associated with visit frequency (odds ratio, 3.4 [95% confidence interval, 2.4-4.8]), statin therapy (1.8 [1.4-2.3]), and healthcare insurance (1.6 [1.2-2.2]) but not poverty index (1.04 [0.96-1.12]). Public or private insurance linked to more frequent healthcare, greater awareness and effective treatment of hypertension, and appropriate statin use could reverse a long-term trend of growing inequity in hypertension control between insured and uninsured adults.

Medication Safety in Primary Care Practice: results from a PPRNet quality improvement intervention.

Reducing medication errors is a fundamental patient safety goal; however, few improvement interventions have been evaluated in primary care settings. The Medication Safety in Primary Care Practice project was designed to test the impact of a multimethod quality improvement intervention on 5 categories of preventable prescribing and monitoring errors in 20 Practice Partner Research Network (PPRNet) practices. PPRNet is a primary care practice-based research network among users of a common electronic health record (EHR). The intervention was associated with significant improvements in avoidance of potentially inappropriate therapy, potential drug-disease interactions, and monitoring of potential adverse events over 2 years. Avoidance of potentially inappropriate dosages and drug-drug interactions did not change over time. Practices implemented a variety of medication safety strategies that may be relevant to other primary care audiences, including use of EHR-based audit and feedback reports, medication reconciliation, decision-support tools, and refill protocols.

Antiinflammatory and antifibrotic effects of the oral direct thrombin inhibitor dabigatran etexilate in a murine model of interstitial lung disease.

OBJECTIVE: Activation of the coagulation cascade leading to generation of thrombin has been documented extensively in various forms of lung injury, including that associated with systemic sclerosis. We previously demonstrated that the direct thrombin inhibitor dabigatran inhibits thrombin-induced profibrotic signaling in lung fibroblasts. This study was undertaken to test whether dabigatran etexilate attenuates lung injury in a murine model of interstitial lung disease. METHODS: Lung injury was induced in female C57BL/6 mice by a single intratracheal instillation of bleomycin. Dabigatran etexilate was given as supplemented chow beginning on day 1 of bleomycin instillation (early treatment, study of antiinflammatory effect) or on day 8 following bleomycin instillation (late treatment, study of antifibrotic effect). Mice were killed 2 weeks or 3 weeks after bleomycin instillation, and lung tissue, bronchoalveolar lavage (BAL) fluid, and plasma were investigated. RESULTS: Both early treatment and late treatment with dabigatran etexilate attenuated the development of bleomycin-induced pulmonary fibrosis. Dabigatran etexilate significantly reduced thrombin activity and levels of transforming growth factor ß1 in BAL fluid, while simultaneously reducing the number of inflammatory cells and protein concentrations. Histologically evident lung inflammation and fibrosis were significantly decreased in dabigatran etexilate-treated mice. Additionally, dabigatran etexilate reduced collagen, connective tissue growth factor, and α-smooth muscle actin expression in mice with bleomycin-induced lung fibrosis, whereas it had no effect on basal levels of these proteins. CONCLUSION: Inhibition of thrombin using the oral direct thrombin inhibitor dabigatran etexilate has marked antiinflammatory and antifibrotic effects in a bleomycin model of pulmonary fibrosis. Our data provide preclinical information about the feasibility and efficacy of dabigatran etexilate as a new therapeutic approach for the treatment of interstitial lung disease.

Analyzing adherence to prenatal supplement: does pill count measure up?

Objective. To determine if adherence as measured by pill count would show a significant association with serum-based measures of adherence. Methods. Data were obtained from a prenatal vitamin D supplementation trial where subjects were stratified by race and randomized into three dosing groups: 400 (control), 2000, or 4000 IU vitamin D(3)/day. One measurement of adherence was obtained via pill counts remaining compared to a novel definition for adherence using serum 25-hydroxy-vitamin D (25-OH-D) levels (absolute change in 25(OH)D over the study period and the subject's steady-state variation in their 25(OH)D levels). A multivariate logistic regression model examined whether mean percent adherence by pill count was significantly associated with the adherence measure by serum metabolite levels. Results. Subjects' mean percentage of adherence by pill count was not a significant predictor of adherence by serum metabolite levels. This finding was robust across a series of sensitivity analyses. Conclusions. Based on our novel definition of adherence, pill count was not a reliable predictor of adherence to protocol, and calls into question how adherence is measured in clinical research. Our findings have implications regarding the determination of efficacy of medications under study and offer an alternative approach to measuring adherence of long half-life supplements/medications.

Liver biopsy results in patients with sickle cell disease on chronic transfusions: poor correlation with ferritin levels.

BACKGROUND: Chronic transfusions are effective in preventing stroke and other complications of sickle cell disease. The aim of this study was to determine whether serum ferritin levels correlated with liver iron content in sickle cell patients on chronic transfusion. PROCEDURE: Forty-four liver biopsy specimens from 38 patients with homozygous sickle cell anemia (HbSS) and one patient with sickle thalassemia receiving chronic transfusions were studied. Five patients underwent a second liver biopsy for follow up. Three ferritin measurements were used to calculate a mean for each patient. The association between serum ferritin levels and liver iron quantitation was measured using the Spearman rank correlation, and sensitivity and specificity were determined for selected threshold values of serum ferritin. RESULTS: Serum ferritin levels ranged from 515 to 6076 ng/ml, liver iron concentration ranged from 1.8 to 67.97 mg/g dry weight. The amount of iron per gram liver dry weight was moderately correlated with serum ferritin values (r = 0.46). The correlation of duration of transfusion with serum ferritin (r = 0.40) and with liver iron content (r = 0.41) also indicated moderate correlation. Liver biopsy results led to changes in the management after 29/44 (66%) of the biopsies. Serum ferritin >/=2500 ng/ml predicted high liver iron content (>/=7 mg/g), with a sensitivity of 62.5% and a specificity of 77.8%. CONCLUSION: We found a poor correlation between serum ferritin levels and liver iron content (LIC). Despite being on chelation therapy, many patients on chronic transfusion had high levels of liver iron. Measurement of LIC is highly recommended in these patients.