The Financial Impact of Genetic Diseases in a Pediatric Accountable Care Organization.

Background: Previous studies revealed patients with genetic disease have more frequent and longer hospitalizations and therefore higher healthcare costs. To understand the financial impact of genetic disease on a pediatric accountable care organization (ACO), we analyzed medical claims from 2014 provided by Partners for Kids, an ACO in partnership with Nationwide Children's Hospital (NCH; Columbus, OH, USA). Methods: Study population included insurance claims from 258,399 children. We assigned patients to four different categories (1-A, 1-B, 2, & 3) based on the strength of genetic basis of disease. Results: We identified 22.7% of patients as category 1A or 1B- having a disease with a "strong genetic basis" (e.g., single gene diseases, chromosomal abnormalities). Total ACO paid claims in 2014 were $379M, of which $161M (42.5%) was attributed to category 1 patients. Furthermore, we identified 23.3% of patients as category 2- having a disease with a suspected genetic component or predisposition (e.g., asthma, type 1 diabetes)- whom accounted for an additional 28.6% of 2014 costs. Category 1 patients were more likely to experience at least one hospitalization compared to category 3 patients- those without genetic disease [odds ratio [OR] = 4.12; 95% confidence interval [CI] = 3.86-4.39; p < 0.0001]. Overall, category 1 patients experienced nearly five times the number of inpatient (IP) admissions and twice the number of outpatient (OP) visits compared to category 3 patients (p < 0.0001). Conclusion: Nearly half (42.5%) of healthcare paid claims cost in 2014 for this study population were accounted for by patients with single-gene diseases or chromosomal abnormalities. These findings precede and support a need for an ACO to plan for effective healthcare strategies and capitation models for children with genetic disease.

Design and Refinement of a Data Quality Assessment Workflow for a Large Pediatric Research Network.

BACKGROUND: Clinical data research networks (CDRNs) aggregate electronic health record data from multiple hospitals to enable large-scale research. A critical operation toward building a CDRN is conducting continual evaluations to optimize data quality. The key challenges include determining the assessment coverage on big datasets, handling data variability over time, and facilitating communication with data teams. This study presents the evolution of a systematic workflow for data quality assessment in CDRNs. IMPLEMENTATION: Using a specific CDRN as use case, the workflow was iteratively developed and packaged into a toolkit. The resultant toolkit comprises 685 data quality checks to identify any data quality issues, procedures to reconciliate with a history of known issues, and a contemporary GitHub-based reporting mechanism for organized tracking. RESULTS: During the first two years of network development, the toolkit assisted in discovering over 800 data characteristics and resolving over 1400 programming errors. Longitudinal analysis indicated that the variability in time to resolution (15day mean, 24day IQR) is due to the underlying cause of the issue, perceived importance of the domain, and the complexity of assessment. CONCLUSIONS: In the absence of a formalized data quality framework, CDRNs continue to face challenges in data management and query fulfillment. The proposed data quality toolkit was empirically validated on a particular network, and is publicly available for other networks. While the toolkit is user-friendly and effective, the usage statistics indicated that the data quality process is very time-intensive and sufficient resources should be dedicated for investigating problems and optimizing data for research.

Impact of a Make-A-Wish experience on healthcare utilization.

OBJECTIVES: To evaluate the impact of receiving a wish from the Make-A-WishR Foundation on (1) patient healthcare utilization and (2) savings benefit measures. STUDY DESIGN: Make-A-WishR arranges experiences, or "wishes," to children with progressive, life-threatening, or life-limiting illness. A retrospective, case-control analysis was performed comparing patients who received or did not receive a wish and associated impact on healthcare utilization and costs across 2 years. Healthcare utilization was defined as visits to primary, urgent, emergent care, and planned/unplanned inpatient hospitalizations. We defined wish savings benefit as a decline in the cost of care from years 1 to 2, which exceeded the average cost of a wish in 2016, $10,130. RESULTS: From 2011 to 2016, 496 Nationwide Children's Hospital patients received a wish. We matched these patients to 496 controls based on age, gender, disease category, and disease complexity. Patients who received a wish were 2.5 and 1.9 times more likely to have fewer unplanned hospital admissions and emergency department visits, respectively. These decreases were associated with a higher likelihood (2.3-fold and 2.2-fold greater odds) of the wish achieving a savings benefit compared to hospital charges. CONCLUSIONS: Participation in the Make-A-WishR program may provide children quality of life relief while reducing hospital visits and healthcare expenditures.

Chronic angiotensin-II treatment potentiates HR slowing in Sprague-Dawley rat during acute behavioral stress.

This study examined the effect of 2-week infusion of angiotensin-II (Ang-II; 175 ng/kg/min) via minipump in rats (n=7) upon the mean arterial blood pressure (mBP) and heart rate (HR) response to an acute stress as compared to rats infused with saline (n=7). The acute stress was produced by a classical aversive conditioning paradigm: a 15s tone (CS+) followed by a half second tail shock. Baseline mBP in Ang-II infused rats (167.7±21.3 mm Hg; mean±SD) significantly exceeded that of controls (127.6±13.5 mm Hg). Conversely, baseline HR in the Ang-II infused rats (348±33) was significantly lower than controls (384±19 bpm). The magnitude of the mBP increase during CS+ did not differ between groups, but the HR slowing during CS+ in the Ang-II infused rats (-13.2±8.9 bpm) was significantly greater than that seen in controls (-4.2±5.5 bpm). This augmented bradycardia may be inferentially attributed to an accentuated increase in cardiac parasympathetic activity during CS+ in the Ang-II infused rats. The mBP increased above baseline immediately post-shock delivery in controls, but fell in the Ang-II infused rats, perhaps because of a 'ceiling effect' in total vascular resistance. This classical conditioning model of 'acute stress' differs from most stress paradigms in rats in yielding a HR slowing concomitant with a pressor response, and this slowing is potentiated by Ang-II.

Estradiol ameliorates diabetes-induced changes in vaginal structure of db/db mouse model.

INTRODUCTION: Women with diabetes experience diminished genital arousal, reduced vaginal lubrication, vaginal atrophy, dyspareunia, and increased infections. Limited studies are available investigating the effects of diabetic complications on the vagina. AIMS: The goals of this study were to investigate type 2 diabetes-induced changes in vaginal structure, and to determine if estradiol treatment ameliorates these changes. METHODS: Eight-week-old female diabetic (db/db) mice (strain BKS*Cg-m+/+Lepr(db)/J) and age-matched control normoglycemic female littermates were used to investigate the effects of type 2 diabetes on vaginal tissue structural integrity. Diabetic animals were divided into two subgroups: diabetic treated with vehicle only and diabetic treated with pellets containing estradiol. At 16 weeks, the animals were sacrificed, and the vaginal tissues were excised and analyzed by histological and immunohistochemical methods to assess diabetes-induced changes in vaginal tissue and the extent by which these parameters are restored by estradiol treatment. MAIN OUTCOME MEASURES: The effects of type 2 diabetes and estradiol supplementation were investigated on vaginal histoarchitecture. RESULTS: Diabetic animals exhibited high blood glucose levels (>600 mg/dL), increased body weight (43.0 +/- 6.0 g vs. 24.4 +/- 2.0 g), and reduced plasma estradiol levels (65.5 +/- 6.6 pg/mL vs. 80.77 +/- 13.2 pg/mL) when compared to control animals. Diabetes resulted in significant thinning of the epithelium (P

Estradiol restores diabetes-induced reductions in sex steroid receptor expression and distribution in the vagina of db/db mouse model.

Sex steroid hormones and receptors play an important role in maintaining vaginal physiology. Disruptions in steroid receptor signaling adversely impact vaginal function. Limited studies are available investigating the effects of diabetic complications on steroid receptor expression and distribution in the vagina. The goals of this study were to investigate type 2 diabetes-induced changes in expression, localization and distribution of estrogen (ER), progesterone (PR) and androgen receptors (AR) in the vagina and to determine if estradiol treatment ameliorates these changes. Eight-week-old female diabetic (db/db) mice (strain BKS.Cg-m+/+ Lepr(db)/J) were divided into two subgroups: untreated diabetic and diabetic animals treated with pellets containing estradiol. Control normoglycemic littermates were subcutaneously implanted with pellets devoid of estradiol. At 16 weeks of age, animals were sacrificed, vaginal tissues excised and analyzed by Western blot and immunohistochemical methods. Diabetes produced marked reductions in protein expression of ER, PR, and AR. Diabetes also resulted in marked differences in the distribution, staining intensity and proportion of immunoreactive cells containing these steroid receptors in the epithelium, lamina propria and muscularis. Treatment of diabetic animals with estradiol restored receptor protein expression and distribution similar to those levels observed in control animals. This study demonstrates that type 2 diabetes markedly reduces steroid receptor protein expression and distribution in the vagina. Estradiol treatment of diabetic animals ameliorates these diabetes-induced changes.

Cutting edge: selective tyrosine dephosphorylation of interferon-activated nuclear STAT5 by the VHR phosphatase.

Cytokine-induced tyrosine phosphorylation of the transcription factor STAT5 is required for its transcriptional activity. In this article we show that the small dual-specificity phosphatase VHR selectively dephosphorylates IFN-alpha- and beta-activated, tyrosine-phosphorylated STAT5, leading to the subsequent inhibition of STAT5 function. Phosphorylation of VHR at Tyr(138) was required for its phosphatase activity toward STAT5. In addition, the Src homology 2 domain of STAT5 was required for the effective dephosphorylation of STAT5 by VHR. The tyrosine kinase Tyk2, which mediates the phosphorylation of STAT5, was also responsible for the phosphorylation of VHR at Tyr(138).

Differential regulation of the expression of estrogen, progesterone, and androgen receptors by sex steroid hormones in the vagina: immunohistochemical studies.

OBJECTIVE: Significant structural changes occur in the rat vagina in response to sex steroid hormone deprivation and replacement. However, the mechanism by which these changes occur is not clearly understood and our current hypothesis is that these effects are mediated, at least in part, by the expression of sex steroid hormone receptors. The goal of this study was to assess changes in steroid hormone receptor expression and distribution in response to sex steroid hormone deprivation and administration. METHODS: Female rats were either kept intact (controls) or ovariectomized. Ovariectomized animals were treated with vehicle, estradiol, testosterone, progesterone, or hormone combinations. Using immunohistochemistry, hormone receptor distribution was assessed in all layers of the vaginal wall. RESULTS: After ovariectomy, estrogen receptor alpha (ERalpha) was up-regulated and progesterone receptor (PR) was down-regulated. Estradiol replacement restored these ovariectomy-induced changes, and this effect was dose-dependent. Androgen receptor (AR) expression was unaffected by ovariectomy or estradiol replacement. However, testosterone treatment resulted in increased AR density in the muscularis. Addition of either testosterone or progesterone to estradiol mitigated but did not abolish the effects of estradiol alone. CONCLUSION: Estradiol down-regulated ERalpha and up-regulated PR expression in the vagina, suggesting this may be a mechanism to prevent continued proliferation of the epithelium by surges of estradiol during the estrous cycle.

An intracardiac accessory thyroid gland.

This report describes a 62-year-old woman with a history of pulmonary embolism who presented with a right ventricular cardiac mass that proved histologically to be normal thyroid tissue. The patient was clinically and biochemically euthyroid. Six months after excision, an iodine-123 whole-body uptake and scan demonstrated no residual ectopic thyroid tissue.

Differential effects of estradiol, progesterone, and testosterone on vaginal structural integrity.

Ovarian steroids are known to be important in maintaining vaginal tissue, and evidence is mounting that imbalances in the hormonal milieu contribute to vaginal pathophysiology. To date, limited data are available on the effects of hormone deprivation and replacement on vaginal tissue morphology and vaginal innervation. The goal of this study was to assess the dynamic changes in vaginal tissue structure in response to sex steroid hormone deprivation and administration. Female Sprague-Dawley rats were either kept intact (controls) or ovariectomized. Ovariectomized animals were treated with vehicle, estradiol, testosterone, progesterone, or a combination of estradiol plus testosterone or progesterone. Histological techniques, including stereological analysis and immunohistochemistry for localization of neuronal markers, were used. Ovariectomy produced a significant decrease in epithelial height that was restored with estradiol replacement. Interestingly, a subphysiological dose of estradiol resulted in hyperplasia of the vaginal epithelium and nonvascular smooth muscle. Neither testosterone nor progesterone had a significant effect on epithelial height or muscularis thickness. However, testosterone treatment resulted in a significant increase in small adrenergic nerve fibers. Addition of either testosterone or progesterone to estradiol mitigated but did not abolish the effects of estradiol alone. This study demonstrates that estradiol and testosterone have differential effects on vaginal tissue parameters and that ovarian hormones are critical for the maintenance of genital tissue structure. Present observations also suggest that combined replacement regimens may be required for an optimal physiological response.