Mutation of breast cancer susceptibility genes increases cerebral microbleeds: A pilot study.

OBJECTIVES: Growing evidence suggests breast cancer susceptibility gene (BRCA) mutations may augment cerebrovascular risk factors. With this influence in mind, we aimed to identify if BRCA mutations increased the prevalence of cerebral small vessel disease (CSVD). METHODS AND MATERIALS: We performed a retrospective cross-sectional analysis of adults undergoing malignancy evaluation with confirmed BRCA mutations compared to BRCA wildtype individuals. A standard-of-care brain MRI was reviewed. Chi-squared or Fisher's, Wilcoxon rank-sum and the Student's t-test analyses were used when appropriate. Adjusted logistic regression models were fit to calculate odds ratio. Multicollinearity was tested by variance inflation factor calculation and for goodness-of-fit via the Hosmer-Lemeshow test. RESULTS: Of 116 individuals, 44.8% (52/116) carried a BRCA mutation. Demographic and cerebrovascular risk factors did not differ. Cerebral microbleeds were more common in those with BRCA mutation: [32.7% (17/52) vs. 17.2% (11/64), p = 0.05] with an adjusted odds ratio of 2.8 (95%CI 1.08-6.89, p = 0.03). Other markers of CSVD were similar amongst the cohort. CONCLUSIONS: We identified a nearly 3-fold increase in identified cerebral microbleed in those with BRCA mutations compared with BRCA wildtype individuals suggestive of an interaction between the BRCA gene and cerebral microbleed formation. Further studies are needed to confirm our findings and to understand clinical implications.

Impact of Hospital Volume on Outcome After Surgical Treatment for Hydrocephalus: A U.S. Population Study From the National Inpatient Sample.

Introduction Hydrocephalus remains a common condition with significant patient morbidity; however, accurate accounting of the incidence of this disease as well as of the impact of hospital volume on outcome remains limited. Methods The National Inpatient Sample was used to evaluate patients who underwent surgical treatment of hydrocephalus from 2009-2013. Patient demographics (e.g., length of stay, disposition, charges), and the impact of hospital volume on outcomes were evaluated. Results A total of 156,205 patients were identified. Ventriculoperitoneal (VP) shunting the most common type of device (35.8%) followed by shunt replacement (23.9%). Treatment charges for hydrocephalus were $332 million in 2009 and $418 million in 2013 nationally. High-volume hospitals had more routine discharges compared with lower-volume hospitals (65.7% vs. 50.9%, p<0.0001), which was a trend that improved over time. Multivariate analysis confirmed that hospital volume was independently associated with routine disposition after adjusting for other factors such as patient age, length of stay, and shunt type. However, hospital volume showed a small association with length of stay (ß = -0.05, p = 0.0001) and did not impact hospital charges on multivariate analysis. Conclusion This analysis provides a recent update of hydrocephalus epidemiology, trends, and outcomes nationally. Estimates from this study suggest that hydrocephalus is a common and costly problem. Hospital volume was for the first time to be associated with important differences in patient outcomes.

Decreased Levels of STAT1 and Interferon-γ-Induced STAT1 Phosphorylation in Rheumatoid Arthritis CD4 and CD8 T Cells.

OBJECTIVE: We investigated whether a previously reported association of IFNGR expression with rheumatoid arthritis (RA) and its radiographic severity reflects differences in proximal interferon-γ (IFN-γ) signaling in T cells from patients with RA compared with healthy controls (HC). METHODS: Using phosphoflow cytometry, we compared IFN-γ-stimulated signal transducer and activator of transcription 1 (STAT1) activation in CD4+ and CD8+ T-cell populations from patients with RA and HC. RESULTS: Compared with controls, patients with RA had a higher proportion of CD4+ T cells, associated with expansion of the CD4+ effector memory subset. Several CD4+ T-cell types exhibited reduced IFN-γ-induced phosphoSTAT1Y701 (pSTAT1Y701 ) in patients with RA compared with HC. Engaging the T-cell receptor (TCR) complex on CD4+ T cells during IFN-γ stimulation abrogated the reduction in STAT1 activation in patients with RA but had no effect in HC. The phosphorylation of STAT1S727 was similar in CD4+ T cells from patients with RA and HC. In contrast to CD4+ T cells, IFN-γ-induced pSTAT1Y701 levels in CD8+ T cells were equivalent or higher in patients with RA compared with HC. Total STAT1 levels (phosphorylated + unphosphorylated) were lower in CD4+ and CD8+ T cells from patients with RA compared with HC. CONCLUSION: We report diminished IFN-γ-induced pSTAT1Y701 levels in CD4+ T cells in patients with RA, which were restored by TCR engagement. There were lower levels of total STAT1 in patients with RA compared with HC, but this likely does not explain diminished IFN-γ-induced pSTAT1Y701 levels in CD4+ T cells because activation in CD8+ T cells was higher or equivalent to that seen in HC. The enhanced IFNGR expression in patients with RA reported previously may reflect a compensatory mechanism to overcome deficiency in IFN-γ responsiveness.

Dysregulated follicular regulatory T cells and antibody responses exacerbate experimental autoimmune encephalomyelitis.

BACKGROUND: Follicular regulatory T (TFR) cells are essential for the regulation of germinal center (GC) response and humoral self-tolerance. Dysregulated follicular helper T (TFH) cell-GC-antibody (Ab) response secondary to dysfunctional TFR cells is the root of an array of autoimmune disorders. The contribution of TFR cells to the pathogenesis of multiple sclerosis (MS) and murine experimental autoimmune encephalomyelitis (EAE) remains largely unclear. METHODS: To determine the impact of dysregulated regulatory T cells (Tregs), TFR cells, and Ab responses on EAE, we compared the MOG-induced EAE in mice with a FoxP3-specific ablation of the transcription factor Blimp1 to control mice. In vitro co-culture assays were used to understand how Tregs and Ab regulate the activity of microglia and central nervous system (CNS)-infiltrating myeloid cells. RESULTS: Mice with a FoxP3-specific deletion of Blimp1 developed severe EAE and failed to recover compared to control mice, reflecting conversion of Tregs into interleukin (IL)-17A/granulocyte-macrophage colony-stimulating factor (GM-CSF)-producing effector T cells associated with increased TFH-Ab responses, more IgE deposition in the CNS, and inability to regulate CNS CD11b+ myeloid cells. Notably, serum IgE titers were positively correlated with EAE scores, and culture of CNS CD11b+ cells with sera from these EAE mice enhanced their activation, while transfer of Blimp1-deficient TFR cells promoted Ab production, activation of CNS CD11b+ cells, and EAE. CONCLUSIONS: Blimp1 is essential for the maintenance of TFR cells and Ab responses in EAE. Dysregulated TFR cells and Ab responses promote CNS autoimmunity.

The tetraspanin CD151 marks a unique population of activated human T cells.

Tetraspanins are a family of proteins with an array of functions that are well studied in cancer biology, but their importance in immunology is underappreciated. Here we establish the tetraspanin CD151 as a unique marker of T-cell activation and, in extension, an indicator of elevated, systemic T-cell activity. Baseline CD151 expression found on a subset of T-cells was indicative of increased activation of the MAPK pathway. Following TCR/CD3 activation, CD151 expression was upregulated on the overall T-cell population, a quintessential feature of an activation marker. CD151+ T-cell frequencies in the spleen, an organ with increased immune activity, were twice as high as in paired peripheral blood samples. This CD151+ T-cell frequency increase was not paralleled by an increase of CD25 or CD38, demonstrating that CD151 expression is regulated independently of other T-cell activation markers. CD151+ T-cells were also more likely to express preformed granzyme B, suggesting that CD151+ T cells are pro-inflammatory. To this end, HIV-1 patients on antiretroviral therapy who are reported to exhibit chronically elevated levels of immune activity, had significantly higher CD4+CD151+ T-cell frequencies than healthy controls, raising the possibility that proinflammatory CD151+ T cells could contribute to the premature immunological aging phenotype observed in these patients.

Increasing Health Care Burden of Chronic Liver Disease Compared With Other Chronic Diseases, 2004-2013.

BACKGROUND & AIMS: Chronic liver disease (CLD) is a common and expensive condition, and studies of CLD-related hospitalizations have underestimated the true burden of disease. We analyzed data from a large, diverse health care system to compare time trends in CLD-related hospitalizations with those in congestive heart failure (CHF) or chronic obstructive pulmonary disease (COPD). METHODS: We collected data from a large health care system in Texas on hospitalizations related to CLD (n = 27,783), CHF (n = 60,415), and COPD (n = 34,199) from January 1, 2004 through December 31, 2013. We calculated annual hospitalization rates (per 100,000) and compared hospital course, inpatient mortality, ancillary services, and readmissions. RESULTS: Compared with patients with CHF (median age, 71 years) or COPD (median age, 69 years), patients with CLD were significantly younger (median age, 57 years) (P < .01 vs CHF and COPD). Higher proportions of patients with CLD were uninsured (11.7% vs 5.4% for CHF and 5.4% for COPD, P < .01) and Hispanic (17% for CLD vs 9.3% for CHF and 5.0% for COPD, P < .01). A lower proportion of patients with CLD had Medicare (41.5% vs 68.6% with CHF and 70.1% with COPD, P < .01). From 2004 through 2013, the rate of CLD-related hospitalization increased by 92% (from 1295/100,000 to 2490/100,000), compared with 6.7% for CHF (from 3843/100,000 to 4103/100,000) and 48.8% for COPD (from 1775/100,000 to 2642/100,000). During this time period, CLD-related hospitalizations covered by Medicare increased from 31.8% to 41.5%, whereas hospitalizations covered by Medicare did not change for CHF (remained at 70%) or COPD (remained at 70%). Patients with CLD had longer hospital stays (7.3 days vs 6.2 days for CHF and 5.9 days for COPD, P < .01). A higher proportion of patients with CLD died or were discharged to hospice (14.2% vs 11.5% of patients with CHF and 9.3% of patients with COPD, P < .01), and a smaller proportion had access to postacute care (13.2% vs 23.2% of patients with CHF and 27.4% of patients with COPD, P < .01). A higher proportion of patients with CLD were readmitted to the hospital within 30 days (25% vs 21.9% of patients with CHF and 20.6% with COPD, P < .01). CONCLUSIONS: Patients with CLD, compared with selected other chronic diseases, had increasing rates of hospitalization, longer hospital stays, more readmissions, and, despite these adverse outcomes, less access to postacute care. Disease management models for CLD are greatly needed to manage the anticipated increase in hospitalizations for CLD.

Overuse of Troponin? A Comprehensive Evaluation of Testing in a Large Hospital System.

Troponin assays are integral to the diagnosis of acute myocardial infarction (AMI), but there is concern that testing is over utilized and may not conform to published guidelines. We reviewed all testing performed at 14 hospitals over 12 months and associated troponin values with the primary and secondary diagnoses for each visit. Troponin was determined to be negative, indeterminate or elevated based on reference ranges. The majority of troponin measurements were single, not serial (64%). The rate of AMI was low, with only 3.5% of tested patients having a primary or secondary diagnosis of AMI. Sensitivity, specificity and negative predictive value were excellent, exceeding 90%. However, positive predictive value was low, suggesting testing of populations with diseases known to be associated with elevated troponin levels in the absence of AMI. The majority (79%) of elevated troponin values were associated with primary diagnoses other than AMI. Only 28% of elevated troponins were associated with a primary or secondary diagnosis of AMI. These data suggest possible overuse of troponin testing in our healthcare system. Journal of Hospital Medicine 2017;12:329-331.

Frequency of Troponin Testing in Inpatient Versus Outpatient Settings.

Troponin elevation is required to diagnose acute myocardial infarction (AMI), yet elevated values are often encountered in noncardiac disease states. We evaluated inpatient (IP) and outpatient (OP) encounters at 14 hospitals in calendar year 2014 and found that troponin assays were performed during 12% of all OP visits and 29% of all IP visits: 82,853 encounters in all. We employed an expert panel to estimate the likelihood of AMI based on primary International Statistical Classification of Diseases and Related Health Problems, 9th edition diagnoses. We compared IP and OP testing, finding that AMI would not be expected in most IP encounters. Sepsis was the most common diagnosis associated with IP troponin testing. We found an association between troponin testing in patients with sepsis and utilization of electrocardiography, echocardiography, and cardiac catheterization. Our data indicate that troponin testing has expanded beyond patient populations in whom AMI might be expected.

Designing Incentives to Change Behaviors: Examining College Student Intent Toward Healthy Diets.

College is a time when young adults establish lifestyle habits. This research examines how personalization and limited resources might be balanced most effectively when designing incentives to shift college students' intentions toward positive dietary changes. A randomized 2 × 2 experiment (Coaching/Coupons × Fruits and Vegetables/Low Fat) was conducted, where respondents were exposed to virtual interventions and asked pre- and post-intervention about their intent to eat healthy. Results suggest that interventions may incentivize students, but are dependent on student characteristics. On-campus students and students with more knowledge about healthy diets were more likely to increase their intent when offered coaching; students living off campus and those with less knowledge resonated with coupons. On- and off-campus students differed in their positive responses to eating fruits and vegetables versus low fat foods, respectively. Younger students may be more susceptible to interventions. Findings may be useful in designing meaningful incentives for college students.

Multilateral contracting and prevention.

Incentives created through contracts can be used as a means of decentralized control in healthcare systems to ensure more efficient healthcare. In this paper, we consider an insurer contracting with a consumer and a provider. We focus on the trade-off between ex ante moral hazard and insurance, and consider both consumer and provider incentives in the insurer's contracting problem in the presence of unobservable preventive efforts. We study two cases of provider efforts: those that complement consumer efforts and those that substitute for consumer efforts. In the first case, our results show that the provider must have greater incentives when the consumer is healthy to induce effort and that inducing provider effort allows an insurer to offer a more complete insurance contract relative to the bilateral benchmark. In the second case, we state conditions under which these conclusions continue to hold. On the basis of our findings, we discuss the implications and challenges of multilateral contracting in practice.