Residential Segregation and Diabetes Risk among Latinos.

OBJECTIVE: To examine whether residence in ethnically segregated metropolitan areas is associated with increased diabetes risk for Latinos in the United States. METHODS: Population data from the 2005 Behavioral Risk Factor Surveillance System and the 2005 American Community Survey were used to determine whether higher levels of Latino-White segregation across metropolitan statistical areas (MSAs) in the United States is associated with increased diabetes risk among Latinos (n=7462). RESULTS: No significant relationship (P<.05) between levels of segregation and diabetes risk was observed. CONCLUSION: The research literature examining the impact of residential segregation on health outcomes remains equivocal for Latinos.

Using "big data" to capture overall health status: properties and predictive value of a claims-based health risk score.

BACKGROUND: Investigators across many fields often struggle with how best to capture an individual's overall health status, with options including both subjective and objective measures. With the increasing availability of "big data," researchers can now take advantage of novel metrics of health status. These predictive algorithms were initially developed to forecast and manage expenditures, yet they represent an underutilized tool that could contribute significantly to health research. In this paper, we describe the properties and possible applications of one such "health risk score," the DxCG Intelligence tool. METHODS: We link claims and administrative datasets on a cohort of U.S. workers during the period 1996-2011 (N = 14,161). We examine the risk score's association with incident diagnoses of five disease conditions, and we link employee data with the National Death Index to characterize its relationship with mortality. We review prior studies documenting the risk score's association with other health and non-health outcomes, including healthcare utilization, early retirement, and occupational injury. RESULTS AND CONCLUSIONS: We find that the risk score is associated with outcomes across a variety of health and non-health domains. These examples demonstrate the broad applicability of this tool in multiple fields of research and illustrate its utility as a measure of overall health status for epidemiologists and other health researchers.

Association between latent proviral characteristics and immune activation in antiretrovirus-treated human immunodeficiency virus type 1-infected adults.

UNLABELLED: Generalized immune activation during HIV infection is associated with an increased risk of cardiovascular disease, neurocognitive disease, osteoporosis, metabolic disorders, and physical frailty. The mechanisms driving this immune activation are poorly understood, particularly for individuals effectively treated with antiretroviral medications. We hypothesized that viral characteristics such as sequence diversity may play a role in driving HIV-associated immune activation. We therefore sequenced proviral DNA isolated from peripheral blood mononuclear cells from HIV-infected individuals on fully suppressive antiretroviral therapy. We performed phylogenetic analyses, calculated viral diversity and divergence in the env and pol genes, and determined coreceptor tropism and the frequency of drug resistance mutations. Comprehensive immune profiling included quantification of immune cell subsets, plasma cytokine levels, and intracellular signaling responses in T cells, B cells, and monocytes. These antiretroviral therapy-treated HIV-infected individuals exhibited a wide range of diversity and divergence in both env and pol genes. However, proviral diversity and divergence in env and pol, coreceptor tropism, and the level of drug resistance did not significantly correlate with markers of immune activation. A clinical history of virologic failure was also not significantly associated with levels of immune activation, indicating that a history of virologic failure does not inexorably lead to increased immune activation as long as suppressive antiretroviral medications are provided. Overall, this study demonstrates that latent viral diversity is unlikely to be a major driver of persistent HIV-associated immune activation. IMPORTANCE: Chronic immune activation, which is associated with cardiovascular disease, neurologic disease, and early aging, is likely to be a major driver of morbidity and mortality in HIV-infected individuals. Although treatment of HIV with antiretroviral medications decreases the level of immune activation, levels do not return to normal. The factors driving this persistent immune activation, particularly during effective treatment, are poorly understood. In this study, we investigated whether characteristics of the latent, integrated HIV provirus that persists during treatment are associated with immune activation. We found no relationship between latent viral characteristics and immune activation in treated individuals, indicating that qualities of the provirus are unlikely to be a major driver of persistent inflammation. We also found that individuals who had previously failed treatment but were currently effectively treated did not have significantly increased levels of immune activation, providing hope that past treatment failures do not have a lifelong "legacy" impact.

Alcohol consumption and risk of melanoma and non-melanoma skin cancer in the Women's Health Initiative.

PURPOSE: The relationship between alcohol consumption and preference of alcohol type with hazard of melanoma (MM) and risk of non-melanoma skin cancer (NMSC) was examined in the Women's Health Initiative (WHI) Observational Study (OS). METHODS: A prospective cohort of 59,575 White postmenopausal women in the WHI OS (mean age 63.6) was analyzed. Cox proportional hazards models and logistic regression techniques were used to assess the hazard and risk of physician-adjudicated MM and self-reported NMSC, respectively, after adjusting for potential confounders including measures of sun exposure and skin type. RESULTS: Over 10.2 mean years of follow-up, 532 MM cases and 9,593 NMSC cases occurred. A significant relationship between amount of alcohol consumed and both MM and NMSC was observed, with those who consume 7+ drinks per week having a higher hazard of MM (HR 1.64 (1.09, 2.49), p global = 0.0013) and higher risk of NMSC (OR 1.23 (1.11, 1.36), p global < 0.0001) compared to non-drinkers. Lifetime alcohol consumption was also positively associated with hazard of MM (p = 0.0011) and risk of NMSC (p < 0.0001). Further, compared to non-drinkers, a preference for either white wine or liquor was associated with an increased hazard of MM (HR 1.52 (1.02, 2.27) for white wine; HR 1.65 (1.07, 2.55) for liquor) and risk of NMSC (OR 1.16 (1.05, 1.28) for white wine; OR 1.26 (1.13, 1.41) for liquor). CONCLUSIONS: Higher current alcohol consumption, higher lifetime alcohol consumption, and a preference for white wine or liquor were associated with increased hazard of MM and risk of NMSC.

Contribution of health status and prevalent chronic disease to individual risk for workplace injury in the manufacturing environment.

OBJECTIVES: An 'information gap' has been identified regarding the effects of chronic disease on occupational injury risk. We investigated the association of ischaemic heart disease, hypertension, diabetes, depression and asthma with acute occupational injury in a cohort of manufacturing workers from 1 January 1997 through 31 December 2007. METHODS: We used administrative data on real-time injury, medical claims, workplace characteristics and demographics to examine this association. We employed a piecewise exponential model within an Andersen-Gill framework with a frailty term at the employee level to account for inclusion of multiple injuries for each employee, random effects at the employee level due to correlation among jobs held by an employee, and experience on the job as a covariate. RESULTS: One-third of employees had at least one of the diseases during the study period. After adjusting for potential confounders, presence of these diseases was associated with increased hazard of injury: heart disease (HR 1.23, 95% CI 1.11 to 1.36), diabetes (HR 1.17, 95% CI 1.08 to 1.27), depression (HR 1.25, 95% CI 1.12 to 1.38) and asthma (HR 1.14, 95% CI 1.02 to 1.287). Hypertension was not significantly associated with hazard of injury. Associations of chronic disease with injury risk were less evident for more serious reportable injuries; only depression and a summary health metric derived from claims remained significantly positive in this subset. CONCLUSIONS: Our results suggest that chronic heart disease, diabetes and depression confer an increased risk for acute occupational injury.

Associations between employee and manager gender: impacts on gender-specific risk of acute occupational injury in metal manufacturing.

BACKGROUND: Prior research has shown increased risk of injury for female employees compared to male employees after controlling for job and tasks, but have not explored whether this increased risk might be moderated by manager gender. The gender of one's manager could in theory affect injury rates among male and female employees through their managers' response to an employee's psychosocial stress or through how employees differentially report injuries. Other explanations for the gender disparity in injury experience, such as ergonomic factors or differential training, are unlikely to be impacted by supervisor gender. This study seeks to explore whether an employee's manager's gender modifies the effect of employee gender with regards to risk of acute injury. METHODS: A cohort of employees and managers were identified using human resources and injury management data between January 1, 2002 and December 31, 2007 for six facilities of a large US aluminum manufacturing company. Cox proportional hazards models were employed to examine the interaction between employee gender and whether the employee had female only manager(s), male only manager(s), or both male and female managers on injury risk. Manager gender category was included as a time varying covariate and reassessed for each employee at the midpoint of each year. RESULTS: The percentage of departments with both female and male managers increased dramatically during the study period due to corporate efforts to increase female representation in management. After adjustment for fixed effects at the facility level and shared frailty by department, manager gender category does not appear to moderate the effect of employee gender (p = 0.717). Manager category was not a significant predictor (p = 0.093) of time to first acute injury. Similarly, having at least one female manager did not modify the hazard of injury for female employees compared to males (p = 0.899) and was not a significant predictor of time to first acute injury (p = 0.601). CONCLUSIONS: Prior findings suggest that female manufacturing employees are at higher risk for acute injury compared to males; this analysis suggests that this relationship is not affected by the gender of the employee's manager(s).

Genetic and environmental determinants of human NK cell diversity revealed by mass cytometry.

Natural killer (NK) cells play critical roles in immune defense and reproduction, yet remain the most poorly understood major lymphocyte population. Because their activation is controlled by a variety of combinatorially expressed activating and inhibitory receptors, NK cell diversity and function are closely linked. To provide an unprecedented understanding of NK cell repertoire diversity, we used mass cytometry to simultaneously analyze 37 parameters, including 28 NK cell receptors, on peripheral blood NK cells from 5 sets of monozygotic twins and 12 unrelated donors of defined human leukocyte antigen (HLA) and killer cell immunoglobulin-like receptor (KIR) genotype. This analysis revealed a remarkable degree of NK cell diversity, with an estimated 6000 to 30,000 phenotypic populations within an individual and >100,000 phenotypes in the donor panel. Genetics largely determined inhibitory receptor expression, whereas activation receptor expression was heavily environmentally influenced. Therefore, NK cells may maintain self-tolerance through strictly regulated expression of inhibitory receptors while using adaptable expression patterns of activating and costimulatory receptors to respond to pathogens and tumors. These findings further suggest the possibility that discrete NK cell subpopulations could be harnessed for immunotherapeutic strategies in the settings of infection, reproduction, and transplantation.

Preference for wine is associated with lower hip fracture incidence in post-menopausal women.

BACKGROUND: Past studies of relationships between alcohol and hip fracture have generally focused on total alcohol consumed and not type of alcohol. Different types of alcohol consist of varying components which may affect risk of hip fracture differentially. This study seeks to examine the relationship between alcohol consumption, with a focus on type of alcohol consumed (e.g. beer, wine, or hard liquor) and hip fracture risk in post-menopausal women. METHODS: The longitudinal cohort consisted of U.S. post-menopausal women aged 50-79 years enrolled between 1993-1998 in the Women's Health Initiative Clinical Trials and Observational Study (N=115,655). RESULTS: Women were categorized as non-drinkers, past drinkers, infrequent drinkers and drinkers by preference of alcohol type (i.e. those who preferred wine, beer, hard liquor, or who had no strong preference). Mean alcohol consumption among current drinkers was 3.3 servings per week; this was similar among those who preferred wine, beer and liquor. After adjustment for potential confounders, alcohol preference was strongly correlated with hip fracture risk (p = 0.0167); in particular, women who preferred wine were at lower risk than non-drinkers (OR=0.78; 95% CI 0.64-0.95), past drinkers (OR=0.85; 95% CI 0.72-1.00), infrequent drinkers (OR=0.73; 95% CI 0.61-0.88), hard liquor drinkers (OR=0.87; 95% CI 0.71-1.06), beer drinkers (OR=0.72; 95% CI 0.55-0.95) and those with no strong preference (OR=0.89; 95% CI 0.89; 95% CI 0.73-1.10). CONCLUSIONS: Preference of alcohol type was associated with hip fracture; women who preferentially consumed wine had a lower risk of hip fracture compared to non-drinkers, past drinkers, and those with other alcohol preferences.

Lower skin cancer risk in women with higher body mass index: the women's health initiative observational study.

The unclear relationship of obesity to incident melanoma and nonmelanoma skin cancer (NMSC) risks was evaluated in the large, geographically diverse longitudinal, prospective Women's Health Initiative (WHI) observational study. Risks of melanoma and NMSC in normal weight women were compared with risks in overweight [body mass index (BMI) = 25-29.0 kg/m(2)] and obese (BMI ≥ 30 kg/m(2)) women, using Cox proportional hazards models for melanoma and logistic regression for NMSC. Over a mean 9.4 years of follow-up, there were 386 melanoma and 9,870 NSMC cases. Risk of melanoma did not differ across weight categories (P = 0.86), whereas in fully adjusted models, NMSC risk was lower in overweight [OR, 0.93; 95% confidence interval (CI), 0.89-0.99] and obese (OR, 0.85; 95% CI, 0.80-0.91) women (P < 0.001). Excess body weight was not associated with melanoma risk in postmenopausal women but was inversely associated with NMSC risk, possibly due to lower sun exposure in overweight and obese women. This supports previous work demonstrating the relationship between excess body weight and skin cancer risk.

Randomized clinical trial to evaluate the efficacy and safety of valganciclovir in a subset of patients with chronic fatigue syndrome.

There is no known treatment for chronic fatigue syndrome (CFS). Little is known about its pathogenesis. Human herpesvirus 6 (HHV-6) and Epstein-Barr virus (EBV) have been proposed as infectious triggers. Thirty CFS patients with elevated IgG antibody titers against HHV-6 and EBV were randomized 2:1 to receive valganciclovir (VGCV) or placebo for 6 months in a double-blind, placebo-controlled trial. Clinical endpoints aimed at measuring physical and mental fatigue included the Multidimensional Fatigue Inventory (MFI-20) and Fatigue Severity Scale (FSS) scores, self-reported cognitive function, and physician-determined responder status. Biological endpoints included monocyte and neutrophil counts and cytokine levels. VGCV patients experienced a greater improvement by MFI-20 at 9 months from baseline compared to placebo patients but this difference was not statistically significant. However, statistically significant differences in trajectories between groups were observed in MFI-20 mental fatigue subscore (P = 0.039), FSS score (P = 0.006), and cognitive function (P = 0.025). VGCV patients experienced these improvements within the first 3 months and maintained that benefit over the remaining 9 months. Patients in the VGCV arm were 7.4 times more likely to be classified as responders (P = 0.029). In the VGCV arm, monocyte counts decreased (P < 0.001), neutrophil counts increased (P = 0.037) and cytokines were more likely to evolve towards a Th1-profile (P < 0.001). Viral IgG antibody titers did not differ between arms. VGCV may have clinical benefit in a subset of CFS patients independent of placebo effect, possibly mediated by immunomodulation and/or antiviral effect. Further investigation with longer treatment duration and a larger sample size is warranted.

Piecewise exponential models to assess the influence of job-specific experience on the hazard of acute injury for hourly factory workers.

BACKGROUND: An inverse relationship between experience and risk of injury has been observed in many occupations. Due to statistical challenges, however, it has been difficult to characterize the role of experience on the hazard of injury. In particular, because the time observed up to injury is equivalent to the amount of experience accumulated, the baseline hazard of injury becomes the main parameter of interest, excluding Cox proportional hazards models as applicable methods for consideration. METHODS: Using a data set of 81,301 hourly production workers of a global aluminum company at 207 US facilities, we compared competing parametric models for the baseline hazard to assess whether experience affected the hazard of injury at hire and after later job changes. Specific models considered included the exponential, Weibull, and two (a hypothesis-driven and a data-driven) two-piece exponential models to formally test the null hypothesis that experience does not impact the hazard of injury. RESULTS: We highlighted the advantages of our comparative approach and the interpretability of our selected model: a two-piece exponential model that allowed the baseline hazard of injury to change with experience. Our findings suggested a 30% increase in the hazard in the first year after job initiation and/or change. CONCLUSIONS: Piecewise exponential models may be particularly useful in modeling risk of injury as a function of experience and have the additional benefit of interpretability over other similarly flexible models.

Self-perceived physical health predicts cardiovascular disease incidence and death among postmenopausal women.

BACKGROUND: Physical and Mental Component Summary (PCS, MCS, respectively) scales of SF- 36 health-related-quality-of-life have been associated with all-cause and cardiovascular disease (CVD) mortality. Their relationships with CVD incidence are unclear. This study purpose was to test whether PCS and/or MCS were associated with CVD incidence and death. METHODS: Postmenopausal women (aged 50-79 years) in control groups of the Women's Health Initiative clinical trials (n = 20,308) completed the SF-36 and standardized questionnaires at trial entry. Health outcomes, assessed semi-annually, were verified with medical records. Cox regressions assessed time to selected outcomes during the trial phase (1993-2005). RESULTS: A total of 1075 incident CVD events, 204 CVD-specific deaths, and 1043 total deaths occurred during the trial phase. Women with low versus high baseline PCS scores had less favorable health profiles at baseline. In multivariable models adjusting for baseline confounders, participants in the lowest PCS quintile (reference = highest quintile) exhibited 1.8 (95%CI: 1.4, 2.3), 4.7 (95%CI: 2.3, 9.4), and 2.1 (95%CI: 1.7, 2.7) times greater risk of CVD incidence, CVD-specific death, and total mortality, respectively, by trial end; whereas, MCS was not significantly associated with CVD incidence or death. CONCLUSION: Physical health, assessed by self-report of physical functioning, is a strong predictor of CVD incidence and death in postmenopausal women; similar self-assessment of mental health is not. PCS should be evaluated as a screening tool to identify older women at high risk for CVD development and death.

Aspirin is associated with lower melanoma risk among postmenopausal Caucasian women: the Women's Health Initiative.

BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) have been associated with decreased risk of gastric, colorectal, and breast cancer. However, the impact of NSAIDs on the risk of melanoma has been inconsistent. The authors evaluated the association between NSAID use and cutaneous melanoma risk in the Women's Health Initiative (WHI) Observational Study (OS). METHODS: At study entry, use of aspirin (acetylsalicylic acid [ASA]) and nonaspirin NSAIDs was assessed among 59,806 postmenopausal Caucasian women ages 50 to 79 years. Cox proportional hazards models were constructed after adjusting for participant skin type, sun exposure history, and medical indications for NSAID use among other confounders. RESULTS: During a median follow-up of 12 years, 548 incident melanomas were confirmed by medical review. Women who used ASA had a 21% lower risk of melanoma (hazard ratio, 0.79; 95% confidence interval, 0.63-0.98) relative to nonusers. Increased duration of ASA use (<1 year, 1-4 years, and ≥ 5 years) was associated with an 11% lower risk of melanoma for each categorical increase (Ptrend = .01), and women with ≥ 5 years of use had a 30% lower melanoma risk (hazard ratio, 0.70; 95% confidence interval, 0.55-0.94). In contrast, use of non-ASA NSAIDs and acetaminophen were not associated with melanoma risk. CONCLUSIONS: Postmenopausal women who used ASA had a significantly lower risk of melanoma, and longer duration of ASA use was associated with greater protection. Although this study was limited by the observational design and self-report of NSAID use, the findings suggest that ASA may have a chemopreventive effect against the development of melanoma and warrant further clinical investigation.

Changes in physical activity and body composition in postmenopausal women over time.

PURPOSE: Higher physical activity (PA) has been associated with greater attenuation of body fat gain and preservation of lean mass across the lifespan. These analyses aimed to determine relationships of change in PA to changes in fat and lean body mass in a longitudinal prospective study of postmenopausal women. METHODS: Among 11,491 women enrolled at three Women's Health Initiative clinical centers who were selected to undergo dual-energy x-ray absorptiometry, 8352 had baseline body composition measurements, with at least one repeated measure at years 1, 3, and 6. PA data were obtained by self-report at baseline and 3 and 6 yr of follow-up. Time-varying PA effect on change in lean and fat mass during the 6-yr study period for age groups (50-59 yr, 60-69 yr, and 70-79 yr) was estimated using mixed effects linear regression. RESULTS: Baseline PA and body composition differed significantly among the three age groups. The association of change in fat mass from baseline and time-varying PA differed across the three age groups (P = 0.0006). In women age 50-59 yr, gain in fat mass from baseline was attenuated with higher levels of PA. Women age 70-79 yr lost fat mass at all PA levels. In contrast, change in lean mass from baseline and time-varying PA did not differ by age group (P = 0.1935). CONCLUSIONS: The association between PA and change in fat mass varies by age group, with younger, but not older, women benefiting from higher levels of aerobic PA. Higher levels of aerobic activity are not associated with changes in lean mass, which tends to decrease in older women regardless of activity level. Greater attention to resistance training exercises may be needed to prevent lean mass loss as women age.

Influence of donor and recipient sex mismatch on heart transplant outcomes: analysis of the International Society for Heart and Lung Transplantation Registry.

BACKGROUND: Prior studies have presented contradictory results after analyzing associations between donor and recipient sex on survival after heart transplantation and causes of death such as acute rejection (AR) and cardiac allograft vasculopathy (CAV). We used the International Society for Heart and Lung Transplantation (ISHLT) Registry, the largest repository of heart transplant outcomes worldwide, to comprehensively address these questions. METHOD: We studied 60,584 adult recipients of heart transplants performed between 1990 and 2008. Outcomes of interest were overall survival, death-censored allograft survival, AR, and CAV, which were studied using regression models. To assess whether donor/recipient sex mismatch affected outcomes, the experience of male recipients with female vs male donors was compared with that of female recipients with female vs male donors through inclusion of an interaction term between donor and recipient sex. RESULTS: Significant differences were observed between male and female recipients in overall survival and death-censored allograft survival for female vs male donors. Male recipients of female allografts had a 10% increase in adjusted mortality relative to male recipients of male allografts, whereas female recipients of female allografts had a 10% decrease in adjusted mortality relative to female recipients of male allografts (p < 0.0001). Findings were similar for death-censored allograft survival. Differences in the effect of donor sex on AR or CAV between male and female recipients were not significant. CONCLUSIONS: Analysis of the ISHLT data set has demonstrated a strong association between donor/recipient sex mismatch and reduced survival after heart transplantation.

Comparative analysis of old-age mortality estimations in Africa.

BACKGROUND: Survival to old ages is increasing in many African countries. While demographic tools for estimating mortality up to age 60 have improved greatly, mortality patterns above age 60 rely on models based on little or no demographic data. These estimates are important for social planning and demographic projections. We provide direct estimations of older-age mortality using survey data. METHODS: Since 2005, nationally representative household surveys in ten sub-Saharan countries record counts of living and recently deceased household members: Burkina Faso, Côte d'Ivoire, Ethiopia, Namibia, Nigeria, Swaziland, Tanzania, Uganda, Zambia, and Zimbabwe. After accounting for age heaping using multiple imputation, we use this information to estimate probability of death in 5-year intervals ((5)q(x)). We then compare our (5)q(x) estimates to those provided by the World Health Organization (WHO) and the United Nations Population Division (UNPD) to estimate the differences in mortality estimates, especially among individuals older than 60 years old. FINDINGS: We obtained information on 505,827 individuals (18.4% over age 60, 1.64% deceased). WHO and UNPD mortality models match our estimates closely up to age 60 (mean difference in probability of death -1.1%). However, mortality probabilities above age 60 are lower using our estimations than either WHO or UNPD. The mean difference between our sample and the WHO is 5.9% (95% CI 3.8-7.9%) and between our sample is UNPD is 13.5% (95% CI 11.6-15.5%). Regardless of the comparator, the difference in mortality estimations rises monotonically above age 60. INTERPRETATION: Mortality estimations above age 60 in ten African countries exhibit large variations depending on the method of estimation. The observed patterns suggest the possibility that survival in some African countries among adults older than age 60 is better than previously thought. Improving the quality and coverage of vital information in developing countries will become increasingly important with future reductions in mortality.

The handling of missing data in molecular epidemiology studies.

Molecular epidemiology studies face a missing data problem, as biospecimen or imaging data are often collected on only a proportion of subjects eligible for study. We investigated all molecular epidemiology studies published as Research Articles, Short Communications, or Null Results in Brief in Cancer Epidemiology, Biomarkers & Prevention from January 1, 2009, to March 31, 2010, to characterize the extent that missing data were present and to elucidate how the issue was addressed. Of 278 molecular epidemiology studies assessed, most (95%) had missing data on a key variable (66%) and/or used availability of data (often, but not always the biomarker data) as inclusion criterion for study entry (45%). Despite this, only 10% compared subjects included in the analysis with those excluded from the analysis and 88% with missing data conducted a complete-case analysis, a method known to yield biased and inefficient estimates when the data are not missing completely at random. Our findings provide evidence that missing data methods are underutilized in molecular epidemiology studies, which may deleteriously affect the interpretation of results. We provide practical guidelines for the analysis and interpretation of molecular epidemiology studies with missing data.

Blocking the NOTCH pathway inhibits vascular inflammation in large-vessel vasculitis.

BACKGROUND: Giant cell arteritis is a granulomatous vasculitis of the aorta and its branches that causes blindness, stroke, and aortic aneurysm. CD4 T cells are key pathogenic regulators, instructed by vessel wall dendritic cells to differentiate into vasculitic T cells. The unique pathways driving this dendritic cell-T-cell interaction are incompletely understood, but may provide novel therapeutic targets for a disease in which the only established therapy is long-term treatment with high doses of corticosteroids. METHODS AND RESULTS: Immunohistochemical and gene expression analyses of giant cell arteritis-affected temporal arteries revealed abundant expression of the NOTCH receptor and its ligands, Jagged1 and Delta1. Cleavage of the NOTCH intracellular domain in wall-infiltrating T cells indicated ongoing NOTCH pathway activation in large-vessel vasculitis. NOTCH activation did not occur in small-vessel vasculitis affecting branches of the vasa vasorum tree. We devised 2 strategies to block NOTCH pathway activation: γ-secretase inhibitor treatment, preventing nuclear translocation of the NOTCH intracellular domain, and competing for receptor-ligand interactions through excess soluble ligand, Jagged1-Fc. In a humanized mouse model, NOTCH pathway disruption had strong immunosuppressive effects, inhibiting T-cell activation in the early and established phases of vascular inflammation. NOTCH inhibition was particularly effective in downregulating Th17 responses, but also markedly suppressed Th1 responses. CONCLUSIONS: Blocking NOTCH signaling depleted T cells from the vascular infiltrates, implicating NOTCH- NOTCH ligand interactions in regulating T-cell retention and survival in vessel wall inflammation. Modulating the NOTCH signaling cascade emerges as a promising new strategy for immunosuppressive therapy of large-vessel vasculitis.