Publications

The host immune response is critical for homeostasis; however, when chronic low level activation of the immune response with or without the driver continues, a cascade of events can trigger immunological dysfunction. Monocytes are key peripheral sensors of the immune response and their activation is instrumental in the development of cognitive impairment. Here, we show that monocytes activated by interferon alpha, lipopolysaccharide or a combination of both generate exosomes carrying significantly altered microRNA profiles compared to non-activated monocytes. These exosomes alone can activate human brain microvascular endothelial cells to stimulate adhesion molecules, CCL2, ICAM1, VCAM1 and cytokines, IL1β and IL6. This activation is through the toll like receptor 4 (TLR4)/myeloid differentiation primary response gene 88 (MyD88) pathway that activates nuclear factor-κB and increases monocyte chemotaxis. Inhibition of monocyte exosome release reverses endothelial cell activation and monocyte chemotaxis. Our study suggests that activated monocytes have an impact on brain vascular function through intercellular exosome signaling.

Wilson's disease is a well-characterized disorder known to cause liver and brain disease due to abnormal copper deposition. Data regarding copper infiltration of the heart is conflicting, and the risk of heart disease has not been well described. We aimed to determine whether Wilson's disease is associated with cardiac myopathy, clinically evident in the atria as atrial fibrillation (AF) and in the ventricles as heart failure (HF). We longitudinally assessed 14.3 million patients in the California Healthcare Cost and Utilization Project database from 2005 through 2009 for diagnoses of Wilson's disease, AF, HF, and covariates using International Classification of Diseases-9th Edition codes. Cirrhosis and appendicitis diagnoses were assessed for positive and negative validation, respectively. We identified 463 patients with Wilson's disease. As expected in validation analyses, patients with Wilson's disease had a threefold greater risk of cirrhosis (hazard ratio [HR] 2.85, 95% confidence interval [CI] 2.81 to 2.90, p <0.0001) and no increased risk of appendicitis (HR 0.24, 95% CI 0.04 to 1.71, p = 0.16). Patients with Wilson's disease exhibited a 29% higher risk of AF after adjusting for age, gender, race, income, hypertension, diabetes, renal disease, hyperlipidemia, obesity, coronary disease, and obstructive sleep apnea (HR 1.29, 95% CI 1.15 to 1.45, p <0.0001). After adjusting for the same covariates, patients with Wilson's disease had a 55% higher risk of incident HF (HR 1.55, 95% CI 1.41 to 1.71, p <0.0001). Patients with Wilson's disease have an increased risk of AF and HF, supporting the need for careful surveillance for heart disease. These findings also suggest that the role of copper metabolism in heart disease should be more broadly investigated.

The majority of genetic variants associated with common human diseases map to enhancers, non-coding elements that shape cell-type-specific transcriptional programs and responses to extracellular cues. Systematic mapping of functional enhancers and their biological contexts is required to understand the mechanisms by which variation in non-coding genetic sequences contributes to disease. Functional enhancers can be mapped by genomic sequence disruption, but this approach is limited to the subset of enhancers that are necessary in the particular cellular context being studied. We hypothesized that recruitment of a strong transcriptional activator to an enhancer would be sufficient to drive target gene expression, even if that enhancer was not currently active in the assayed cells. Here we describe a discovery platform that can identify stimulus-responsive enhancers for a target gene independent of stimulus exposure. We used tiled CRISPR activation (CRISPRa) to synthetically recruit a transcriptional activator to sites across large genomic regions (more than 100 kilobases) surrounding two key autoimmunity risk loci, CD69 and IL2RA. We identified several CRISPRa-responsive elements with chromatin features of stimulus-responsive enhancers, including an IL2RA enhancer that harbours an autoimmunity risk variant. Using engineered mouse models, we found that sequence perturbation of the disease-associated Il2ra enhancer did not entirely block Il2ra expression, but rather delayed the timing of gene activation in response to specific extracellular signals. Enhancer deletion skewed polarization of naive T cells towards a pro-inflammatory T helper (T17) cell state and away from a regulatory T cell state. This integrated approach identifies functional enhancers and reveals how non-coding variation associated with human immune dysfunction alters context-specific gene programs.

CONTEXT

Risk profiling of oncology patients based on their symptom experience assists clinicians to provide more personalized symptom management interventions. Recent findings suggest that oncology patients with distinct symptom profiles can be identified using a variety of analytic methods.

OBJECTIVES

The objective of this study was to evaluate the concordance between the number and types of subgroups of patients with distinct symptom profiles using latent class analysis and K-modes analysis.

METHODS

Using data on the occurrence of 25 symptoms from the Memorial Symptom Assessment Scale, that 1329 patients completed prior to their next dose of chemotherapy (CTX), Cohen's kappa coefficient was used to evaluate for concordance between the two analytic methods. For both latent class analysis and K-modes, differences among the subgroups in demographic, clinical, and symptom characteristics, as well as quality of life outcomes were determined using parametric and nonparametric statistics.

RESULTS

Using both analytic methods, four subgroups of patients with distinct symptom profiles were identified (i.e., all low, moderate physical and lower psychological, moderate physical and higher Psychological, and all high). The percent agreement between the two methods was 75.32%, which suggests a moderate level of agreement. In both analyses, patients in the all high group were significantly younger and had a higher comorbidity profile, worse Memorial Symptom Assessment Scale subscale scores, and poorer QOL outcomes.

CONCLUSION

Both analytic methods can be used to identify subgroups of oncology patients with distinct symptom profiles. Additional research is needed to determine which analytic methods and which dimension of the symptom experience provide the most sensitive and specific risk profiles.

OBJECTIVES

To enhance understanding of the relationship between multimorbidity, symptom burden, and functional status in individuals with life-limiting illness.

DESIGN

Secondary analysis of baseline data from a randomized clinical trial conducted in the Palliative Care Research Cooperative Group. Group differences were tested using a t-test; multivariate regression analysis was used to determine the effect of multiple variables on functional status and symptom burden.

SETTING

Fifteen Palliative Care Research Cooperation sites.

PARTICIPANTS

Adults who participated in a parent statin-discontinuation clinical trial were included in the analysis (N = 381). Inclusion criteria were diagnosis of a life-limiting illness, statin use for 3 months or longer, life expectancy longer than 1 month, and declining functional status.

MEASUREMENTS

Cancer diagnosis (solid organ and hematologic malignancies), multimorbidity (Charlson Comorbidity Index (CCI) score), symptom burden (Edmonton Symptom Assessment Scale (ESAS) score, number of symptoms with ESAS severity score >4), functional status (Australia-modified Karnofsky Performance Scale (AKPS)).

RESULTS

Fifty-one percent had a primary diagnosis of cancer; mean age 74.1 ± 11.6. Participants had multiple comorbid illnesses (CCI score 4.9 ± 2.8), multiple symptoms (ESAS score 27.2 ± 15.9), and poor functional status (AKPS = 53 ± 13). In univariate and multivariate analyses, multimorbidity was associated with greater symptom burden (4.2 vs 3.1 moderate or severe symptoms (t = -3.2, P = .002), 12% vs 6% with severe symptoms (t = -3.7, P < .001)), but cancer diagnosis was not. In univariate and multivariate analyses, higher symptom burden was associated with poorer functional status (F = 11.6, P < .001), but multimorbidity was not.

CONCLUSION

Symptoms cannot be attributed solely to a diagnosis of cancer. The association between symptom burden and functional status underscores the importance of clinical attention to symptoms in individuals with multimorbidity.

BACKGROUND AND AIMS

Methamphetamine use is increasingly prevalent and associated with HIV transmission. Early-phase human studies suggested naltrexone reduced amphetamine use among dependent individuals. We tested if extended-release naltrexone (XRNTX) reduces methamphetamine use and associated sexual risk behaviors among high-risk methamphetamine-dependent men who have sex with men (MSM).

DESIGN

Double-blind, placebo-controlled, randomized trial of XRTNX versus placebo over 12 weeks from 2012 to 2015.

SETTING

San Francisco Department of Public Health, California, USA.

PARTICIPANTS

One hundred community-recruited, sexually-active, actively-using methamphetamine-dependent MSM. Mean age was 43.2 years; 96% were male, 3% transfemale, and 1% transmale; 55.0% were white, 19.0% African American, and 18.0% Latino.

INTERVENTIONS

XRNTX 380 mg (n = 50) or matched placebo (n = 50) administered by gluteal injection at 4-week intervals.

MEASUREMENTS

Regression estimated average level and change in level of positive urines during the period 2-12 weeks (primary outcomes) and sexual risk behaviors (secondary outcome).

FINDINGS

Ninety per cent of visits were completed. By intent-to-treat, participants assigned to XRNTX had similar differences during 2-12 weeks in methamphetamine-positive urines as participants assigned to placebo [incidence rate ratio (IRR) = 0.95, 95% confidence interval (CI) = 0.76-1.20; Bayes factor < 0.3]. Observed urine positivity declined from 78 to 70% in the XRNTX arm and 74 to 64% in the placebo arm. Adherence to injections was 96.7% in the XRNTX arm and 91.3% in the placebo arm. Sexual risk behaviors declined similarly among participants in both arms (all P > 0.05). There were no serious adverse events related to study drug and no differences in frequency of adverse events by treatment arm.

CONCLUSIONS

Notwithstanding very high medication adherence for this study, extended-release naltrexone does not appear to reduce methamphetamine use or sexual risk behaviors among methamphetamine-dependent men who have sex with men compared with placebo.