In Inflammatory Bowel Disease (IBD), the colon and small intestine are chronically inflamed due, at least in part, to increased epithelial permeability and an inappropriate immune response to luminal antigens. IFN-gamma is a prominent pro-inflammatory cytokine that increases permeability of the intestinal epithelium and T-Cell Protein Tyrosine Phosphatase (TCPTP) is a negative regulator of IFN-gamma signaling. This research explores the effects of a probiotic preparation on TCPTP abundance, resolution of inflammatory signaling, and intestinal epithelial permeability by studying a probiotic blend called VSL#3. Research showed that in T84 colonic epithelial cells, VSL#3 was able to increase TCPTP protein levels by 150 ± 3% and enzymatic activity by 100 ± 5% (106 CFU/mL for 9 hours). Moreover, VSL#3 was able to decrease epithelial monolayer permeability by 25 ± 2% over 9 hours (106 CFU/mL). When IFN-gamma and VSL#3 were co-incubated, VSL#3 attenuated the increase in permeability that resulted from 24 hours pre-treatment of T84 cells with IFN-gamma by 120 ± 2%. Moreover, levels of phosphorylated STAT-1 (a downstream effect of IFN-gamma signaling) decreased when VSL#3 and IFN-gamma were co- incubated and TCPTP levels showed an increase as VSL#3 doses were increased. Results were inconclusive as to whether VSL#3's effects on transepithelial resistance in IFN-gamma pre-treated cells were TCPTP-mediated because the TCPTP inhibitor failed to display its expected action. Overall, the findings of this thesis indicate that VSL#3 can repair epithelial permeability defects caused by IFN- gamma and this may be due in part to upregulation of a negative regulator of IFN-gamma signaling, TCPTP

The menopausal transition is a time of accelerating risk of cardiovascular disease (CVD), and promoting cardiovascular health during midlife is an important period of time to prevent CVD in women. The association of menopause with cardiovascular risk factors or subclinical atherosclerosis has not previously been evaluated in South Asian American women, a population with a disproportionately higher CVD burden compared with other race/ethnic groups. The objective of this study was to evaluate the association of menopause with CVD risk factors and subclinical cardiometabolic disease markers. We studied women aged 40 to 84 years from the Mediators of Atherosclerosis in South Asians Living in America study. The association of self-reported menopausal status with multiple demographic and clinical variables was assessed with linear and logistic regression adjusted for age and cardiovascular health behaviors. In a secondary ("age-restricted") analysis, postmenopausal participants outside the age range of premenopausal participants were excluded. In the age-restricted sample, menopause was associated with a higher adjusted odds of hypertension (odds ratio = 1.19, 95% confidence interval [CI] 1.02 to 1.41), and higher systolic blood pressure (β = 6.34, 95% CI 0.82 to 11.87), and significantly higher subcutaneous fat area (β = 42.8, 95% CI 5.8 to 91.4). No significant associations between menopause and ectopic fat deposition, coronary artery calcium, or carotid intima-media thickness were observed. In South Asian American women in the Mediators of Atherosclerosis in South Asians Living in America study, menopause was associated with cardiovascular risk factors and higher subcutaneous fat deposition. Menopausal status is an important factor to examine and address CVD risk factors.

Background

VSL#3 is a probiotic compound that has been used in the treatment of inflammatory bowel disease. T-cell protein tyrosine phosphatase (TCPTP) is the protein product of the inflammatory bowel disease candidate gene, PTPN2, and we have previously shown that it protects epithelial barrier function. The aim of this study was to investigate whether VSL#3 improves intestinal epithelial barrier function against the effects of the inflammatory bowel disease-associated proinflammatory cytokine, interferon-gamma (IFN-γ) through activation of TCPTP.

Methods

Polarized monolayers of T84 intestinal epithelial cells were treated with increasing concentrations of VSL#3 to determine effects on TCPTP expression and enzymatic activity. Therapeutic effects of VSL#3 against barrier disruption by IFN-γ were measured by transepithelial electrical resistance and fluorescein isothiocyanate-dextran permeability. A novel TCPTP-deficient HT-29 intestinal epithelial cell line was generated to study the role of TCPTP in mediating the effects of VSL#3. Tight junction protein distribution was assessed with confocal microscopy.

Results

VSL#3 increased TCPTP protein levels and enzymatic activity, correlating with a VSL#3-induced decrease in IFN-γ signaling. VSL#3 corrected the decrease in transepithelial electrical resistance and the increase in epithelial permeability induced by IFN-γ. Moreover, the restorative effect of VSL#3 against IFN-γ signaling, epithelial permeability defects, altered expression and localization of the tight junction proteins claudin-2, occludin, and zonula occludens-1, were not realized in stable TCPTP/(PTPN2)-deficient HT-29 intestinal epithelial cells.

Conclusions

VSL#3 reduces IFN-γ signaling and IFN-γ-induced epithelial barrier defects in a TCPTP-dependent manner. These data point to a key role for TCPTP as a therapeutic target for restoration of barrier function using probiotics.

Background and aims

We conducted a retrospective cohort study comparing the risk of malignancy between patients treated with vedolizumab vs. tumor necrosis factor-α (TNFα) antagonists in patients with inflammatory bowel diseases (IBD).

Methods

Using an administrative claims database, we identified patients with IBD without prior malignancy who were new users of either vedolizumab or TNFα antagonists between 2014-2018, with no prior exposure to either biologic or in preceding 1 y and had insurance coverage for at least 1 y after treatment initiation. We estimated incidence rate of malignancy (solid organ, hematological or skin cancers) in patients treated with vedolizumab and TNFα antagonists, and compared risk using Cox proportional hazard analysis.

Results

We included 4807 patients treated with TNFα antagonists (age, 41 ± 15 y, 60% with Crohn's disease [CD]) of whom 65 developed malignancy over 7214 person-year [PY] follow-up (incidence rate [IR], 9.0 per 1000-PY), and 759 patients treated with vedolizumab (age, 46 ± 16y, 42% CD) of whom 11 developed malignancy over 950-PY follow-up (IR, 11.6). No difference was observed in the incidence of malignancy between vedolizumab versus TNFα antagonists (incidence rate ratio, 1.28; 95% CI, 0.61-2.45). After adjusting for age, sex, race, comorbidity burden, disease phenotype and concomitant use of immunomodulators, no difference was observed in time to incident malignancy between vedolizumab versus TNFα antagonists (HR, 1.15; 95% CI, 0.61-2.19). Similar results were observed on stratified analysis by age and concomitant immunomodulators, and after excluding non-melanoma skin cancers.

Conclusions

In an observational study of patients with IBD, no differences were observed in the risk of incident malignancy in patients treated with vedolizumab versus TNFα antagonists.

Importance

In older adults with multiple serious comorbidities and functional limitations, the harms of intensive glycemic control likely exceed the benefits.

Objectives

To examine glycemic control levels among older adults with diabetes mellitus by health status and to estimate the prevalence of potential overtreatment of diabetes.

Design, setting, and participants

Cross-sectional analysis of the data on 1288 older adults (≥65 years) with diabetes from the National Health and Nutrition Examination Survey (NHANES) from 2001 through 2010 who had a hemoglobin A1c (HbA1c) measurement. All analyses incorporated complex survey design to produce nationally representative estimates.

Exposures

Health status categories: very complex/poor, based on difficulty with 2 or more activities of daily living or dialysis dependence; complex/intermediate, based on difficulty with 2 or more instrumental activities of daily living or presence of 3 or more chronic conditions; and relatively healthy if none of these were present.

Main outcomes and measures

Tight glycemic control (HbA1c level, <7%) and use of diabetes medications likely to result in hypoglycemia (insulin or sulfonylureas).

Results

Of 1288 older adults with diabetes, 50.7% (95% CI, 46.6%-54.8%), representing 3.1 million (95% CI, 2.7-3.5), were relatively healthy, 28.1% (95% CI, 24.8%-31.5%), representing 1.7 million (95% CI, 1.4-2.0), had complex/intermediate health, and 21.2% (95% CI, 18.3%-24.4%), representing 1.3 million (95% CI, 1.1-1.5), had very complex/poor health. Overall, 61.5% (95% CI, 57.5%-65.3%), representing 3.8 million (95% CI, 3.4-4.2), had an HbA1c level of less than 7%; this proportion did not differ across health status categories (62.8% [95% CI, 56.9%-68.3%]) were relatively healthy, 63.0% (95% CI, 57.0%-68.6%) had complex/intermediate health, and 56.4% (95% CI, 49.7%-62.9%) had very complex/poor health (P = .26). Of the older adults with an HbA1c level of less than 7%, 54.9% (95% CI, 50.4%-59.3%) were treated with either insulin or sulfonylureas; this proportion was similar across health status categories (50.8% [95% CI, 45.1%-56.5%] were relatively healthy, 58.7% [95% CI, 49.4%-67.5%] had complex/intermediate health, and 60.0% [95% CI, 51.4%-68.1%] had very complex/poor health; P = .14). During the 10 study years, there were no significant changes in the proportion of older adults with an HbA1c level of less than 7% (P = .34), the proportion with an HbA1c level of less than 7% who had complex/intermediate or very complex/poor health (P = .27), or the proportion with an HbA1c level of less than 7% who were treated with insulin or sulfonylureas despite having complex/intermediate or very complex/poor health (P = .65).

Conclusions and relevance

Although the harms of intensive treatment likely exceed the benefits for older patients with complex/intermediate or very complex/poor health status, most of these adults reached tight glycemic targets between 2001 and 2010. Most of them were treated with insulin or sulfonylureas, which may lead to severe hypoglycemia. Our findings suggest that a substantial proportion of older adults with diabetes were potentially overtreated.

We describe cardiovascular health (CVH) in second-generation (U.S.-born) South Asian Americans in the MASALA study, a population for whom CVH is not previously described. CVH factors in second-generation (N = 21) compared with first-generation (N = 495) South Asian Americans included: total cholesterol (199 ± 31 versus 191 ± 35 mg/dL, p = 0.25), low-density lipoprotein cholesterol (121 ± 27 versus 115 ± 30 mg/dL, p = 0.41), triglycerides (163 ± 197 versus 138 ± 72 mg/dL, p = 0.10), diet score (66 ± 8 versus 70 ± 6 points, p = 0.06), BMI (27.6 ± 4.9 versus 26.2 ± 4.1 kg/m², p = 0.12), and CAC prevalence (26.3% versus 23.9%, p = 0.34). Age- and sex-adjusted differences were not statistically significant. Further investigation of CVH in this risk-enhanced population may help identify differences between second-generation and first-generation immigrant South Asians in the U.S.

Objectives

The 2018 and 2019 U.S. guidelines for the management of cholesterol and primary prevention of atherosclerotic cardiovascular disease (ASCVD) recommend consideration of cardiovascular risk-enhancing factors (REFs), including South Asian ancestry, to refine ASCVD risk estimation. However, the associations of REFs with atherosclerosis are unclear in South Asian American adults, who have a disproportionately elevated premature coronary heart disease risk. In the Mediators of Atherosclerosis in South Asians Living in America (MASALA) cohort, we investigated associations of individual REFs, or the number of REFs, with coronary artery calcium (CAC).

Methods

Using baseline and follow-up data from MASALA, we evaluated the association of REFs (family history of ASCVD, low-density lipoprotein cholesterol ≥160 mg/dL, triglycerides ≥175 mg/dL, lipoprotein(a) >50 mg/dL, high-sensitivity C-reactive protein [hsCRP] ≥2.0 mg/dL, ankle-brachial index <0.9, chronic kidney disease, metabolic syndrome), individually and combined, with baseline prevalent CAC, any CAC progression (including incident CAC and CAC progression), and annual CAC progression rates using multivariable logistic regression and generalized linear models.

Results

Among 866 adults, mean age was 55 [SD 9] years and 47% were female. There were no significant associations of REFs with baseline prevalent CAC or any CAC progression (incident CAC and CAC progression at Exam 2) after adjustment. Among the 56% of participants who had any CAC progression, having 3+ REFs was associated with a significantly higher annual CAC progression rate (adjusted rate ratio [aRR] 1.94, 95% CI 1.39-2.72) vs. having 0 REFs. The annual CAC progression rate was 20% higher per additional REF (aRR 1.20, 95% CI 1.09-1.32). Findings were similar after excluding statin users, and among those with low 10-year ASCVD risk (<5%).

Conclusions

Among South Asian American adults, we found no association of REFs with prevalent CAC at baseline or having any CAC progression. Among those with any CAC progression, a higher number of REFs was associated with higher annual CAC progression rates.

Importance

It is critical to develop a better understanding of the strategies provider organizations use to improve the performance of frontline clinicians and whether ACO participation is associated with differential adoption of these tools.

Objectives

Characterize the strategies that physician practices use to improve clinician performance and determine their association with ACOs and other payment reforms.

Data sources

The National Survey of Healthcare Organizations and the National Survey of ACOs fielded 2017-2018 (response rates = 47 percent and 48 percent).

Study design

Descriptive analysis for practices participating and not participating in ACOs among 2190 physician practice respondents. Linear regressions to examine characteristics associated with counts of performance domains for which a practice used data for feedback, quality improvement, or physician compensation as dependent variables. Logistic and fractional regression to examine characteristics associated with use of peer comparison and shares of primary care and specialist compensation accounted for by performance bonuses, respectively.

Principal findings

ACO-affiliated practices feed back clinician-level information and use it for quality improvement and compensation on more performance domains than non-ACO-affiliated practices. Performance measures contribute little to physician compensation irrespective of ACO participation.

Conclusion

ACO-affiliated practices are using more performance improvement strategies than other practices, but base only a small fraction of compensation on quality or cost.

South Asians in the United States have disproportionately high burden of cardiovascular disease compared to other race/ethnic groups but are a heterogenous population, so we evaluated differences in prevalence and adjusted odds of cardiovascular risk factors including diabetes, hypertension, dyslipidemia, and obesity between North Indian, South Indian, and Pakistani immigrants in the United States in the Mediators of Atherosclerosis in South Asians Living in America (MASALA) study. Given cultural differences among residents of Indian regions, for example in dietary patterns, we categorized Indian participants as North or South Indian. In 1,018 participants (728 North Indian [47% women], 223 South Indian [43% women], 67 Pakistani [52% women]), unadjusted diabetes and obesity prevalence was highest in Pakistani participants (33% and 48%, respectively); hypertension prevalence was highest in North Indian participants (54%); dyslipidemia prevalence was highest in South Indian and Pakistani participants (55%); and South Indian participants had a higher odds of dyslipidemia (OR 1.77, 95% CI 1.27, 2.47) compared with North Indian participants in fully adjusted models. As differences in cardiovascular risk factors were observed across South Asian American subgroups, identifying the determinants of suboptimal cardiovascular health within South Asian American subgroups may help to better tailor cardiovascular disease prevention strategies.

Background

Identifying biologic-treated patients with inflammatory bowel diseases (IBDs) at higher risk of serious infections is a priority. We conducted a retrospective cohort study evaluating frailty and risk of serious infections in biologic-treated patients with IBD.

Methods

Using an administrative claims database, we identified biologic-treated patients with IBD between 2014 and 2018 with follow-up 1 year before and after treatment initiation. Using a validated claims-based hospital frailty risk scoring system, patients were classified as frail and nonfrail. We compared the risk of serious infections (infections requiring hospitalization) between frail and nonfrail patients using Cox proportional hazard analysis adjusting for age, comorbidities, disease characteristics, health care utilization, use of corticosteroids, immunomodulators, and opiates.

Results

We included 5987 biologic-treated patients with IBD (4881 on TNFα antagonists, 1106 on vedolizumab), of whom 2350 (39.3%) were classified as frail; over 7115 person-years of follow-up was included, and 520 patients developed serious infection. Frailty was not associated with increased risk of serious infection (adjusted hazard ratio [aHR], 1.12; 95% CI, 0.93-1.36), whereas advanced age (older than 60 years), high comorbidity burden, corticosteroid use, opiate use, and prior serious infection were associated with increased risk of serious infection. On stratified analysis, frailty was associated with increased risk of serious infections in vedolizumab-treated patients (aHR, 1.69; 95% CI, 1.03-2.79) but not in TNFα antagonist-treated patients (aHR, 1.03; 95% CI, 0.83-1.27).

Conclusions

In biologic-treated patients with IBD, frailty assessed using a claims-based frailty index was not independently associated with increased risk of serious infections. Future studies evaluating objective and biological measures of frailty are warranted to risk-stratify older patients with IBD.