Second-year results from CINEMA: A novel, patient-centered, team-based intervention for patients with Type 2 diabetes or prediabetes at high cardiovascular risk.

Background: The care for patients with type 2 diabetes mellitus (T2DM) necessitates a multidisciplinary team approach to reduce cardiovascular (CV) risk but implementation of effective integrated strategies has been limited. Methods and Results: We report 2-year results from a patient-centered, team-based intervention called CINEMA at University Hospitals Cleveland Medical Center. Patients with T2DM or prediabetes at high-risk for CV events, including those with established atherosclerotic CVD, elevated coronary artery calcium score ≥100, chronic heart failure with reduced ejection fraction, chronic kidney disease (CKD) stages 2-4, and/or prevalent metabolic syndrome were included. From May 2020 through September 2022, 426 patients were enrolled in the CINEMA program. A total of 227 (54%) completed ≥1 follow-up visit after an initial baseline visit with median (IQR) follow-up time 4 [3], [4], [5], [6], [7] months with maximum follow-up time 19 months. Mean age was 60 years, 47 % were women, and 37 % were Black and 85% had prevalent T2DM, 48 % had established ASCVD, 29% had chronic HF, 27% had CKD and mean baseline 10-year ASCVD risk estimate was 25.1 %; baseline use of a SGLT2i or GLP-1RA was 21 % and 18 %, respectively. Patients had significant reductions from baseline in body weight (-5.5 lbs), body mass index (-0.9 kg/m2), systolic (-3.6 mmHg) and diastolic (-1.2 mmHg) blood pressure, Hb A1c (-0.5 %), total (-10.7 mg/dL) and low-density lipoprotein (-9.0 mg/dL) cholesterol, and triglycerides (-13.5 mg/dL) (p<0.05 for all). Absolute 10-year predicted ASCVD risk decreased by ∼2.4 % (p<0.001) with the intervention. In addition, rates of guideline-directed cardiometabolic medication prescriptions significantly increased during follow-up with the most substantive changes seen in rates of SGLT2i and GLP-1RA use which approximately tripled from baseline (21 % to 57 % for SGLT2i and 18 % to 65 % for GLP-1RA, p<0.001 for both). Conclusions: The CINEMA program, an integrated, patient-centered, team-based intervention for patients with T2DM or prediabetes at high risk for cardiovascular disease has continued to demonstrate effectiveness with significant improvements in ASCVD risk factors and improved use of evidence-based therapies. Successful implementation and dissemination of this care delivery paradigm remains a key priority.

Disparities in statin prescription among patients with severe hypercholesterolemia in an integrated healthcare system.

Background: Severe hypercholesterolemia (SH), defined as a low-density lipoprotein cholesterol (LDL-C) level ≥ 190 mg/dl, is associated with an increased risk for premature atherosclerotic cardiovascular disease. Despite guideline recommendations, many patients with severe hypercholesterolemia remain untreated. We conducted an observational analysis of a large pool of SH patients, exploring demographic and social factors contributing to disparities in the prescription of statin and other lipid-lowering therapies. Methods: We included all adults (age 18 or older) in the University Hospitals Health Care System, with an LDL-C ≥ 190 mg/dl on a lipid profile drawn between January 2, 2014, and March 15, 2022. Variables were compared across relevant categories of age, gender, race and ethnicity, medical history, prescription medication status, insurance type, and provider referral type. We used the Fischer exact test and Pearson Chi-square (χ 2) for variable comparisons. Results: A total of 7,942 patients were included in the study. The median age was 57 [IQR 48-66] years with 64% female, and 17% Black patients. Only 58% of the total cohort was prescribed statin therapy. Higher age was independently associated with a higher likelihood of receiving a statin, with an odds ratio of 1.25 (95% CI [1.21 - 1.30] per 10 years, p<0.001). Additional factors that were associated with higher rates of statin prescription in patients with SH were Black race (OR 1.90, 95% CI [1.65 - 2.17], p<0.001), smoking (OR 2.42, 95% CI [2.17 -2.70], p<0.001), and presence of diabetes (OR 3.88, 95% CI [3.27 - 4.60], p<0.001). Similar trends were also seen with other lipid-lowering therapies such as ezetimibe and fibrates. Conclusions: In our Northeast Ohio healthcare system, less than two-thirds of patients with severe hypercholesterolemia are prescribed a statin. Statin prescription rates were highly dependent on age and the presence of additional ASCVD risk factors.

Effects of Parental Internalizing and Externalizing Behavior Problems on Children's Limbic Brain Structures-An MRI Study.

Parental behavior problems have long-term effects on children's limbic brain structures and functions. Parental behavior problems-related brain changes in children may lead to mental disorders and behavior dysfunction later in life. However, our understanding of the relationship between parental behavior and children's brain structures is less obvious when children and adolescents are studied in a general population without mental disorders. The majority of studies on the relationship between parental behavior and adolescent brain structure have been focused on severe forms of the following parental behavior problems: (1) internalizing behavior associated with mood and anxiety disorders, and (2) externalizing behavior associated with substance use and violence. A few studies examined the effect of normative variations or subtle differences in parental behavior. Therefore, we utilized a large study-Adolescent Brain Cognitive Development (ABCD)-to determine relationships between normative variation in parental internalizing and externalizing behavior and limbic brain structures in children and adolescents without mental disorders. Quantile (median) regression models were used to compute associations between parental behavior and children's limbic structures. We found that parental internalizing and externalizing behaviors are uniquely associated with children's limbic structures after adjustment for biological confounders and parental socioeconomic status. Our findings indicate that normative parental behavior may have a significant early influence on limbic structures of normally developing children and adolescents. Accelerated or delayed limbic structure maturation may account for children's and adolescents' behavioral inadequacies and a risk of developing specific mood disorders or substance abuse problems later in life.

Prevalence of Raynaud's Phenomenon in Saudi Arabia.

Purpose: Raynaud's phenomenon (RP) is defined as frequent ischaemic attacks in the fingers and toes due to vascular vasospasm. Studies have been conducted in many countries worldwide to determine the prevalence of RP. The aim of the current study was to assess the prevalence of RP in the Saudi Arabian population. Patients and Methods: An online survey based on international consensus criteria used to diagnose RP was conducted to collect data from individuals from the Saudi population. Participants were considered positive if they had triphasic or biphasic colours of the extremities with cold-related sensitivity. Awareness of RP was also assessed. Results: A total of 1025 responses were collected and included in the final analysis. The prevalence of RP was 4.29%, including 22% men and 77% women. The most common age group among women was 26-40 years (36.3%). Familiarity with RP was low, with 56.82% of participants lacking adequate awareness regarding RP. Only 32% of patients with RP reported attending doctor visits regarding symptoms of the disease. Conclusion: The RP prevalence in Saudi Arabia is comparable to that reported in the international literature. Public awareness activities should be conducted to increase knowledge about RP. Trial Registration: Not applicable.

Ambient air pollution is associated with vascular disease in Ugandan HIV-positive adolescents.

OBJECTIVE: In this study, we aim to investigate the relationship between particulate matter, a common proxy indicator for air pollution, and markers of inflammation, monocyte activation, and subclinical vascular disease. DESIGN: A cross-sectional study. METHODS: Adolescents with perinatally acquired HIV (PHIV) and HIV-uninfected adolescents between 10 and 18years living near Kampala, Uganda were included. Daily ambient concentrations of particulate matter (PM2.5) were measured from the Eastern Arica GEOHealth Hub. Outcome variables measured were carotid intima-media thickness (IMT), as well as plasma markers of systemic inflammation, oxidized lipids, and gut integrity. Multivariable quantile regression models were used to explore the relationship between PM2.5 and IMT. RESULTS: One hundred and nineteen participants (69 PHIV, 50 HIV-uninfected) were included. The median (Q1, Q3) age was 12.7 (11.4,14.2) years, 55% were girls. Median daily PM2.5 exposure was 29.08 µg/m3 (23.40, 41.70). There was no significant difference in exposure of PM2.5 between groups (P  = 0.073). PM2.5 significantly correlated with intestinal permeability (zonulin; r = 0.43, P < 0.001), monocyte activation (soluble CD163: r  = 0.25, P = 0.053), and IMT (r  = 0.35, P = 0.004) in PHIV but not in HIV-uninfected (P ≥ 0.05). In multivariable quantile regression, after adjusting for age, sex, poverty level, soluble CD163, and zonulin, daily PM2.5 concentrations remained associated with IMT [ß  = 0.005, 95% CI (0.0003-0.010), P = 0.037] in adolescents with PHIV. CONCLUSION: Adolescents in urban Uganda are exposed to high levels of air pollution. Both PM2.5 and HIV have independently been observed to contribute to atherosclerotic disease, and our findings suggest the combined effects of HIV and air pollution may amplify the development of cardiovascular disease.

Inflammatory Markers and Risk of Heart Failure With Reduced to Preserved Ejection Fraction.

Chronic systemic inflammation is associated with an increased risk of heart failure (HF). We sought to determine the association between biomarkers of systemic inflammation interleukin (IL)-6, IL-2, tumor necrosis factor alpha (TNF-α), and C-reactive protein (CRP) with those of HF and its subtypes. We hypothesize that inflammatory biomarkers IL-6, IL-2, TNF-α, and CRP are associated with HF and its subtypes. We included participants from the Multi-Ethnic Study of Atherosclerosis (a prospective population-based cohort study [2000 to 2002]), without a history of HF, and with available baseline inflammatory biomarkers. We explored the association of IL-6, IL-2, TNF-α, and CRP with incident HF, HF with reduced ejection fraction (left ventricular ejection fraction [LVEF] <40%, HFrEF), HF with midrange EF (LVEF 40% to 50%, HFmrEF), and HF with preserved ejection fraction (LVEF >50%, HFpEF). Among 6,814 participants, 195 developed HF over 10.9 years (56 HFrEF, 30 HFmrEF, and 57 HFpEF). In the models adjusted for clinical risk factors of HF, IL-6 (hazard ratio [HR] 1.33 per doubling; 95% confidence interval [CI] 1.10 to 1.60), TNF-α (HR 2.49 per doubling; 95% CI 1.18 to 5.28), and CRP (HR 1.18 per doubling; 95% CI 1.06 to 1.30) were associated with all HF, and IL-6 (HR 1.51 per doubling; 95% CI 1.09 to 2.10) and CRP (HR 1.21 per doubling; 95% CI: 1.01 to 1.45) were associated with incident HFpEF, whereas none of the examined biomarkers were associated with HFmrEF or HFrEF. In conclusion, inflammatory biomarkers (IL-6, TNF-α, and CRP) are independently associated with incident HF. IL-6 and CRP are associated with incident HFpEF but not HFrEF or HFmrEF. These findings suggest that activation of the IL-6/CRP pathway (as cause, consequence, or epiphenomenon) may be unique to HFpEF.

Myocardial Injury and the Risk of Stroke in Patients With Chronic Kidney Disease (From the Chronic Renal Insufficiency Cohort Study).

Patients with chronic kidney disease (CKD) are at increased risk for stroke. High-sensitivity troponin (hsTP), a marker of myocardial injury, has been associated with stroke risk in patients without CKD, but whether this applies to patients with CKD is not known. We assessed whether hsTP levels is associated with incident stroke in patients with mild-to-moderate CKD without a history of stroke enrolled in the Chronic Renal Insufficiency Cohort. Patients were followed for incident stroke, and the association with hsTP was assessed. A total of 3477 patients without prior stroke were included in this investigation. Over a median follow-up of 7.3 years, 101 (2.8%) patients had an incident stroke. Baseline hsTP was associated with a 9-year risk of stroke (quartile 1: 1.8%, quartile 2: 3.8%, quartile 3: 4.9%, quartile 4: 7.3%; P < .001). After adjusting for traditional stroke risk factors, patients in the fourth quartile (hazard ratio: 2.52, 95% CI: 1.10-5.76, P = .021) had higher risk of stroke when compared with the lowest quartile of hsTP. In conclusion, hsTP levels are associated with increased risk of incident stroke in patients with mild to moderate CKD, and this association remains significant despite the adjustment for traditional risk factors and CKD.

Lipidome association with vascular disease and inflammation in HIV+ Ugandan children.

OBJECTIVE: HIV infection and antiretroviral therapy (ART) have both been linked to dyslipidemia and increased cardiovascular disease (CVD). The relationships among the lipidome, immune activation, and subclinical vascular disease in children with perinatally acquired HIV (PHIV) have not been investigated. METHODS: Serum lipid composition, including 13 lipid classes constituting 850 different lipid species were measured by direct infusion-tandem mass spectrometry in samples from 20 ART-treated PHIV and 20 age-matched and sex-matched HIV- Ugandan children. All participants were between 10 and 18 years of age with no other known active infections. PHIVs had HIV-1 RNA level 50 copies/ml or less. In addition, common carotid artery intima--media thickness (IMT), as well as plasma marker of systemic inflammation (hsCRP, IL6, sTNFRa I), monocyte activation (soluble CD14 and CD163), and T-cell activation (expression of CD38 and HLA-DR on CD4+ and CD8+) were evaluated. RESULTS: Median age (Q1, Q3) of study participants was 13 years (11, 15), 37% were boys, 75% were on an NNRTI-based ART regimen. The concentrations of cholesterol ester, LCER, phosphatidylcholines, and sphingomyelin lipid classes were significantly increased in serum of PHIV compared with HIV (P≤0.04). Biomarkers associated with CVD risk including hsCRP, sCD163, and T-cell activation were directly correlated with lipid species in PHIV (P ≤ 0.04). Contents of free fatty acids including palmitic (16 : 0), stearic (18 : 0), and arachidic acid (20 : 0) were positively correlated with IMT in PHIV. CONCLUSION: Serum lipidome is altered in young virally suppressed PHIV on ART. A direct association between inflammation and lipid species known to be associated with CVD was observed.

Anisocytosis is Associated With Short-Term Mortality in COVID-19 and May Reflect Proinflammatory Signature in Uninfected Ambulatory Adults.

BACKGROUND: Red cell distribution width (RDW), a measure of anisocytosis, is observed in chronic inflammation and is a prognostic marker in critically ill patients without COVID-19, but data in COVID-19 are limited. METHODS: Between March 12 and April 19, 2020, 282 individuals with confirmed COVID-19 and RDW available within 7 days prior to COVID-19 confirmation were evaluated. Individuals were grouped by quartiles of RDW. Association between quartiles of RDW and mortality was assessed using the Kaplan-Meier method and statistical significance was assessed using the log-rank test. The association between RDW and all-cause mortality was further assessed using a Cox proportional hazards model. Plasma cytokine levels in uninfected ambulatory adults without cardiovascular disease (n=38) were measured and bivariate Spearman correlations and principle components analysis were used to identify relationships between cytokine concentrations with RDW. RESULTS: After adjusting for age, sex, race, cardiovascular disease, and hemoglobin, there was an association between RDW and mortality (Quartile 4 vs Quartile 1: HR 4.04 [1.08-15.07]), with each 1% increment in RDW associated with a 39% increased rate of mortality (HR 1.39 [1.21-1.59]). Remote RDW was also associated with mortality after COVID-19 infection. Among uninfected ambulatory adults without cardiovascular disease, RDW was associated with elevated pro-inflammatory cytokines (TNF-α, IL8, IL6, IL1b), but not regulatory cytokines (TGFb). CONCLUSIONS: Anisocytosis predicts short-term mortality in COVID-19 patients, often predates viral exposure, and may be related to a pro-inflammatory phenotype. Additional study of whether the RDW can assist in the early identification of pending cytokine storm is warranted.

Monocyte activation and gut barrier dysfunction in South African youth on antiretroviral therapy and their associations with endothelial dysfunction.

BACKGROUND: There is evidence for endothelial dysfunction in youth living with perinatally acquired HIV (YLPHIV). However, little data exist on its mechanisms. METHODS: YLPHIV and age-matched HIV-uninfected (HIV-) youth enrolled in the Cape Town Adolescent Antiretroviral Cohort in South Africa between 9 and 14 years of age were included. YLPHIV were on antiretroviral therapy more than 6 months with viral load less than 400 copies/ml at baseline and 24 months. Serum biomarkers of systemic inflammation, monocyte activation, intestinal integrity, and oxidized LDL-cholesterol were measured at baseline and after 24 months. Endothelial function was measured at 24 months using reactive hyperemic index (RHI); endothelial dysfunction was defined as RHI less than 1.35. Spearman correlation coefficient and quantile regression were used to examine associations between RHI and different biomarkers. RESULTS: We included 266 YLPHIV and 69 HIV- participants. At baseline, median (Q1, Q3) age was 12 (11, 13) years and 53% were females. YLPHIV had poorer endothelial function compared with HIV- youth (RHI = 1.36 vs. 1.52, P < 0.01). At baseline and 24 months, YLPHIV had higher markers of monocyte activation (soluble CD14), gut barrier dysfunction (intestinal fatty acid binding protein) and oxidized LDL-cholesterol (P ≤ 0.04) compared with HIV- youth. Among YLPHIV, soluble CD14 remained associated with endothelial dysfunction after adjusting for age, sex, Tanner stage, and antiretroviral therapy duration (ß: -0.05, P = 0.01). CONCLUSION: Despite viral suppression, South African YLPHIV have poor endothelial function and persistent evidence of monocyte activation and gut barrier dysfunction compared with HIV- youth. The long-term clinical significance of gut integrity and monocyte activation needs to be further assessed in YLPHIV.

Relationship between economic insecurity, inflammation, monocyte activation and intestinal integrity in children living with HIV in Uganda.

We aimed to evaluate differences in socio-economic variables in a Ugandan cohort of children with perinatally acquired HIV (PHIVs), HIV exposed uninfected (HEU) and HIV unexposed uninfected (HIV-) children and their associations with markers of inflammation and intestinal integrity. This is a cross-sectional study in 57 PHIV, 59 HEU and 56 HIV - children aged 2-10 years old enrolled in Uganda. Mean age of all participants was 7 years and 55% were girls. Compared to HEU and HIV - children, PHIVs were more likely to have parents that only completed a primary education, live in a household without electricity and live in poverty (p≤0.034). PHIVs living in poverty had higher IL-6 (p=0.006), those with lack of electricity had higher hsCRP, IL6, sTNFRII and d-dimer (p≤0.048) and PHIVs with an unprotected water source had higher IL6 and d-dimer (p≤0.016). After adjusting for demographic and HIV variables, IL-6 and d-dimer remained associated with lack of electricity and having an unprotected water source only in PHIVs (p<0.019). Our findings suggest that addressing economic insecurity may mitigate the persistent low-level inflammation in HIV that lead to many end organ disease. Longitudinal studies are needed to better understand the impact of socioeconomic factors on HIV inflammation and comorbidities.

Increased monocyte and T-cell activation in treated HIV+ Ugandan children: associations with gut alteration and HIV factors.

INTRODUCTION: The pathophysiology of immune activation and its mechanisms in children living with perinatally acquired HIV (PHIV) in sub-Saharan Africa has been understudied. METHODS: We enrolled 101 children living with PHIV and 96 HIV-negative controls (HIV-). All participants were between 10 and 18 years of age with no known active infections. PHIVs were on ART with HIV-1 RNA level 400 copies/ml or less. We measured plasma and cellular markers of monocyte activation, T-cell activation (expression of CD38 and HLA-DR on CD4 and CD8), oxidized lipids, markers of gut integrity and fungal translocation. Spearman correlations and linear regression models were used. RESULTS: Overall median (Q1; Q3) age was 13 years (11; 15) and 52% were girls. Groups were similar by age, sex and BMI. Median ART duration was 10 years (8; 11). PHIVs had higher monocyte and T-cell activation; higher sCD14 (P = 0.01) and elevated frequencies of nonclassical monocytes (P < 0.001 for both). Markers of systemic inflammation (hsCRP), fungal translocation (BDG), intestinal permeability (zonulin) and oxidized lipids (ox LDL) correlated with monocyte and T-cell activation in PHIV (≤0.05). After adjusting for age, sex, ART duration, protease inhibitor and nonnucleoside reverse transcriptase inhibitor use, a modest association between BDG and activated CD4 T cells was observed (ß=0.65, P < 0.01). Oxidized LDL was inversely associated with activated T cells, inflammatory and nonclassical monocytes (P < 0.01). CONCLUSION: Ugandan children with perinatally acquired HIV with viral suppression have evidence of ongoing immune activation. Intestinal barrier dysfunction and fungal translocation may be involved in chronic immune dysfunction.

Subclinical Vascular Disease in Children With Human Immunodeficiency Virus in Uganda Is Associated With Intestinal Barrier Dysfunction.

BACKGROUND: The risk of cardiovascular disease (CVD) and its mechanisms in children living with perinatally acquired HIV (PHIV) in sub-Saharan Africa has been understudied. METHODS: Mean common carotid artery intima-media thickness (IMT) and pulse-wave velocity (PWV) were evaluated in 101 PHIV and 96 HIV-negative (HIV-) children. PHIV were on ART, with HIV-1 RNA levels ≤400 copies/mL. We measured plasma and cellular markers of monocyte activation, T-cell activation, oxidized lipids, and gut integrity. RESULTS: Overall median (interquartile range, Q1-Q3) age was 13 (11-15) years and 52% were females. Groups were similar by age, sex, and BMI. Median ART duration was 10 (8-11) years. PHIV had higher waist-hip ratio, triglycerides, and insulin resistance (P ≤ .03). Median IMT was slightly thicker in PHIVs than HIV- children (1.05 vs 1.02 mm for mean IMT and 1.25 vs 1.21 mm for max IMT; P < .05), while PWV did not differ between groups (P = .06). In univariate analyses, lower BMI and oxidized LDL, and higher waist-hip ratio, hsCRP, and zonulin correlated with thicker IMT in PHIV (P ≤ .05). After adjustment for age, BMI, sex, CD4 cell count, triglycerides, and separately adding sCD163, sCD14, and hsCRP, higher levels of intestinal permeability as measured by zonulin remained associated with IMT (ß = 0.03 and 0.02, respectively; P ≤ .03). CONCLUSIONS: Our study shows that African PHIV have evidence of CVD risk and structural vascular changes despite viral suppression. Intestinal intestinal barrier dysfunction may be involved in the pathogenesis of subclinical vascular disease in this population.