John G. Ryan

Sample Design and Cohort Selection in the Hispanic Community Health Study/Study of Latinos

PURPOSE The Hispanic Community Health Study (HCHS)/Study of Latinos (SOL) is a multicenter, community-based cohort study of Hispanic/Latino adults in the United States. A diverse participant sample is required that is both representative of the target population and likely to remain engaged throughout follow-up. The choice of sample design, its rationale, and benefits and challenges of design decisions are described in this study. METHODS The study design calls for recruitment and follow-up of a cohort of 16,000 Hispanics/Latinos 18-74 years of age, with 62.5% (10,000) over 44 years of age and adequate subgroup sample sizes to support inference by Hispanic/Latino background. Participants are recruited in community areas surrounding four field centers in the Bronx, Chicago, Miami, and San Diego. A two-stage area probability sample of households is selected with stratification and oversampling incorporated at each stage to provide a broadly diverse sample, offer efficiencies in field operations, and ensure that the target age distribution is obtained. CONCLUSIONS Embedding probability sampling within this traditional, multisite cohort study design enables competing research objectives to be met. However, the use of probability sampling requires developing solutions to some unique challenges in both sample selection and recruitment, as described here.

Aging Down-Regulates the Transcription Factor E2A, Activation-Induced Cytidine Deaminase, and Ig Class Switch in Human B Cells

Elderly humans have compromised humoral and cellular immune responses, which lead to reduced protection to infectious agents and to vaccines. Currently, available vaccines suboptimally protect the elderly population. The capacity to class switch the Ig H chain is critical to the effectiveness of humoral immune responses in mice and humans. We have previously shown in mice that the E2A-encoded transcription factor E47, which regulates many B cell functions, is down-regulated in old splenic B cells. This leads to a reduction in the activation-induced cytidine deaminase (AID), which is known to induce class switch recombination and Ig somatic hypermutation. The old activated murine B cells also have less AID and less switched Abs. We have extended our study here to investigate whether aging also affects Ab production and E47 and AID expression in B cells isolated from the peripheral blood of human subjects (18–86 years). Our results obtained with activated CD19+ B cells show that the expression of E47, AID, and Igγ1 circle transcripts progressively decrease with age. We also show an age-related decline in the percentage of switch memory B cells (IgG+/IgA+), an increase in that of naive B cells (IgG−/IgA−/CD27−) for most individuals, and no decrease in that of IgM memory cells in peripheral blood, consistent with our data on the decrease seen in class switch recombination in vitro. Our results provide a possible molecular mechanism for a B cell intrinsic defect in the humoral immune response with aging and suggest avenues for improvement of vaccine response in elderly humans.

Intrinsic defects in B cell response to seasonal influenza vaccination in elderly humans.

We have evaluated the serum response to seasonal influenza vaccination in subjects of different ages and associated this with the specific B cell response to the vaccine in vitro. Although the serum response has previously been shown to decrease with age, this has largely been associated to decreased T cell functions. Our results show that in response to the vaccine, the specific response of B cells in vitro, as measured by AID (activation-induced cytidine deaminase), the in vivo serum HI (hemagglutination inhibition) response, and the in vivo generation of switch memory B cells are decreased with age, as evaluated in the same subjects. This is the first report to demonstrate that intrinsic B cell defects with age contribute to reduced antibody responses to the influenza vaccine. The level of AID in response to CpG before vaccination can also predict the robustness of the vaccine response. These results could contribute to developing more effective vaccines to protect the elderly as well as identifying those most at risk.

Cost and Policy Implications From the Increasing Prevalence of Obesity and Diabetes Mellitus

BACKGROUND The increasing prevalence of obesity and type 2 diabetes mellitus (DM), among children and adults, has posed important policy and budgetary considerations to government, health insurance companies, employers, physicians, and health care delivery systems. OBJECTIVE This article examines issues that are common to obesity and DM, including cost, clinical research, and treatment barriers, and proposes health policies to address these issues. METHOD A manual review was performed of authoritative literature from peer-reviewed medical publications and recently published medical textbooks. RESULTS Obesity has been disproportionately prevalent among women and minorities, accompanied by an increased risk for DM. Women have experienced an increased risk for the metabolic syndrome, DM, and cardiovascular disease after onset of menopause. Obesity has been related to an increased risk for breast cancer among women, and may be a barrier that prevents women from being screened for colon and breast cancers. Maternal obesity has been a risk factor for gestational DM. CONCLUSIONS Obesity and DM represent crises for the health care system and the health of the public, incurring costs and disease burden for adults and children, with increasing costs and prevalence expected unless more coordinated efforts to address the causes of these conditions at the national level are implemented. An investment in infrastructure to promote increased physical activity and reward weight management may be budget neutral in the long term by reducing the costs of morbidity and mortality. About two thirds of the costs from DM complications could be averted with appropriate primary care.

Erectile dysfunction and its association with metabolic syndrome and endothelial function among patients with type 2 diabetes mellitus

CONTEXT Evidence suggests that numerous comorbid conditions contribute to erectile dysfunction (ED) among patients with type 2 diabetes mellitus (T2DM). OBJECTIVE To review the relationship and mechanism between diabetes, metabolic syndrome, cardiovascular disease (CVD), and ED. METHODS A manual review of authoritative literature from peer-reviewed publications from January 2001 through July 2010 was performed. These publications were further mined to consider the impact of metabolic syndrome as a comorbid condition. Publications from key references were also consulted. RESULTS The associations between obesity, dyslipidemia, metabolic syndrome, T2DM, CVD, and depression with sexual dysfunction suggest that sexual dysfunction, particularly ED, is a precursor to CVD. Because these conditions share important risk factors with CVD, identifying them and their relationships with the pathogenesis of ED is likely to be critical to the manner in which primary care physicians screen for and manage this condition. CONCLUSIONS Primary care physicians ought to establish trusting relationships with their patients, providing opportunities for them to probe such sensitive issues as sexual activities, as a means of addressing the possibility of ED. When making the new diagnosis of sexual dysfunction in the absence of metabolic disease or CVD, physicians ought to consider the risk for T2DM and CVD. Associations between metabolic disease, heart disease, and sexual dysfunction further suggest that all patients who are obese and have dyslipidemia, T2DM, and/or depression should be further screened for ED.

Young and elderly patients with type 2 diabetes have optimal B cell responses to the seasonal influenza vaccine

We evaluated immune response to the seasonal influenza vaccine in young and elderly patients with type 2 diabetes (T2D). Immune measures included the in vivo serum response to the vaccine by hemagglutination inhibition (HAI) and ELISA in 22 patients (14 young, 8 elderly) and 65 healthy age-matched controls (37 young, 28 elderly). B cell-specific biomarkers of optimal vaccine response were measured ex vivo by switched memory B cells and plasmablasts and in vitro by activation-induced cytidine deaminase (AID) in stimulated cells. Markers of systemic and B cell-intrinsic inflammation were also measured. Results show that in vivo responses, as well as B cell-specific markers identified above, decrease by age in healthy individuals but not in T2D patients. This occurred despite high levels of B cell-intrinsic inflammation (TNF-α) in T2D patients, which was surprising as we had previously demonstrated this negatively impacts B cell function. These results altogether suggest that valid protection against influenza can be achieved in T2D patients and proposed mechanisms are discussed.

Short and Long-Term Outcomes from a Multisession Diabetes Education Program Targeting Low-Income Minority Patients: A Six-Month Follow Up

BACKGROUND A diabetes self-management education (DSME) program was offered to patients at a primary care clinic serving low-income people. OBJECTIVES The purpose of the analyses presented here was to understand the feasibility of the program and effectiveness of the intervention. METHODS The program was facilitated by a nurse and licensed dietician. Data were collected at baseline, after each class, and after 6 months. Patients were interviewed to identify diabetes self-care behaviors before the first class, after the fourth class, and at 6 months. Knowledge related to content areas was measured before and after each class. Glycosylated hemoglobin (HbA(1c)), blood pressure, weight, and body mass index (BMI) were collected at baseline and after 6 months. Medical records were reviewed for LDL levels, co-morbidity, and diabetes management. Frequencies, χ(2) and t tests, and repeated measures t tests were used to analyze data. RESULTS Patients were mostly non-Hispanic black or Hispanic (93.1%); mean BMI was 34.89 kg/m(2). About one-half (41.95%) completed the program. Significant improvements were observed for knowledge related to each of the 4 content areas: diet (P < 0.001), diabetes management (P = 0.003), monitoring blood glucose (P < 0.001), and preventing complications (P = 0.001). Among long-term outcomes, mean HbA(1c) was significantly reduced (0.82%), from 8.60% to 7.78% (P = 0.007), with 26.67% of patients reducing HbA(1c) from ≥7.0% at baseline to <7% at follow up (P < 0.001). Patients demonstrated a significant improvement in readiness to improve dietary behaviors (P = 0.016). CONCLUSIONS Outcomes suggested that minority patients with a high risk for poor diabetes outcomes might be retained in a multisession DSME program and benefit from increasing knowledge of diabetes content. Further evaluation is necessary to determine the cost-effectiveness of this intervention.

Practice-based Research Networks (PBRNs): Meeting the Challenges of the Future

Practice-based research networks (PBRNs) are useful tools for conducting studies in the busy primary care setting, but their continued existence is threatened by a range of challenges. PBRNs must position themselves now to be prepared to face the challenges ahead. For example, experience with the Clinical Translational Science Awards has placed PBRNs at the center of university efforts toward greater community engagement. Networks must use this opportunity to solicit infrastructure support and partner with experienced principal investigators from other disciplines. Successful networks must make greater use of health information technology to solicit clinician involvement, identify and recruit potential subjects, and disseminate key findings. To maintain the active participation of busy clinicians in the clinical research enterprise, networks must find new ways to engage their members and simplify study participation. Networks should pursue clinically relevant projects that create meaning and connect busy practitioners to the larger agenda of primary care research. Finally, collaborating with other networks in a structured and ongoing manner is one way for PBRNs to extend their reach while making maximal use of their unique resources and local expertise.

Feasibility of an Internet-Based Intervention for Improving Diabetes Outcomes Among Low-Income Patients With a High Risk for Poor Diabetes Outcomes Followed in a Community Clinic

Purpose The purpose of this study was to determine the feasibility of an Internet-based intervention, targeting very low-income minority patients with a high risk for not engaging in diabetes self-management, to increase diabetes self-management and improve diabetes outcomes. Methods Patients with diabetes followed in a community clinic were enrolled in the 13-month trial. Participants were requested to test blood sugar and upload glucometer data every day and login to the program at least once every second day. Feasibility data included process measures; diabetes outcomes consisted of changes from baseline to follow-up for levels of glycosylated hemoglobin (A1C), LDL, HDL, triglyceride and total cholesterol, and health-related quality of life using the SF-36. Results Only 22% of participants had health insurance. Participants had an average of 4.39 comorbidities and 7.06 prescriptions. Participants uploaded glucometer data at least twice each week and logged into the application at least once each week. Participants demonstrated reductions statistically or clinically important changes in A1C, LDL cholesterol, total cholesterol, and triglyceride levels. Participants engaging in more frequent chat messages and interactive activities demonstrated greater reductions in LDL cholesterol levels; however, engaging in more frequent chat messages also was associated with increased triglyceride levels. Participants rated fewer role limitations from physical health problems at follow-up. Conclusions The intervention produced good outcomes; however, an alternative platform may be a less expensive approach.

Clinical outcomes and incremental costs from a medication adherence pilot intervention targeting low-income patients with diabetes at risk of cost-related medication nonadherence.

PURPOSE The extent to which reducing cost-related barriers affects diabetes outcomes and medication adherence among uninsured patients is not known. The purpose of these analyses was to understand the clinical impact and cost considerations of a prescription assistance program targeting low-income, minority patients with diabetes and at high risk for cost-related medication nonadherence. METHODS Patients received diabetes medications without copayments for 12 months. Change in diabetes control was calculated by using glycosylated hemoglobin (HbA1c) level at follow-up compared with baseline. Clinical data were collected from the electronic health record. Medication adherence for diabetes medications was estimated by using proportion of days covered (PDC). Incremental acquisition and per-patient costs, based on actual hospital medication costs, were calculated for different baseline HbA1c levels. FINDINGS Patients with baseline HbA1c levels ≥7%, ≥8%, and ≥9% experienced mean HbA1c reductions of 0.82% (P = 0.008), 1.02% (P = 0.010), and 1.47% (P = 0.010), respectively, during the 12-month period. The average PDC was 70.55%; 45.24% had a PDC ≥80%, indicating an adequate level of medication adherence. Medication adherence ≥80% was associated with ethnicity (P = 0.015), whereas mean PDC was associated with number of diabetes medication classes used (P = 0.031). Acquisition cost for 1242 prescriptions filled by 103 patients was