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The risk of future coronary heart disease (CHD) in subjects with diabetes and "metabolic dyslipidemia" (high triglyceride [TGs] and low high-density cholesterol levels) remains a matter of concern. Little is known regarding the risk of CHD for this phenotype with low-density lipoprotein cholesterol (LDL-C) levels

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Aims To evaluate the effectiveness of automated symptom and side effect monitoring on quality of life among individuals with symptomatic diabetic peripheral neuropathy. Methods We conducted a pragmatic, cluster randomized controlled trial (July 2014 to July 2016) within a large healthcare system. We randomized 1834 primary care physicians and prospectively recruited from their lists 1270 individuals with neuropathy who were newly prescribed medications for their symptoms. Intervention participants received automated telephone-based symptom and side effect monitoring with physician feedback over 6 months. The control group received usual care plus three non-interactive diabetes educational calls. Our primary outcomes were quality of life (EQ-5D) and select symptoms (e.g. pain) measured 4-8 weeks after starting medication and again 8 months after baseline. Process outcomes included receiving a clinically effective dose and communication between individuals with neuropathy and their primary care provider over 12 months. Interviewers collecting outcome data were blinded to intervention assignment. Results Some 1252 participants completed the baseline measures [mean age (sd): 67 (11.7), 53% female, 57% white, 8% Asian, 13% black, 20% Hispanic]. In total, 1179 participants (93%) completed follow-up (619 control, 560 intervention). Quality of life scores (intervention: 0.658 ± 0.094; control: 0.653 ± 0.092) and symptom severity were similar at baseline. The intervention had no effect on primary [EQ-5D: -0.002 (95% CI -0.01, 0.01), P = 0.623; pain: 0.295 (-0.75, 1.34), P = 0.579; sleep disruption: 0.342 (-0.18, 0.86), P = 0.196; lower extremity functioning: -0.079 (-1.27, 1.11), P = 0.896; depression: -0.462 (-1.24, 0.32); P = 0.247] or process outcomes. Conclusions Automated telephone monitoring and feedback alone were not effective at improving quality of life or symptoms for people with symptomatic diabetic peripheral neuropathy. Trial registration ClinicalTrials.gov (NCT02056431).

The Pan American Health Organization (PAHO)-World Hypertension League (WHL) Hypertension Monitoring and Evaluation Framework is summarized. Standardized indicators are provided for monitoring and evaluating national or subnational hypertension control programs. Five core indicators from the World Health Organization hearts initiative and a single PAHO-WHL core indicator are recommended to be used in all hypertension control programs. In addition, hypertension control programs are encouraged to select from 14 optional qualitative and 33 quantitative indicators to facilitate progress towards enhanced hypertension control. The intention is for hypertension programs to select quantitative indicators based on the current surveillance mechanisms that are available and what is feasible and to use the framework process indicators as a guide to program management. Programs may wish to increase or refine the number of indicators they use over time. With adaption the indicators can also be implemented at a community or clinic level. The standardized indicators are being pilot tested in Cuba, Colombia, Chile, and Barbados.

This cohort study of US women participating in the Nurses’ Health Study II prospectively evaluates the association of a history of gestational diabetes with incident cardiovascular risk.

Optimal cardiovascular risk factors control among individuals with diabetes remains a challenge. We evaluated changes in glucose, lipid, and blood pressure control among diabetes patients after implementation of a large-scale population management program, known as Preventing Heart Attacks and Strokes Everyday, at Kaiser Permanente Northern California (KPNC), during 2004-2013.We used National Committee for Quality Assurance Healthcare Effectiveness Data and Information Set cut points to identify prevalence of poor glycemic (hemoglobin A1c 9%) control, good lipid control (low-density lipoprotein cholesterol 100 mg/dL), and good blood pressure control (blood pressure 140/90 mm Hg) in each year (N range = 98,345 to 122,177 over the entire period). We assessed trends in risk factor control based on Joinpoint regression and average annual percentage change (AAPC) compared with published National Committee for Quality Assurance Healthcare Effectiveness Data and Information Set commercial rates.We found that the prevalence of poor glycemic control (hemoglobin A1c 9%) declined in both KPNC and nationally, but was statistically significant only in KPNC (AAPC = -4.8; P .05). The prevalence of good lipid control (low-density lipoprotein cholesterol 100 mg/dL) increased significantly in KPNC (47% to 71%; AAPC = +4.3; P .05), but there was no significant improvement nationally (40% to 44%; AAPC = +1.4; P = .2). The prevalence of blood pressure control (140/90 mm Hg) was higher in KPNC (77% to 82%; AAPC = +1.1; P .05) versus nationally (57% to 62%; AAPC = +1.9; P .05) during the reported years 2007-2013.Relative to national benchmarks, a substantially greater improvement in risk factor control among adults with diabetes was observed after implementation of a comprehensive population management program.

Background The long-term downward national U.S. trend in heart disease-related mortality slowed substantially during 2011–2014 before turning upward in 2015. Examining mortality trends in the major subgroups of heart disease may provide insight into potentially more targeted and effective prevention and treatment approaches to promote favorable trajectories. We examined national trends between 2000 and 2015 in mortality attributed to major heart disease subgroups including ischemic heart disease, heart failure, and all other types of heart disease. Methods Using the Centers for Disease Control and Prevention Wide-ranging Online Data for Epidemiologic Research (WONDER) data system, we determined national trends in age-standardized mortality rates attributed to ischemic heart disease, heart failure, and other heart diseases from January 1, 2000, to December 31, 2011, and from January 1, 2011, to December 31, 2015. Annual rate of changes in mortality attributed to ischemic heart disease, heart failure, and other heart diseases for 2000–2011 and 2011–2015 were compared. Results Death attributed to ischemic heart disease declined from 2000 to 2015, but the rate of decline slowed from 4.96% (95% confidence interval 4.77%–5.15%) for 2000–2011 to 2.66% (2.00%–3.31%) for 2011–2015. In contrast, death attributed to heart failure and all other causes of heart disease declined from 2000 to 2011 at annual rates of 1.94% (1.77%–2.11%) and 0.64% (0.44%–0.82%) respectively, but increased from 2011 to 2015 at annual rates of 3.73% (3.21% 4.26%) and 1.89% (1.33–2.46%). Differences in 2000–2011 and 2011–2015 decline rates were statistically significant for all 3 endpoints overall, by sex, and all race/ethnicity groups except Asian/Pacific Islanders (heart failure only significant) and American Indian/Alaskan Natives. Conclusions While the long-term decline in death attributed to heart disease slowed between 2011 and 2014 nationally before turning upward in 2015, heterogeneity existed in the trajectories attributed to heart disease subgroups, with ischemic heart disease mortality continuing to decline while death attributed to heart failure and other heart diseases switched from a downward to upward trend. While systematic efforts to prevent and treat ischemic heart disease continue to be effective, urgent attention is needed to address the challenge of heart failure.

The ability to reliably evaluate the impact of interventions and changes in hypertension prevalence and control is critical if the burden of hypertension-related disease is to be reduced. Previously, a World Hypertension League Expert Committee made recommendations to standardize the reporting of population blood pressure surveys. We have added to those recommendations and also provide modified recommendations from a Pan American Health Organization expert meeting for "performance indicators" to be used to evaluate clinical practices. Core indicators for population surveys are recommended to include: (1) mean systolic blood pressure and (2) mean diastolic blood pressure, and the prevalences of: (3) hypertension, (4) awareness of hypertension, (5) drug-treated hypertension, and (6) drug-treated and controlled hypertension. Core indicators for clinical registries are recommended to include: (1) the prevalence of diagnosed hypertension and (2) the ratio of diagnosed hypertension to that expected by population surveys, and the prevalences of: (3) controlled hypertension, (4) lack of blood pressure measurement within a year in people diagnosed with hypertension, and (5) missed visits by people with hypertension. Definitions and additional indicators are provided. Widespread adoption of standardized population and clinical hypertension performance indicators could represent a major step forward in the effort to control hypertension.

The purpose of this study was to explore communication barriers as independent predictors and potential mediators of variation in clinical recognition of diabetic peripheral neuropathy (DPN). In this cross-sectional analysis, we estimated the likelihood of having a DPN diagnosis among 4,436 patients with DPN symptoms. We controlled for symptom frequency, demographic and clinical characteristics, and visit frequency using a modified Poisson regression model. We then evaluated 4 communication barriers as independent predictors of clinical documentation and as possible mediators of racial/ethnic differences: difficulty speaking English, not talking to one's doctor about pain, limited health literacy, and reports of suboptimal patient-provider communication. Difficulty speaking English and not talking with one's doctor about pain were independently associated with not having a diagnosis, though limited health literacy and suboptimal patient-provider communication were not. Limited English proficiency partially attenuated, but did not fully explain, racial/ethnic differences in clinical documentation among Chinese, Latino, and Filipino patients. Providers should be encouraged to talk with their patients about DPN symptoms, and health systems should consider enhancing strategies to improve timely clinical recognition of DPN among patients who have difficult speaking English. More work is needed to understand persistent racial/ethnic differences in diagnosis.

Objectives Heart disease and stroke remain among the leading causes of death nationally. We examined whether differences in recent trends in heart disease, stroke, and total mortality exist in the United States and Kaiser Permanente Northern California (KPNC), a large integrated healthcare delivery system. Methods The main outcome measures were comparisons of US and KPNC total, age-specific, and sex-specific changes from 2000 to 2015 in mortality rates from heart disease, coronary heart disease, stroke, and all causes. The Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research data system was used to determine US mortality rates. Mortality rates for KPNC were determined from health system, Social Security vital status, and state death certificate databases. Results Declines in age-adjusted mortality rates were noted in KPNC and the United States for heart disease (36.3% in KPNC vs 34.6% in the United States), coronary heart disease (51.0% vs 47.9%), stroke (45.5% vs 38.2%), and all-cause mortality (16.8% vs 15.6%). However, steeper declines were noted in KPNC than the United States among those aged 45 to 65 years for heart disease (48.3% KPNC vs 23.6% United States), coronary heart disease (55.6% vs 35.9%), stroke (55.8% vs 26.0%), and all-cause mortality (31.5% vs 9.1%). Sex-specific changes were generally similar. Conclusions Despite significant declines in heart disease and stroke mortality, there remains an improvement gap nationally among those aged less than 65 years when compared with a large integrated healthcare delivery system. Interventions to improve cardiovascular mortality in the vulnerable middle-aged population may play a key role in closing this gap.

Introduction Racial/ethnic differences in diabetes and cardiovascular disease are well documented, but disease estimates are often confounded by differences in access to quality health care. The objective of this study was to evaluate the ethnic differences in risk of future coronary heart disease in patient populations stratified by status of diabetes mellitus and prior coronary heart disease among those with uniform access to care in an integrated healthcare delivery system in Northern California. Methods A cohort was constructed consisting of 1,344,899 members with self-reported race/ethnicity, aged 30–90 years, and followed from 2002 through 2012. Cox proportional hazard regression models were specified to estimate race/ethnicity-specific hazard ratios for coronary heart disease (with whites as the reference category) separately in four clinical risk categories: (1) no diabetes with no prior coronary heart disease; (2) no diabetes with prior coronary heart disease; (3) diabetes with no prior coronary heart disease; and (4) diabetes with prior coronary heart disease. Analyses were performed in 2015. Results The median follow-up was 10 years (10,980,800 person-years). Compared with whites, blacks, Latinos, and Asians generally had lower risk of coronary heart disease across all clinical risk categories, with the exception of blacks with prior coronary heart disease and no diabetes having higher risk than whites. Findings were not substantively altered after multivariate adjustments. Conclusions Identification of health outcomes in a system with uniform access to care reveals residual racial/ethnic differences and point to opportunities to improve health in specific subgroups and to improve health equity.

For more than a decade, the presence of diabetes has been considered a coronary heart disease (CHD) "risk equivalent".The objective of this study was to revisit the concept of risk equivalence by comparing the risk of subsequent CHD events among individuals with or without history of diabetes or CHD in a large contemporary real-world cohort over a period of 10 years (2002 to 2011).Population-based prospective cohort analysis.We studied a cohort of 1,586,061 adult members (ages 30-90 years) of Kaiser Permanente Northern California, an integrated health care delivery system.We calculated hazard ratios (HRs) from Cox proportional hazard models for CHD among four fixed cohorts, defined by prevalent (baseline) risk group: no history of diabetes or CHD (None), prior CHD alone (CHD), diabetes alone (DM), and diabetes and prior CHD (DM + CHD).We observed 80,012 new CHD events over the follow-up period (~10,980,800 person-years). After multivariable adjustment, the HRs (reference: None) for new CHD events were as follows: CHD alone, 2.8 (95% CI, 2.7-2.85); DM alone 1.7 (95% CI, 1.66-1.74); DM + CHD, 3.9 (95% CI, 3.8-4.0). Individuals with diabetes alone had significantly lower risk of CHD across all age and sex strata compared to those with CHD alone (12.2 versus 22.5 per 1000 person-years). The risk of future CHD for patients with a history of either DM or CHD was similar only among those with diabetes of long duration (≥10 years).Not all individuals with diabetes should be unconditionally assumed to be a risk equivalent of those with prior CHD.

Background: The accuracy of the 2013 American College of Cardiology/American Heart Association (ACC/AHA) Pooled Cohort Risk Equation for atherosclerotic cardiovascular disease (ASCVD) events across different levels of obesity is not known. Methods: The target population for consideration of primary

Importance Heart disease (HD) and cancer are the 2 leading causes of death in the United States. During the first decade of the 21st century, HD mortality declined at a much greater rate than cancer mortality and it appeared that cancer would overtake HD as the leading cause of death. Objectives To determine whether changes in national trends had occurred in recent years in mortality rates due to all cardiovascular disease (CVD), HD, stroke, and cancer and to evaluate the gap between mortality rates from HD and cancer. Design, Setting, and Participants The Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research data system was used to determine national trends in age-adjusted mortality rates due to all CVD, HD, stroke, and cancer from January 1, 2000, to December 31, 2011, and January 1, 2011, to December 31, 2014, overall, by sex, and by race/ethnicity. The present study was conducted from December 30, 2105, to January 18, 2016. Main Outcomes and Measures Comparison of annual rates of change and trend in gap between HD and cancer mortality rates. Results The rate of the decline in all CVD, HD, and stroke mortality decelerated substantially after 2011, and the rate of decline for cancer mortality remained relatively stable. Reported as percentage (95% CI), the annual rates of decline for 2000-2011 were 3.79% (3.61% to 3.97%), 3.69% (3.51% to 3.87%), 4.53% (4.34% to 4.72%), and 1.49% (1.37% to 1.60%) for all CVD, HD, stroke, and cancer mortality, respectively; the rates for 2011-2014 were 0.65% (−0.18% to 1.47%), 0.76% (−0.06% to 1.58%), 0.37% (−0.53% to 1.27%), and 1.55% (1.07% to 2.04%), respectively. Deceleration of the decline in all CVD mortality rates occurred in males, females, and all race/ethnicity groups. For example, the annual rates of decline for total CVD mortality for 2000-2011 were 3.69% (3.48% to 3.89%) for males and 3.98% (3.81% to 4.14%) for females; for 2011-2014, the rates were 0.23% (−0.71% to 1.16%) and 1.17% (0.41% to 1.93%), respectively. The gap between HD and cancer mortality persisted. Conclusions and Relevance Deceleration in the decline of all CVD, HD, and stroke mortality rates has occurred since 2011. If this trend continues, strategic goals for lowering the burden of CVD set by the American Heart Association and the Million Hearts Initiative may not be reached.

The smaller form of the GABA-synthesizing enzyme glutamic acid decarboxylase (GAD65) is a major autoantigen in two human diseases that affect its principal sites of expression. Thus, destruction of pancreatic beta cells, which results in insulin-dependent diabetes mellitus (IDDM), and impairment of GABA-ergic synaptic transmission in Stiff-Man syndrome (SMS) are both characterized by circulating autoantibodies to GAD65. Anti-GAD65 autoantibodies in IDDM are predominantly directed to conformational epitopes. Here we report the characterization of humoral autoimmune responses to GAD65 in 35 SMS patients, of whom 13 (37%) also had IDDM. All SMS patients immunoprecipitated native GAD65 and the main titers were orders of magnitude higher than in IDDM patients. Furthermore, in contrast to the situation in IDDM, autoantibodies in 35 of 35 (100%) of SMS patients recognized denatured GAD65 on Western blots. Two major patterns of epitope specificity were identified on Western blots. The first pattern, detected in 25 of 35 SMS patients (71%), of whom 11 had IDDM (44%), was predominantly reactive with a linear NH2-terminal epitope residing in the first eight amino acids of GAD65. Nine of nine individuals who were HLA-haplotyped in this group carried an IDDM susceptibility haplotype and HLA-DR3, DQw2 was particularly abundant. The second pattern, detected in 10 of 35 patients (29%) of whom two had IDDM (20%), included reactivity with the NH2-terminal epitope plus strong reactivity with one or more additional epitope(s) residing COOH-terminal to amino acid 101. The second epitope pattern may represent epitope spreading in the GAD65 molecule, but may also include some cases of epitope recognition associated with IDDM resistant HLA-haplotypes. The principal NH2-terminal linear epitope in GAD65 distinguishes the reactivity of SMS and IDDM autoantibodies and may be a determinant of pathogenicity for GABA-ergic neurons. The greater magnitude and distinct specificity of the humoral response to GAD65 in SMS may reflect a biased involvement of the T helper cell type 2 (Th2) subset of CD4+ T cells and antibody responses, whereas IDDM is likely mediated by the Th1 subset of CD4+ T cells and cytotoxic T cell responses.

Following a symposium on hypertension sponsored by the National Heart, Lung, and Blood Institute in San Francisco in April, 2000, a panel was convened to discuss the management of high-risk hypertensive patients with comorbid diseases. The roundtable consisted of Nancy Houston Miller of Stanford University School of Medicine; Dr. Marc Jaffe of the Kaiser Permanente Medical Group of Northern California; and Dr. Ray Gifford, Jr., Emeritus Chief of Hypertension and Nephrology at the Cleveland Clinic. The panel was chaired by Dr. Marvin Moser of the Yale University School of Medicine.

Small studies have been published on the effect of hypertension programs on blood pressure (BP) control, but few studies have reported the efficacy of a large-scale hypertension programs. Kaiser Foundation Health Plan of Northern California is a not-for-profit integrated health care delivery system with a membership of over 2.3 million adult members. In 2001, the Kaiser Permanente Northern California Hypertension Project was developed as an evidence-based program to increase BP control for members with hypertension. We previously reported our experience from 2001 to 2009, and in this report we describe the results from 2009 to 2012. In 2001, the Kaiser Permanente Northern California Hypertension Project was established. A registry of patients with hypertension was created to identify at-risk patients. Physician level and Medical Center level metrics were established to measure performance over time. An evidence based clinical practice guideline was developed, disseminated, reviewed and updated every 2 years. Clinicians were systematically educated on the guidelines and updated on their individual and group hypertension control performance measurements. Infrastructure was established including the creation of medical assistant BP checks and promotion of single pill combination medical therapy with angiotensin-converting enzyme inhibitor (ACEI) and hydrochlorothiazide (HCTZ). Medical centers that

Importance The US federal government is spending billions of dollars in physician incentives to encourage the meaningful use of electronic health records (EHRs). Although the use of EHRs has potential to improve patient health outcomes, the existing evidence has been limited and inconsistent. Objective To examine the association between implementing a commercially available outpatient EHR and emergency department (ED) visits, hospitalizations, and office visits for patients with diabetes mellitus. Design, Setting, and Population Staggered EHR implementation across outpatient clinics in an integrated delivery system (Kaiser Permanente Northern California) between 2005 and 2008 created an opportunity for studying changes associated with EHR use. Among a population-based sample of 169 711 patients with diabetes between 2004 and 2009, we analyzed 4 997 585 person-months before EHR implementation and 4 648 572 person-months after an EHR was being used by patients’ physicians. Main Outcomes and Measures We examined the association between EHR use and unfavorable clinical events (ED visits and hospitalizations) and office visit use among patients with diabetes, using multivariable regression with patient-level fixed-effect analyses and adjustment for trends over time. Results In multivariable analyses, use of the EHR was associated with a statistically significantly decreased number of ED visits, 28.80 fewer visits per 1000 patients annually (95% CI, 20.28 to 37.32), from a mean of 519.12 visits per 1000 patients annually without using the EHR to 490.32 per 1000 patients when using the EHR. The EHR was also associated with 13.10 fewer hospitalizations per 1000 patients annually (95% CI, 7.37 to 18.82), from a mean of 251.60 hospitalizations per 1000 patients annually with no EHR to 238.50 per 1000 patients annually when using the EHR. There were similar statistically significant reductions in nonelective hospitalizations (10.92 fewer per 1000 patients annually) and hospitalizations for ambulatory care–sensitive conditions (7.08 fewer per 1000 patients annually). There was no statistically significant association between EHR use and office visit rates. Conclusions and Relevance Among patients with diabetes, use of an outpatient EHR in an integrated delivery system was associated with modest reductions in ED visits and hospitalizations but not office visit rates. Further studies are needed to quantify the association of EHR use with changes in costs.

Hypertension control for large populations remains a major challenge.To describe a large-scale hypertension program in Northern California and to compare rates of hypertension control in that program with statewide and national estimates.The Kaiser Permanente Northern California (KPNC) hypertension program included a multifaceted approach to blood pressure control. Patients identified as having hypertension within an integrated health care delivery system in Northern California from 2001-2009 were included. The comparison group comprised insured patients in California between 2006-2009 who were included in the Healthcare Effectiveness Data and Information Set (HEDIS) commercial measurement by California health insurance plans participating in the National Committee for Quality Assurance (NCQA) quality measure reporting process. A secondary comparison group was included to obtain the reported national mean NCQA HEDIS commercial rates of hypertension control between 2001-2009 from health plans that participated in the NCQA HEDIS quality measure reporting process.Hypertension control as defined by NCQA HEDIS.The KPNC hypertension registry included 349,937 patients when established in 2001 and increased to 652,763 by 2009. The NCQA HEDIS commercial measurement for hypertension control within KPNC increased from 43.6% (95% CI, 39.4%-48.6%) to 80.4% (95% CI, 75.6%-84.4%) during the study period (P .001 for trend). In contrast, the national mean NCQA HEDIS commercial measurement increased from 55.4% to 64.1%. California mean NCQA HEDIS commercial rates of hypertension were similar to those reported nationally from 2006-2009 (63.4% to 69.4%).Among adults diagnosed with hypertension, implementation of a large-scale hypertension program was associated with a significant increase in hypertension control compared with state and national control rates. Key elements of the program included a comprehensive hypertension registry, development and sharing of performance metrics, evidence-based guidelines, medical assistant visits for blood pressure measurement, and single-pill combination pharmacotherapy.

Physicians can receive federal payments for meaningful use of complete certified electronic health records (EHRs). Evidence is limited on how EHR use affects clinical care and outcomes.To examine the association between use of a commercially available certified EHR and clinical care processes and disease control in patients with diabetes.Quasi-experimental design with outpatient EHR implementation sequentially across 17 medical centers. Multivariate analyses adjusted for patient characteristics, medical center, time trends, and facility-level clustering.Kaiser Permanente Northern California, an integrated delivery system.169 711 patients with diabetes mellitus.Use of a commercially available certified EHR.Drug treatment intensification and hemoglobin A(1c) (HbA(1c)) and low-density lipoprotein cholesterol (LDL-C) testing and values.Use of an EHR was associated with statistically significant improvements in treatment intensification after HbA(1c) values of 9% or greater (odds ratio, 1.10 [95% CI, 1.05 to 1.15]) or LDL-C values of 2.6 to 3.3 mmol/L (100 to 129 mg/dL) (odds ratio, 1.06 [CI, 1.00 to 1.12]); increases in 1-year retesting for HbA(1c) and LDL-C levels among all patients, with the most dramatic change among patients with the worst disease control (HbA(1c) levels ≥9% or LDL-C levels ≥3.4 mmol/L [≥130 mg/dL]); and decreased 90-day retesting among patients with HbA(1c) levels less than 7% or LDL-C levels less than 2.6 mmol/L (100 mg/dL). The EHR was also associated with statistically significant reductions in HbA(1c) and LDL-C levels, with the largest reductions among patients with the worst control (0.06-mmol/L [2.19-mg/dL] reduction among patients with baseline LDL-C levels ≥3.4 mmol/L [≥130 mg/dL]; P0.001).The EHR was implemented in a setting with strong baseline performance on cardiovascular care quality measures.Use of a commercially available certified EHR was associated with improved drug treatment intensification, monitoring, and physiologic control among patients with diabetes, with greater improvements among patients with worse control and less testing in patients already meeting guideline-recommended glycemic and lipid targets.National Institute of Diabetes and Digestive and Kidney Diseases.

Background Blood pressure, lipid, and glycemic control are essential for reducing cardiovascular disease (CVD) risk. Many health care systems have successfully shifted aspects of chronic disease management, including population-based outreach programs designed to address CVD risk factor control, to non-physicians. The purpose of this study is to evaluate provision of new information to non-physician outreach teams on need for treatment intensification in patients with increased CVD risk. Methods Cluster randomized trial (July 1-December 31, 2008) in Kaiser Permanente Northern California registry of members with diabetes mellitus, prior CVD diagnoses and/or chronic kidney disease who were high-priority for treatment intensification: blood pressure ≥ 140 mmHg systolic, LDL-cholesterol ≥ 130 mg/dl, or hemoglobin A1c ≥ 9%; adherent to current medications; no recent treatment intensification). Randomization units were medical center-based outreach teams (4 intervention; 4 control). For intervention teams, priority flags for intensification were added monthly to the registry database with recommended next pharmacotherapeutic steps for each eligible patient. Control teams used the same database without this information. Outcomes included 3-month rates of treatment intensification and risk factor levels during follow-up. Results Baseline risk factor control rates were high (82-90%). In eligible patients, the intervention was associated with significantly greater 3-month intensification rates for blood pressure (34.1 vs. 30.6%) and LDL-cholesterol (28.0 vs 22.7%), but not A1c. No effects on risk factors were observed at 3 months or 12 months follow-up. Intervention teams initiated outreach for only 45-47% of high-priority patients, but also for 27-30% of lower-priority patients. Teams reported difficulties adapting prior outreach strategies to incorporate the new information. Conclusions Information enhancement did not improve risk factor control compared to existing outreach strategies at control centers. Familiarity with prior, relatively successful strategies likely reduced uptake of the innovation and its potential for success at intervention centers. Trial registration ClinicalTrials.gov Identifier NCT00517686

A major question regarding the autoimmune destruction of pancreatic @-cells is the nature of the primary autoantigen. The definition of such an antigen includes that it elicits 0cell destruction. If that destruction is mediated by CD8 + cytotoxic T-cells then this antigen would be the initial target. If p-cells are indirectly destroyed following homing of CD4’ T-cells to the islets of Langerhans, then the primary antigen can be defined as the initiating antigen or a protein crossreacting with the initiating antigen, which can be from a virus. Those criteria again include that the primary antigen is &cell specific, since other tissues are not destroyed, or that the protein is only visible or accessible to the immune system in the &cells, i.e. if it is expressed in other tissues then it is invisible to or protected from the immune system. If tolerance is absent or lost toward the primary antigen, autoimmunity and destruction can result. We know however from transgenic models of @cell autoimmunity that even in the absence of tolerance to a 0-cell antigen there can be absence of autoimmunity and destruction until a triggering event such as an infection with a virus containing the same or a crossreacting antigen (1,2). If active tolerance to the primary autoantigen is maintained there should be no autoimmunity and no disease. The smaller form of the enzyme glutamic acid decarbosylase, GAD,,, as well as a 38kD 0-cell protein are two potential primary autoantigens in type 1 diabetes. Both proteins have been identified using circulating islet cell autoantibodies in type 1 diabetic sera to probe extracts of islet cell proteins. This approach reveals whether candidate autoantibodies are of sufficient affinity and specificity to bind their target antigen and form immuno complexes in the presence of an excess of other islet cell proteins. Both GAD65 and 38kD antibodies are IgG antibodies and both are present at the very early stages of &cell destruction. GADss was first detected as a protein which was immunoprecipitated by IgG antibodies in about 80% of newly diagnosed type 1 diabetic patients but not present in healthy individuals (3). This molecule defined as a 64kD protein doublet (a and 0) with an isoelectric point of 6.7 (4) was identified as GAD,, (5,6). A second molecule of Mr 65kD, which coprecipitated with the 64kD antigen in cytosol but not membrane fractions of rat islets was identified as the larger form of glutamic acid decarboxylase, GAD67 (5,6). GAD,, and GAD,, are encoded for by two non-allelic genes that may have developed from a common ancestral gene. GAD,, and GAD,, are highly diverse in the first 95 amino acids but share an extensive homology in the remainder of the molecule (7). GAD,, is clearly a dominant autoantigen in type 1 diabetes whereas GAD,, seems to play only a secondary role. The 38kD protein was first sporadically detected in immunoprecipitates with type 1 diabetic sera in rare preparations of human and rat islet cell proteins. Recently however an improved extraction method has resulted in consistant detection of the 38kD antigen in immunoprecipitates from all islet cell preparations with a subgroup of diabetic sera (8).

The value of a test for islet cell cytoplasmic antibodies together with a test for GAD65 antibodies to predict the subsequent development of diabetes over a period of 11.5 years was assessed in an open childhood population comprising 2,805 individuals. A single serum sample was obtained from each individual between 1975 and 1977 and screened for islet cell cytoplasmic antibodies for which eight individuals were positive (0.29%). During the average follow-up period of 11.5 years, four of eight islet cell antibody positive and three islet cell antibody negative individuals developed clinical diabetes. Sera from all individuals, who were islet cell antibody positive and/ or developed diabetes (total of 11) and from 100 randomly selected control subjects were analysed for GAD65 antibodies. Six of eight islet cell antibody positive individuals were GAD65 antibody positive including all four who subsequently developed IDDM. Furthermore, one of the three islet cell antibody negative individuals who developed IDDM was GAD65 antibody positive both in 1976 and in 1989. Thus, a positive test for GAD65 antibodies alone correctly predicted diabetes in five of seven children, who developed the disease. Only one of the children, who developed diabetes was positive for insulin autoantibodies and this individual was also positive for islet cell cytoplasmic antibodies and GAD65 antibodies. One of the 100 control subjects was positive for GAD65 antibodies (1%). The results suggest that a single GAD65 antibody test may have a higher sensitivity for predicting IDDM than a test for islet cell cytoplasmic antibodies, but that a combined positive test for both antibodies increases the specificity for predicting IDDM over a period of 11.5 years.