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Introduction: Coronary artery calcification (CAC) score, physical activity (PA), and cardiorespiratory fitness (CRF) are all associated with cardiovascular disease (CVD) risk. While a U-shaped relationship between PA and CRF with CAC has been reported, CAC presence among highly fit individuals was suggested to be benign. Objective: To determine interactive associations of PA/CRF and CAC with outcomes in a cohort of middle-aged adults and to evaluate the relationship of PA/CRF with CAC incidence. Methods: CARDIA participants with CT-assessed CAC at year 20 (2005-06) were included (n=3141, mean age 45y, 57% female, 45% Black). Moderate to vigorous intensity PA (MVPA) was assessed by self-report and accelerometer. CRF was estimated with a treadmill test. Incident CVD events were adjudicated, and mortality data were obtained through 2019. CAC was reassessed at year 25 (2010-11). Cox models assessed hazard ratios (HRs) for CVD and mortality in groups defined by CAC and MVPA/CRF. Logistic models assessed associations with CAC incidence. Results: At baseline, more favorable CVD risk was found among participants with higher MVPA, higher CRF (> median sex-specific duration), and absence of CAC. During a mean follow-up of 13 years, 166 CVD events and 171 deaths occurred. After multivariable adjustment, compared with no CAC and higher CRF (ref), the HRs (95% CIs) for CVD were 5.04 (2.49-10.20) for CAC and higher CRF, 2.26 (1.24-4.12) for no CAC and lower CRF, and 4.27 (2.24-8.14) for CAC and lower CRF (Figure, left panel). The respective HRs for mortality were 1.12 (0.45-2.77), 1.54 (0.91-2.60), and 3.23 (1.82-5.72) (Figure, right panel). Similar findings were observed with self-reported or accelerometer MVPA replacing CRF. Higher CRF and accelerometer MVPA were dose-responsively associated with a lower probability of developing CAC in a 5-year follow-up (P < .01). Conclusions: PA and CRF were inversely associated with CAC incidence in middle-aged adults. CAC presence eliminated the cardiovascular risk advantage of high PA or high CRF.

The substantial expansion of secure messaging (SM) via the patient portal in the last decade suggests that it is becoming a standard of care, but few have examined SM use longitudinally. We examined SM patterns among a diverse cohort of patients with diabetes (N = 19 921) and the providers they exchanged messages with within a large, integrated health system over 10 years (2006-2015), linking patient demographics to SM use. We found a 10-fold increase in messaging volume. There were dramatic increases overall and for patient subgroups, with a majority of patients (including patients with lower income or with self-reported limited health literacy) messaging by 2015. Although more physicians than nurses and other providers messaged throughout the study, the distribution of health professions using SM changed over time. Given this rapid increase in SM, deeper understanding of optimizing the value of patient and provider engagement, while managing workflow and training challenges, is crucial.

Objective To develop novel, scalable, and valid literacy profiles for identifying limited health literacy patients by harnessing natural language processing. Data Source With respect to the linguistic content, we analyzed 283 216 secure messages sent by 6941 diabetes patients to physicians within an integrated system's electronic portal. Sociodemographic, clinical, and utilization data were obtained via questionnaire and electronic health records. Study Design Retrospective study used natural language processing and machine learning to generate five unique “Literacy Profiles” by employing various sets of linguistic indices: Flesch‐Kincaid (LP_FK); basic indices of writing complexity, including lexical diversity (LP_LD) and writing quality (LP_WQ); and advanced indices related to syntactic complexity, lexical sophistication, and diversity, modeled from self‐reported (LP_SR), and expert‐rated (LP_Exp) health literacy. We first determined the performance of each literacy profile relative to self‐reported and expert‐rated health literacy to discriminate between high and low health literacy and then assessed Literacy Profiles’ relationships with known correlates of health literacy, such as patient sociodemographics and a range of health‐related outcomes, including ratings of physician communication, medication adherence, diabetes control, comorbidities, and utilization. Principal Findings LP_SR and LP_Exp performed best in discriminating between high and low self‐reported (C‐statistics: 0.86 and 0.58, respectively) and expert‐rated health literacy (C‐statistics: 0.71 and 0.87, respectively) and were significantly associated with educational attainment, race/ethnicity, Consumer Assessment of Provider and Systems (CAHPS) scores, adherence, glycemia, comorbidities, and emergency department visits. Conclusions Since health literacy is a potentially remediable explanatory factor in health care disparities, the development of automated health literacy indicators represents a significant accomplishment with broad clinical and population health applications. Health systems could apply literacy profiles to efficiently determine whether quality of care and outcomes vary by patient health literacy; identify at‐risk populations for targeting tailored health communications and self‐management support interventions; and inform clinicians to promote improvements in individual‐level care.

The relationship between achieved low-density lipoprotein cholesterol (LDL-C) levels and risk of incident atherosclerotic cardiovascular disease events among patients with diabetes and metabolic dyslipidemia has not been well described.We conducted an observational cohort study of statin-treated adults (ages 21-90 years) with type 2 diabetes without established atherosclerotic cardiovascular disease (as of January 1, 2006) who had metabolic dyslipidemia (elevated triglycerides ≥150 mg/dL and low high-density lipoprotein cholesterol,50 mg/dL [women] and40 mg/dL [men]). All subjects were members of Kaiser Permanente Northern California, an integrated health care delivery system. Adjusted multivariable Cox models were specified to estimate hazard ratios (HRs) for incident atherosclerotic cardiovascular disease events by achieved LDL-C levels (50, 50-70, 70-100, and ≥100 mg/dL). Incident atherosclerotic cardiovascular disease events were defined as a composite of nonfatal myocardial infarction, ischemic stroke, or coronary heart disease death through December 31, 2013.A total of 19,095 individuals met the selection criteria. Mean age was 63.4 years, 53.5% were women, and the mean follow-up was 5.9 years. Unadjusted rates of atherosclerotic cardiovascular disease events were not significantly different across specified LDL-C categories. In models adjusted for demographics and clinical characteristics, the risk was significantly lower with decreasing achieved LDL-C levels (P0.0001 for trend). Relative to achieved LDL-C ≥100 mg/dL, LDL-C50 mg/dL had an hazard ratio of 0.66 (95% confidence interval [CI] 0.52-0.82).In a large, contemporary cohort of statin-treated patients with type 2 diabetes and metabolic dyslipidemia without established atherosclerotic cardiovascular disease, lower achieved LDL-C levels were associated with a monotonically lower risk of incident atherosclerotic cardiovascular disease events. The benefits of achieving very-low LDL-C (50 mg/dL) in this population requires further evaluation in prospective interventional studies.

There is great interest in understanding the cellular mechanisms controlling autophagy, a tightly regulated catabolic and stress-response pathway. Prior work has uncovered links between autophagy and the Golgi reassembly stacking protein of 55 kDa (GRASP55), but their precise interrelationship remains unclear. Intriguingly, both autophagy and GRASP55 have been functionally and spatially linked to the endoplasmic reticulum (ER)­­-Golgi interface, broaching this compartment as a site where GRASP55 and autophagy may intersect. Here, we uncover that loss of GRASP55 enhances LC3 puncta formation, indicating that GRASP55 restricts autophagosome formation. Additionally, using proximity-dependent biotinylation, we identify a GRASP55 proximal interactome highly associated with the ER-Golgi interface. Both nutrient starvation and loss of GRASP55 are associated with coalescence of early secretory pathway markers. In light of these findings, we propose that GRASP55 regulates spatial organization of the ER-Golgi interface, which suppresses early autophagosome formation., Summary: The Golgi protein GRASP55 restricts early-stage autophagy and regulates spatial organization of the early secretory network. We also identify a GRASP55 proximal interactome enriched at the ER-Golgi interface.

BACKGROUND: Low literacy skills impact important aspects of communication, including health-related information exchanges. Unsuccessful communication on the part of physician or patient contributes to lower quality of care, is associated with poorer chronic disease control, jeopardizes patient safety and can lead to unfavorable healthcare utilization patterns. To date, very little research has focused on digital communication between physicians and patients, such as secure messages sent via electronic patient portals. METHOD: The purpose of the current study is to develop an automated readability formula to better understand what elements of physicians’ digital messages make them more or less difficult to understand. The formula is developed using advanced natural language processing (NLP) to predict human ratings of physician text difficulty. RESULTS: The results indicate that NLP indices that capture a diverse set of linguistic features predict the difficulty of physician messages better than classic readability tools such as Flesch Kincaid Grade Level. Our results also provide information about the textual features that best explain text readability. CONCLUSION: Implications for how the readability formula could provide feedback to physicians to improve digital health communication by promoting linguistic concordance between physician and patient are discussed.

BACKGROUND: Little is known about patients who have caregiver proxies communicate with healthcare providers via portal secure messaging (SM). Since proxy portal use is often informal (e.g., sharing patient accounts), novel methods are needed to estimate the prevalence of proxy-authored SMs. OBJECTIVE: (1) Develop an algorithm to identify proxy-authored SMs, (2) apply this algorithm to estimate predicted proxy SM (PPSM) prevalence among patients with diabetes, and (3) explore patient characteristics associated with having PPSMs. DESIGN: Retrospective cohort study. PARTICIPANTS: We examined 9856 patients from Diabetes Study of Northern California (DISTANCE) who sent ≥ 1 English-language SM to their primary care physician between July 1, 2006, and Dec. 31, 2015. MAIN MEASURES: Using computational linguistics, we developed ProxyID, an algorithm that identifies phrases frequently found in registered proxy SMs. ProxyID was validated against blinded expert categorization of proxy status among an SM sample, then applied to identify PPSM prevalence across patients. We examined patients’ sociodemographic and clinical characteristics according to PPSM penetrance, “none” (0%), “low” (≥ 0–50%), and “high” (≥ 50–100%). KEY RESULTS: Only 2.3% of patients had ≥ 1 registered proxy-authored SM. ProxyID demonstrated moderate agreement with expert classification (Κ = 0.58); 45.7% of patients had PPSMs (40.2% low and 5.5% high). Patients with high percent PPSMs were older than those with low percent and no PPSMs (66.5 vs 57.4 vs 56.2 years, p

Objective In the National Library of Medicine funded ECLIPPSE Project (Employing Computational Linguistics to Improve Patient-Provider Secure Emails exchange), we attempted to create novel, valid, and scalable measures of both patients’ health literacy (HL) and physicians’ linguistic complexity by employing natural language processing (NLP) techniques and machine learning (ML). We applied these techniques to > 400,000 patients’ and physicians’ secure messages (SMs) exchanged via an electronic patient portal, developing and validating an automated patient literacy profile (LP) and physician complexity profile (CP). Herein, we describe the challenges faced and the solutions implemented during this innovative endeavor. Materials and methods To describe challenges and solutions, we used two data sources: study documents and interviews with study investigators. Over the five years of the project, the team tracked their research process using a combination of Google Docs tools and an online team organization, tracking, and management tool (Asana). In year 5, the team convened a number of times to discuss, categorize, and code primary challenges and solutions. Results We identified 23 challenges and associated approaches that emerged from three overarching process domains: (1) Data Mining related to the SM corpus; (2) Analyses using NLP indices on the SM corpus; and (3) Interdisciplinary Collaboration. With respect to Data Mining, problems included cleaning SMs to enable analyses, removing hidden caregiver proxies (e.g., other family members) and Spanish language SMs, and culling SMs to ensure that only patients’ primary care physicians were included. With respect to Analyses, critical decisions needed to be made as to which computational linguistic indices and ML approaches should be selected; how to enable the NLP-based linguistic indices tools to run smoothly and to extract meaningful data from a large corpus of medical text; and how to best assess content and predictive validities of both the LP and the CP. With respect to the Interdisciplinary Collaboration, because the research required engagement between clinicians, health services researchers, biomedical informaticians, linguists, and cognitive scientists, continual effort was needed to identify and reconcile differences in scientific terminologies and resolve confusion; arrive at common understanding of tasks that needed to be completed and priorities therein; reach compromises regarding what represents “meaningful findings” in health services vs. cognitive science research; and address constraints regarding potential transportability of the final LP and CP to different health care settings. Discussion Our study represents a process evaluation of an innovative research initiative to harness “big linguistic data” to estimate patient HL and physician linguistic complexity. Any of the challenges we identified, if left unaddressed, would have either rendered impossible the effort to generate LPs and CPs, or invalidated analytic results related to the LPs and CPs. Investigators undertaking similar research in HL or using computational linguistic methods to assess patient-clinician exchange will face similar challenges and may find our solutions helpful when designing and executing their health communications research.

Aldehyde dehydrogenases (ALDHs) catalyze the conversion of various aliphatic and aromatic aldehydes into corresponding carboxylic acids. Traditionally considered as housekeeping enzymes, new biochemical roles are being identified for members of ALDH family. Recent work showed that AldA from the plant pathogen Pseudomonas syringae strain PtoDC3000 (PtoDC3000) functions as an indole-3-acetaldehyde dehydrogenase for the synthesis of indole-3-acetic acid (IAA). IAA produced by AldA allows the pathogen to suppress salicylic acid-mediated defenses in the model plant Arabidopsis thaliana. Here we present a biochemical and structural analysis of the AldA indole-3-acetaldehyde dehydrogenase from PtoDC3000. Site-directed mutants targeting the catalytic residues Cys302 and Glu267 resulted in a loss of enzymatic activity. The X-ray crystal structure of the catalytically inactive AldA C302A mutant in complex with IAA and NAD+ showed the cofactor adopting a conformation that differs from the previously reported structure of AldA. These structures suggest that NAD+ undergoes a conformational change during the AldA reaction mechanism similar to that reported for human ALDH. Site-directed mutagenesis of the IAA binding site indicates that changes in the active site surface reduces AldA activity; however, substitution of Phe169 with a tryptophan altered the substrate selectivity of the mutant to prefer octanal. The present study highlights the inherent biochemical versatility of members of the ALDH enzyme superfamily in P. syringae.

Prior studies found a higher risk of acute cardiovascular disease (CVD) around population-wide psychosocial or environmental stressors. Less is known about acute CVD risk in relation to political events.To examine acute CVD hospitalizations following the 2020 presidential election.This retrospective cohort study examined acute CVD hospitalizations following the 2020 presidential election. Participants were adult members aged 18 years or older at Kaiser Permanente Southern California and Kaiser Permanente Northern California, 2 large, integrated health care delivery systems. Statistical analysis was performed from March to July 2021.2020 US presidential election.Hospitalizations for acute CVD around the 2020 presidential election were examined. CVD was defined as hospitalizations for acute myocardial infarction (AMI), heart failure (HF), or stroke. Rate ratios (RR) and 95% CIs were calculated comparing rates of CVD hospitalization in the 5 days following the 2020 election with the same 5-day period 2 weeks prior.Among 6 396 830 adults (3 970 077 [62.1%] aged 18 to 54 years; 3 422 479 [53.5%] female; 1 083 128 [16.9%] Asian/Pacific Islander, 2 101 367 [32.9%] Hispanic, and 2 641 897 [41.3%] White), rates of hospitalization for CVD following the election (666 hospitalizations; rate = 760.5 per 100 000 person-years [PY]) were 1.17 times higher (95% CI, 1.05-1.31) compared with the same 5-day period 2 weeks prior (569 hospitalizations; rate = 648.0 per 100 000 PY). Rates of AMI were significantly higher following the election (RR, 1.42; 95% CI, 1.13-1.79). No significant difference was found for stroke (RR, 1.02; 95% CI, 0.86-1.21) or HF (RR, 1.18; 95% CI, 0.98-1.42).Higher rates of acute CVD hospitalization were observed following the 2020 presidential election. Awareness of the heightened risk of CVD and strategies to mitigate risk during notable political events are needed.

Introduction: Studies evaluating the relationship of severe hypoglycemia (SH) with the risk of atherosclerotic cardiovascular disease (ASCVD) events are limited by size, confounding and inconsistent outcome definitions. The aim of this study was to assess the association of SH, as defined by hypoglycemia-related hospital utilization, with risk of ASCVD. Methods: We conducted an observational cohort study of adults with diabetes with or without established ASCVD (as of 1/1/2014). All subjects were members of Kaiser Permanente Northern California, an integrated health care delivery system. Baseline was determined by the date of the first hypoglycemia-related utilization (primary diagnosis of hypoglycemia in the emergency department or principal diagnosis in the hospital) during 1/1/2013 - 12/31/2013. Baseline for those without SH, was a randomly assigned date in 2013. Multivariate Cox proportional hazard models were specified to estimate hazard ratios (HRs) for SH in adjusted models of time to incident ASCVD events. This outcome was defined as a composite of nonfatal myocardial infarction, ischemic stroke, or coronary heart disease death through 12/31/2017. Results: Among 233,696 eligible individuals, mean age was 63.6 years, 47.6% were women, and mean follow-up was 3.8 years. There were 2,179 episodes of SH. Age-sex-race adjusted risk of ASCVD among those with SH versus those without was HR 2.59 (95% CI 2.3-2.9). When additionally adjusted for prior ASCVD, the HR was still more than double, HR 2.32 (95% CI 2.1-2.6). In a fully saturated model with additional adjustments for diabetes type, diabetes duration, HbA1c, GFR, Charlson score, insulin use, sulfonylureas, and quartiles of neighborhood deprivation, SH was associated with a 30% increased risk (HR 1.31, 95% CI 1.16-1.5). The substantial attenuation in risk after more comprehensive adjustment suggests that patients at higher risk of SH are likely at higher risk of ASCVD. Conclusions: In a large, diverse and contemporary cohort of patients with diabetes, SH as defined by hypoglycemia-related hospital utilization is associated with greater risk of ASCVD. Increased awareness in recognizing this risk and vigilance in care for this higher risk population is warranted.

Meta-analyses and reviews of observational cohorts have reported a relationship between severe hypoglycemia (SH) and atherosclerotic cardiovascular disease (ASCVD) events, but estimates of effect vary widely and many studies are limited by size and diversity, ability to adjust for confounders, and inconsistent definitions of exposures and outcomes (1–4). We studied the association of SH events and risk of ASCVD in a large, diverse cohort of patients. This study was approved by the Kaiser Permanente Northern California (KPNC) Institutional Review Board. This observational cohort study included adults (age ≥18 years) with diabetes who were members of KPNC, an integrated health care delivery system, with continuous membership during the 2 years prior to baseline. The outcomes of interest were ASCVD events, defined as a composite of nonfatal myocardial infarction, fatal or nonfatal ischemic stroke, or death due to coronary heart disease. The exposure of interest …

Seven-year surveillance study (2005-2011) to evaluate race/ethnic differences in the trends in rates of severe hypoglycemia (SH) in a population of insured, at-risk adults with diabetes.SH events were identified via any primary or principal diagnosis from emergency department or inpatient encounters among African American, Asian, Latino and White adult diabetes patients treated with insulin or secretagogues (Sulfonylureas or Meglitinides), receiving care from integrated healthcare delivery systems across the United States. We calculated age- and sex-standardized annual SH rates and average annual percent change (AAPC) in SH rates.Annual SH rates ranged from 1.8% to 2.1% during this 7-year observation period (2,200,471 person-years). African Americans had consistently higher SH rates compared with Whites, while Latinos and Asians had consistently lower rates compared with Whites in each of the 7 years (all p0.01). The trend increased significantly only among African Americans (AAPC = +4.3%; 95% CI: +2.1, +6.5%); in the other groups, the AAPC was not significantly different from zero.Surveillance efforts should monitor the racial/ethnic-specific rates. The factors underlying substantially higher rates of hypoglycemia in African Americans should be evaluated. Clinically and culturally-appropriate strategies to reduce the risk of SH need to be developed and tested.

Aims To classify trajectories of long term HbA1c values in patients after diagnosis of type 2 diabetes and examine each trajectory's associations with subsequent microvascular and macrovascular events and mortality. Methods A longitudinal follow-up of 28,016 patients newly diagnosed with type 2 diabetes was conducted. Latent growth mixture modeling was used to identify ten-year HbA1c trajectories. Cox proportional hazards models were used to assess how HbA1c trajectories were associated with events (microvascular and macrovascular) and mortality. Results We identified 5 HbA1c trajectories: “low stable” (82.5%), “moderate increasing late” (5.1%), “high decreasing early” (4.9%), “moderate peaking late” (4.1%) and “moderate peaking early” (3.3%). After adjusting for average HbA1c, compared to the low stable trajectory, all non-stable trajectories were associated with higher incidences of microvascular events (hazard ratio (HR) range, 1.28 (95% CI, 1.08–1.53) (high decreasing early) to 1.45 (95% CI, 1.20–1.75) (moderate peaking early)). The high decreasing early trajectory was associated with an increased mortality risk (HR, 1.27 (95% CI, 1.03–1.58)). Trajectories were not associated with macrovascular events. Conclusions Non-stable HbA1c trajectories were associated with greater risk of microvascular events and mortality. These findings suggest a potential benefit of early diabetes detection, prioritizing good glycemic control, and maintaining control over time.

The contemporary literature is unclear regarding the joint that is most "at risk" to yield a nonunion in the performance of triple arthrodesis of the foot. There is also a debate regarding the best methods of joint preparation. A retrospective radiographic review was conducted of all primary triple arthrodeses performed within in a Northern California health maintenance organization between January 2007 and June 2013. Data documenting joint preparation techniques were collected, and postoperative imaging was reviewed to measure time to osseous union. Patient demographics were also collected. One hundred fifty-two patients (157 procedures) met the inclusion criteria. The overall nonunion rate for triple arthrodesis in this series was 29.9% (47/157). The nonunion rate of the talonavicular joint was 20.4% (32/157); the nonunion rate of the calcaneocuboid joint was 17.2% (27/157); and the nonunion rate of the subtalar joint was 8.9% (14/157). In conclusion, we found the most likely joint to obtain nonunion during triple arthrodesis was the talonavicular joint. Furthermore, the most efficacious joint preparation technique was a combination joint resection or curettage with fish scaling.

Objective: This study is aimed at evaluating the incidence of bleeding among women having outpatient corticosteroid injection compared to matched controls, using mailed surveys and electronic health records. Study Design: Prospective survey study of women receiving outpatient corticosteroid injection for joint or back pain (cases) compared to women matched for visit, diagnosis of joint/back pain, and age, who did not receive an injection (controls). A survey was mailed 45 days following outpatient visit, inquiring about menstrual history, abnormal bleeding, and potential risk factors. The proportion of women reporting abnormal bleeding was compared between cases and controls, and stratified by menopausal status. Results: One thousand and sixty two surveys were mailed to 531 identified cases/control pairs, and 40% response was seen from each group. Of 379 analyzable responders, 135 (36%) were premenopausal and 244 (64%) postmenopausal. Postmenopausal women who had a corticosteroid injection were more likely to report recent abnormal bleeding compared to controls (17 vs. 7%, p = 0.02), whereas rates were similar among premenopausal women (50 vs. 43%, p = 0.39). When logistic regression was performed, injection was associated with bleeding among postmenopausal women, independent of body mass index and hormone use. Conclusions: Corticosteroid injection is associated with increased abnormal vaginal bleeding among postmenopausal women.

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

Limited health literacy is a barrier to optimal healthcare delivery and outcomes. Current measures requiring patients to self-report limitations are time-consuming and may be considered intrusive by some. This makes widespread classification of patient health literacy challenging. The objective of this study was to develop and validate “literacy profiles” as automated indicators of patients’ health literacy to facilitate a non-intrusive, economic and more comprehensive characterization of health literacy among a health care delivery system’s membership. To this end, three literacy profiles were generated based on natural language processing (combining computational linguistics and machine learning) using a sample of 283,216 secure messages sent from 6,941 patients to their primary care physicians. All patients were participants in Kaiser Permanente Northern California’s DISTANCE Study. Performance of the three literacy profiles were compared against a gold standard of patient self-reported health literacy. Associations were analyzed between each literacy profile and patient demographics, health outcomes and healthcare utilization. T-tests were used for numeric data such as A1C, Charlson comorbidity index and healthcare utilization rates, and chi-square tests for categorical data such as sex, race, poor adherence and severe hypoglycemia. Literacy profiles varied in their test characteristics, with C-statistics ranging from 0.61–0.74. Relations between literacy profiles and health outcomes revealed patterns consistent with previous health literacy research: patients identified via literacy profiles indicative of limited health literacy: (a) were older and more likely of minority status; (b) had poorer medication adherence and glycemic control; and (c) exhibited higher rates of hypoglycemia, comorbidities and healthcare utilization. This represents the first successful attempt to employ natural language processing to estimate health literacy. Literacy profiles can offer an automated and economical way to identify patients with limited health literacy and greater vulnerability to poor health outcomes.

OBJECTIVE To examine for a legacy effect of early glycemic control on diabetic complications and death. RESEARCH DESIGN AND METHODS This cohort study of managed care patients with newly diagnosed type 2 diabetes and 10 years of survival (1997–2013, average follow-up 13.0 years, N = 34,737) examined associations between HbA1c RESULTS Compared with HbA1c CONCLUSIONS Among patients with newly diagnosed diabetes and 10 years of survival, HbA1c levels ≥6.5% (≥48 mmol/mol) for the 1st year after diagnosis were associated with worse outcomes. Immediate, intensive treatment for newly diagnosed patients may be necessary to avoid irremediable long-term risk for diabetic complications and mortality.

The relevance of low-density lipoprotein cholesterol (LDL-C) or non-high-density lipoprotein cholesterol (non-HDL-C) goals for primary prevention of atherosclerotic cardiovascular disease (ASCVD) among patients with diabetes was assessed. This retrospective cohort study included patients with type 2 diabetes, age 21 to 90years, taking statins, with no history of ASCVD as of January 1, 2006, in Kaiser Permanente Northern California, an integrated healthcare delivery system. Multivariate cox models were utilized to estimate hazard ratios (HRs) for incident ASCVD events by achieved LDL-C and non-HDL-C levels with adjustment for potential confounders. Incident ASCVD events were defined as a composite of myocardial infarction, ischemic stroke, or coronary heart disease death. A cohort of 62,428 patients, with mean age of 64.1years, 46.9% women, and mean follow-up of 6.0 years, was identified. After adjustment, the risk of incident ASCVD for these statin-treated patients was monotonically lower with decreasing achieved LDL-C levels (p0.0001 for trend) and non-HDL-C levels (p0.0001 for trend). Relative to achieved LDL-C ≥130 mg/dl, LDL-C50 mg/dl had HR = 0.58 (95% confidence interval 0.49 to 0.69). Relative to achieved non-HDL-C ≥160mg/dl, non-HDL-C80 mg/dl had HR = 0.59 (95% confidence interval 0.51 to 0.68). In a large cohort of statin-treated diabetic patients without ASCVD, a monotonically lower risk of incident ASCVD events was associated with lower achieved lipid levels. These findings support the use of LDL-C ornon-HDL-C treatment goals for ASCVD primary prevention in diabetic patients.

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.

Secondary prevention after an acute coronary syndrome (ACS) hospitalization is critical to prevent additional morbidity and mortality. While poor adherence to prescribed cardio-protective medications is a known problem,1,2 it is unknown whether an ACS event might motivate patients to achieve better adherence. In a large integrated health care population, we examined initiation and adherence to newly prescribed cardio-protective medications among post-ACS event patients compared to patients who were prescribed these same medications in usual care.

Objectives: To explore racial and ethnic (ethnic hereafter) differences in health-related quality of life (HRQL) in older adults with diabetes mellitus in an integrated delivery system. Design: Observational cross-sectional study. Setting: Kaiser Permanente Northern California. Participants: Ethnic-stratified, random sample of 6,096 adults with diabetes mellitus aged 60 to 75 who completed a HRQL questionnaire. Measurements: Physical and mental HRQL were measured based on the Medical Outcomes Study 8-item Short Form Survey (range 0�100, mean 50). Age- and sex-adjusted weighted linear regression models estimated associations between ethnicity and HRQL and evaluated potential mediators (socioeconomic status, acculturation, health behaviors, diabetes mellitus�related conditions). Differences in ethnic-specific, adjusted mean HRQL scores were tested (reference whites). Results: Physical HRQL was better for Filipinos (48.3, 95% confidence interval (CI) = 47.0�49.6, P < .001), Asians (48.1, 95% CI = 46.8�49.3, P < .001), Hispanics (45.1, 95% CI = 44.2�46.0, P < .001), and blacks (44.2, 95% CI = 43.3�45.1, P = .04) than whites (42.9, 95% CI = 42.6�43.2). Adjusting for potential mediators did not change these relationships. Mental HRQL was better only for Asians (52.7, 95% CI = 51.6�53.7, P = .01) than for whites (51.0, 95% CI = 50.7�51.3), but this difference was small and became nonsignificant after adjustment for socioeconomic status, acculturation, health behaviors, and diabetes mellitus�related conditions. Conclusion: In older adults with diabetes mellitus in a well-established integrated healthcare delivery system, ethnic minorities had better physical HRQL than whites. Equal access to care in an integrated delivery system may hold promise for reducing health disparities in diabetes mellitus-related patient-reported outcomes.

OBJECTIVE We estimated the prevalence and incidence of diabetes among specific subgroups of Asians and Pacific Islanders (APIs) in a multiethnic U.S. population with uniform access to care. RESEARCH DESIGN AND METHODS This prospective cohort analysis included 2,123,548 adult members of Kaiser Permanente Northern California, including 1,704,363 with known race/ethnicity (white, 56.9%; Latino, 14.9%; African American, 8.0%; Filipino, 4.9%; Chinese, 4.0%; multiracial, 2.8%; Japanese, 0.9%; Native American, 0.6%; Pacific Islander, 0.5%; South Asian, 0.4%; and Southeast Asian, Korean, and Vietnamese, 0.1% each). We calculated age-standardized (to the 2010 U.S. population) and sex-adjusted diabetes prevalence at baseline and incidence (during the 2010 calendar year). Poisson models were used to estimate relative risks. RESULTS There were 210,632 subjects with prevalent diabetes as of 1 January 2010 and 15,357 incident cases of diabetes identified during 2010. The crude diabetes prevalence was 9.9% and the incidence was 8.0 cases per 1,000 person-years and, after standardizing by age and sex to the 2010 U.S. Census, 8.9% and 7.7 cases per 1,000 person-years. There was considerable variation among the seven largest API subgroups. Pacific Islanders, South Asians, and Filipinos had the highest prevalence (18.3, 15.9, and 16.1%, respectively) and the highest incidence (19.9, 17.2, and 14.7 cases per 1,000 person-years, respectively) of diabetes among all racial/ethnic groups, including minorities traditionally considered high risk (e.g., African Americans, Latinos, and Native Americans). CONCLUSIONS High rates of diabetes among Pacific Islanders, South Asians, and Filipinos are obscured by much lower rates among the large population of Chinese and several smaller Asian subgroups.

OBJECTIVE To evaluate associations between health-related quality of life (HRQL) and geriatric syndromes, diabetes complications, and hypoglycemia in older adults with diabetes. RESEARCH DESIGN AND METHODS A race-stratified random sample of 6,317 adults with type 2 or type 1 diabetes, aged 60 to 75 years, enrolled in Kaiser Permanente Northern California, who completed a survey that included a HRQL instrument based on the Short Form 8-item health survey. Administrative records were used to ascertain diagnoses of geriatric syndromes, diabetes complications, and hypoglycemia. Associations were estimated between HRQL and exposures in exposure-specific and combined exposure models (any syndrome, any complication, or hypoglycemia). Conservatively, differences of ≥3 points were considered the minimally important difference in HRQL scores. RESULTS HRQL was lower with nearly all exposures of interest. The lowest physical HRQL was associated with amputation. In combined exposure models, geriatric syndromes (−5.3 [95% CI −5.8 to −4.8], P < 0.001) and diabetes complications (−3.5 [−4.0 to −2.9], P < 0.001) were associated with lower physical HRQL. The lowest mental HRQL was associated with depression, underweight (BMI CONCLUSIONS Geriatric syndromes and hypoglycemia are associated with lower HRQL to a comparable degree as diabetes complications. Addressing geriatric syndromes and avoiding hypoglycemia should be given as high a priority as preventing diabetes complications in older adults with diabetes.

OBJECTIVE To identify the range of glycemic levels associated with the lowest rates of complications and mortality in older diabetic patients. RESEARCH DESIGN AND METHODS We conducted a retrospective cohort study (2004–2008) of 71,092 patients with type 2 diabetes, aged ≥60 years, enrolled in Kaiser Permanente Northern California. We specified Cox proportional hazards models to evaluate the relationships between baseline glycated hemoglobin (A1C) and subsequent outcomes (nonfatal complications [acute metabolic, microvascular, and cardiovascular events] and mortality). RESULTS The cohort (aged 71.0 ± 7.4 years [means ± SD]) had a mean A1C of 7.0 ± 1.2%. The risk of any nonfatal complication rose monotonically for levels of A1C >6.0% (e.g., adjusted hazard ratio 1.09 [95% CI 1.02–1.16] for A1C 6.0–6.9% and 1.86 [1.63–2.13] for A1C ≥11.0%). Mortality had a U-shaped relationship with A1C. Compared with the risk with A1C CONCLUSIONS Observed relationships between A1C and combined end points support setting a target of A1C

OBJECTIVE To determine the association between triglyceride levels and lower-extremity amputation (LEA) risk in a large diabetic cohort. RESEARCH DESIGN AND METHODS This is a 10-year survey follow-up study (from 1995–2006) of 28,701 diabetic patients with a baseline triglyceride measure. All patients were fully insured members of the Kaiser Permanente Medical Care Program and responded to a survey at baseline that included information on ethnicity, socioeconomic status, education, behavioral factors, and information required to determine type of diabetes. The relationship between triglycerides and time to incident nontraumatic LEA, defined by primary hospitalization discharge or procedures, was evaluated using Cox proportional hazards models. RESULTS Triglyceride level was an independent, stepwise risk factor for nontraumatic LEAs within this large diabetic cohort: triglycerides 150–199 mg/dL, hazard ratio (HR) 1.10 (95% CI 0.92–1.32); 200–499 mg/dL, 1.27 (1.10–1.47); >500 mg/dL, 1.65 (1.30–2.10) (reference CONCLUSIONS Hypertriglyceridemia is a significant risk factor for LEA in diabetic patients even after controlling for known socioeconomic, health behavioral, and clinical factors. This previously unrecognized clinical risk needs to be further investigated to determine if treatment of triglycerides can reduce amputation risk.

Internet-based patient portals are intended to improve access and quality, and will play an increasingly important role in health care, especially for diabetes and other chronic diseases. Diabetes patients with limited health literacy have worse health outcomes, and limited health literacy may be a barrier to effectively utilizing internet-based health access services. We investigated use of an internet-based patient portal among a well characterized population of adults with diabetes. We estimated health literacy using three validated self-report items. We explored the independent association between health literacy and use of the internet-based patient portal, adjusted for age, gender, race/ethnicity, educational attainment, and income. Among 14,102 participants (28% non-Hispanic White, 14% Latino, 21% African-American, 9% Asian, 12% Filipino, and 17% multiracial or other ethnicity), 6099 (62%) reported some limitation in health literacy, and 5671 (40%) respondents completed registration for the patient portal registration. In adjusted analyses, those with limited health literacy had higher odds of never signing on to the patient portal (OR 1.7, 1.4 to 1.9) compared with those who did not report any health literacy limitation. Even among those with internet access, the relationship between health literacy and patient portal use persisted (OR 1.4, 95% CI 1.2 to 1.8). Diabetes patients reporting limited health literacy were less likely to both access and navigate an internet-based patient portal than those with adequate health literacy. Although the internet has potential to greatly expand the capacity and reach of health care systems, current use patterns suggest that, in the absence of participatory design efforts involving those with limited health literacy, those most at risk for poor diabetes health outcomes will fall further behind if health systems increasingly rely on internet-based services.

This study examines the proportion of all severe hypoglycemic events that are captured by surveillance based on health care utilization alone among pharmacologically treated patients with diabetes.

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.

Aims Our aim was to examine the associations of alcohol consumption with six diabetes self-care behaviours. Methods We determined levels of alcohol consumption and examined associations between alcohol consumption and six self-care behaviours in 65 996 adults with diabetes who received care through Kaiser Permanente Northern California and who responded to a 1994–1997 survey. Adherence with recommendations for self monitoring of blood glucose, HbA1c testing, and diabetes medications were determined from electronic records; smoking and use of diet and exercise to treat diabetes were self reported. Multiple logistic regression models were used to determine the associations between alcohol consumption (average number of drinks/day in the past year) and the probability of adherence to each self-care behaviour. Results Current alcohol consumption was reported by 50.8% of adults with diabetes. In adjusted models, we observed a gradient of increasing risk for poor adherence to diabetes self-care behaviours with increasing alcohol consumption, starting with those who consume even one drink a day. Former drinkers had the greatest compliance with each self-care behaviour, except for current smoking. Conclusions Alcohol consumption is a marker for poorer adherence to diabetes self-care behaviours. These findings highlight the importance of routine assessment of alcohol intake in people with diabetes, particularly as half of adults with diabetes consume alcohol. Given extant evidence that moderate alcohol intake may have cardiovascular benefits for patients with diabetes, examination of the trade-offs between cardiovascular benefits vs. potential risk of lower adherence with self-care behaviours deserves study.

When patients miss scheduled medical appointments, continuity and effectiveness of healthcare delivery is reduced, appropriate monitoring of health status lapses, and the cost of health services increases. We evaluated the relationship between missed appointments and glycemic control (glycosylated hemoglobin or HbA1c) in a large, managed care population of diabetic patients.Missed appointment rate was related cross-sectionally to glycemic control among 84,040 members of the Kaiser Permanente Northern California Diabetes Registry during 2000. Adjusted least-square mean estimates of HbA1c were derived by level of appointment keeping (none missed, 1-30% missed, and30% missed appointments for the calendar year) stratified by diabetes therapy.Twelve percent of the subjects missed more than 30% of scheduled appointments during 2000. Greater rates of missed appointments were associated with significantly poorer glycemic control after adjusting for demographic factors (age, sex), clinical status, and health care utilization. The adjusted mean HbA1c among members who missed30% of scheduled appointments was 0.70 to 0.79 points higher (P0.0001) relative to those attending all appointments. Patients who missed more than 30% of their appointments were less likely to practice daily self-monitoring of blood glucose and to have poor oral medication refill adherence.Patients who underuse care lack recorded information needed to determine level of risk. Frequently missed appointments were associated with poorer glycemic control and suboptimal diabetes self-management practice, are readily ascertained in clinical settings, and therefore could have clinical utility as a risk-stratifying criterion indicating the need for targeted case management.

Background. Social risk factors for hypoglycemia are not well understood. Methods. Cross-sectional analysis from the DISTANCE study, a multi-language, ethnically-stratified random sample of adults in the Kaiser Permanente Northern California diabetes registry, conducted in 2005-2006 (response rate 62%). Exposures were income and educational attainment; outcome was patient report of severe hypoglycemia. To test the association, we used multivariable logistic regression to adjust for demographic and clinical factors. Results. 14,357 patients were included. Reports of severe hypoglycemia were common (11%), and higher in low-income vs. high-income (16% vs. 8.8) and low-education vs. high-education (11.9% vs. 8.9%) groups. In multivariable analysis, incomes of less than $15,000 (OR 1.51 95%CI 1.19-1.91), $15,000-$24,999 (OR 1.57 95%CI 1.27-1.94), and high school or less education (OR 1.42, 95% CI 1.24-1.63) were associated with increased hypoglycemia, similar to insulin use (OR 1.44 95%CI 1.19-1.74). Conclusions. Low income and educational attainment are important risk factors for hypoglycemia. © Meharry Medical College.

BackgroundData-sharing is encouraged to fulfill the ethical responsibility to transform research data into public health knowledge, but data sharing carries risks of improper disclosure and potential harm from release of individually identifiable data.MethodsThe study objective was to develop and implement a novel method for scientific collaboration and data sharing which distributes the analytic burden while protecting patient privacy. A procedure was developed where in an investigator who is external to an analytic coordinating center (ACC) can conduct original research following a protocol governed by a Publications and Presentations (P&P) Committee. The collaborating investigator submits a study proposal and, if approved, develops the analytic specifications using existing data dictionaries and templates. An original data set is prepared according to the specifications and the external investigator is provided with a complete but de-identified and shuffled data set which retains all key data fields but which obfuscates individually identifiable data and patterns; this" scrambled data set" provides a "sandbox" for the external investigator to develop and test analytic code for analyses. The analytic code is then run against the original data at the ACC to generate output which is used by the external investigator in preparing a manuscript for journal submission.ResultsThe method has been successfully used with collaborators to produce many published papers and conference reports.ConclusionBy distributing the analytic burden, this method can facilitate collaboration and expand analytic capacity, resulting in more science for less money.

OBJECTIVE—In women with diabetes, the changes that accompany menopause may further diminish glycemic control. Little is known about how hormone replacement therapy (HRT) affects glucose metabolism in diabetes. The aim of this study was to examine whether HbA1c levels varied by current HRT among women with type 2 diabetes. RESEARCH DESIGN AND METHODS—In a cohort of 15,435 women with type 2 diabetes who were members of a health maintenance organization, HbA1c and HRT were assessed by reviewing records in the health plan’s computerized laboratory and pharmacy systems. Sociodemographic and clinical information were collected by survey. RESULTS—The mean age was 64.7 years (SD ± 8.7). The study cohort comprised 55% non-Hispanic whites, 14% non-Hispanic blacks, 12% Hispanics, 11% Asians, 4% “other” ethnic groups, and 4% with missing ethnicity data. Current HRT was observed in 25% of women. HbA1c levels were significantly lower in women currently using HRT than in women not using HRT (age-adjusted mean ± SE: 7.9 ± 0.03 vs. 8.5 ± 0.02, respectively, P = 0.0001). No differences in HbA1c level were observed between women using unopposed estrogens and women using opposed estrogens. In a Generalized Estimating Equation model, which took into account patient clustering within physician and adjusted for age, ethnicity, education, obesity, hypoglycemic therapy, diabetes duration, self-monitoring of blood glucose, and exercise, HRT remained significantly and independently associated with decreased HbA1c levels (P = 0.0001). CONCLUSIONS—HRT was independently associated with decreased HbA1c level. Clinical trials will be necessary to understand whether HRT may improve glycemic control in women with diabetes.

Importance In the coming decades, the population of older adults with type 2 diabetes mellitus is expected to grow substantially. Understanding the clinical course of diabetes in this population is critical for establishing evidence-based clinical practice recommendations, identifying research priorities, allocating resources, and setting health care policies. Objective To contrast the rates of diabetes complications and mortality across age and diabetes duration categories. Design, Setting, and Participants This cohort study (2004-2010) included 72 310 older (≥60 years) patients with type 2 diabetes enrolled in a large, integrated health care delivery system. Incidence densities (events per 1000 person-years) were calculated for each age category (60-69, 70-79, and ≥80 years) and duration of diabetes (shorter [0-9 years] vs longer [≥10 years]). Main Outcomes and Measures Incident acute hyperglycemic events, acute hypoglycemic events (hypoglycemia), microvascular complications (end-stage renal disease, peripheral vascular disease, lower limb amputation, and diabetic eye disease), cardiovascular complications (coronary artery disease, cerebrovascular disease, and congestive heart failure), and all-cause mortality. Results Among older adults with diabetes of short duration, cardiovascular complications followed by hypoglycemia were the most common nonfatal complications. For example, among individuals aged 70 to79 years with a short duration of diabetes, coronary artery disease and hypoglycemia rates were higher (11.47 per 1000 person-years and 5.03 per 1000 person-years, respectively) compared with end-stage renal disease (2.60 per 1000 person-years), lower limb amputation (1.28 per 1000 person-years), and acute hyperglycemic events (0.82 per 1000 person-years). We observed a similar pattern among patients in the same age group with a long duration of diabetes, with some of the highest incidence rates in coronary artery disease and hypoglycemia (18.98 per 1000 person-years and 15.88 per 1000 person-years, respectively) compared with end-stage renal disease (7.64 per 1000 person-years), lower limb amputation (4.26 per 1000 person-years), and acute hyperglycemic events (1.76 per 1000 person-years). For a given age group, the rates of each outcome, particularly hypoglycemia and microvascular complications, increased dramatically with longer duration of the disease. However, for a given duration of diabetes, rates of hypoglycemia, cardiovascular complications, and mortality increased steeply with advancing age, and rates of microvascular complications remained stable or declined. Conclusions and Relevance Duration of diabetes and advancing age independently predict diabetes morbidity and mortality rates. As long-term survivorship with diabetes increases and as the population ages, more research and public health efforts to reduce hypoglycemia will be needed to complement ongoing efforts to reduce cardiovascular and microvascular complications.