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Background: Despite the potential to significantly reduce complications, many patients do not consistently receive diabetes preventive care. Our research team recently applied user-centered design sprint methodology to develop a patient portal intervention empowering patients to address selected diabetes care gaps (eg, no diabetes eye examination in last 12 months)., Objective: This study aims to evaluate the effect of our novel diabetes care gap intervention on completion of selected evidence-based diabetes preventive care services and secondary outcomes., Methods: We are conducting a pragmatic randomized controlled trial of the effect of the intervention on diabetes care gaps. Adult patients with diabetes mellitus (DM) are recruited from primary care clinics affiliated with Vanderbilt University Medical Center. Participants are eligible if they have type 1 or 2 DM, can read in English, are aged 18-75 years, have a current patient portal account, and have reliable access to a mobile device with internet access. We exclude patients with medical conditions that prevent them from using a mobile device, severe difficulty seeing, pregnant women or women who plan to become pregnant during the study period, and patients on dialysis. Participants will be randomly assigned to the intervention or usual care. The primary outcome measure will be the number of diabetes care gaps among 4 DM preventive care services (diabetes eye examination, pneumococcal vaccination, hemoglobin A 1c , and urine microalbumin) at 12 months after randomization. Secondary outcomes will include diabetes self-efficacy, confidence managing diabetes in general, understanding of diabetes preventive care, diabetes distress, patient portal satisfaction, and patient-initiated orders at baseline, 3 months, 6 months, and 12 months after randomization. An ordinal logistic regression model will be used to quantify the effect of the intervention on the number of diabetes care gaps at the 12-month follow-up. For dichotomous secondary outcomes, a logistic regression model will be used with random effects for the clinic and provider variables as needed. For continuous secondary outcomes, a regression model will be used., Results: This study is ongoing. Recruitment was closed in February 2022; a total of 433 patients were randomized. Of those randomized, most (n=288, 66.5%) were non-Hispanic White, 33.5% (n=145) were racial or ethnic minorities, 33.9% (n=147) were aged 65 years or older, and 30.7% (n=133) indicated limited health literacy., Conclusions: The study directly tests the hypothesis that a patient portal intervention-alerting patients about selected diabetes care gaps, fostering understanding of their significance, and allowing patients to initiate care-will reduce diabetes care gaps compared with usual care. The insights gained from this study may have broad implications for developing future interventions to address various care gaps, such as gaps in cancer screening, and contribute to the development of effective, scalable, and sustainable approaches to engage patients in chronic disease management and prevention., Trial Registration: ClinicalTrials.gov NCT04894903; https://classic.clinicaltrials.gov/ct2/show/NCT04894903., International Registered Report Identifier (irrid): DERR1-10.2196/56123., (©Amber J Hackstadt, Tom A Elasy, Sapna Gangaputra, Kryseana J Harper, Lindsay S Mayberry, Lyndsay A Nelson, Neeraja B Peterson, S Trent Rosenbloom, Zhihong Yu, William Martinez. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 28.06.2024.)

Introduction: Teledermatology adoption continues to increase, in part, spurred by the COVID-19 pandemic. This study analyzes the utility and cost savings of a store-and-forward teledermatology consultative system within the Veterans Health Administration (VA). Methods: Retrospective cohort of 4,493 patients across 14 remote sites in Tennessee and Kentucky from May 2017 through August 2019. The study measured the agreement between the teledermatology diagnoses and follow-up face-to-face clinic evaluations as well as the cost effectiveness of the teledermatology program over the study period. Results: Fifty-four percent of patients were recommended for face-to-face appointment for biopsy or further evaluation. Most patients, 80.5% received their face-to-face care by a VA dermatologist. There was a high level of concordance between teledermatologist and clinic dermatologist for pre-malignant and malignant cutaneous conditions. Veterans were seen faster at a VA clinic compared with a community dermatology site. Image quality improved as photographers incorporated teledermatologist feedback. From a cost perspective, teledermatology saved the VA system $1,076,000 in community care costs. Discussion: Teledermatology is a useful diagnostic tool within the VA system providing Veteran care at a cost savings.

Objective: To validate an algorithm that identifies fractures using billing codes from the International Classification of Diseases Ninth Revision (ICD-9) and Tenth Revision (ICD-10) for inpatient, outpatient, and emergency department visits in a population of patients., Methods: We identified and reviewed a random sample of 543 encounters for adults receiving care within a single Veterans Health Administration healthcare system and had a first fracture episode between 2010 and 2019. To determine if an encounter represented a true incident fracture, we performed chart abstraction and assessed the type of fracture and mechanism. We calculated the positive predictive value (PPV) for the overall algorithm and each component diagnosis code along with 95% confidence intervals. Inverse probabilities of selection sampling weights were used to reflect the underlying study population., Results: The algorithm had an initial PPV of 73.5% (confidence interval [CI] 69.5, 77.1), with low performance when weighted to reflect the full population (PPV 66.3% [CI 58.8, 73.1]). The modified algorithm was restricted to diagnosis codes with PPVs > 50% and outpatient codes were restricted to the first outpatient position, with the exception of one high performing code. The resulting unweighted PPV improved to 90.1% (CI 86.2, 93.0) and weighted PPV of 91.3% (CI 86.8, 94.4). A confirmation sample demonstrated verified performance with PPV of 87.3% (76.0, 93.7). PPVs by location of care (inpatient, emergency department and outpatient) remained greater than 85% in the modified algorithm., Conclusions: The modified algorithm, which included primary billing codes for inpatient, outpatient, and emergency department visits, demonstrated excellent PPV for identification of fractures among a cohort of patients within the Veterans Health Administration system., (Published 2023. This article is a U.S. Government work and is in the public domain in the USA.)

Background: The effectiveness of glucagon-like peptide-1 receptor agonists (GLP1RA) and sodium-glucose cotransporter-2 inhibitors (SGLT2i) in preventing major adverse cardiac events (MACE) is uncertain for those without preexisting cardiovascular disease., Objective: To test the hypothesis that MACE incidence was lower with the addition of GLP1RA or SGLT2i compared with dipeptidyl peptidase-4 inhibitors (DPP4i) for primary cardiovascular prevention., Design: Retrospective cohort study of U.S. veterans from 2001 to 2019., Setting: Veterans aged 18 years or older receiving care from the Veterans Health Administration, with data linkage to Medicare, Medicaid, and the National Death Index., Patients: Veterans adding GLP1RA, SGLT2i, or DPP4i onto metformin, sulfonylurea, or insulin treatment alone or in combination. Episodes were stratified by history of cardiovascular disease., Measurements: Study outcomes were MACE (acute myocardial infarction, stroke, or cardiovascular death) and heart failure (HF) hospitalization. Cox models compared the outcome between medication groups using pairwise comparisons in a weighted cohort adjusted for covariates., Results: The cohort included 28 759 GLP1RA versus 28 628 DPP4i weighted pairs and 21 200 SGLT2i versus 21 170 DPP4i weighted pairs. Median age was 67 years, and diabetes duration was 8.5 years. Glucagon-like peptide-1 receptor agonists were associated with lower MACE and HF versus DPP4i (adjusted hazard ratio [aHR], 0.82 [95% CI, 0.72 to 0.94]), yielding an adjusted risk difference (aRD) of 3.2 events (CI, 1.1 to 5.0) per 1000 person-years. Sodium-glucose cotransporter-2 inhibitors were not associated with MACE and HF (aHR, 0.91 [CI, 0.78 to 1.08]; aRD, 1.28 [-1.12 to 3.32]) compared with DPP4i., Limitation: Residual confounding; use of DPP4i, GLP1RA, and SGLT2i as first-line therapies were not examined., Conclusion: The addition of GLP1RA was associated with primary reductions of MACE and HF hospitalization compared with DPP4i use; SGLT2i addition was not associated with primary MACE prevention., Primary Funding Source: VA Clinical Science Research and Development and supported in part by the Centers for Diabetes Translation Research., Competing Interests: Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M22-2751.

Background: Diabetes often causes kidney disease. In this study, we sought to evaluate if metformin use was associated with death or kidney events in patients with diabetes and concurrent reduced kidney function., Methods: We used data from the Veterans Health Administration, Medicare and National Death Index databases to assemble a national retrospective cohort of veterans who were using metformin or sulfonylureas from 2001 through 2016 and who began follow-up at an estimated glomerular filtration rate (eGFR) of less than 60 mL/min/1.73 m 2 . The primary composite outcome was a kidney event (i.e., 40% decline in eGFR or end-stage renal disease) or death. The secondary outcome was a kidney event (eGFR decline or end-stage renal disease). We weighted the cohort using propensity scores and used Cox proportional models to estimate the cause-specific hazard of outcomes and of treatment nonpersistence as a competing risk. We stratified follow-up into 2 periods, namely the first 360 days from the start of follow-up, and 361 days and beyond., Results: In the first 360 days, the propensity score-weighted cohort included 24 883 patients who used metformin and 24 998 who used sulfonylureas. There were 33.5 (95% confidence interval [CI] 30.9-36.3) and 43.0 (95% CI 40.1-46.0) deaths or kidney events per 1000 person-years for patients who used metformin or sulfonylureas, respectively (hazard ratio [HR] 0.78, 95% CI 0.71-0.85). For the secondary outcome of kidney events, the HR was 0.94 (95% CI 0.67-1.33). In the second period from 361 days onward, the primary outcome event rate was 26.5 (95% CI 24.7-28.5) per 1000 person-years for those who used metformin, compared with 36.3 (95% CI 34.2-38.6) per 1000 person-years for those who used sulfonylureas (HR 0.73, 95% CI 0.67-0.79). Results were consistent for kidney events alone (HR 0.73, 95% CI 0.59-0.91)., Interpretation: Metformin use for 361 days or longer after reaching an eGFR of less than 60 mL/min/1.73 m 2 was associated with decreased likelihood of kidney events or death in patients with diabetes, compared with use of sulfonylureas. Metformin provided end-organ protection, in addition to glucose control., Competing Interests: Competing interests: Outside the submitted work, Adriana Hung reports funding from Veterans Affairs and the Vertex trial; consulting fees from the National Heart, Lung, and Blood Institute; and speaking fees from Stanford Medical Grand Rounds. Amber Hackstadt reports participation with the data safety and monitoring board for the PILOT trial, and with the independent monitoring committee for a study on telehealth and pain. Carlos Grijalva reports funding from Campbell Alliance, Syneos Health, Sanofi, the United States Centers for Disease Control and Prevention, the Agency for Healthcare Research and Quality, the National Institutes of Health and the US Food and Drug Administration. He also reports consulting fees from Merck, Pfizer and Sanofi-Pasteur. Christianne Roumie reports funding from the Center for Diabetes Translation Research. No other competing interests were declared., (© 2023 CMA Impact Inc. or its licensors.)

Background: My Diabetes Care (MDC) is a multi-faceted intervention embedded within an established patient portal, My Health at Vanderbilt. MDC is designed to help patients better understand their diabetes health data and support self-care. MDC uses infographics to visualize and summarize patients' diabetes health data, incorporates motivational strategies, provides literacy-level appropriate educational resources, and links to a diabetes online patient support community and diabetes news feeds., Objective: This study aims to evaluate the effects of MDC on patient activation in adult patients with type 2 diabetes mellitus. Moreover, we plan to assess secondary outcomes, including system use and usability, and the effects of MDC on cognitive and behavioral outcomes (eg, self-care and self-efficacy)., Methods: We are conducting a 6-month, 2-arm, parallel-design, pragmatic pilot randomized controlled trial of the effect of MDC on patient activation. Adult patients with type 2 diabetes mellitus are recruited from primary care clinics affiliated with Vanderbilt University Medical Center. Participants are eligible for the study if they are currently being treated with at least one diabetes medication, are able to speak and read in English, are 21 years or older, and have an existing My Health at Vanderbilt account and reliable access to a desktop or laptop computer with internet access. We exclude patients living in long-term care facilities, patients with known cognitive deficits or severe visual impairment, and patients currently participating in any other diabetes-related research study. Participants are randomly assigned to MDC or usual care. We collect self-reported survey data, including the Patient Activation Measure (R) at baseline, 3 months, and 6 months. We will use mixed-effects regression models to estimate potentially time-varying intervention effects while adjusting for the baseline measure of the outcome. The mixed-effects model will use fixed effects for patient-level characteristics and random effects for health care provider variables (eg, primary care physicians)., Results: This study is ongoing. Recruitment was closed in May 2020; 270 patients were randomized. Of those randomized, most (214/267, 80.1%) were non-Hispanic White, and 13.1% (35/267) were non-Hispanic Black, 43.7% (118/270) reported being 65 years or older, and 33.6% (90/268) reported limited health literacy. We obtained at least 95.6% (258/270) completion among participants through the 3-month follow-up assessment., Conclusions: This randomized controlled trial will be one of the first to evaluate a patient-facing diabetes digital health intervention delivered via a patient portal. By embedding MDC into Epic's MyChart platform with more than 127 million patient records, our intervention is directly integrated into routine care, highly scalable, and sustainable. Our findings and evolving patient portal functionality will inform the continued development of MDC to best meet users' needs and a larger trial focused on the impact of MDC on clinical end points., Trial Registration: ClinicalTrials.gov NCT03947333; https://clinicaltrials.gov/ct2/show/NCT03947333., International Registered Report Identifier (irrid): DERR1-10.2196/25955., (©William Martinez, Amber J Hackstadt, Gerald B Hickson, S Trent Rosenbloom, Tom A Elasy. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 25.05.2021.)

Background: My Diabetes Care (MDC) is a novel, multifaceted patient portal intervention designed to help patients better understand their diabetes health data and support self-management. MDC uses infographics to visualize and summarize patients' diabetes health data, incorporates motivational strategies, and provides literacy level-appropriate educational resources., Objectives: We aimed to assess the usability, acceptability, perceptions, and potential impact of MDC., Methods: We recruited 69 participants from four clinics affiliated with Vanderbilt University Medical Center. Participants were given 1 month of access to MDC and completed pre- and post-questionnaires including validated measures of usability and patient activation, and questions about user experience., Results: Sixty participants completed the study. Participants' mean age was 58, 55% were females, 68% were Caucasians, and 48% had limited health literacy (HL). Most participants (80%) visited MDC three or more times and 50% spent a total of ≥15 minutes on MDC. Participants' median System Usability Scale (SUS) score was 78.8 [Q1, Q3: 72.5, 87.5] and significantly greater than the threshold value of 68 indicative of "above average" usability ( p  < 0.001). The median SUS score of patients with limited HL was similar to those with adequate HL (77.5 [72.5, 85.0] vs. 82.5 [72.5, 92.5]; p  = 0.41). Participants most commonly reported the literacy level-appropriate educational links and health data infographics as features that helped them better understand their diabetes health data (65%). All participants (100%) intended to continue to use MDC. Median Patient Activation Measure® scores increased postintervention (64.3 [55.6, 72.5] vs. 67.8 [60.6, 75.0]; p  = 0.01)., Conclusion: Participants, including those with limited HL, rated the usability of MDC above average, anticipated continued use, and identified key features that improved their understanding of diabetes health data. Patient activation improved over the study period. Our findings suggest MDC may be a beneficial addition to existing patient portals., Competing Interests: None declared., (Thieme. All rights reserved.)

Background Metformin and sulfonylurea are commonly prescribed oral medications for type 2 diabetes mellitus. The association of metformin and sulfonylureas on heart failure outcomes in patients with reduced estimated glomerular filtration rate remains poorly understood. Methods and Results This retrospective cohort combined data from National Veterans Health Administration, Medicare, Medicaid, and the National Death Index. New users of metformin or sulfonylurea who reached an estimated glomerular filtration rate of 60 mL/min per 1.73 m 2 or serum creatinine of 1.5 mg/dL and continued metformin or sulfonylurea were included. The primary outcome was hospitalization for heart failure. Echocardiogram reports were obtained to determine each patient's ejection fraction (EF) (reduced EF <40%; midrange EF 40%-49%; ≥50%). The primary analysis estimated the cause-specific hazard ratios for metformin versus sulfonylurea and estimated the cumulative incidence functions for heart failure hospitalization and competing events. The weighted cohort included 24 685 metformin users and 24 805 sulfonylurea users with reduced kidney function (median age 70 years, estimated glomerular filtration rate 55.8 mL/min per 1.73 m 2 ). The prevalence of underlying heart failure (12.1%) and cardiovascular disease (31.7%) was similar between groups. There were 16.9 (95% CI, 15.8-18.1) versus 20.7 (95% CI, 19.5-22.0) heart failure hospitalizations per 1000 person-years for metformin and sulfonylurea users, respectively, yielding a cause-specific hazard of 0.85 (95% CI, 0.78-0.93). Among heart failure hospitalizations, 44.5% did not have echocardiogram information available; 29.3% were categorized as reduced EF, 8.9% as midrange EF, and 17.2% as preserved EF. Heart failure hospitalization with reduced EF (hazard ratio, 0.79; 95% CI, 0.67-0.93) and unknown EF (hazard ratio, 0.84; 95% CI 0.74-96) were significantly lower in metformin versus sulfonylurea users. Conclusions Among patients with type 2 diabetes mellitus who developed worsening kidney function, persistent metformin compared with sulfonylurea use was associated with reduced heart failure hospitalization.

Objective: To compare the risk of lactic acidosis hospitalization between patients treated with metformin versus sulfonylureas following development of reduced kidney function., Research Design and Methods: This retrospective cohort combined data from the National Veterans Health Administration, Medicare, Medicaid, and the National Death Index. New users of metformin or sulfonylureas were followed from development of reduced kidney function (estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m 2 or serum creatinine ≥1.4 mg/dL [female] or 1.5 mg/dL [male]) through hospitalization for lactic acidosis, death, loss to follow-up, or study end. Lactic acidosis hospitalization was defined as a composite of primary discharge diagnosis or laboratory-confirmed lactic acidosis (lactic acid ≥2.5 mmol/L and either arterial blood pH <7.35 or serum bicarbonate ≤19 mmol/L within 24 h of admission). We report the cause-specific hazard of lactic acidosis hospitalization between metformin and sulfonylureas from a propensity score-matched weighted cohort and conduct an additional competing risks analysis to account for treatment change and death., Results: The weighted cohort included 24,542 metformin users and 24,662 sulfonylurea users who developed reduced kidney function (median age 70 years, median eGFR 55.8 mL/min/1.73 m 2 ). There were 4.18 (95% CI 3.63, 4.81) vs. 3.69 (3.19, 4.27) lactic acidosis hospitalizations per 1,000 person-years among metformin and sulfonylurea users, respectively (adjusted hazard ratio [aHR] 1.21 [95% CI 0.99, 1.50]). Results were consistent for both primary discharge diagnosis (aHR 1.11 [0.87, 1.44]) and laboratory-confirmed lactic acidosis (1.25 [0.92, 1.70])., Conclusions: Among veterans with diabetes who developed reduced kidney function, occurrence of lactic acidosis hospitalization was uncommon and not statistically different between patients who continued metformin and those patients who continued sulfonylureas., (© 2020 by the American Diabetes Association.)

Aim: To evaluate whether weight change or hypoglycaemia mediates the association between insulin use and death., Materials and Methods: In a retrospective cohort of veterans who filled a new prescription for metformin and added insulin or sulphonylurea (2001-2012), we assessed change in body mass index (BMI) and hypoglycaemia during the first 12 months of treatment intensification. Cox proportional hazards models compared the risk of death between treatment groups. Using the difference method, we estimated the indirect effect and proportion mediated through each mediator. A sensitivity analysis assessed mediators in the first 6 months of intensified therapy., Results: Among 28 892 patients surviving 12 months, deaths per 1000 person-years were 15.4 for insulin users and 12.9 for sulphonylurea users (HR 1.20, 95% CI 0.87, 1.64). Change in BMI and hypoglycaemia mediated 13% (-98, 98) and -1% (-37, 71) of this association, respectively. Among 30 214 patients surviving 6 months, deaths per 1000 person-years were 34.8 for insulin users and 21.3 for sulphonylurea users (HR 1.66, 95% CI 1.28, 2.15). Change in BMI and hypoglycaemia mediated 9% (1, 23) and 0% (-9, 4) of this association, respectively., Conclusions: We observed an increased risk of death among metformin users intensifying treatment with insulin versus sulphonylurea and surviving 6 months of intensified therapy, but not among those surviving 12 months. This association was mediated in part by weight change., (Published 2019. This article is a U.S. Government work and is in the public domain in the USA.)

Importance: Before 2016, safety concerns limited metformin use in patients with kidney disease; however, the effectiveness of metformin on clinical outcomes in patients with reduced kidney function remains unknown., Objective: To compare major adverse cardiovascular events (MACE) among patients with diabetes and reduced kidney function who continued treatment with metformin or a sulfonylurea., Design, Setting, and Participants: Retrospective cohort study of US veterans receiving care within the national Veterans Health Administration, with data supplemented by linkage to Medicare, Medicaid, and National Death Index data from 2001 through 2016. There were 174 882 persistent new users of metformin and sulfonylureas who reached a reduced kidney function threshold (estimated glomerular filtration rate <60 mL/min/1.73 m2 or creatinine ≥1.4 mg/dL for women or ≥1.5 mg/dL for men). Patients were followed up from reduced kidney function threshold until MACE, treatment change, loss to follow-up, death, or study end (December 2016)., Exposures: New users of metformin or sulfonylurea monotherapy who continued treatment with their glucose-lowering medication after reaching reduced kidney function., Main Outcomes and Measures: MACE included hospitalization for acute myocardial infarction, stroke, transient ischemic attack, or cardiovascular death. The analyses used propensity score weighting to compare the cause-specific hazard of MACE between treatments and estimate cumulative risk accounting for the competing risks of changing therapy or noncardiovascular death., Results: There were 67 749 metformin and 28 976 sulfonylurea persistent monotherapy users; the weighted cohort included 24 679 metformin and 24 799 sulfonylurea users (median age, 70 years [interquartile range {IQR}, 62.8-77.8]; 48 497 men [98%]; and 40 476 white individuals [82%], with median estimated glomerular filtration rate of 55.8 mL/min/1.73 m2 [IQR, 51.6-58.2] and hemoglobin A1c level of 6.6% [IQR, 6.1%-7.2%] at cohort entry). During follow-up (median, 1.0 year for metformin vs 1.2 years for sulfonylurea), there were 1048 MACE outcomes (23.0 per 1000 person-years) among metformin users and 1394 events (29.2 per 1000 person-years) among sulfonylurea users. The cause-specific adjusted hazard ratio of MACE for metformin was 0.80 (95% CI, 0.75-0.86) compared with sulfonylureas, yielding an adjusted rate difference of 5.8 (95% CI, 4.1-7.3) fewer events per 1000 person-years of metformin use compared with sulfonylurea use., Conclusions and Relevance: Among patients with diabetes and reduced kidney function persisting with monotherapy, treatment with metformin, compared with a sulfonylurea, was associated with a lower risk of MACE.

Background: Earlier palliative care consultation is associated with less intensive medical care and improved quality outcomes for patients with cancer. However, there are limited data about how the timing of palliative care affects utilization among noncancer patients exposed to palliative care consultation. Objective: Comparison of health care utilization for hospice decedents who received early versus late palliative care. Design: A retrospective cohort study utilizing hospital and hospice administrative databases. Setting/Subjects: Patients with cancer and noncancer diagnoses who received specialty palliative care consultation before dying at a local hospice. Measurements: Comparing early (>90 days before death) versus late (<90 days before death) palliative care, outcome measures included intensive care unit (ICU) utilization and hospice length of stay (LOS). Results: Of 233 hospice decedents in 2014 who had palliative care referrals, 36 (15.4%) had early and 197 (84.5%) had late referrals. Nearly half of the patients had a noncancer hospice diagnosis. Only 6% of the early group used the ICU in the last month of life, whereas 56% of the late group did. Patients receiving early palliative care had a longer median hospice LOS than those with late palliative care (138 days vs. 8 days). Conclusions: Early palliative care appears to reduce intensive medical care and increase hospice LOS for patients with a variety of end-stage diseases.

Purpose: To evaluate the accuracy of a composite definition for the identification of hypoglycemia events that used both administrative claims and laboratory data in a cohort of patients., Methods: We reviewed medical records in a sample of presumed hypoglycemia events among patients who received care at the Veterans Health Administration Tennessee Valley Healthcare System in 2001 to 2012. A hypoglycemia event was defined as a hospitalization or emergency department visit judged by the treating clinician to be due to hypoglycemia, or an outpatient laboratory or point-of-care blood glucose measurement <60 mg/dL. Based on medical record review, each event was classified as true positive (severe, documented symptomatic, documented asymptomatic) or false positive (probable symptomatic, not hypoglycemia). The positive predictive values (PPV) of the individual event types (hospitalization, emergency department, and outpatient) were estimated., Results: Of 2250 events identified through the composite definition, 321 events (15 hospitalizations, 103 emergency department visits, and 203 outpatient events) were reviewed. The PPVs were 80% for hospitalization events, 48% for emergency department events, and 96% for outpatient events. The emergency department definition included a nonspecific diagnosis code for diabetic complications which captured many false positive events. Excluding this code from the definition improved the PPV for emergency department events to 70% and missed one true event., Conclusions: Our composite definition for hypoglycemia performed moderately well in a cohort of Veterans. Further evaluation of the emergency department events may be needed., (© 2019 John Wiley & Sons, Ltd.)

Background: Women diagnosed with gestational diabetes mellitus (GDM) substantially modify their diets during pregnancy to control hyperglycemia. These changes could also affect maternal weight management. Materials and Methods: From July 2014 to December 2015 we enrolled women with and without GDM in a prospective cohort study to compare their mean rates of (1) weight gain before GDM screening, (2) weight gain after GDM screening, and (3) postpartum weight loss. All GDM-affected women were referred to Medical Nutrition Therapy and asked to self-monitor blood glucose until delivery. Rate comparisons were conducted separately for each interval using weighted t -tests and inverse probability of treatment weighting (IPTW) to account for age and prepregnancy body mass index (BMI). Linear regression models were developed to characterize the association of GDM status and rate of weight change. Results: The study included 40 women with GDM and 49 women without GDM. The IPTW analysis found that (1) women with and without GDM had similar mean rates of gestational weight gain before GDM screening (0.41 ± 0.26 kg/week vs. 0.45 ± 0.35 kg/week, respectively, p  = 0.86), (2) women with GDM gained weight at a significantly lower mean rate than women without GDM following GDM screening (0.30 ± 0.28 kg/week vs. 0.53 ± 0.28 kg/week, respectively, p  = 0.001), and (3) women with and without GDM had similar mean rates of postpartum weight loss (-1.37 ± 0.58 kg/week vs. -1.28 ± 0.46 kg/week, respectively, p  = 0.73). The linear regression model (adjusted for age and prepregnancy BMI) demonstrated that women with GDM gained 0.19 kg/week less than women without GDM ( p  = 0.004) during pregnancy after GDM screening. Conclusions: In the postpartum period, women with GDM lose weight at similar rates to women without GDM despite gaining weight at significantly lower rates following GDM screening. Diagnosis and treatment of GDM may improve maternal weight management, but this benefit is limited to late pregnancy.

Aim: To evaluate whether recent low adherence to metformin monotherapy is associated with hypoglycaemia after addition of a sulfonylurea., Methods: We assembled a retrospective cohort of veterans who filled a new prescription for metformin between 2001 and 2011 and intensified treatment with a sulfonylurea after ≥1 year of metformin use. We calculated metformin adherence from pharmacy data using the proportion of days covered in the 180-day period before intensification. The primary outcome was hypoglycaemia, defined as a hospitalization or emergency department visit for hypoglycaemia or an outpatient blood glucose measurement <3.3 mmol/l in the year following intensification. Cox proportional hazards models were used to compare the risk of hypoglycaemia between participants with low (<80%) and high (≥80%) adherence. Adherence was also modelled as a continuous variable using restricted cubic splines., Results: Of 187 267 participants who initiated metformin monotherapy, 49 424 added a sulfonylurea after ≥1 year. The median (interquartile range) rate of treatment adherence was 87 (50-100)% and 43% had adherence <80%. Hypoglycaemia rates per 1000 person-years were 23.1 (95% CI 21.1-25.4) and 24.5 (95% CI 22.7-26.4) in participants with low and high adherence, respectively (adjusted hazard ratio 0.95, 95% CI 0.84-1.08). The risk of hypoglycaemia was similar across all levels of adherence when adherence was modelled as a continuous variable., Conclusions: We found no evidence that past low adherence to metformin monotherapy was associated with hypoglycaemia after intensification with a sulfonylurea., (Published 2018. This article is a U.S. Government work and is in the public domain in the USA.)

Purpose: Several observational studies suggest that metformin reduces incidence cancer risk; however, many of these studies suffer from time-related biases and several cancer outcomes have not been investigated due to small sample sizes., Methods: We constructed a propensity score-matched retrospective cohort of 84,434 veterans newly prescribed metformin or a sulfonylurea as monotherapy. We used Cox proportional hazard regression to assess the association between metformin use compared to sulfonylurea use and incidence cancer risk for 10 solid tumors. We adjusted for clinical covariates including hemoglobin A1C, antihypertensive and lipid-lowering medications, and body mass index. Incidence cancers were defined by ICD-9-CM codes., Results: Among 42,217 new metformin users and 42,217 matched-new sulfonylurea users, we identified 2,575 incidence cancers. Metformin was inversely associated with liver cancer (adjusted hazard ratio [aHR] = 0.44, 95% CI 0.31, 0.64) compared to sulfonylurea. We found no association between metformin use and risk of incidence bladder, breast, colorectal, esophageal, gastric, lung, pancreatic, prostate, or renal cancer when compared to sulfonylurea use., Conclusions: In this large cohort study that accounted for time-related biases, we observed no association between the use of metformin and most cancers; however, we found a strong inverse association between metformin and liver cancer. Randomized trials of metformin for prevention of liver cancer would be useful to verify these observations.

Background: A central challenge in toxicity testing is the large number of chemicals in commerce that lack toxicological assessment. In response, the Tox21 program is re-focusing toxicity testing from animal studies to less expensive and higher throughput in vitro methods using target/pathway-specific, mechanism-driven assays., Objectives: Our objective was to use an in-depth mechanistic study approach to prioritize and characterize the chemicals affecting mitochondrial function., Methods: We used a tiered testing approach to prioritize for more extensive testing 622 compounds identified from a primary, quantitative high-throughput screen of 8,300 unique small molecules, including drugs and industrial chemicals, as potential mitochondrial toxicants by their ability to significantly decrease the mitochondrial membrane potential (MMP). Based on results from secondary MMP assays in HepG2 cells and rat hepatocytes, 34 compounds were selected for testing in tertiary assays that included formation of reactive oxygen species (ROS), upregulation of p53 and nuclear erythroid 2-related factor 2/antioxidant response element (Nrf2/ARE), mitochondrial oxygen consumption, cellular Parkin translocation, and larval development and ATP status in the nematode Caenorhabditis elegans ., Results: A group of known mitochondrial complex inhibitors (e.g., rotenone) and uncouplers (e.g., chlorfenapyr), as well as potential novel complex inhibitors and uncouplers, were detected. From this study, we identified four not well-characterized potential mitochondrial toxicants (lasalocid, picoxystrobin, pinacyanol, and triclocarban) that merit additional in vivo characterization., Conclusions: The tier-based approach for identifying and mechanistically characterizing mitochondrial toxicants can potentially reduce animal use in toxicological testing. https://doi.org/10.1289/EHP2589.

Exposure to particulate matter (PM) air pollution has been associated with a range of adverse health outcomes, including cardiovascular disease hospitalizations and other clinical parameters. Determining which sources of PM, such as traffic or industry, are most associated with adverse health outcomes could help guide future recommendations aimed at reducing harmful pollution exposure for susceptible individuals. Information obtained from multisite studies, which is generally more precise than information from a single location, is critical to understanding how PM impacts health and to informing local strategies for reducing individual-level PM exposure. However, few methods exist to perform multisite studies of PM sources, which are not generally directly observed, and adverse health outcomes. We developed SHared Across a REgion (SHARE), a hierarchical modeling approach that facilitates reproducible, multisite epidemiologic studies of PM sources. SHARE is a two-stage approach that first summarizes information about PM sources across multiple sites. Then, this information is used to determine how community-level (i.e., county-level or city-level) health effects of PM sources should be pooled to estimate regional-level health effects. SHARE is a type of population value decomposition that aims to separate out regional-level features from site-level data. Unlike previous approaches for multisite epidemiologic studies of PM sources, the SHARE approach allows the specific PM sources identified to vary by site. Using data from 2000 to 2010 for 63 northeastern US counties, we estimated regional-level health effects associated with short-term exposure to major types of PM sources. We found that PM from secondary sulfate, traffic, and metals sources was most associated with cardiovascular disease hospitalizations. Copyright © 2017 John Wiley & Sons, Ltd., (Copyright © 2017 John Wiley & Sons, Ltd.)

Background: Medications that impact insulin sensitivity or cause weight gain may increase heart failure risk. Our aim was to compare heart failure and cardiovascular death outcomes among patients initiating sulfonylureas for diabetes mellitus treatment versus metformin., Methods and Results: National Veterans Health Administration databases were linked to Medicare, Medicaid, and National Death Index data. Veterans aged ≥18 years who initiated metformin or sulfonylureas between 2001 and 2011 and whose creatinine was <1.4 (females) or 1.5 mg/dL (males) were included. Each metformin patient was propensity score-matched to a sulfonylurea initiator. The outcome was hospitalization for acute decompensated heart failure as the primary reason for admission or a cardiovascular death. There were 126 867 and 79 192 new users of metformin and sulfonylurea, respectively. Propensity score matching yielded 65 986 per group. Median age was 66 years, and 97% of patients were male; hemoglobin A 1c 6.9% (6.3, 7.7); body mass index 30.7 kg/m 2 (27.4, 34.6); and 6% had heart failure history. There were 1236 events (1184 heart failure hospitalizations and 52 cardiovascular deaths) among sulfonylurea initiators and 1078 events (1043 heart failure hospitalizations and 35 cardiovascular deaths) among metformin initiators. There were 12.4 versus 8.9 events per 1000 person-years of use (adjusted hazard ratio 1.32, 95%CI 1.21, 1.43). The rate difference was 4 heart failure hospitalizations or cardiovascular deaths per 1000 users of sulfonylureas versus metformin annually., Conclusions: Predominantly male patients initiating treatment for diabetes mellitus with sulfonylurea had a higher risk of heart failure and cardiovascular death compared to similar patients initiating metformin., (© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

Recent intervention studies targeted at reducing indoor air pollution have demonstrated both the ability to improve respiratory health outcomes and to reduce particulate matter (PM) levels in the home. However, these studies generally do not address whether it is the reduction of PM levels specifically that improves respiratory health. In this paper we apply the method of principal stratification to data from a randomized air cleaner intervention designed to reduce indoor PM in homes of children with asthma. We estimate the health benefit of the intervention amongst study subjects who would experience a substantial reduction in PM in response to the intervention. For those subjects we find an increase in symptom-free days that is almost three times as large as the overall intention-to-treat effect. We also explore the presence of treatment effects amongst those subjects whose PM levels would not respond to the air cleaner. This analysis demonstrates the usefulness of principal stratification for environmental intervention trials and its potential for much broader application in this area.

Previous research has found evidence of an association between indoor air pollution and asthma morbidity in children. Environmental intervention studies have been performed to examine the role of household environmental interventions in altering indoor air pollution concentrations and improving health. Previous environmental intervention studies have found only modest effects on health outcomes and it is unclear if the health benefits provided by environmental modification are comparable with those provided by medication. Traditionally, the statistical analysis of environmental intervention studies has involved performing two intention-to-treat analyses that separately estimate the effect of the environmental intervention on health and the effect of the environmental intervention on indoor air pollution concentrations. We propose a principal stratification approach to examine the extent to which an environmental intervention's effect on health outcomes coincides with its effect on indoor air pollution. We apply this approach to data from a randomized air cleaner intervention trial conducted in a population of asthmatic children living in Baltimore, Maryland, USA. We find that among children for whom the air cleaner reduced indoor particulate matter concentrations, the intervention resulted in a meaningful improvement of asthma symptoms with an effect generally larger than previous studies have shown. A key benefit of using principal stratification in environmental intervention studies is that it allows investigators to estimate causal effects of the intervention for sub-groups defined by changes in the indoor air pollution concentration., (Copyright © 2014 John Wiley & Sons, Ltd.)

Time series studies have suggested that air pollution can negatively impact health. These studies have typically focused on the total mass of fine particulate matter air pollution or the individual chemical constituents that contribute to it, and not source-specific contributions to air pollution. Source-specific contribution estimates are useful from a regulatory standpoint by allowing regulators to focus limited resources on reducing emissions from sources that are major contributors to air pollution and are also desired when estimating source-specific health effects. However, researchers often lack direct observations of the emissions at the source level. We propose a Bayesian multivariate receptor model to infer information about source contributions from ambient air pollution measurements. The proposed model incorporates information from national databases containing data on both the composition of source emissions and the amount of emissions from known sources of air pollution. The proposed model is used to perform source apportionment analyses for two distinct locations in the United States (Boston, Massachusetts and Phoenix, Arizona). Our results mirror previous source apportionment analyses that did not utilize the information from national databases and provide additional information about uncertainty that is relevant to the estimation of health effects.

Background: Due to the large number of hypothesis tests performed during the process of routine analysis of microarray data, a multiple testing adjustment is certainly warranted. However, when the number of tests is very large and the proportion of differentially expressed genes is relatively low, the use of a multiple testing adjustment can result in very low power to detect those genes which are truly differentially expressed. Filtering allows for a reduction in the number of tests and a corresponding increase in power. Common filtering methods include filtering by variance, average signal or MAS detection call (for Affymetrix arrays). We study the effects of filtering in combination with the Benjamini-Hochberg method for false discovery rate control and q-value for false discovery rate estimation., Results: Three case studies are used to compare three different filtering methods in combination with the two false discovery rate methods and three different preprocessing methods. For the case studies considered, filtering by detection call and variance (on the original scale) consistently led to an increase in the number of differentially expressed genes identified. On the other hand, filtering by variance on the log2 scale had a detrimental effect when paired with MAS5 or PLIER preprocessing methods, even when the testing was done on the log2 scale. A simulation study was done to further examine the effect of filtering by variance. We find that filtering by variance leads to higher power, often with a decrease in false discovery rate, when paired with either of the false discovery rate methods considered. This holds regardless of the proportion of genes which are differentially expressed or whether we assume dependence or independence among genes., Conclusion: The case studies show that both detection call and variance filtering are viable methods of filtering which can increase the number of differentially expressed genes identified. The simulation study demonstrates that when paired with a false discovery rate method, filtering by variance can increase power while still controlling the false discovery rate. Filtering out 50% of probe sets seems reasonable as long as the majority of genes are not expected to be differentially expressed.