Divergent acute versus prolonged pharmacological GLP-1R responses in adult ß cell-specific ß-arrestin 2 knockout mice.

The glucagon-like peptide-1 receptor (GLP-1R) is a major type 2 diabetes therapeutic target. Stimulated GLP-1Rs are rapidly desensitized by ß-arrestins, scaffolding proteins that not only terminate G protein interactions but also act as independent signaling mediators. Here, we have assessed in vivo glycemic responses to the pharmacological GLP-1R agonist exendin-4 in adult ß cell-specific ß-arrestin 2 knockout (KO) mice. KOs displayed a sex-dimorphic phenotype consisting of weaker acute responses that improved 6 hours after agonist injection. Similar effects were observed for semaglutide and tirzepatide but not with biased agonist exendin-phe1. Acute cyclic adenosine 5'-monophosphate increases were impaired, but desensitization reduced in KO islets. The former defect was attributed to enhanced ß-arrestin 1 and phosphodiesterase 4 activities, while reduced desensitization co-occurred with impaired GLP-1R recycling and lysosomal targeting, increased trans-Golgi network signaling, and reduced GLP-1R ubiquitination. This study has unveiled fundamental aspects of GLP-1R response regulation with direct application to the rational design of GLP-1R-targeting therapeutics.

Protocol - Evaluating the Effect of ACA Medicaid Expansion on Mortality During the COVID-19 Pandemic Using County-level Matching.

States are able to choose whether to expand Medicaid as part of the Affordable Care Act (ACA); thus it is of interest to understand the impact of this policy choice. In this protocol, we outline a study on the impact of Medicaid expansion as part of the ACA on mortality during the COVID-19 pandemic in the United States. County-level matching using full, optimal matching with a propensity score model is used to estimate causal effects in this observational study. Due to the provisional nature of mortality data in 2020 as reported by the CDC, we outline a modified aligned rank test to account for censored data as well as reporting lags for different states. We aim to make connections between statistical and ethnographic methodologies by particularly examining adjacent counties and similar counties that are in the same region of the US and in vastly different regions of the US. Finally, we aim to add to the growing literature about the effect of ACA Medicaid expansion on mortality by calculating effects, disaggregating by race.

The "Dry-Run" Analysis: A Method for Evaluating Risk Scores for Confounding Control.

A propensity score (PS) model's ability to control confounding can be assessed by evaluating covariate balance across exposure groups after PS adjustment. The optimal strategy for evaluating a disease risk score (DRS) model's ability to control confounding is less clear. DRS models cannot be evaluated through balance checks within the full population, and they are usually assessed through prediction diagnostics and goodness-of-fit tests. A proposed alternative is the "dry-run" analysis, which divides the unexposed population into "pseudo-exposed" and "pseudo-unexposed" groups so that differences on observed covariates resemble differences between the actual exposed and unexposed populations. With no exposure effect separating the pseudo-exposed and pseudo-unexposed groups, a DRS model is evaluated by its ability to retrieve an unconfounded null estimate after adjustment in this pseudo-population. We used simulations and an empirical example to compare traditional DRS performance metrics with the dry-run validation. In simulations, the dry run often improved assessment of confounding control, compared with the C statistic and goodness-of-fit tests. In the empirical example, PS and DRS matching gave similar results and showed good performance in terms of covariate balance (PS matching) and controlling confounding in the dry-run analysis (DRS matching). The dry-run analysis may prove useful in evaluating confounding control through DRS models.

Comparative effectiveness and safety of a catheterization laboratory-only eptifibatide dosing strategy in patients undergoing percutaneous coronary intervention.

BACKGROUND: Eptifibatide, a small-molecule glycoprotein IIb/IIIa inhibitor, is conventionally administered as a bolus plus infusion. A growing number of clinicians are using a strategy of catheterization laboratory-only eptifibatide (an off-label use) as procedural pharmacotherapy for patients undergoing percutaneous coronary intervention although the comparative effectiveness of this approach is unknown. METHODS AND RESULTS: We compared the in-hospital outcome of patients undergoing percutaneous coronary intervention across 47 hospitals and treated with eptifibatide bolus plus infusion with those treated with a catheterization laboratory-only regimen. We used optimal matching to link the use of catheterization laboratory-only eptifibatide with clinical outcomes, including mortality, myocardial infarction, bleeding, and need for transfusion. Of the 84 678 percutaneous coronary interventions performed during 2010 to 2011, and meeting our inclusion criteria, eptifibatide was administered to 21 296 patients. Of these, a catheterization laboratory-only regimen was used in 4511 patients, whereas 16 785 patients were treated with bolus plus infusion. In the optimally matched analysis, compared with bolus plus infusion, a catheterization laboratory-only regimen was associated with a reduction in bleeding (optimally matched adjusted odds ratio, 0.74; 95% confidence interval, 0.58-0.93; P=0.014) and need for transfusion (optimally matched adjusted odds ratio, 0.70; 95% confidence interval, 0.52-0.92; P=0.012), with no difference in mortality or myocardial infarction. CONCLUSIONS: A catheterization laboratory-only eptifibatide regimen is commonly used in clinical practice and is associated with a significant reduction in bleeding complications in patients undergoing contemporary percutaneous coronary intervention.

Comparative safety of vascular closure devices and manual closure among patients having percutaneous coronary intervention.

BACKGROUND: The role of vascular closure devices (VCDs) in patients having percutaneous coronary intervention (PCI) is controversial, and recommendations for use vary. OBJECTIVE: To examine the use of and outcomes associated with VCDs in real-world practice. DESIGN: Observational cohort study. SETTING: 32 hospitals in Michigan that participate in a large multicenter quality improvement collaborative. PATIENTS: Consecutive patients having emergent and nonemergent PCI from 2007 to 2009. MEASUREMENTS: Vascular complications and the need for transfusion. RESULTS: Of the 85 048 PCIs performed during the study that met the inclusion criteria, 28 528 (37%) procedures used VCDs. In propensity score-matched analysis, VCDs were associated with reductions in vascular complications (odds ratio [OR], 0.78 [95% CI, 0.67 to 0.90]; P = 0.001) and postprocedure transfusions (OR, 0.85 [CI, 0.74 to 0.96]; P = 0.011). These findings were consistent across many prespecified subgroups except for patients with a body mass index (BMI) less than 25 kg/m2 and those treated with platelet glycoprotein (GP) IIb/IIIa inhibitors, in whom the benefit of VCDs over manual closure was attenuated. When the specific subtypes of vascular complications were evaluated, VCDs were associated with fewer hematomas (OR, 0.69 [CI, 0.58 to 0.83]; P < 0.001) or pseudoaneurysms (OR, 0.54 [CI, 0.38 to 0.76]; P < 0.001) but an increase in the odds of retroperitoneal bleeding (OR, 1.57 [CI, 1.12 to 2.20]; P = 0.009). LIMITATION: Unmeasured confounding cannot be excluded despite the study having measured and balanced many confounders. CONCLUSION: Vascular closure devices were associated with a significant reduction in vascular complications and need for transfusion in this large cohort of patients having transfemoral PCI. This benefit was lost in patients receiving GP IIb/IIIa inhibitors and those with normal or lean BMI and was counterbalanced by a small increase in the more serious risk for retroperitoneal bleeding.

Reducing violence by transforming neighborhoods: a natural experiment in Medellín, Colombia.

Neighborhood-level interventions provide an opportunity to better understand the impact that neighborhoods have on health. In 2004, municipal authorities in Medellín, Colombia, built a public transit system to connect isolated low-income neighborhoods to the city's urban center. Transit-oriented development was accompanied by municipal investment in neighborhood infrastructure. In this study, the authors examined the effects of this exogenous change in the built environment on violence. Neighborhood conditions and violence were assessed in intervention neighborhoods (n = 25) and comparable control neighborhoods (n = 23) before (2003) and after (2008) completion of the transit project, using a longitudinal sample of 466 residents and homicide records from the Office of the Public Prosecutor. Baseline differences between these groups were of the same magnitude as random assignment of neighborhoods would have generated, and differences that remained after propensity score matching closely resembled imbalances produced by paired randomization. Permutation tests were used to estimate differential change in the outcomes of interest in intervention neighborhoods versus control neighborhoods. The decline in the homicide rate was 66% greater in intervention neighborhoods than in control neighborhoods (rate ratio = 0.33, 95% confidence interval: 0.18, 0.61), and resident reports of violence decreased 75% more in intervention neighborhoods (odds ratio = 0.25, 95% confidence interval 0.11, 0.67). These results show that interventions in neighborhood physical infrastructure can reduce violence.

Understanding social disparities in hypertension prevalence, awareness, treatment, and control: the role of neighborhood context.

The spatial segregation of the US population by socioeconomic position and especially race/ethnicity suggests that the social contexts or "neighborhoods" in which people live may substantially contribute to social disparities in hypertension. The Chicago Community Adult Health Study did face-to-face interviews, including direct measurement of blood pressure, with a representative probability sample of adults in Chicago. These data were used to estimate socioeconomic and racial-ethnic disparities in the prevalence, awareness, treatment, and control of hypertension, and to analyze how these disparities are related to the areas in which people live. Hypertension was significantly negatively associated with neighborhood affluence/gentrification, and adjustments for context eliminated the highly significant disparity between blacks/African-Americans and whites, and reduced the significant educational disparity by 10-15% to borderline statistical significance. Awareness of hypertension was significantly higher in more disadvantaged neighborhoods and in places with higher concentrations of blacks (and lower concentrations of Hispanics and immigrants). Adjustment for context completely eliminated blacks' greater awareness, but slightly accentuated the lesser awareness of Hispanics and the greater levels of awareness among the less educated. There was no consistent evidence of either social disparities in or contextual associations with treatment of hypertension, given awareness. Among those on medication, blacks were only 40-50% as likely as whites to have their hypertension controlled, but context played little or no role in either the level of or disparities in control of hypertension. In sum, residential contexts potentially play a large role in accounting for racial/ethnic and, to a lesser degree, socioeconomic disparities in hypertension prevalence and, in a different way, awareness, but not in treatment or control of diagnosed hypertension.