Faculty Bibliography

The rs6923761 (Gly168Ser) missense variant in the glucagon-like peptide-1 receptor (GLP-1R) has been associated with favorable anthropometric and metabolic parameters in individuals with obesity but decreased responsiveness to incretin-based therapies. Here, we performed a pre-specified analysis of a randomized-controlled trial in individuals with obesity and pre-diabetes comparing treatment with the GLP-1R agonist liraglutide, the dipeptidyl peptidase 4 inhibitor sitagliptin or hypocaloric diet, and evaluated the effects of the rs6923761 variant on outcomes. We found significantly greater weight loss to liraglutide with each copy of the variant allele present, indicating a gene dose effect. In addition, individuals with the variant allele exhibited a significant reduction in the pro-thrombotic and pro-inflammatory factor plasminogen activator inhibitor-1 after liraglutide treatment. There was no effect of genotype on fasting glucose after liraglutide treatment, yet individuals with the variant allele exhibited decreased responsiveness to liraglutide and hypocaloric diet in measurements of fasting insulin, C-peptide, glucagon, and HOMA-IR. In conclusion, we found that the GLP-1R rs6923761 variant exerts a dual impact on liraglutide efficacy-enhancing weight loss while diminishing metabolic benefits. The observed associations could be consistent with the constitutive activation of the GLP-1R in the presence of this variant with reduced activation/signaling in response to pharmacologic agents, a pattern that has been observed with the rs10305492 variant in animal models. Future studies are needed to investigate the molecular mechanisms of associations with the rs6923761 variant.

BACKGROUND:Glucagon-like peptide-1 receptor agonists (GLP1RA) provide survival benefits in people with diabetes, including kidney transplant (KT) recipients with pre-existing diabetes. Post-transplant diabetes mellitus (PTDM) is common, but the benefits of GLP1RAs remain undefined in this population. We aim to describe current usage practices and outcomes in PTDM. METHODS:We used USRDS and Medicare claims data (2013-2022) to conduct a drug utilization profile of GLP1RA among 7681 first-time adult KT recipients with PTDM. We used survival analysis to estimate GLP1RA initiation incidence and associated patient, graft, and safety outcomes. RESULTS:A total of 430 adult KT recipients with PTDM were prescribed GLP1RA. Dulaglutide was the most commonly prescribed medication (46.1%). The 5-year cumulative incidence of GLP-1 receptor agonists prescription was 9.8%. Median (interquartile range) time from PTDM diagnosis to first prescription was 1.7 (0.6, 3.4) years. GLP1RA use was not associated with a difference in the risk of mortality or graft failure but was associated with a 1.80-fold (95% confidence interval [CI]: 1.11-2.91) increased risk of diabetic retinopathy. No increased risk of pancreatitis, biliary complications, or medullary thyroid cancer were identified. CONCLUSIONS:GLP1RA use in KT recipients with PTDM was not associated with graft or patient survival, though longer follow-up is necessary. GLP1RA use was associated with an increased risk of diabetic retinopathy, and care should be taken when initiating these agents.

BACKGROUND:Germline genetic variants are important for prostate cancer (PCa) management and hereditary cancer risk assessment, but testing is underused. Furthermore, patients are often unaware of the genetic connections to PCa. Social media is increasingly serving as a source of awareness for health information and a method to gather data from a large population. OBJECTIVE:There were three objectives: to (1) create and test social media messages related to PCa genetics and genetic testing, (2) determine which social media message was most engaging, and (3) assess knowledge of and attitudes toward PCa genetic testing through an online survey using the most engaging social media message. METHODS:A paid social media campaign was developed to disseminate targeted messages about PCa and genetics. We tested combinations of 8 images and 8 messages that were created or selected by the research team and reviewed by a study-specific advisory board. We targeted men and women older than 35 years living in the United States. The campaign was launched on Facebook for 6 days (June 3-8, 2023). We tracked the reach and impressions of each post. The survey, administered directly after someone viewed a post, assessed knowledge about PCa and cancer genetics as well as beliefs about cancer risk and genetic testing. Descriptive and multivariable analyses were used to analyze survey data. RESULTS:Most posts were viewed by women (13,675/16,224, 84.3% of impressions) and people over the age of 55 years (19,997/22,906, 87.3% of impressions). The 2 most engaging images were a group of men of different races and ethnicities (reach: 28,151 people; impressions: 33,727 views), followed by a Hispanic family (reach: 16,026 people; impressions: 20,113 views). The following message had the most engagement: "Breast cancer and prostate cancer may be related because they can arise from the same gene mutation in a family" (reach: 58,980 people; impressions: 74,834 views). A total of 875 people (n=796, 91% male; mean age 43.42, SD 14.1 years; n=224, 25.6% Black or African American individuals; n=255, 29.1% Hispanic individuals) completed the survey. In total, 75.2% (658/875) strongly or somewhat agreed that genetics play a role in the development of PCa, and 84% (735/875) would want to know if they had a genetic predisposition to PCa. CONCLUSIONS:It is feasible to use social media platforms to test and disseminate messages that raise awareness about PCa genetics and the connection with other cancers (eg, breast cancer), as well as to deploy surveys that reach a wide audience.

Social media can benefit prostate cancer care through education and empowerment, but also have the potential for exposure to misinformation, leading to adverse health and/or economic impacts for patients and damaging the patient-physician relationship. Clinicians should promote digital health literacy and provide recommended sources of reliable online content for additional information.

BACKGROUND:Fall injury is a sentinel event for mortality among older adults, and activity intensity may play a role in mitigating this outcome. This study assessed the relationship between activity intensity and all-cause mortality following fall injury among community-dwelling U.S. older adults. METHODS:For this retrospective cohort study, we pooled 12 years of data from the National Health Interview Survey and identified older adults (aged 65 years and older) who sustained fall injuries (N = 2454). The outcome variable was time to death following a fall injury. We defined activity intensity as a binary variable, none-to-low and normal-to-high, using the American Heart Association's weekly 500 Metabolic Equivalent of Task (MET) as a cutoff. We controlled for sociodemographic, healthcare access, and health characteristics; performed survey-weighted Cox proportional hazard regression analysis; and reported the adjusted mortality risks (plus 95% confidence interval (CI)). RESULTS:The survey comprised 2454 older adults with fall injuries, representing 863,845 US older adults. The population was predominantly female (68%), non-Hispanic White (85%), and divorced/separated (54%). During the follow-up period, 45% of the study population died. Approximately 81% of the study population had low activity levels. However, between 2006 and 2017, the proportion of the study population with low physical activity decreased from 90% to 67%. After adjusting for sociodemographic, healthcare access, and health characteristics, none-to-low activity intensity was associated with 50% increased mortality risk (aHR: 1.50; 95% CI: 1.20-1.87). CONCLUSIONS:Promoting higher physical activity levels may significantly reduce the all-cause mortality risk following fall injury among older adults.

BACKGROUND:Glaucoma Research Foundation's third Catalyst for a Cure team (CFC3) was established in 2019 to uncover new therapies for glaucoma, a leading cause of blindness. In the 2021 meeting "Solving Neurodegeneration," (detailed in Mol Neurodegeneration 17(1), 2022) the team examined the failures of investigational monotherapies, issues with translatability, and other significant challenges faced when working with neurodegenerative disease models. They emphasized the need for novel, humanized models and proposed identifying commonalities across neurodegenerative diseases to support the creation of pan-neurodegenerative disease therapies. Since then, the fourth Catalyst for a Cure team (CFC4) was formed to explore commonalities between glaucoma and other neurodegenerative diseases. This review summarizes outcomes from the 2023 "Solving Neurodegeneration 2" meeting, a forum for CFC3 and CFC4 to share updates, problem solve, plan future research collaborations, and identify areas of unmet need or opportunity in glaucoma and the broader field of neurodegenerative disease research. MAIN BODY/METHODS:We summarize the recent progress in the field of neurodegenerative disease research and present the newest challenges and opportunities moving forward. While translatability and disease complexity continue to pose major challenges, important progress has been made in identifying neuroprotective targets and understanding neuron-glia-vascular cell interactions. New challenges involve improving our understanding of the disease microenvironment and timeline, identifying the optimal approach(es) to neuronal replacement, and finding the best drug combinations and synergies for neuroprotection. We propose solutions to common research questions, provide prescriptive recommendations for future studies, and detail methodologies, strategies, and approaches for addressing major challenges at the forefront of neurodegenerative disease research. CONCLUSIONS:This review is intended to serve as a research framework, offering recommendations and approaches to validating neuroprotective targets, investigating rare cell types, performing cell-specific functional characterizations, leveraging novel adaptations of scRNAseq, and performing single-cell sorting and sequencing across neurodegenerative diseases and disease models. We focus on modeling neurodegeneration using glaucoma and other neurodegenerative pathologies to investigate the temporal and spatial dynamics of neurodegenerative disease pathogenesis, suggesting researchers aim to identify pan-neurodegenerative drug targets and drug combinations leverageable across neurodegenerative diseases.

BACKGROUND:Moral distress, which occurs when the ethically correct action cannot be taken because of internal or external constraints, is associated with depression, burnout, and the desire to leave the healthcare profession among healthcare workers. This study compares internal medicine (IM) residents’ experiences of moral distress while caring for patients with COVID-19 in the year prior to and during the first year of the COVID-19 pandemic. METHODS:This is a mixed methods prospective observational cohort study that enrolled IM residents on a rolling basis beginning December 2018. Moral distress was evaluated via the validated Moral Distress Score-Revised (MDS-R) and Measure of Moral Distress for Healthcare Professionals (MDD-HP) and open-ended questions every 4-months via online surveys and through five resident focus groups. The moral distress scores (MDS) before and during the COVID-19 pandemic were compared using paired t-tests. Transcripts and free text were independently coded by investigators and analyzed by major themes and sub-themes. RESULTS: < .05). Qualitive findings included the exacerbation of existing moral distress and the emergence of new drivers of moral distress, including personal protective equipment, visitor policies, lack of moral framework, and tension between protecting one’s own health and caring for others. CONCLUSIONS:The results of this preliminary analysis suggest that the COVID-19 pandemic exacerbated pre-existing experiences of moral distress and brought to light new and different morally distressing situations for trainees. This analysis of the impact of the pandemic is valuable not only for identifying leverage points for intervention, but also for informing future crisis preparedness and cultivating moral resilience in trainees and the healthcare workforce. SUPPLEMENTARY INFORMATION:The online version contains supplementary material available at 10.1186/s12910-025-01274-6.

Exposure to organophosphate pesticides (OPPs) has been linked to adverse birth outcomes, including low birthweight. Maternal biomarkers are commonly used as proxies for fetal exposure, but fetal exposure also depends on placental transport mechanisms. In 240 mother-newborn pairs, we explored how genetic variation in membrane transporters influences the association between maternal OPP concentrations and birthweight. Single nucleotide polymorphisms (SNPs) in the OAT4/SLC22A11 and OATP2B1/SLCO2B1 membrane transporters modified the relationship between OPP exposure and birthweight-for-gestational age, with significant inverse associations observed only among individuals with variant transporter genotypes. In this small study, we found that transporter genotype may influence the placental disposition of environmental chemicals and perinatal susceptibility to toxicity.