Faculty Bibliography

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:The nasal microbiome is directly in contact with the external environment and may play a role in respiratory health. This study aimed to evaluate the association of the nasal microbiome with air pollutants, meteorological conditions, and respiratory health in adolescents. METHODS:, temperature, humidity, residential greenness) and respiratory outcomes (asthma, hay fever, wheezing, IgE, aeroallergen sensitization, FeNO, lung function) through regression models adjusted for confounders and corrected using a false discovery rate (FDR) < 5%. RESULTS:, temperature) and respiratory outcomes (hay fever, wheezing, IgE, FeNO, lung function) (FDR < 0.05). Staphylococcus, Corynebacterium, Pelomonas, Lactococcus, Lachnospiraceae (unclassified), and Faecalibacterium abundance were associated with both environmental exposures and respiratory traits. CONCLUSIONS:, and temperature exposure. Multiple short-to-medium-term environmental exposures and respiratory outcomes were associated with nasotypes and bacterial genera abundance in adolescents.

INTRODUCTION/BACKGROUND:The impact of maternal SARS-CoV-2 infection on fetal brain development during pregnancy remains unclear. Prior research has associated other antenatal infections with adverse neurodevelopmental outcomes in offspring. OBJECTIVE:To compare neurodevelopmental outcomes in infants born to mothers infected with SARS-CoV-2 during pregnancy (COVID+) to infants without congenital exposure (COVID-). METHODS:This study included 77 COVID+ infants and 157 COVID- infants assessed at 6 and/or 12 months. Outcomes were based on maternal self-report, observed infant behavior and brain fMRI. RESULTS:Overall, COVID+ and COVID- infant groups showed no significant differences across a range of neurobehavioral measures. However, analyses not adjusted for multiple comparisons revealed differences: fewer night awakenings at 6 (t(154) = 2.24, p < 0.03) and 12 months (t(107) = 1.94, p < 0.05), and reduced duration of orienting at 12 months (t(55.38) = 2.15, p < 0.04) in COVID+ infants. Neural differences were noted in posterior-anterior midline, insular-frontal, insular-posterior cingulate, and frontal-cingulate regions at an uncorrected threshold of p < 0.01. CONCLUSION/CONCLUSIONS:This study of multi-level infant development suggests that infants born to mothers infected with COVID during pregnancy are not experiencing harmful effects of that exposure. IMPACT/CONCLUSIONS:This study contributes comprehensive data on infant neurodevelopmental outcomes following prenatal SARS-CoV-2 exposure, evaluating a wide range of behavioral and neural measures to address gaps in previous research. Findings suggest that congenital exposure to SARS-CoV-2 does not result in significant neurodevelopmental impairments in infants, offering reassurance amidst concerns about potential long-term effects of maternal prenatal COVID-19 infection. Results indicate that any observed differences, such as fewer night awakenings and functional neural connectivity patterns, may reflect a more mature developmental profile in the exposed group. Continued longitudinal research is necessary to understand behaviorally relevant and lasting neurodevelopmental effects of prenatal SARS-CoV-2 exposure.

The U.S. Drug Enforcement Administration (DEA) proposed a rule in which they intend to place the psychedelic phenethylamines 2,5-dimethoxy-4-chloroamphetamine (DOC) and 2,5-dimethoxy-4-iodoamphetamine (DOI) into Schedule I of the Controlled Substances Act. We examined the epidemiology of use and availability of these substances. We examined national trends in seizures of these compounds (which indicate availability) using DEA National Forensic Laboratory Information System (NFLIS) and High Intensity Drug Trafficking Areas (HIDTA) data. We also examined the prevalence of self-reported use on the National Survey of Drug Use and Health (NSDUH), a nationally representative sample of noninstitutionalized individuals aged ≥12 in the United States. The scientific literature was also systematically searched for reports of poisonings linked to use. Between 2005 and 2024, NFLIS received 795 submissions of drugs testing positive for DOC, with a peak of 152 in 2012. There was then a decrease through 2024, with only two submissions containing DOC in 2023-2024. Forty submissions contained DOI, with no submissions testing positive in 2019-2024. Three DOC seizures were recorded by HIDTA in 2017-2021, with none in 2022-2024. HIDTA had no recorded seizures of DOI. Between 2005 and 2023, there were 37 and 10 type-in mentions of lifetime DOC and DOI use, respectively, in NSDUH responses, suggesting a lifetime prevalence of < 0.01% among the noninstitutionalized U.S. population. We located three reports of poisonings linked to DOC use (in 2008-2024) and none linked to DOI use. Availability, recreational use, and poisoning related to the use of DOC and especially DOI appear to be rare.

BACKGROUND:The United States has one of the highest incarceration rates in the world. Prior incarceration is associated with adverse health effects. While the era of "mass incarceration" began in 1973, little work has focused on older adults, whose lives have spanned the five decades of mass incarceration. METHODS:We conducted a cross-sectional analysis using data on adults 50 or older from the nationally representative Family History of Incarceration Survey to test the independent association between prior incarceration and self-reported physical and mental health. In logistic regression models, we controlled for age, gender, race/ethnicity, education, income, employment, and marital status. We also tested for effect modification by race/ethnicity, gender, and time since last incarceration, as well as financial and social wellbeing. RESULTS:Among 1318 older adults, 21% had been incarcerated. Formerly incarcerated older adults were more likely to be men; non-Hispanic Black or "other" race/ethnicity; meet criteria for disability; be unmarried; and have lower income and education compared with those never incarcerated. In fully adjusted models, prior incarceration was independently associated with greater odds of reporting "fair" or "poor" physical health (aOR:1.88, 95% CI: 1.19-2.98; p = 0.007). Prior incarceration was associated with reporting "fair" or "poor" mental health after adjusting for demographic covariates (aOR: 2.12, 95% CI: 1.24-3.65; p = 0.006) but was nonsignificant after adding socioeconomic covariates. Length of time from last incarceration did not moderate the observed association, meaning that even those incarcerated > 10 years ago had poor self-reported health. Financial wellbeing moderated the association between incarceration and mental health. CONCLUSION/CONCLUSIONS:Prior incarceration is a social determinant of health for older adults, even those with distant incarceration history, and is strongly associated with current poverty and meeting criteria for disability. Further research is needed to understand the mechanisms of these associations and means to mitigate health harms associated with prior incarceration.

BACKGROUND:Cardiovascular disease is the most common cause of morbidity and mortality in kidney transplant recipients. Screening for coronary disease is frequently required prior to kidney transplantation, but coronary intervention has not been shown to be beneficial except in complex coronary artery disease. The likelihood of finding significant coronary artery disease and the benefits of routine pre-transplant screening are uncertain. METHODS:We performed a systematic review and meta-analysis. Medline & Embase were searched to identify manuscripts published between 1998 and 2024 reporting the results of pre-transplant screening. The primary endpoints were the frequency of detecting significant coronary lesions for which there are AHA class 1 indications for revascularization: a) >50% left main stenosis; or b) multi-vessel disease with ejection fraction < 35% during pre-kidney transplant screening. Secondary endpoints included frequency of detecting multivessel disease, proximal left anterior descending artery (LAD) disease, and number of patients who underwent invasive coronary angiography. Meta-regression was used to explore outcome heterogeneity according to the presence of hypertension, diabetes, and age. RESULTS:We identified 1273 studies out of which 44 met eligibility criteria. The mean prevalence of class 1 indications was 2%, although the heterogeneity was high with estimates ranging from 0% to 17%. Estimated prevalence of proximal LAD disease was 2% and left main stenosis was 1%, whereas 10% of patients had multi-vessel coronary artery disease, and 35% were referred for invasive angiography. There was no evidence of significant heterogeneity according to sex of the population or prevalence of diabetes or hypertension. CONCLUSIONS:Identification of class I indications for revascularization during pre-transplant coronary screening was rare.

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.