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OBJECTIVE: To quantify the effect of neighborhood socioeconomic vulnerability as it relates to racial disparity in uterine cancer treatment and survival. METHODS: Patients with a diagnosis of uterine cancer who underwent hysterectomy in New York State from 2004 to 2017 were included in this retrospective cohort study. Neighborhood socioeconomic vulnerability as quantified by the Area Deprivation Index was calculated. Primary outcome was guideline adherent treatment; secondary outcome was 5 year overall survival. RESULTS: A total of 34,356 patients were included in the final cohort. Residence within a vulnerable neighborhood was associated with a lower likelihood of receiving appropriate adjuvant chemotherapy (59.7% vs 75.7% with aRR = 0.81; 95% CI, 0.77-0.86) and timely surgery (63.7% vs. 74.5% with aRR = 0.85; 95% CI, 0.82-0.87). All-cause mortality was 24% higher for those who resided in vulnerable neighborhoods compared to affluent neighborhoods (aHR = 1.24; 95% CI, 1.16-1.32). The greatest Black/White racial disparity in 5 year overall survival was seen in the most affluent neighborhoods at 18.6%, with survival being 79.8% for White patients and 61.2% for Black patients (aHR 1.31; 95% CI 1.14-1.51). For patients with advanced stage disease, this disparity was driven by improved survival for White patients with increasing neighborhood affluence but no change in survival for Black patients. On adjusted analysis controlling for age, comorbidities, insurance, tumor histology, stage, and grade, the disparity remained widest in the most affluent neighborhoods in NYC (aHR = 1.59; 95%CI 1.26-1.2.01). CONCLUSIONS: Neighborhood socioeconomic vulnerability is associated with poor outcomes for patients with uterine cancer. The greatest Black/White survival disparities are in the wealthiest neighborhoods. Neighborhood affluence may not affect survival of Black patients with advanced stage endometrial cancer.
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Background: Rib fractures are common injuries associated with considerable morbidity, long-term disability, and mortality. Early, adequate analgesia is important to mitigate complications such as pneumonia and respiratory failure. Regional anesthesia has been proposed for rib fracture pain control due to its superior side effect profile compared with systemic analgesia. Our objective was to evaluate the effect of emergency physician-performed, ultrasound-guided serratus anterior plane block (SAPB) on pain and respiratory function in emergency department patients with multiple acute rib fractures. Methods: This was a prospective observational cohort study of adult patients at a level 1 trauma center who had two or more acute unilateral rib fractures. Eligible patients received a SAPB if an emergency physician trained in the procedure was available at the time of diagnosis. Primary outcomes were the absolute change in pain scores and percent change in expected incentive spirometry volumes from baseline to 3 hours after rib fracture diagnosis. Results: 38 patients met eligibility criteria, 15 received the SAPB and 23 did not. The SAPB group had a greater decrease in pain scores at 3 hours (-3.7 vs. -0.9; p=0.003) compared with the non-SAPB group. The SAPB group also had an 11% (CI 1.5% to 17%) increase in percent expected spirometry volumes at 3 hours which was significantly better than the non-SAPB group, which had a -3% (CI -9.1% to 2.7%) decrease (p=0.008). Conclusion: Patients with rib fractures who received SAPB as part of a multimodal pain control strategy had a greater improvement in pain and respiratory function compared with those who did not. Larger trials are indicated to assess the generalizability of these initial findings.
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BACKGROUND: The accessibility of pharmacies has been associated with overall health and wellbeing. Past studies have suggested that low income and racial minority communities are underserved by pharmacies. However, the literature is inconsistent in finding links between area-level income or racial and ethnic composition and access to pharmacies. Here we aim to assess area-level spatial access to pharmacies across New York State (NYS), hypothesizing that Census Tracts with higher poverty rates and higher percentages of Black and Hispanic residents would have lower spatial access. METHODS: The population weighted mean shortest road network distance (PWMSD) to a pharmacy in 2018 was calculated for each Census Tract in NYS. This statistic was calculated from the shortest road network distance to a pharmacy from the centroid of each Census block within a tract, with the mean across census blocks weighted by the population of the census block. Cross-sectional analyses were conducted to assess links between Tract-level socio demographic characteristics and Tract-level PWMSD to a pharmacy. RESULTS: Overall the mean PWMSD to a pharmacy across Census tracts in NYS was 2.07 Km (SD = 3.35, median 0.85 Km). Shorter PWMSD to a pharmacy were associated with higher Tract-level % poverty, % Black/African American (AA) residents, and % Hispanic/Latino residents and with lower Tract-level % of residents with a college degree. Compared to tracts in the lowest quartile of % Black/AA residents, tracts in the highest quartile had a 70.7% (95% CI 68.3-72.9%) shorter PWMSD to a pharmacy. Similarly, tracts in the highest quartile of % poverty had a 61.3% (95% CI 58.0-64.4%) shorter PWMSD to a pharmacy than tracts in the lowest quartile. CONCLUSION: The analyses show that tracts in NYS with higher racial and ethnic minority populations and higher poverty rates have higher spatial access to pharmacies.
Subject(s)
Ethnicity , Pharmacies , Humans , New York , Cross-Sectional Studies , Health Services Accessibility , Minority GroupsABSTRACT
AbstractGregarious species must distinguish group members from nongroup members. Olfaction is important for group recognition in social insects and mammals but rarely studied in birds, despite birds using olfaction in social contexts from species discrimination to kin recognition. Olfactory group recognition requires that groups have a signature odor, so we tested for preen oil and feather chemical similarity in group-living smooth-billed anis (Crotophaga ani). Physiology affects body chemistry, so we also tested for an effect of egg-laying competition, as a proxy for reproductive status, on female chemical similarity. Finally, the fermentation hypothesis for chemical recognition posits that host-associated microbes affect host odor, so we tested for covariation between chemicals and microbiota. Group members were more chemically similar across both body regions. We found no chemical differences between sexes, but females in groups with less egg-laying competition had more similar preen oil, suggesting that preen oil contains information about reproductive status. There was no overall covariation between chemicals and microbes; instead, subsets of microbes could mediate olfactory cues in birds. Preen oil and feather chemicals showed little overlap and may contain different information. This is the first demonstration of group chemical signatures in birds, a finding of particular interest given that smooth-billed anis live in nonkin breeding groups. Behavioral experiments are needed to test whether anis can distinguish group members from nongroup members using odor cues.
Subject(s)
Birds , Feathers , Animals , Female , Birds/physiology , Reproduction , Smell , MammalsABSTRACT
Structural racism in the United States has resulted in neighborhoods with higher proportions of non-Hispanic Black (Black) or Hispanic/Latine residents having more features that intensify, and less that cool, the local-heat environment. This study identifies areas of New York City (NYC) where racial/ethnic heat exposure disparities are concentrated. We analyzed data from the 2013-2017 American Community Survey, U.S Landsat-8 Analysis Ready Data on summer surface temperatures, and NYC Land Cover Dataset at the census tract-level (n = 2098). Four cross-sectional regression modeling strategies were used to estimate the overall City-wide association, and associations across smaller intra-city areas, between tract-level percent of Black and percent Hispanic/Latine residents and summer day surface temperature, adjusting for altitude, shoreline, and nature-cover: overall NYC linear, borough-specific linear, Community District-specific linear, and geographically weighted regression models. All three linear regressions identified associations between neighborhood racial and ethnic composition and summer day surface temperatures. The geographically weighted regression models, which address the issue of spatial autocorrelation, identified specific locations (such as northwest Bronx, central Brooklyn, and uptown Manhattan) within which racial and ethnic disparities for heat exposures are concentrated. Through examining the overall effects and geographic effect measure modification across spatial scales, the results of this study identify specific geographic areas for intervention to mitigate heat exposure disparities experienced by Black and Hispanic/Latine NYC residents.
Subject(s)
Hot Temperature , New York City , Humans , Hispanic or Latino/statistics & numerical data , Cross-Sectional Studies , Black or African American/statistics & numerical data , Health Status Disparities , Ethnicity/statistics & numerical dataABSTRACT
Medical evaluation for military applicants is an intricate process that requires an understanding of the terminology, standards, and guidelines. Allergy providers are often called to provide medical evaluations for patients who desire to join the military services. Without understanding the complexities and nuances of military medical evaluations, a provider may delay or not be able to assist their patient in obtaining the desired goal of joining the services. This article reviews the terminology of military medical evaluations and the guidelines and processes for these evaluations. We also focus our discussion on common allergic conditions that may be disqualifying for service and provide expert opinions of the subtleties of these conditions to provide the allergist with a practical approach to medical evaluations. Finally, we provide a list of resources that are accessible to any provider engaged in military medical evaluations for accessions.
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Hypersensitivity , Military Personnel , Humans , Hypersensitivity/diagnosis , Practice Guidelines as TopicABSTRACT
Chronic immune thrombocytopenic purpura (ITP) is an acquired hematologic condition that involves immune-mediated platelet destruction with resultant bleeding of variable severity. Refractory ITP occurs when patients fail to tolerate and/or respond to multiple treatment modalities. In this case, we examine the clinical course of a 39-year-old female with refractory ITP and discuss how we navigated a multitude of challenges by adapting an established desensitization protocol to meet our patient's needs. To our knowledge, we describe the first successful desensitization to ofatumumab for use in ITP in the current literature.
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BACKGROUND: Living in neighborhoods with higher levels of walkability has been associated with a reduced risk of obesity and higher levels of physical activity. Obesity has been linked to increased risk of 13 cancers in women. However, long-term prospective studies of neighborhood walkability and risk for obesity-related cancer are scarce. OBJECTIVES: We evaluated the association between long-term average neighborhood walkability and obesity-related cancer risk in women. METHODS: The New York University Women's Health Study (NYUWHS) is a prospective cohort with 14,274 women recruited between 1985 and 1991 in New York City and followed over nearly three decades. We geocoded residential addresses for each participant throughout follow-up and calculated an average annual measure of neighborhood walkability across years of follow-up using data on population density and accessibility to destinations associated with geocoded residential addresses. We used ICD-9 codes to characterize first primary obesity-related cancers and employed Cox proportional hazards models to assess the association between average neighborhood walkability and risk of overall and site-specific obesity-related cancers. RESULTS: Residing in neighborhoods with a higher walkability level was associated with a reduced risk of overall and site-specific obesity-related cancers. The hazards ratios associated with a 1-standard deviation increase in average annual neighborhood walkability were 0.88 (95% CI: 0.85, 0.93) for overall obesity-related cancer, 0.89 (95% CI: 0.84, 0.95) for postmenopausal breast cancer, 0.82 (95% CI: 0.68, 0.99) for ovarian cancer, 0.87 (95% CI: 0.76, 0.99) for endometrial cancer, and 0.68 (95% CI: 0.49, 0.94) for multiple myeloma, adjusting for potential confounders at both the individual and neighborhood level. The association between neighborhood walkability and risk of overall obesity-related cancer was stronger among women living in neighborhoods with higher levels of poverty compared with women living in areas with lower poverty levels (pInteraction=0.006). DISCUSSION: Our study highlights a potential protective role of neighborhood walkability in preventing obesity-related cancers in women. https://doi.org/10.1289/EHP11538.
Subject(s)
Neoplasms , Walking , Humans , Female , Prospective Studies , Universities , Environment Design , Obesity/epidemiology , Residence Characteristics , Women's Health , Neoplasms/epidemiology , New York City/epidemiologyABSTRACT
BACKGROUND: To date, it is still controversial whether tau phosphorylation plays a role in Huntington's disease (HD), as previous studies demonstrated either no alterations or increases in phosphorylated tau (pTau) in HD postmortem brain and mouse models. OBJECTIVE: The goal of this study was to determine whether total tau and pTau levels are altered in HD. METHODS: Immunohistochemistry, cellular fractionations, and western blots were used to measure total tau and pTau levels in a large cohort of HD and control postmortem prefrontal cortex (PFC). Furthermore, western blots were performed to assess tau, and pTau levels in HD and control isogenic embryonic stem cell (ESC)-derived cortical neurons and neuronal stem cells (NSCs). Similarly, western blots were used to assess tau and pTau levels in HttQ111 and transgenic R6/2 mice. Lastly, total tau levels were assessed in HD and healthy control plasma using Quanterix Simoa assay. RESULTS: Our results revealed that, while there was no difference in total tau or pTau levels in HD PFC compared to controls, the levels of tau phosphorylated at S396 were increased in PFC samples from HD patients 60 years or older at time of death. Additionally, tau and pTau levels were not changed in HD ESC-derived cortical neurons and NSCs. Similarly, total tau or pTau levels were not altered in HttQ111 and transgenic R6/2 mice compared to wild-type littermates. Lastly, tau levels were not changed in plasma from a small cohort of HD patients compared to controls. CONCLUSIONS: Together these findings demonstrate that pTau-S396 levels increase significantly with age in HD PFC.
Subject(s)
Huntington Disease , Mice , Animals , Humans , Huntington Disease/metabolism , Phosphorylation , Serine/metabolism , Mice, Transgenic , Prefrontal Cortex/metabolism , Disease Models, AnimalABSTRACT
An investigation into the inspection capabilities of in-field advanced ultrasound detection for use on ultra-thick (20 to 100 mm) glass fibre-reinforced polyester composites is presented. Plates were manufactured using custom moulding techniques, such that delamination flaws were created at calibrated depths. The full matrix capture technique with an on-board total focussing method was used to detect flaws scanned by a 0.5 MHz linear array probe. Flaw through-thickness dimensions were altered to assess the threshold for crack face separation at which delaminations could be identified. Furthermore, part thickness and in-plane flaw dimensions were varied to identify the inspection capability limitations of advanced ultrasonics for thick composites. The results presented in this study demonstrate an inverse relationship between the ability to find delaminations and plate thicknesses, with inspections successful at depths up to 74 mm. When the delamination thickness exhibited surface-to-surface contact, the inspection capability was reduced to 35 mm. There was an exponential decay relationship between the accuracy of the flaw depth measurement and plate thickness, likely due to the necessity of low probe frequencies. The effective inspection depth was determined to be in the range of 1 to 20 times the wavelength. It is speculated that the accuracy of measurements could be improved using probes with novel coupling solutions, and detectors with optimised signal processing/filtration algorithms.
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Background: To date, it is still controversial whether tau phosphorylation plays a role in Huntington's disease (HD), as previous studies demonstrated either no alterations or increases in phosphorylated tau (pTau) in HD post-mortem brain and mouse models. Objectives: The goal of this study was to determine whether total tau and pTau levels are altered in HD. Methods: Immunohistochemistry, cellular fractionations, and western blots were used to measure tau and pTau levels in a large cohort of HD and control post-mortem prefrontal cortex (PFC). Furthermore, western blots were performed to assess tau, and pTau levels in HD and control isogenic embryonic stem cell (ESC)-derived cortical neurons and neuronal stem cells (NSCs). Similarly, western blots were used to assess tau and pTau in Htt Q111 and transgenic R6/2 mice. Lastly, total tau levels were assessed in HD and healthy control plasma using Quanterix Simoa assay. Results: Our results revealed that, while there was no difference in tau or pTau levels in HD PFC compared to controls, tau phosphorylated at S396 levels were increased in PFC samples from HD patients 60 years or older at time of death. Additionally, tau and pTau levels were not changed in HD ESC-derived cortical neurons and NSCs. Similarly, tau or pTau levels were not altered in Htt Q111 and transgenic R6/2 mice compared to wild-type littermates. Lastly, tau levels were not changed in plasma from a small cohort of HD patients compared to controls. Conclusion: Together these findings demonstrate that pTau-S396 levels increase significantly with age in HD PFC.
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Neighborhood walkability-features of the built environment that promote pedestrian activity-has been associated with greater physical activity and lower body mass index (BMI; calculated as weight (kg)/height (m)2) among neighborhood residents. However, much of the literature has been cross-sectional and only a few cohort studies have assessed neighborhood features throughout follow-up. Using data from the Reasons for Geographic and Racial Differences in Stroke Study (2003-2016) and a neighborhood walkability index (NWI) measured annually during follow-up, we assessed whether the cumulative experience of neighborhood walkability (NWI-years) predicted BMI and waist circumference after approximately 10 years of follow-up, controlling for these anthropometric measures at enrollment. Analyses were adjusted for individual-level sociodemographic covariates and the cumulative experience of neighborhood poverty rate and neighborhood greenspace coverage. Almost a third (29%) of participants changed address at least once during follow-up. The first change of residence, on average, brought the participants to neighborhoods with higher home values and lower NWI scores than their originating neighborhoods. Compared with those having experienced the lowest quartile of cumulative NWI-years, those who experienced the highest quartile had 0.83 lower BMI (95% confidence interval, -1.5, -0.16) and 1.07-cm smaller waist circumference (95% confidence interval, -1.96, -0.19) at follow-up. These analyses provide additional longitudinal evidence that residential neighborhood features that support pedestrian activity are associated with lower adiposity.
Subject(s)
Exercise , Walking , Humans , Waist Circumference , Cross-Sectional Studies , Obesity , Residence Characteristics , Environment DesignABSTRACT
Importance: Infants born with unhealthy birth weight are at greater risk for long-term health complications, but little is known about how neighborhood characteristics (eg, walkability, food environment) may affect birth weight outcomes. Objective: To assess whether neighborhood-level characteristics (poverty rate, food environment, and walkability) are associated with risk of unhealthy birth weight outcomes and to evaluate whether gestational weight gain mediated these associations. Design, Setting, and Participants: The population-based cross-sectional study included births in the 2015 vital statistics records from the New York City Department of Health and Mental Hygiene. Only singleton births and observations with complete birth weight and covariate data were included. Analyses were performed from November 2021 to March 2022. Exposures: Residential neighborhood-level characteristics, including poverty, food environment (healthy and unhealthy food retail establishments), and walkability (measured by both walkable destinations and a neighborhood walkability index combining walkability measures like street intersection and transit stop density). Neighborhood-level variables categorized into quartiles. Main Outcomes and Measures: The main outcomes were birth certificate birth weight measures including small for gestational age (SGA), large for gestational age (LGA), and sex-specific birth weight for gestational age z-score. Generalized linear mixed-effects models and hierarchical linear models estimated risk ratios for associations between density of neighborhood-level characteristics within a 1-km buffer of residential census block centroid and birth weight outcomes. Results: The study included 106â¯194 births in New York City. The mean (SD) age of pregnant individuals in the sample was 29.9 (6.1) years. Prevalence of SGA and LGA were 12.9% and 8.4%, respectively. Residence in the highest density quartile of healthy food retail establishments compared with the lowest quartile was associated with lower adjusted risk of SGA (with adjustment for individual covariates including gestational weight gain z-score: risk ratio [RR], 0.89; 95% CI 0.83-0.97). Higher neighborhood density of unhealthy food retail establishments was associated with higher adjusted risk of delivering an infant classified as SGA (fourth vs first quartile: RR, 1.12; 95% CI, 1.01-1.24). The RR for the association between density of unhealthy food retail establishments and risk of LGA was higher after adjustment for all covariates in each quartile compared with quartile 1 (second: RR, 1.12 [95% CI, 1.04-1.20]; third: RR, 1.18 [95% CI, 1.08-1.29]; fourth: RR, 1.16; [95% CI, 1.04-1.29]). There were no associations between neighborhood walkability and birth weight outcomes (SGA for fourth vs first quartile: RR, 1.01 [95% CI, 0.94-1.08]; LGA for fourth vs first quartile: RR, 1.06 [95% CI, 0.98-1.14]). Conclusions and Relevance: In this population-based cross-sectional study, healthfulness of neighborhood food environments was associated with risk of SGA and LGA. The findings support use of urban design and planning guidelines to improve food environments to support healthy pregnancies and birth weight.
Subject(s)
Gestational Weight Gain , Infant , Female , Pregnancy , Male , Humans , Adult , Birth Weight , Cross-Sectional Studies , New York City , FoodABSTRACT
Despite the extensive use of intermittent catheters (ICs) in healthcare, various issues persist for long-term IC users, such as pain, discomfort, infection, and tissue damage, including strictures, scarring and micro-abrasions. A lubricous IC surface is considered necessary to reduce patient pain and trauma, and therefore is a primary focus of IC development to improve patient comfort. While an important consideration, other factors should be routinely investigated to inform future IC development. An array of in vitro tests should be employed to assess IC's lubricity, biocompatibility and the risk of urinary tract infection development associated with their use. Herein, we highlight the importance of current in vitro characterisation techniques, the demand for optimisation and an unmet need to develop a universal 'toolkit' to assess IC properties.
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BACKGROUND: Nocturnal syncope is a common presentation in the emergency department, often related to orthostatic hypotension and subsequent loss of cerebral perfusion when patients get up from sleep to use the restroom faster than their cardiac output and vascular tone can accommodate. Poor hydration status and antihypertensive medications can increase this risk. Patients with syncope who present to the emergency department with a pacemaker are usually evaluated with a pacemaker interrogation to evaluate for runs of nonperfusing rhythms (e.g., ventricular tachycardia or fibrillation). Sleep rate mode (SRM) is a relatively new feature of modern pacemakers and is not currently recognized by emergency physicians. It was implemented to accommodate more physiologic fluctuations in heart rate during rapid eye movement sleep. There is a paucity of evidence supporting the clinical benefit of SRM and similarly no documentation of prior complications of SRM in the current literature. CASE REPORT: We report the case of a 92-year-old woman with a Medtronic Avisa pacemaker presenting with recurrent nocturnal syncope and bradycardia resulting in multiple emergency department visits. These episodes ultimately resolved by turning off SRM on her pacemaker. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: SRM is not currently flagged on interrogation report summaries provided to emergency physicians. This report highlights the importance of recognizing this mode as a potential etiology of nocturnal syncope related to chronotropic incompetence in patients with pacemakers.
Subject(s)
Pacemaker, Artificial , Female , Humans , Aged, 80 and over , Pacemaker, Artificial/adverse effects , Syncope/complications , Arrhythmias, Cardiac/complications , Bradycardia , SleepABSTRACT
BACKGROUND: Subcutaneous Immunotherapy (SCIT) provides long-lasting benefits when administered for 3 to 5 years. OBJECTIVE: We evaluated SCIT adherence and factors associated with adherence in a military health care system with no out-of-pocket expenses. METHODS: We performed a combined retrospective and prospective observational electronic medical record review of SCIT from 2005 to 2012 to determine the start of therapy, time to maintenance dose (MD), duration of MD, and associated factors. RESULTS: We enrolled 897 patients selected for SCIT. A total of 421/897 (47%) were of male sex, 269/897 (30%) had asthma, and 113/897 (13%) had a systemic reaction. Ages ranged from 1 to 74 years (mean 34.8). There were 751/897 (84%) who were on aeroallergen immunotherapy, 108/897 (12%) on imported fire ant immunotherapy, and 54/897 (6%) on venom immunotherapy. Therapy was not initiated in 130/897 (14%) patients. There were 538/897(60%) who received at least 1 MD; 307/897 (34%) completed 3 or more years of MD SCIT, 26% completed 4 or more years of MD SCIT, and 19% completed 5 years or more of MD SCIT. For those reaching MD, the mean total duration was 4.23 years and the mean time on MD was 3.17 years. Men were 271/421 (64%) more likely to reach MD (P = .01). The presence of asthma, age, venom immunotherapy/fire ant immunotherapy vs aeroallergen immunotherapy, and systemic reaction were not associated with reaching MD. After achieving MD, none of the identified factors were associated with SCIT duration. CONCLUSION: Even with no out-of-pocket expenses, adherence to an adequate course of SCIT was 34%. Only the male sex was significantly associated with reaching MD. No factors were associated with the duration of SCIT after MD.
Subject(s)
Ants , Asthma , Animals , Humans , Male , Infant , Child, Preschool , Child , Adolescent , Young Adult , Adult , Middle Aged , Aged , Retrospective Studies , Allergens , Asthma/drug therapy , Desensitization, Immunologic , Immunotherapy , Health Expenditures , Injections, SubcutaneousABSTRACT
The granin neuropeptide family is composed of acidic secretory signaling molecules that act throughout the nervous system to help modulate synaptic signaling and neural activity. Granin neuropeptides have been shown to be dysregulated in different forms of dementia, including Alzheimer's disease (AD). Recent studies have suggested that the granin neuropeptides and their protease-cleaved bioactive peptides (proteoforms) may act as both powerful drivers of gene expression and as a biomarker of synaptic health in AD. The complexity of granin proteoforms in human cerebrospinal fluid (CSF) and brain tissue has not been directly addressed. We developed a reliable nontryptic mass spectrometry assay to comprehensively map and quantify endogenous neuropeptide proteoforms in the brain and CSF of individuals diagnosed with mild cognitive impairment and dementia due to AD compared to healthy controls, individuals with preserved cognition despite AD pathology ("Resilient"), and those with impaired cognition but no AD or other discernible pathology ("Frail"). We drew associations between neuropeptide proteoforms, cognitive status, and AD pathology values. Decreased levels of VGF proteoforms were observed in CSF and brain tissue from individuals with AD compared to controls, while select proteoforms from chromogranin A showed the opposite effect. To address mechanisms of neuropeptide proteoform regulation, we showed that the proteases Calpain-1 and Cathepsin S can cleave chromogranin A, secretogranin-1, and VGF into proteoforms found in both the brain and CSF. We were unable to demonstrate differences in protease abundance in protein extracts from matched brains, suggesting that regulation may occur at the level of transcription.
Subject(s)
Alzheimer Disease , Neuropeptides , Humans , Alzheimer Disease/pathology , Chromogranins/metabolism , Chromogranin A/metabolism , Peptide Fragments/metabolism , Neuropeptides/metabolism , Brain/metabolism , Biomarkers , Peptide Hydrolases/metabolism , Amyloid beta-Peptides/metabolismABSTRACT
Loneliness and social isolation are detrimental to mental health and may lead to cognitive impairment and neurodegeneration. Although several molecular signatures of loneliness have been identified, the molecular mechanisms by which loneliness impacts the brain remain elusive. Here, we performed a bioinformatics approach to untangle the molecular underpinnings associated with loneliness. Co-expression network analysis identified molecular 'switches' responsible for dramatic transcriptional changes in the nucleus accumbens of individuals with known loneliness. Loneliness-related switch genes were enriched in cell cycle, cancer, TGF-ß, FOXO, and PI3K-AKT signaling pathways. Analysis stratified by sex identified switch genes in males with chronic loneliness. Male-specific switch genes were enriched in infection, innate immunity, and cancer-related pathways. Correlation analysis revealed that loneliness-related switch genes significantly overlapped with 82% and 68% of human studies on Alzheimer's (AD) and Parkinson's diseases (PD), respectively, in gene expression databases. Loneliness-related switch genes, BCAM, NECTIN2, NPAS3, RBM38, PELI1, DPP10, and ASGR2, have been identified as genetic risk factors for AD. Likewise, switch genes HLA-DRB5, ALDOA, and GPNMB are known genetic loci in PD. Similarly, loneliness-related switch genes overlapped in 70% and 64% of human studies on major depressive disorder and schizophrenia, respectively. Nine switch genes, HLA-DRB5, ARHGAP15, COL4A1, RBM38, DMD, LGALS3BP, WSCD2, CYTH4, and CNTRL, overlapped with known genetic variants in depression. Seven switch genes, NPAS3, ARHGAP15, LGALS3BP, DPP10, SMYD3, CPXCR1, and HLA-DRB5 were associated with known risk factors for schizophrenia. Collectively, we identified molecular determinants of loneliness and dysregulated pathways in the brain of non-demented adults. The association of switch genes with known risk factors for neuropsychiatric and neurodegenerative diseases provides a molecular explanation for the observed prevalence of these diseases among lonely individuals.