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Multi-modal choroid plexus pathology in aging and Alzheimer's disease [preprint]
No full textThis article is a preprint. Preprints are preliminary reports of work that have not been certified by peer review.Brain barriers, cerebrospinal fluid (CSF) dynamics, and peripheral factors are implicated as significant contributors to Alzheimer's disease (AD). The choroid plexus (ChP) is a blood-brain interface that produces CSF and forms the blood-CSF barrier. However, how ChP pathology develops across the lifespan and contributes to AD has not been systematically characterized. Here, we report a multi-modal ChP atlas integrating single-nucleus transcriptomics from 49 individuals, AI-assisted quantitative histopathology across >500 postmortem samples age 16 to 105, spatial transcriptomics, and functional studies in 5xFAD mice. We identify fibrosis, calcification, and macrophage abnormalities as hallmarks of ChP aging, with AD pathology conferring additional effects, including expansion of a pro-inflammatory fibroblast-macrophage signaling niche. In 5xFAD mice, macrophage dysfunction is associated with impaired epithelial barrier maintenance and repair. Together, these data provide a foundational resource for understanding ChP dysfunction in aging and AD and propose the macrophage-fibroblast-epithelial barrier axis as a driver of ChP pathology.No embarg
Adulting Shorts: Money Moves — Zero-Based Budgeting Made Easy
No full textZero-based budgeting is a financial planning method where you allocate every dollar of your income to specific categories—such as expenses, savings, or debt repayment—so that your total income minus your total expenses equals zero at the end of each budgeting period (often monthly). This approach helps you plan intentionally, knowing exactly where your money goes, and makes it easier to adjust priorities as your needs change. This comic by the Learning & Working RRTC provides a visually engaging, concise guide to zero-based budgeting. Designed to support young adults and those transitioning to independence, the comic breaks down the steps of zero-based budgeting in an accessible and relatable way, helping readers gain confidence and control over their finances.The contents of this comic were supported in part under grants with funding from the National Institute on Disability, Independent Living, and Rehabilitation Research, (NIDILRR), United States Departments of Health and Human Services (NIDILRR grant number 90RTE0012, The Learning and Working RRTC). NIDILRR is a Center within the Administration for Community Living (ACL), Department of Health and Human Services (HHS). The contents of this comic do not necessarily represent the policy of NIDILRR, ACL, or HHS and you should not assume endorsement by the Federal Government.No embarg
School Health Staff Perspectives on the Implementation of Single Maintenance and Reliever Therapy (SMART) for Children with Asthma
No full textINTRODUCTION: Single maintenance and reliever therapy (SMART) uses a single inhaler for daily maintenance and as-needed relief. Despite evidence that SMART is more effective in reducing exacerbations than traditional therapy, it is not widely implemented. Successful SMART implementation requires participation from school health staff (SHS), who are a critical part of pediatric asthma management.
METHODS: Using a descriptive convergent mixed methods design and grounded in the Consolidated Framework for Implementation Research, we conducted surveys and semi-structured interviews with SHS to explore their perspectives on SMART implementation in schools. We calculated descriptive statistics for survey items and used rapid qualitative analysis to synthesize interview data.
RESULTS: A total of 11 SHS completed an interview and 22 completed a survey. Nearly all participants were familiar with SMART and 45% reported experience administering SMART. Most participants (59%) believed that SMART would be simpler for their students. In interviews, many participants highlighted that having one inhaler would also be simpler for them to manage. To support SMART implementation, communication with prescribing providers was highlighted as a primary need; 64% wanted a brief phone call with a provider, 59% wanted an email, and 82% wanted to receive a SMART-specific Asthma Action Plan.
DISCUSSION: School health staff reported familiarity with SMART and confidence in their ability to administer it. Multilevel needs include clear communication from pediatric providers when children initiate SMART and availability of SMART inhalers. Future research should explore development and implementation of strategies to address these needs while integrating perspectives of providers and families.No embarg
An expanded registry of candidate cis-regulatory elements
No full textMammalian genomes contain millions of regulatory elements that control the complex patterns of gene expression. Previously, the ENCODE consortium mapped biochemical signals across hundreds of cell types and tissues and integrated these data to develop a registry containing 0.9 million human and 300,000 mouse candidate cis-regulatory elements (cCREs) annotated with potential functions. Here we have expanded the registry to include 2.37 million human and 967,000 mouse cCREs, leveraging new ENCODE datasets and enhanced computational methods. This expanded registry covers hundreds of unique cell and tissue types, providing a comprehensive understanding of gene regulation. Functional characterization data from assays such as STARR-seq, massively parallel reporter assay, CRISPR perturbation and transgenic mouse assays have profiled more than 90% of human cCREs, revealing complex regulatory functions. We identified thousands of novel silencer cCREs and demonstrated their dual enhancer and silencer roles in different cellular contexts. Integrating the registry with other ENCODE annotations facilitates genetic variation interpretation and trait-associated gene identification, exemplified by the identification of KLF1 as a novel causal gene for red blood cell traits. This expanded registry is a valuable resource for studying the regulatory genome and its impact on health and disease.No embarg
The PRogram In Support of Moms (PRISM): Increasing obstetric practice capacity to implement the depression care pathway
No full textBACKGROUND: Perinatal depression is common yet undertreated. The Massachusetts Child Psychiatry Access Program (MCPAP) for Moms is a state-wide program to improve access to perinatal depression care by providing training, consultation, and referrals to healthcare professionals serving perinatal women. The PRogram In Support of Moms (PRISM) includes MCPAP for Moms plus practice-level implementation support. This cluster randomized controlled trial compared MCPAP for Moms vs. PRISM in implementation of the perinatal depression care pathway, inclusive of screening, assessment, treatment, follow-up and monitoring, and transition of care.
METHODS: Ten obstetric practices were randomized to MCPAP for Moms or PRISM. We abstracted medical record data for perinatal individuals enrolled in the study with elevated depression symptoms (n = 294). Generalized linear mixed-effects models, accounting for clustering of practices, compared post-intervention implementation of the depression care pathway. We also examined changes in implementation via practice leadership surveys.
RESULTS: Patients in PRISM practices were more likely to be screened for bipolar disorder (OR = 385.0, p = .001), have treatment engagement documented (OR = 2.8, p = .011), receive follow-up monitoring (OR = 4.0, p = .003), and receive a transition of care plan (OR = 2.7, p = .016). Patients in PRISM practices were more likely to be identified as having perinatal depression (OR = 2.3, p = .001). Practice leadership reported greater increase in capacity to address perinatal depression in PRISM practices (3.7 points, p = .005).
CONCLUSIONS: PRISM was associated with greater depression care pathway implementation and improved identification of patients with perinatal depression. In order to help implement new initiatives (i.e. bipolar disorder screening) aligned with the depression care pathway, practice-level assistance may be needed.No embarg
Cultural-Social-Economic Background and Community Engagement Impacting COVID-19 Vaccination Uptake Among Pregnant and Lactating Refugee Women
No full textCOVID-19 vaccine uptake in pregnant and lactating refugee women remains understudied despite their high risk of severe health outcomes. Our survey of 672 refugee women who gave birth at an urban hospital in a southwestern U.S. state between 2020 and 2023 revealed a concerningly low vaccination rate, with only 45.4% receiving one or more COVID-19 vaccine doses. Vaccination status was highly heterogeneous, with uptake ranging from 76.9% among women relocated from Afghanistan and South Asia to merely 23.8% among those from Congo, Tanzania, and several other African nations. Women residing in low-income areas and socioeconomically segregated communities were less likely to be vaccinated. Importantly, engagement with cultural health navigators (CHNs)-certified, multilingual, and bicultural individuals who share lived experiences of forced displacement with refugees and facilitate their healthcare navigation, education, and trust-building-helped mitigate these disparities. CHN support increased vaccination uptake among initially reluctant individuals, with some initiating vaccination during pregnancy. The effectiveness of CHN support varied by country of origin, underscoring the need for culturally tailored interventions to promote health equity in underserved populations.No embarg
Cooperativity and communication between the active sites of the dimeric SARS-CoV-2 main protease
Full text linkThe coronaviral main protease (M) has been the subject of various biochemical and structural studies and a drug target against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. SARS-CoV-2 M is active as a dimer, but despite apparent cooperativity in catalytic activity, how the two distal active sites communicate and modulate binding and/or catalysis is unclear. Here, we have investigated the interplay between cooperativity, dimerization, and substrate cleavage in SARS-CoV-2 M through a combination of enzymatic assays, crystal structures, and protein characterization. To disentangle the contribution of each active site to the observed enzymatic activity, we developed a cleavage assay involving heterodimers of active and inactive (catalytic residue mutated or inhibitor-bound) monomers. Notably, we found that heterodimerization increased cleavage efficiency per active monomer. In addition, we mapped a network of critical residues bridging the two active sites and probed this network through engineered mutations. By dissecting the cooperativity and communication between the active sites, we provide insights into the M reaction cycle and functional significance of its dimeric architecture.No embarg
Utilizing Latent Dirichlet Allocation and Differential Abundance to Identify Microbial Communities in both the Oral and Fecal Microbiome Associated with Alzheimer’s Disease
Full text linkBackground: Several studies have found that oral and gut microbiome and their
byproducts can impact Alzheimer’s Disease (AD). The objective of our study is to
analyze metagenomic sequencing data from paired oral and fecal microbiomes, along
with clinical variables, to identify communities of bacteria associated with AD. This
research aims to improve our understanding of the microbiome community matrix, and
how these communities interact and correlate with AD status compared to healthy
controls (HC) through an oral-gut microbial axis.
Method: The study includes 223 HC and 43 individuals with AD. During each
visit, paired oral and fecal samples were collected, along with clinical variables.
Metagenomic profiling was done on all samples. Latent Dirichlet Allocation (LDA) was
applied to identify differences in microbial species groups between these two body
sites in realtion to AD status. LDA is used as a topic modeling method to uncover the
complex structure and function of microbial communities. Subsequently, differential
abundance (DA) analysis was performed to identify species with differential
abundance at each body site.
Result: We identified microbiotal communities sharing similar characteristics and
pinpointed representative bacteria within these communities that are highly relevant
to AD. Within the oral microbiome, we have identified 27 topics, including several
bacteria that are highly relevant to AD. These included Alistipes (beta = 3.919232e-01),
Paraprevotella xylaniphila (beta = 1.227791e-01), Desulfovibrio (beta = 6.013213e-
02), and Lachnospiraceae (beta = 2.304369e-02). In the gut, we have identified 50
topics, reflecting the gut is more complex the oral microbiome. Notable bacteria in
the gut microbiome include Actinomyces oricola (beta = 6.959554e-01), Roseburia (beta = 8.861444e-02), Bacteroidetes (beta = 5.010610e-01), and Actinomyces gerencseriae
(beta = 3.048668e-02).
Conclusion: Our study has identified a variety of bacteria that exhibit novel community
patterns that associate with AD. In the gut, A. gerencseriae and other oral microbiomes
were observed in AD patients. Also, the microbial communities differ between AD
and HC. Thereforth, we conclude that translocation of oral and gut microbiota may
contribute to AD through an oral-gut-microbiome axis.No embarg
Adolescent onset of volitional ethanol intake normalizes sex differences observed with adult-onset ethanol intake and negative affective behaviors during protracted forced abstinence
Full text linkRationale: Negative affect during ethanol abstinence can lead to relapse and dependence. Voluntary ethanol drinking models are crucial for examining negative affect following chronic ethanol access, but female rodents often drink more ethanol than males, complicating comparisons between sexes. Since chronic adolescent ethanol use poses a substantial risk for later alcohol use disorder, we hypothesize that adolescence is a critical window for consolidating drinking behavior before major hormonal changes affect ethanol consumption.
Objectives: This study compared sex differences in voluntary ethanol consumption and negative affective behavior in mice that initiated ethanol consumption during early adolescence (~ PND30) or early adulthood (~ PND53).
Methods: Male and female C57BL/6J mice underwent the Chronic Drinking Forced Abstinence (CDFA) paradigm, with the "Ethanol" group given two-bottle choice access to ethanol and water, and the "Water" group given two water bottles. Ethanol intake and preference were measured over six weeks. Two weeks following ethanol removal, mice underwent behavioral testing for negative affective-like behavior.
Results: Adult-onset female mice consumed significantly more ethanol and displayed higher ethanol preference compared to adult-onset male mice. In contrast, adolescent-onset male and female mice consumed similar ethanol levels and displayed similar preference. We observed increased immobility during the forced swim test in adult-onset ethanol females, but not males, during protracted abstinence. However, both sexes of adolescent-onset ethanol mice displayed increased immobility during forced abstinence.
Conclusions: These findings highlight adolescence as a critical period during which both sexes voluntarily consume ethanol and are equally vulnerable to the behavioral disturbances associated with ethanol abstinence.No embarg
The Association of Long COVID and CKD: Findings from the National Clinical Cohort Collaborative (N3C)
Full text linkBackground: Among patients with acute coronavirus disease-19 (COVID-19), the association of chronic kidney disease (CKD) and Long COVID has not been reported in large multi-center cohorts.
Methods: This study used data from 59 healthcare systems across the United States, in the National Clinical Cohort Collaborative (N3C) COVID Enclave, to analyze the relationship between CKD and Long COVID among adults diagnosed with acute COVID-19 between October 2021 and September 2023. We conducted two main analyses. First analysis: we tested if baseline CKD (estimated glomerular filtration rates (eGFR) <60 ml/min/1.73m2 or diagnostic code) or baseline end-stage kidney disease (ESKD) are risk factors for Long COVID (identified using ICD-10-CM code U09.9). We secondarily assessed associations between baseline mild CKD (Stage 3a, eGFR 45 -59 ml/min/1.73m2) and Long COVID. Second Analysis: among patients without baseline CKD/ESKD, we examined if incident CKD/ESKD and eGFR decline (≥20% in one year) were associated with Long COVID. We used propensity score matching (PSM) for demographics and data-contributing site, with models adjusted for risk factors and competing risk of death. All outcomes were evaluated within a 365-day follow-up period from the onset of acute COVID-19.
Results: First analysis: From an unmatched cohort of 2,385,20 patients with acute COVID-19, those with baseline CKD/ESKD had a higher risk of Long COVID (adjusted sub-distribution hazard ratio [sHR] 1.13, 95% confidence interval [CI] 1.09-1.18) after matching. A similar risk was noted even among those with mild CKD (sHR: 1.15, 95% CI 1.05-1.25). Second Analysis: Among patients with acute COVID-19 and without baseline CKD/ESKD, Long COVID was associated with incident CKD/ESKD (sHR 1.65, 95% CI 1.51-1.81) and 20% or greater eGFR decline (sHR 1.21, 95% CI 1.04-1.40) within one year.
Conclusions: CKD, even mild, was associated with an higher risk of Long COVID. Among those without baseline CKD, Long COVID was associated with incident CKD and eGFR decline.1 year2026/08/0