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Identifying trajectories of joint space width loss among previously injured knees: Data from the Osteoarthritis Initiative
Get PDFOBJECTIVES: To identify trajectories of joint space width loss, a proxy measure of tibiofemoral cartilage loss, among previously injured knees. To describe the relationship of trajectory groups with sociodemographic and clinical risk factors. METHODS: Using data from the Osteoarthritis Initiative, we identified right knees with a history of injury. We used group-based trajectory modeling to identify trajectories of joint space width loss over 96-months. Once trajectories were identified, we compared baseline statistics of key risk factors across trajectory groups. RESULTS: Our primary cohort included 772 previously injured right knees. We also analyzed a subset of 251 more recently injured right knees. Across each cohort, we identified three distinct trajectories for men and women separately, differentiated by low, medium, and high baseline joint space width. Rates of JSW loss were similar between trajectories. Those assigned to the high baseline JSW trajectory were younger at study baseline than those assigned to other two trajectories. Among women assigned to the low baseline JSW group, mean age at the time of knee injury was older than the other two trajectories. Among both men and women, the proportion of knees that had undergone a surgery or arthroscopy was highest in the low baseline JSW group. CONCLUSIONS: Among knees with a history of injury, thinner JSW may be associated with knee surgical history and older age. Moving forward, exploring additional risk factors for OA development among previously injured knees may provide new opportunities to target treatments towards those at the greatest risk for the disease
NF-κB RelA regulates temporal oligodendrocyte differentiation in the postnatal brains
Get PDFThe NF-κB signaling pathway responds to a diverse range of cytokines and extracellular stresses, regulating immune responses, inflammation, cell proliferation, and cell death. However, the requirement of NF-κB in oligodendrocyte development and differentiation remains debatable. In this study, we generated conditional knockout mice of the RelA gene in the oligodendrocyte-lineage cells, which encodes a major subunit of NF-κB, and assessed its impact on oligodendrocyte differentiation. In RelA cKO mice, we observed a transient delay of oligodendrocyte differentiation in the postnatal cerebral cortex, albeit in a spatially and temporally restricted manner. Similarly, in the primary cultured oligodendrocyte differentiation model, the loss of RelA resulted in impaired terminal differentiation. Transcriptome analysis revealed a significant downregulation of numerous oligodendrocyte-related genes, including predicted NF-κB target genes. Furthermore, a comprehensive splicing analysis identified aberrant alternative splicing of Plp1, a most abundant and key gene involved in myelin sheath formation. These findings suggest that NF-κB/RelA contributes to the temporal and special control of oligodendrocyte development and differentiation in the postnatal brains. Our results highlight a previously underappreciated role of NF-κB in oligodendrocyte biology and encourage a re-evaluation of its physiological significance in the glial lineage
Data for "Quantification of the relative contribution of phase aberration and reverberation in transcranial ultrasound imaging: an experimentally calibrated fullwave study in 2-D and 3-D" Part 5
No full textData for "Quantification of the relative contribution of phase aberration and reverberation in transcranial ultrasound imaging: an experimentally calibrated fullwave study in 2-D and 3-D
Mapping the nuclear landscape with multiplexed super-resolution fluorescence microscopy
Get PDFThe nucleus coordinates many different processes. Visualizing how these are spatially organized requires imaging protein complexes, epigenetic marks, and DNA across scales from single molecules to the whole nucleus. To accomplish this, we develop a multiplexed imaging protocol to localize 13 different nuclear targets with nanometer precision. Within single cells, we show that nuclear specification into active and repressive states exists along a spectrum of length scales, emerging below one micron and becoming strengthened at the nanoscale with unique organizational principles in both heterochromatin and euchromatin. HP1α was positively correlated with DNA at the microscale but uncorrelated at the nanoscale. RNA Polymerase II, p300, and CDK9 were positively correlated at the microscale but became partitioned below 300 nm. Perturbing histone acetylation or transcription disrupted nanoscale organization but had less effect at the microscale. We envision that our imaging and analysis pipeline will be useful to reveal the organizational principles not only of the cell nucleus but also other cellular compartments
Proceedings from the 2023 transdisciplinary conference for future leaders in precision public health “Applying Implementation Science to Precision Public Health”
Get PDFPrecision public health (PPH) approaches use big data to inform tailored, population-level interventions. The field has roots in genomics, but it has expanded to encompass data-informed public health programs across various types of data or applications. The Precision Public Health Network hosted a 2023 conference focused on implementation science—the study of how to integrate PPH programs into practice. Some implementation needs that emerged across speakers included establishing robust evidence of clinical utility and feasibility, disseminating clinical best practices through guidelines and tools for providers, sharing tools or information to reduce duplicated efforts across settings, and considering context-specific factors. Considering feasibility, setting-specific factors, and meaningful engagement with relevant user groups throughout the research and implementation process are critical to the successful and sustainable implementation of PPH programs. The Network also hosted an interactive workshop to generate ideas and ongoing collaboration on essential outcomes or data measures for PPH programs, and strategies to center health equity in PPH. This conference and workshop are part of the ongoing work of the PPHN to convene experts across disciplines and settings, share knowledge, and galvanize the field of PPH
Association of liver related biomarkers with incident cardiovascular disease and all-cause mortality in the Hispanic community health study/study of Latinos (HCHS/SOL), a population-based cohort study
Get PDFBackground Metabolic dysfunction-associated steatotic liver disease (MASLD) increases risk of cardiovascular disease (CVD). Despite the high prevalence of MASLD among Hispanic populations, there is a scarcity of research on the associations between non-invasive markers of liver disease and incident CVD and all-cause mortality. In this study we investigated the association of liver related biomarkers with CVD events and all-cause mortality in a population based Hispanic/Latino cohort. Methods We included 15,216 participants from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) aged 18–74 years with no pre-existing CVD. The composite outcome combined incident CVD and all-cause mortality. Having “elevated ALT/AST” was defined as ALT > 40 IU/mL or AST > 37 IU/mL for males, and ALT or AST > 31 IU/mL for females. We estimated adjusted hazard ratios (HR) and 95% confidence intervals (CI) relating our composite outcome to elevated ALT/AST, FIB-4 and MASLD. Using interaction terms, we assessed whether the relationship between elevated ALT/AST and the composite outcome differed by MASLD status. Results The study population was 40 years old on average, 52.7% female and had 740 CVD or all-cause mortality events. Elevated FIB-4 had the strongest association with incident CVD or all-cause mortality (comparing FIB-4 > 2.67 versus ≤ 2.67, HR:3.47; CI:2.34–5.14). Elevated AST was found to be associated with incident CVD or all-cause mortality (HR:1.53; CI:1.14–2.05). MASLD was not associated with incident CVD or all-cause mortality (HR:1.14; CI: 0.94–1.40), but it was associated with incident CVD alone (HR:1.69; CI:1.19–2.39). The relationship between elevated ALT/AST and incident or all-cause mortality was modified by MASLD, such that the strongest association between elevated ALT/AST and incident CVD or all-cause mortality was in the absence of MASLD (HR:1.95; CI:1.20–3.18). Conclusions Among Hispanic adults FIB-4 was strongly associated with CVD or all-cause mortality and among persons without MASLD, elevated ALT/AST were associated with CVD or all-cause mortality
Leveraging infant visit PrEP screening INtegration & tasK shifting to improve post-partum HIV prevention in Malawi (LINK): a cluster-randomized trial evaluation of a postpartum HIV prevention package among breastfeeding women in Malawi
Get PDFBackground Elimination of vertical transmission of HIV remains a major global public health priority. In Malawi, more than one-third of pediatric HIV acquisitions are attributed to perinatal HIV acquisition during breastfeeding. HIV pre-exposure prophylaxis (PrEP) is a crucial biomedical tool to keep women free of HIV and eliminate vertical transmission, but effectiveness has been hampered by poor uptake and premature discontinuation. Implementation science approaches are needed to improve uptake, persistence, and adherence to PrEP among postpartum women at risk of HIV. Methods LINK is a type I hybrid effectiveness implementation cluster-randomized trial conducted at 12 service delivery sites within Lilongwe district, Malawi. The LINK model is a novel postpartum HIV prevention package that uses implementation strategies of integration and task-shifting/sharing and includes the following evidence-based practices: (1) maternal HIV testing integrated with Expanded Programme for Immunization (EPI) sites for infant immunizations [integration], (2) PrEP screening and referral for mothers who test HIV-negative, (3) engagement of male partner(s), and (4) community-facility linkage (CFL) peer mother model for PrEP (re)engagement [integration and task shift/share]. Clinics are randomized 1:1 to intervention or control conditions. Effectiveness outcomes include PrEP uptake, adherence, and 6-month persistence among breastfeeding women at intervention compared to control sites. Implementation outcomes assessed at intervention sites include reach, adoption, acceptability, fidelity, scalability, sustainability and cost-effectiveness. We will analyze effectiveness outcomes with routine medical records, surveys, and PrEP drug metabolites via dried blood spots which will provide additional insights into HIV risk and PrEP usage and will facilitate a “constructed cohort” of PrEP eligible postpartum women. Implementation outcomes rely on in-depth interviews, surveys, site assessments, structured observations, and other tools. Human centered design workshops prior to implementation will further inform site-specific procedures for LINK model integration and launch. Discussion The study establishes a simple, scalable model, building on existing HIV and maternal and child health service delivery platforms, to accelerate efforts toward eliminating vertical transmission. If the LINK model is successful at improving PrEP usage among postpartum women, feasible, and cost-effective, we will have the knowledge to support quickly sustaining and scaling the intervention in Malawi and beyond. Trial registration Clinicaltrials.gov NCT06506188 (registered: 2024/07/17)
Large language models can extract metadata for annotation of human neuroimaging publications
Get PDFWe show that recent (mid-to-late 2024) commercial large language models (LLMs) are capable of good quality metadata extraction and annotation with very little work on the part of investigators for several exemplar real-world annotation tasks in the neuroimaging literature. We investigated the GPT-4o LLM from OpenAI which performed comparably with several groups of specially trained and supervised human annotators. The LLM achieves similar performance to humans, between 0.91 and 0.97 on zero-shot prompts without feedback to the LLM. Reviewing the disagreements between LLM and gold standard human annotations we note that actual LLM errors are comparable to human errors in most cases, and in many cases these disagreements are not errors. Based on the specific types of annotations we tested, with exceptionally reviewed gold-standard correct values, the LLM performance is usable for metadata annotation at scale. We encourage other research groups to develop and make available more specialized “micro-benchmarks,” like the ones we provide here, for testing both LLMs, and more complex agent systems annotation performance in real-world metadata annotation tasks
Bridging the gap: ctDNA, genomics, and equity in breast cancer care
Get PDFCirculating tumor DNA (ctDNA) has emerged as a powerful tool in precision oncology, offering a noninvasive approach to tumor profiling, minimal residual disease (MRD), and treatment monitoring. In breast cancer, ctDNA has shown promise in both metastatic and early-stage settings. However, its application and benefits have not been equitably realized across all populations. In this review, we examined the current evidence on ctDNA detection, assay performance, and clinical utility specifically within racially, ethnically, and geographically underrepresented populations. We synthesized data from genomic studies, ctDNA-based trials, and implementation research to identify disparities in ctDNA levels, mutational profiles, testing utilization, and access to genotype-matched therapies. These disparities were further compounded by structural barriers such as insurance coverage, geographic access, and limited inclusion in clinical research. Global data from low- and middle-income countries reinforced both the feasibility and the challenges of ctDNA implementation in resource-constrained settings. While ctDNA holds considerable potential to personalize breast cancer care, our findings underscore the urgent need to integrate equity into its validation, clinical application, and policy development to avoid perpetuating existing disparities
Temporal evolution of hemodynamics in murine arteriovenous fistula: A micro-CT based CFD study.
Get PDFIn this study, we investigated the hemodynamic characteristics of arteriovenous fistulas (AVFs) in murine models using micro-CT based computational fluid dynamics (CFD). By combining high-resolution micro-CT imaging with ultrasound flow measurements, our methodology offers a cost-effective and efficient alternative to traditional MRI-based approaches. CFD simulations performed at 7 and 21 days post-surgery revealed significant temporal changes in both geometry and hemodynamics. Geometric analysis showed that the proximal artery diameter increased from 0.29 mm to 0.38 mm, whereas the initial 2 mm fistula segment showed a 21.6% decrease (0.74 mm to 0.58 mm). Blood flow through the AVF nearly doubled from 1.33 mL/min to 2.57 mL/min. Time-averaged wall shear stress (TAWSS) peak values and locations changed from 142 Pa (day 7) within the proximal artery to 200 Pa (day 21) in the stenotic region. The oscillatory shear index (OSI) showed marked elevation at the anastomosis (increasing from 0.22 to 0.48), indicating disturbed flow development. An inverse relationship between TAWSS and OSI was identified, consistent with previous studies. Our methodology demonstrates the capability to analyze relationships between early hemodynamics and subsequent geometric changes. This approach could enable identification of regions susceptible to stenosis development and monitoring of AVF maturation, which could ultimately lead to quantitative metrics to evaluate surgical outcomes and early therapeutic interventions