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Storage-dependent variability in Alzheimer disease-related plasma biomarker results using the Fujirebio Lumipulse G1200 platform
Full text linkAlzheimer disease plasma biomarkers have emerged as minimally invasive, cost-effective tools for early diagnosis and disease monitoring yet their stability under common "real world" pre-analytical conditions remains incompletely characterized. We evaluated the stability of six plasma biomarkers, Aβ40, Aβ42, pTau181, pTau217, NfL, and glial fibrillary acidic protein (GFAP) using the Fujirebio Lumipulse G1200 platform. Plasma samples were initially collected from four healthy and cognitively unimpaired volunteers. Samples were stored under four conditions: room temperature (0-4 h), +4 °C (1-10 days), -20 °C (1-3 weeks), and -80 °C (4-8 weeks). In this pilot study, Aβ40 and Aβ42 remained generally stable. In contrast, pTau181 readings exhibited marked elevations in frozen samples, while pTau217 showed modest early fluctuations followed by significant decreases with prolonged storage. Next, we recruited 12 additional participants (six cognitively normal and six with mild cognitive impairment [MCI]), and their plasma samples were analyzed both fresh and after 4 weeks of storage at -80 °C. Among these participants, pTau181 readouts were significantly higher, and pTau217 were lower, in -80 °C frozen in comparison to never-frozen samples. These findings underscore the critical need for biomarker-specific sample workup and handling protocols and indicate that results for fresh plasma cannot be assumed to be the same as for frozen samples
Single-cell and Spatial Omics Reveals Region-Specific Plasticity and Therapeutic Vulnerabilities in Metastatic High-Risk Neuroblastoma
Full text linkNeuroblastoma, a deadly pediatric cancer derived from sympathetic ganglia of the peripheral nervous system, frequently metastasizes, driving poor outcomes. Primary neuroblastomas are well-characterized, but the mechanisms underlying metastasis remain poorly understood. Here, by applying single-cell and spatial multi-omics analyses to primary and metastatic tumors, we found that lymph-node metastases in high-risk neuroblastomas display distinctive cellular heterogeneity and plasticity, marked by mesenchymal-like and stem-like states and heightened epithelial-to-mesenchymal transition activity compared to primary adrenal tumors. Additionally, compared to primary adrenal masses, the metastatic niche display increased immunosuppressive myeloid programs, heightened immune checkpoint signaling, and lymphocyte exhaustion, which are indicative of immune evasion and dysfunction. Notably, metastatic neuroblastomas show elevated eIF4F translation machinery and XPO1 levels. Dual inhibition of eIF4A and XPO1 synergistically halted tumor growth and prolonged survival in xenograft models. Together, our multi-omics studies reveal the molecular and cellular plasticity that contributes to therapy resistance and highlight exploitable therapeutic vulnerabilities in high-risk metastatic neuroblastomas
A geological carbon cycle sink hosted by ocean crust talus breccias
Full text linkCalcium carbonate precipitation in ageing ocean crust sequesters carbon dioxide dissolved in seawater through seafloor weathering reactions, influencing atmospheric CO2 concentrations on million-year timescales. However, this crustal carbon sink, and the extent it balances CO2 degassing during crustal formation at mid-ocean ridges, remain poorly quantified due to limited sampling of the vast ridge flanks where CO2 uptake continues for millions of years. Here we quantify the carbon sink hosted within talus breccias that accumulated through mass wasting 61 million years ago during rift faulting at the slow spreading Mid-Atlantic Ridge, cored during International Ocean Discovery Program South Atlantic Transect Expedition 390. After 40 million years of carbonate cementation, these breccias contain ~7.5 wt% seawater-derived CO2, 2 to 40 times more than previously cored upper crust. Our estimates of talus breccia abundance based on fault geometries indicate that talus formed at slow-spreading ridges can accommodate a CO2 sink equivalent to a large proportion of the CO2 released during accretion of the underlying crust. The proportion of plate divergence accommodated by faulting, and hence talus abundance, increases nonlinearly with decreasing spreading rate. Consequently, past variations in spreading rate may have impacted the balance between ocean crust CO2 release and uptake in Earth’s carbon cycle
Concomitant antithrombotic therapy and substance use in older adult trauma patients: a secondary evaluation of an EAST Multicenter Trial
Full text linkBackground: The concurrent use of antithrombotic agents and intoxicants in older trauma patients (≥65) poses a potential risk for adverse outcomes. As the prevalence of substance use among older adults rises, understanding the impact of these combined factors on trauma outcomes is crucial. This study evaluates the impact of combined intoxication and antithrombotic use on trauma outcomes in older adults.
Methods: We conducted a secondary analysis of data from an Eastern Association for the Surgery of Trauma-sponsored multicenter prospective observational study involving 15 Level I and II trauma centers from February 2018 to June 2019. Included patients were on antithrombotic therapy and had blood alcohol concentration (BAC) and/or urine toxicology (UT) samples collected at trauma evaluation. Intoxication was defined as BAC >0.08 mg/dL or a positive UT. Patient demographics, injury characteristics, and outcomes were analyzed using linear and logistic regression models.
Results: Of 2793 trauma patients on antithrombotics, 862 met inclusion criteria, with 155 (18.0%) testing positive for intoxicants. Positive tests were associated with younger age (74 years vs 79 years, p<0.001), lower Charlson Comorbidity Index (4 vs 5, p<0.001), and similar Injury Severity Scores (6 vs 9, p=0.38). Patients with positive tests had more penetrating mechanisms of injury (11.0% vs 3.7%, p=0.01) and similar hospital stays (3 days vs 4 days, p=0.311). ICU admission rates were lower (32.9% vs 42.2%, p=0.041), with no difference in ICU length of stay or mortality. Higher ICU admissions (p=0.039) and increased ICU stays were seen in those on two substances (OR: 5.26, 95% CI 0.76 to 9.76, p=0.022).
Conclusions: Older trauma patients on antithrombotic therapy with concurrent intoxicant use did not exhibit worse clinical outcomes, despite higher rates of penetrating injuries and polysubstance use. These findings underscore the importance of tailored discharge planning and comprehensive care strategies for this vulnerable population
Sex Differences in the Diffusion of Tau Neurofibrillary Tangles Across Functional Brain Networks
Full text linkBackground:
Alzheimer's disease is characterized by the accumulation and spread of tau neurofibrillary tangles across cortical regions, driving cognitive decline. However, many cortical regions exhibit little tau, despite their functional connections to regions with high levels. In fact, recent evidence links elevated tau to hypoconnectivity in the default mode network (DMN) during early phases of disease, suggesting possible differential tau diffusion across functional networks. Therefore, the aim of this study is to examine tau diffusion (spreading of tau across functionally connected regions) and whether this is differentiated by functional network. To do this, novel multilevel network diffusion models are proposed to compare diffusion across functional networks and examine whether this differs by sex.
Method:
Included are 321 subjects from the third phase of the Alzheimer's Disease Neuroimaging Initiative (ADNI 3). Multilevel network diffusion models, first proposed by Frank et al. as social influence models to study the dynamics of teacher interactions, were adapted to examine diffusion. Diffusion is defined as the spreading of tau via neighboring (functionally connected) regions. Functional networks include DMN, limbic system (LSN), frontoparietal (FPN), dorsal attention (DAN), sensorimotor (SMN), visual (VISN), and ventral attention (VAN), which were parcellated according to the Desikan‐Killiany Atlas. We compared diffusion across these networks and investigated its interactions with sex.
Result:
Analyses reveal significant diffusion differences within DAN (Estimate=.243, p <.001), LSN (Estimate=‐.038, p <.001), SMN (Estimate=.084, p <.001), VAN (Estimate=‐.039, p = .004), and VISN (Estimate=‐.079, p <.001) compared to the DMN. Figure 1 illustrates the rate of diffusion across networks with highest diffusion found in FPN and DMN, and lowest in SMN and VISN. Additionally, we found sex differences in LSN diffusion (Estimate=.047, p = .037; see Figure 2), with stronger diffusion in females, suggesting that tau spreads faster in females than males. These findings are based on two models: one for diffusion differences across networks and another for sex‐based diffusion differences across networks.
Conclusion:
This study represents an in‐depth investigation of tau diffusion, showing highest diffusion in the FPN and DMN, consistent with previous research on network‐specific glucose metabolism. Additionally, higher tau diffusion in the LSN of females supports prior studies showing greater tau distribution in limbic regions of women
Genome‐wide interaction and stratified study reveals CR1‐Alzheimer's disease association is moderated by education level
Full text linkBackground:
Genetic and environmental factors contribute to Alzheimer's disease (AD) risk. Understanding gene‐environment interactions may provide insight into unexplained AD heritability. Higher educational attainment is associated with lower AD risk, but the mechanism remains unclear. We conducted a genome‐wide association study (GWAS) to explore genetic‐education‐related associations with AD through SNP‐education interaction and education‐stratified analyses.
Method:
Educational attainment data were available and analyzed among 23,642 non‐Hispanic white (NHW; 10,272 cases) and 3,461 African American (AFA; 1064 cases) participants from the AD Genetic Consortium and the Framingham Heart Study. Educational attainment was dichotomized by median years of education across cohorts, which equated to completing four years of college. Across 35 datasets, we conducted separate GWAS: 1) including a SNP‐by‐education interaction term and 2) stratifying by median education status. MAGEE was used to estimate SNP‐by‐education interaction effects and SAIGE was used to estimate SNP effects in stratified analysis. GWAS models adjusted for age, sex, and principal components for population structure. METAL was used for inverse‐variance weighted within‐ancestry fixed‐effects meta‐analysis and METASOFT was used to estimate cross‐ancestry effects. Top GWAS hits were further analyzed for association with longitudinal trajectories of harmonized memory, language, and executive function factor scores in education‐stratified linear mixed effects models.
Result:
Stratified GWAS identified a genome‐wide significant association among participants with lower educational attainment in CR1, a well‐known AD‐associated locus on chromosome 1 (top SNP: rs12037841; lower educational attainment: MAF=0.19, OR=1.33, p = 3.1x10‐10; higher educational attainment: MAF=0.19, OR=1.09, p = 0.03; interaction‐model: βsnpXedu=‐0.18, p = 0.0018). Effects among those with lower educational attainment were present in both ancestries (NHW: MAF=0.19, OR=1.30, p = 1.8x10‐9; AFA: MAF=0.03, OR=1.64, p = 0.02). In analysis with neuropsychological factor scores, rs12037841 was associated with faster decline in memory and language among participants with lower educational attainment (memory: βsnpXtime=‐0.010, 95% CI:[‐0.016,‐0.004], p = 0.0019; language: βsnpXtime=‐0.006, 95% CI:[‐0.011,‐0.002], p = 0.0083). Weaker, non‐significant effects were observed among participants with higher educational attainment.
Conclusion:
In educational attainment‐stratified GWAS of AD, we identified stronger association of known AD‐related gene CR1, among those with lower educational attainment. The finding implicating CR1, a complement pathway gene, suggests that the risk education confers on AD may be moderated by immune‐related mechanisms
Development of an HPV 16 rapid test founded in user-centered design with primary care clinicians
Full text linkDespite effective screening modalities, cervical cancer remains a leading cause of cancer-related death among women in the United States aged 20 to 39 years old, and incidence is rising in women aged 30-44 years old. Up to 25% of patients who are screened for cervical cancer by testing for human papillomavirus (HPV) do not receive necessary follow-up care with current laboratory-based testing. Applying a user-centered design approach, we surveyed and interviewed practicing clinicians to establish the use case, value proposition, and user requirements of a cervical cancer screening test for use in Indiana, USA. Insights from these stakeholders directly informed design specifications for a point-of-care HPV test capable of providing same-visit results to improve patient follow-up and retention. Guided by these requirements, we designed an isothermal nucleic acid amplification platform suitable for outpatient clinics. The test accepts swabbed endocervical cells, amplifies HPV16 L1 DNA via recombinase polymerase amplification, and provides results within 40 minutes on a lateral flow assay. Further, the test achieves a clinically relevant limit of detection of 1000 HPV 16 copies per reaction and verifies swabbing technique and test operation with a sample adequacy control. The test operation was designed for a minimally-trained user and decreases time-sensitive steps that would interfere with clinical flow. By integrating clinician input to inform development decisions, our device is uniquely tailored to meet the context-specific needs of primary care clinics. This work exemplifies how user-centered design can yield novel diagnostic technologies with greater clinical impact and adoption potential
Developing Interpretable Data Mining Frameworks for Addressing Biomedical Challenges in Genomics and Imaging
Full text linkIUIThe global burden of disease has evolved significantly in recent decades. Since the early 2000s, we have witnessed multiple widespread outbreaks of respiratory viruses including Influenza A and SARS-CoV-2, alongside a marked increase in chronic conditions such as diabetic retinopathy (DR). These diseases pose serious health threats – respiratory infections can progress to fatal multi-organ failure, while untreated DR may result in vision impairment or complete blindness. Given the impacts of these conditions on individual quality of life and healthcare systems worldwide, it is imperative to develop a comprehensive set of computational methods for studying and detecting these diseases.
This dissertation highlights the need for accessible and interpretable data visualization techniques and models in studying respiratory viruses and DR. My work extends previous approaches that have been developed for studying SARS-CoV-2 host-pathogen interactions, diagnostic assays for respiratory virus detection, and analysis of spatiotemporal trends in SARS-CoV-2 variant transmission. My work also focuses on developing explainable deep learning models that extract latent and explicit information from retina fundus images to detect DR and identify DR stages. The methods discussed in this dissertation contribute to the research community by consolidating information and extracting hidden insights from publicly available data sources through interpretable data visualization approaches and models. Moreover, my efforts in DR detection and grading demonstrate the utility of using clinically grounded data in both model design and post-model decision analysis. Taken together, these approaches show how novel computational methods and models can be used to provide valuable insights and drive innovation in diverse biomedical domains
Minimally important difference and responsiveness to change for numerical rating scale of menstrual pain severity: a psychometric study
Full text linkBackground: Menstrual pain affects 45%-95% of reproductive-age females and increases the risk of other chronic pain conditions. Psychometrically sound measurement tools are essential for advancing research and clinical care in menstrual pain. Numerical rating scales (NRS) are widely used to measure pain severity. However, the minimally important difference (MID) and responsiveness to change of the NRS in the context of menstrual pain are not well understood. Understanding MID and responsiveness to change helps guide the evaluation of treatment efficacy and clinical decision-making. This study evaluated the MID and responsiveness to change in the NRS, ranging from 0 to 10, for menstrual pain severity.
Methods: Participants who were menstruating (aged 14-42, N = 100) completed two surveys 24 h apart. In both surveys, we measured menstrual pain severity (worst, least, average menstrual pain in the past 24 h, and current menstrual pain) on a 0 (no pain) to 10 (extremely severe) NRS. MIDs were estimated using distribution-based approaches (standard error of measurement and effect size) and anchor-based approaches (using symptom interference and retrospective recall of change as anchors). Responsiveness to change was evaluated using standard response means and area-under-the-curve analysis.
Results: The MID estimates were close to 1 point. The NRS of menstrual pain severity was responsive to menstrual pain improvement (standard response means ranged from 0.44 to 0.61, p < 0.001 for between-group comparisons). Area-under-the-curve estimates ranged from 0.66 to 0.70.
Conclusions: The findings can inform the design and interpretation of studies testing interventions for menstrual pain, while also guiding clinicians in monitoring and adjusting treatment
Predictive correlates of poor sleep associated with increased risk of severe asthma exacerbations among children with moderate-to-severe asthma
Full text linkBackground: Sleep studies (polysomnography) are a diagnostic tool used to monitor various physiological parameters during sleep to diagnose and manage sleep disorders. However, the prognostic utility of sleep measures for the prediction of childhood asthma severe exacerbation (SE) risk is unknown.
Methods: Retrospective cohort analysis to identify correlates and quantify the prognostic utility of poor sleep measures for the prediction of SE risk among children with moderate or severe asthma.
Results: The study cohort included 161 patients (36% female, 33% African American, mean (standard deviation [SD]) age of 10 [4] years). A higher sleep arousal index (i.e., sleep fragmentation measured as disruptions in brainwave activity) was associated with increased risk of SE among male (adjusted odds ratio [aOR]: 1.13, 95% CI: 1.04, 1.23) but not female patients (aOR: 0.97, 95% CI: 0.88, 1.07). A history of SE(s) and use of inhaled glucocorticoid plus a long-acting β2-agonists (ICS plus LABA) were associated with higher odds of SE; conversely, a history of sleep latency reducing medication was associated with lower odds of SEs (p < .05). Inclusion of these sleep-related factors in the multivariable model to predict SE had higher prognostic accuracy than a model based on history of SE(s) alone (p < .01).
Conclusion: In addition to prior SE(s), elevated sleep arousal index among male children, use of ICS plus LABA, and history of untreated sleep disturbance can improve the accuracy of SE risk prognosis to inform targeted preventive interventions to reduce excess acute healthcare utilization among children with comorbid sleep problems and moderate/severe asthma