Frontiers in Cell and Developmental Biology

Background: Despite the success of combination antiretroviral therapy (cART), vascular comorbidities, including cerebrovascular disease, are more prominent in people living with HIV (PLWH) compared to people without HIV (PWOH). However, quantitative assessments of cerebrovascular morphometry and their associations with cognitive outcomes in the context of HIV are still limited. In this study, we explore this missing link. Methods: Magnetic Resonance Angiography (MRA) data, blood markers, and neurocognitive assessments were collected from 73 PWOH subjects (male: 57, female: 16; age: 53 {+/-} 16) and 99 PLWH subjects (male: 66, female: 30, age: 53 {+/-} 11). Vessel morphometric features were quantified using intraCranial Artery Feature Extraction (iCafe) to investigate associations between vessel morphometry, markers of monocytes, endothelial cell activation, and cognitive performance. Results: HIV status predicted a lower total number of branches ({beta} = -0.224, p = 0.001, d = -0.517) and shorter total distal length ({beta} = -0.173, p = 0.021, d = -0.370) with a moderate effect size. Total branch number was found to be negatively associated with plasma levels of monocyte markers (sCD14: r = -0.167, p = 0.033; sCD163: r = -0.157, p = 0.045) and positively correlated with white matter cerebral blood flow (r = 0.550; p [≤] 0.05). HIV status was the strongest predictor of overall cognitive performance in ANCOVA model ({beta} = -0.219, p = 0.006, d = -0.453). Conclusions: Our results suggest that cognitive impairment in PLWH is associated with vessel morphology metrics. Monocyte immune activation may contribute to changes in vessel morphology.

Introduction Obstructive lung diseases (OLDs) are responsible for high rates of illness and death worldwide. Inflammation, chronic airflow limitation, and bronchial remodeling occur in OLD and eventually result in the unique respiratory sounds. Despite its subjective and having low reproducibility, still traditional auscultation using a manual stethoscope is the main method used to identify the lung sounds. Nevertheless, the combination of recent advancements in digital stethoscopes and AI (Artificial Intelligence) has permitted the objective measurement of lung sounds. Nevertheless, there is a lack of standardized, region-specific databases for AI training and validation. Even though lung sound classification is an emerging aspect in research and telerehabilitation the lobar wise acoustic pattern is still novel due to lack of prevailing database to train AI models. Identifying this gap this study aims to develop an acoustic repository and analyze the data using segmental lung sounds from patients with OLDs and healthy controls through an electronic stethoscope. Methods and analysis This is a cross sectional observational study involving 120 participants (60 OLD patients and 60 healthy controls). Lobar wise acoustic signals will be captured using an electronic stethoscope in healthy and diseases population. The data will be analyzed using Audacity software for annotations and then it will be used for feature extraction and statistical analysis. The acoustic features extracted through Audacity, will include frequency, intensity, pitch, and root mean square (RMS) energy. Repeated measures ANOVA will be applied to compare mean sound intensities across lung segments while Pearson correlation will be used to assess associations with body composition parameters. The data will then be standardized for AI-based diagnostic applications. Ethics and dissemination The study is being reviewed from the Ethics Review Committee, Faculty of Medicine, University of Peradeniya (2025/EC/87) will be sought. Informed consent will be obtained in writing. The dissemination of results will take place through peer-reviewed publications and the creation of a public database containing lung sounds from the region.

Background & Aims: Metabolic Dysfunction Associated Steatotic Liver Disease (MASLD) is the leading cause of chronic liver disease in children. However, accurate, noninvasive diagnostic tools remain limited. Current screening methods are invasive or lack sensitivity. Breath-based volatile organic compound (VOC) analysis offers a simple approach with potential for point of care screening. This study aimed to identify and validate breath VOC signatures of pediatric MASLD. Approach & Results: We conducted a prospective IRB approved cohort study at the Childrens Hospital of Philadelphia (CHOP). Children aged between 7 and 20 years with MASLD (n=22), as defined by hepatic steatosis either by liver biopsy or imaging and 1 cardiometabolic risk factor, and a control group without MASLD (n=20) were enrolled. Breath samples were collected using a standardized protocol and analyzed by untargeted comprehensive two-dimensional gas chromatography-mass spectrometry (GCGCMS). Machine learning and unsupervised clustering were applied to identify discriminatory VOCs and assess heterogeneity. Untargeted GCGCMS analysis identified a distinct breath VOC signature in children with MASLD compared with non MASLD controls. A Random Forest model achieved a sensitivity of 73% and specificity of 65%, with AUC of 0.84. The VOC 2,4-dimethyl-1-heptene demonstrated strong diagnostic performance in the discovery cohort with a sensitivity of 85%, specificity of 77% and an AUC of 0.81. Unsupervised clustering revealed four MASLD subgroups with distinct volatile phenotypes associated with differences in liver enzymes and metabolic parameters. External validation in a second pediatric cohort confirmed reproducible reductions in o/p-xylene in subjects with MASLD. Conclusions: Pediatric MASLD is associated with a reproducible breath VOC signature identified by untargeted GCGCMS. These findings support breath analysis as a scalable, noninvasive screening and stratification tool for pediatric MASLD and warrant validation in larger, longitudinal studies.

Background: Citrin deficiency, caused by biallelic pathogenic variants in SLC25A13, must be identified early to prevent serious complications such as hyperammonemia and liver failure. However, clinical diagnosis is often delayed due to its nonspecific presentation and limited sensitivity of amino acid-based newborn screening methods. Although genome-based evaluations are being investigated to address these issues, concerns about their cost, turnaround time, variant interpretation ability, and data handling highlight the need for a more practical yet reliable alternative. We investigated the feasibility of applying proteomic approach on dried blood spots (DBS), which are routinely used in newborn screening. Methods: We performed untargeted liquid chromatography-tandem mass spectrometry to analyze the proteome of DBS using a previously developed "non-targeted analysis of non-specifically DBS-absorbed proteins" (NANDA) workflow. SLC25A13 protein abundance was quantified in individuals with biallelic loss-of-function mutations, compound loss-of-function/missense mutations, and heterozygous carriers; this was also evaluated in healthy and diseased controls representing relevant differential diagnoses. To leverage proteomic information, we derived a multivariate proteomic signature using feature selection and evaluated its performance with leave-one-out cross-validation. Biological relevance was assessed by enrichment analysis, and complementary transcriptomics was performed using RNA sequencing. Results: A total of 7,474 proteins, including SLC25A13, were consistently detected in DBS. SLC25A13 was undetectable in individuals with biallelic loss-of-function mutations. However, individuals with compound loss-of-function/missense genotypes showed reduced but measurable SLC25A13 levels, comparable to those observed in heterozygous carriers. In contrast, a compact 15-protein signature accurately identified individuals with compound loss-of-function/missense genotypes (AUC, 0.99; sensitivity, 1.00; specificity, 0.95). The signature was enriched for Ca2+-response, and transcriptomics showed downregulation of genes related to multimodal ion channels in affected individuals compared to controls. Conclusions: DBS-based proteomic profiling may assist in the diagnosis of citrin deficiency through SLC25A13-quantification and a biologically plausible multivariate signature. More broadly, this strategy offers a promising new diagnostic layer for protein disorders, providing a proteomic readout in a clinically practical DBS format with potential utility for future diagnostic and screening applications.

Objective To examine the effects of combined oral contraceptive (OC) use on clinical markers of ovarian reserve by comparing Anti-Muellerian Hormone (AMH), antral follicle count (AFC), and ovarian volume (OV) before and after starting or stopping OC. Methods This analysis is based on data from a prospective cohort study conducted at the University Hospital Tubingen, Germany, as part of the IRTG-2804 project. A total of 54 healthy women were included and categorized into three groups based on their OC use status: OC starters (n = 12), stoppers (n = 16), and long-term OC-users (n = 26). Each participant underwent a transvaginal ultrasound (including AFC and OV) and serum sampling (including AMH) at two time points (S1 and S2), three to six months apart. OC starters were assessed first during the early follicular phase (day 1-7) and then during active OC intake (day 8-21), while stoppers were assessed in the reverse order. Long-term users were assessed twice during active OC intake. Results OC stoppers showed significant within-group increases in all ovarian reserve markers, including AMH ({Delta} = 2.57 ng/mL, p < .001), AFC ({Delta} = 3.88, p = .004), and OV, which almost doubled (1.94-fold increase; 95% CI [1.35, 2.80], p < .001). In contrast, OC starters exhibited a significant decline in AMH ({Delta} = -1.25 ng/mL, p = .013), but no changes in AFC or OV. No significant longitudinal changes were observed among long-term OC users. Conclusion AMH levels decrease after starting OC use whereas AFC and OV are not affected. In contrast, AMH, AFC, and OV recover within three to six months after stopping OC, suggesting a reversible suppression of ovarian reserve markers during OC use. These findings are clinically relevant for fertility counseling and for the interpretation of ovarian reserve markers in women using hormonal contraception.

Background: Non-invasive diagnosis, reliable recurrence surveillance remain critical unmet needs in gliomas. Glioma induces profound systemic immune alterations despite its anatomical confinement to the central nervous system. Circulating immune cells, particularly monocytes, are key mediators of tumor-host crosstalk and may retain tumor-induced transcriptional imprints. However, their potential clinical utility as blood-based biomarkers for detection and monitoring, remain largely unexplored. Methods and findings: In this study, we performed integrated single-cell RNA sequencing of blood immune cells and demonstrated that circulating CD14+ monocytes are significantly expanded in glioma patients, exhibiting features of differentiation arrest and increased transcriptional plasticity. These cells harbor glioma-specific molecular signatures distinct from those observed in healthy controls and patients with other tumors. Leveraging these findings, we developed an ensemble machine learning diagnostic model based on transcriptomic profiles of circulating CD14+ monocytes (training cohort, n=107), which achieved a mean area under the receiver operating characteristic curve (AUC) of 0.971 during cross-validation. In an independent cohort of 567 participants, the model maintained high diagnostic accuracy, yielding an AUC of 0.877 for distinguishing glioma from controls and other tumors. And it achieved a recurrence detection AUC of 0.969 in 51 postoperative samples. Moreover, in a prospective follow-up study involving 30 glioma patients, lower model-derived scores of postoperation were significantly associated with prolonged progression-free survival (log-rank test, P=0.043), supporting its prognostic utility. Conclusion: We demonstrate circulating CD14+ monocytes undergo glioma-specific transcriptional reprogramming, generating systemic tumor-associated signal captured via transcriptomic profiling. This blood-based diagnostic model provides non-invasive, scalable approach for glioma detection, recurrence surveillance, outcome prediction.

BACKGROUND & AIMS Conventional reusable endoscopes incur significant expenses in the form of purchase, maintenance, reprocessing, and disinfection. Reprocessing is frequently ineffective even following the use of high-level disinfectants (HLDs). Disposable gastroscopy might be a strategy to decrease infectious outbreaks associated with reusable endoscope. The aim of this study was to analyze and evaluate the performance, efficiency and safety in gastroscopy observation and subsequent potential EMR procedure via the disposable gastroscope in a clinical setting. METHODS Patients who required gastroscopies and met the criteria were recruited to this prospective, open-label, non-inferiority study. After obtaining the written informed content, the enrolled subjects selected themselves independently to the disposable group or reusable group. The primary measure was to evaluate the acceptable image quality and whether the disposable endoscope devices could meet the basic clinical demands with a noninferiority margin of -8%. The second measures were to analyze and evaluate the image conditions, accepted endoscopic maneuverability, efficiency and safety of observation and advanced potential EMR procedure. Appropriate statistical methods were conducted via PASS software and SAS 9.4. A two-tailed P value < 0.05 was considered statistically significant. RESULTS A total of 90 individuals (the number of those in disposable group and reusable group was both 45) were recruited to this study. The success rate of acceptable image quality via photographing iconic anatomical sites between two groups was 100.0% (45/45, 95% confidence interval (CI): 0.9213,1.0000) and the lower limit of the 95%CI (-7.8654%, 7.8654%) was larger than the noninferiority margin of -8% (Newcombe-Wilson score method). Significant differences were showed in the measures of image conditions (image acquisition, image quality, brightness, contrast and sharpness) and accepted endoscopic maneuverability (endoscopy body rigidity). No significant differences were observed in the field of knob operation, sharp angle adaptability, and the auxiliary features including air supply, water supply and suction. In terms of efficiency, the total operating time, insertion time and withdrawal time were longer in the disposable group. The En-bloc resection rate of those observed polyps and required to EMR procedure due to relatively larger diameter (5mm-15mm) was the same 100% in both groups (26/26 vs 23/23, 95%CI: 0.8713,1.0000). Nevertheless, the procedure time of EMR for each polyp was significantly longer in the disposable group. This study showed no intraoperative bleeding, delayed bleeding, perforation or other study-related adverse events among 90 patients. No dramatic fluctuations in vital signs were showed in perioperative period. CONCLUSIONS In consideration of the efficiency, efficacy and safety evaluation, the disposable gastroscopes might represent an alternative to conventional reusable gastroscopes in routine examination and endoscopic mucosal resection.

Polycystic ovary syndrome (PCOS) is linked to adverse pregnancy outcomes and increased cardiometabolic risk in offspring, yet the placental mechanisms underlying these risks remain poorly understood. Metformin is prescribed during PCOS pregnancies despite limited mechanistic justification. Using multi-modal molecular analyses of placentas from healthy controls and women with PCOS randomized to placebo or metformin (PregMet trial), restricted to uncomplicated pregnancies, we characterized direct PCOS associated placental alterations independent of confounding complications. PCOS placentas showed transcriptional downregulation across multiple cell types and shifts in cell type proportions. Specifically, syncytiotrophoblasts exhibited reduced expression activity of growth hormone receptor signaling and glycosaminoglycan biosynthesis. Endothelial cells displayed diminished receptor tyrosine kinase pathway activity, including VEGFC, despite increased cell proportion and hypervascularity. Intercellular communication networks were globally suppressed, including reductions in PDGF signaling from Hofbauer cells to fibroblasts. Notably, metformin did not reverse most PCOS-associated molecular alterations and induced transcriptional changes correlated to birth weight and childhood BMI. These findings indicate that PCOS-associated placental features are driven by cell type specific dysregulation of growth factor, angiogenic signaling pathways that are largely unresponsive to metformin. This underscores the need to develop mechanism based, placenta targeted therapeutic alternatives for future pregnancy management.

Background: Chronic rhinosinusitis (CRS) is a heterogeneous inflammatory airway disease associated with impaired mucociliary clearance and persistent inflammation. While prior work has focused on inflammatory and molecular pathways, the physicochemical properties of mucus itself remain poorly characterized. This study aimed to define compositional and biophysical features of CRS mucus that may contribute to dysfunction. Methods: A prospective cross-sectional study was conducted in 15 adults undergoing endoscopic sinus surgery (11 CRS, 4 controls). Mucus was collected from the middle meatus. Hydration was measured by lyophilization. Ionic composition was quantified using mass spectrometry. Viscoelasticity was assessed via oscillatory shear rheology. Total protein, total carbohydrate, sialic acid (Sia) and fucose (Fuc) content were quantified using enzymatic and chemical assays. Statistical comparisons were performed using nonparametric tests. Results: CRS mucus exhibited significantly higher Ca2+; and Mg2+; concentrations (approximately two-fold; p<0.05) and increased variability in hydration and ion content compared to controls. Rheology showed greater heterogeneity and a non-significant trend toward increased viscoelasticity in CRS. Total protein and carbohydrate content were not significantly different; however, the carbohydrate-to-protein ratio was significantly reduced in CRS (p=0.04). Sia content and Sia-to-carbohydrate ratio were significantly elevated in CRS (p=0.04 and p=0.002), particularly in CRS with nasal polyps. Fuc content did not differ between groups. Conclusions: CRS mucus demonstrates coordinated alterations in ionic composition and glycosylation, characterized by increased cation content, hypersialylation, and reduced carbohydrate-to-protein ratios. These changes may contribute to altered mucus properties and impaired mucociliary clearance, highlighting mucus composition as a potential therapeutic target in CRS.

Abstract Schizophrenia (SCZ) and bipolar disorder (BPD) are highly heritable psychiatric disorders with complex polygenic architectures. Genome-wide association studies (GWASs) have identified numerous common variant associations, but rarer variants detectable through whole-genome sequencing (WGS) remain underexplored. We conducted rare variant association analysis using WGS data from the Portuguese Island Collection (PIC), including 28 families with SCZ (n = 53) and 41 families with BPD (n = 83) cases, and population controls (n = 62). Following ANNOVAR and CADD annotation, burden analysis of deleterious variants showed that both affected and unaffected family members from SCZ and BPD pedigrees had significantly higher burdens of rare deleterious variants compared to controls (p < 0.0001), with no significant differences observed between affected and unaffected relatives, consistent with shared familial genetic liability. Polygenic Risk Score (PRS) analysis confirmed significant genetic contributions to both disorders within PIC. Association analyses were subsequently performed using SAIGE-GENE+ identifying 483 and 583 nominally significant (suggestive associations) gene sets (p-value [&le;] 0.05; FDR > 0.05) for SCZ and BPD, respectively, including gene sets related to neurotransmission, synaptic function and structure, neurodevelopment, and neuroinflammation as well as major signaling pathways. Cross disorder overlaps also identified shared suggestive enrichment of GABA and glutamate signaling, synaptic signaling, and Wnt signaling gene sets in both SCZ and BPD. These findings support shared rare variant burden within multiplex psychiatric families and highlight the role of gene-set based rare variant analysis in identifying neurobiological pathways relevant to SCZ and BPD. Keywords: WGS, Rare Variants, Schizophrenia, Bipolar Disorder

Objectives: The Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diet has been associated with the risk of IBD, but its impact on clinical outcomes is uncertain. This study evaluated the association between MIND diet adherence and the risk of IBD-related surgery in a prospective cohort. Methods: This study included 2,288 participants with diagnosis of Crohn's disease (CD, n=777) or ulcerative colitis (UC, n=1,511) who completed valid WebQ 24-hour dietary recall from the UK Biobank. Dietary adherence was derived from a 15-component score based on 24-hour dietary recalls. Associations with IBD-related surgery were evaluated using Cox proportional hazards models, with nonlinear trends and examined via restricted cubic splines. Effect modification was explored in pre-specified subgroups, and multiple sensitivity analyses were conducted to assess robustness. Results: During 10.9 years of follow-up, 166 incident IBD-related surgery cases occurred. Higher MIND diet adherence was associated with reduced surgical risk. Compared with the lowest tertile of adherence, the highest tertile showed a 36% reduction in surgical risk in IBD (HR 0.64, 95% CI: 0.44-0.94, P = 0.024). Notably, this protective effect was pronounced in patients with CD, exhibiting a clear linear inverse association. In contrast, a reverse J-shaped association was observed in UC, with a steep initial decline in surgical risk followed by a plateau emerging at a MIND score of approximately 5, beyond which further adherence conferred minimal additional benefit. At the component level, higher vegetable consumption and lower intake of butter and fried foods were identified as independent protective factors against surgery. Stronger inverse associations were observed among patients with shorter disease duration and those with complicated disease behavior, including stricturing or penetrating phenotypes (all P interaction < 0.05). Conclusion: Greater MIND diet adherence is associated with reduced IBD-related surgery risk among patients with IBD and CD. These findings support the MIND diet as a feasible dietary strategy to improve IBD prognosis.

Precision medicine aims to advance our ability from a "one-size-fits-all" approach to personalized and predictive healthcare across diverse populations. It promotes integration of multi-omics and phenotypic data to understand disease mechanisms and discover novel biomarkers and risk factors, which could be used to predict and prevent critical diseases in individual patients across diverse populations. The potential implications of precision medicine approach can accelerate our ability to classify patients at higher risk of developing critical diseases, improve diagnostic capabilities, develop deeper understanding of individual risk, investigate racial differences and demographic characteristics, and find relationships between genetic variants, expressions, and diseases. This study focuses on implementing an innovative and data driven framework of translational bioinformatics and Machine Learning (ML) techniques to analyze multi-omics, including RNA-seq and Whole-Genome Sequencing (WGS) data, generated using blood samples of randomly consented patients. First, we utilized bioinformatics pipelines to identify differentially expressed genes and their pathogenic and likely pathogenic variants for the downstream data analysis, annotation, and visualization. Then, applied a nexus of ML models for multi-omics biomarker discovery, disease prediction, density-based clustering, single-patient profiling, and pathogenicity classification. WGS data analysis supported the exploration of genetic variation and diversity among patients to identify known and novel biomarkers, whereas RNA-seq data analysis improved our understanding of functional and biological pathways that underlying disease states. We classified and clustered pathogenic variants and expressions across various genes and discovered numerous diseases leading risk factors. Our results include gene-disease associations and captured common pathways across the broader population, demonstrating a level of sensitivity and accuracy that has broad clinical implications. We validated our results through clinical records, and state of the science literature. This study delves into the strengths of multi-omics data integration and capabilities of ML application in genetically diverse and complex patient cohorts. Our approach has the potential to elucidate complex gene-disease interactions for genetically diverse populations, which can support earlier diagnoses for patients in many disease realms.

This work focuses on the global and partial identification problem for fractional differential equations. We provide a general numerical procedure based on global and local optimization algorithms with two refinements for biological systems that ensure solution positivity and homogeneous parameter units. The method is applied to a new fractional model of Dengue outbreak called the Fractional Homogeneous Nishiura (FHN) model, calibrated using data of newly infected people in Cape Verde. We show that our identification method yields a better fit between data and model solutions than previous approaches and that our FHN model captures the dynamics of Dengue more closely than existing systems.

Background Preterm birth (PTB) rates among Hispanic/Latina individuals in the United States have risen over the past decade. Data suggests this rise may be driven in part by psychosocial stress. Leukocyte telomere length (LTL), a marker of cumulative cellular aging that shortens under chronic stress, may capture stress-related biological vulnerability, but has not been examined as a potential population-level contributor to PTB in Hispanic/Latina pregnancies. Objective To examine the association between mid-pregnancy maternal LTL and PTB in a population-based Hispanic/Latina cohort. Methods In a case-control study nested within a California singleton birth cohort (n = 436 Hispanic/Latina individuals; 215 PTB, 221 term births), LTL was measured by quantitative PCR from biobank specimens collected from 15 to 20 weeks of gestation. Covariates from linked birth certificate and hospital discharge records were included. Logistic regression estimated ORs and 95% CIs of PTB by LTL examined continuously and by percentile category (<=10th, 11th-89th, >=90th) with and without adjustment for covariates. Results Mean and median LTL did not differ between PTB and term births. LTL at or below the 10th percentile was associated with elevated odds of PTB relative to full-term birth (12.6% versus 4.3%; ORc = 3.2, 95% CI 1.3-7.9), persisting after partial (ORadj1 = 3.2, 95% CI 1.3-8.3) and full covariate adjustment (ORadj2 = 3.4, 95% CI 1.3-9.3). Subgroup analyses showed consistent directional patterns across PTB subgroups and for early term birth (ORadj2 = 5.1, 95% CI 1.5-17.0). Conclusions Mid-pregnancy maternal LTL <=10th percentile was associated with more than three times the odds of PTB, with risk concentrated at the extreme low tail of the distribution. Consistent with a cumulative allostatic load model, markedly short LTL at mid-gestation may reflect elevated stress-related biological risk for preterm delivery. These findings support upstream investment in stress reduction and prospective LTL research in high-burden populations.

People living with HIV (PLWH) are known to maintain a degree of immune deficiency despite efficient antiretroviral therapy and may exhibit diminished responses to vaccines. In this study, we assessed the immune response to SARS-CoV-2 infection and vaccines in two geographically distinct PLWH populations. PLWH and HIV-negative (HIV-) participants were recruited from Qu&bec City (QC), Canada, and Bobo-Dioulasso (BD), Burkina Faso, for two visits at 24-week intervals during the predominance of the Omicron variant, from May 2022 to September 2023. Blood samples were collected at each visit for the detection of antibodies against spike (anti-S) and nucleocapsid (anti-N) proteins of SARS-CoV-2 in platelet-free plasma. A total of 360 participants were enrolled. We detected anti-S antibodies in 99% of participants, indicating that nearly all had prior exposure to the SARS-CoV-2 spike antigen, either through vaccination or prior infection. Anti-S titers showed no difference between PLWH and HIV& participants in each location, while significantly higher titers were observed in participants from QC compared to BD. In contrast, anti-N antibodies, indicative of prior infection, were detected in 39% and 86% of the participants in QC and BD, respectively, suggesting that the virus circulated largely in the latter population. No difference in anti-N levels was observed between PLWH and HIV& participants in BD. However, participants in QC had significantly lower titers compared to HIV participants. Overall, this study shows that PLWH develop robust antibody responses to SARS-CoV-2 vaccination, comparable to those observed in HIV& participants. Significant geographic differences were observed in anti-S titers, irrespective of HIV status, with participants from QC displaying higher titers. In contrast, participants from BD had higher anti-N antibody prevalence and titers, reflecting more SARS-CoV-2 infections in BD than in QC. Finally, analysis of anti-S antibody titers against several circulating variants revealed significantly lower levels in unvaccinated participants and in those vaccinated with monovalent vaccines in BD. No significant difference was observed between monovalent and bivalent vaccines administered in QC. All authors have seen and approved the manuscript.

Background African immigrants in the United States bear a disproportionate HIV burden, with incidence approximately sixfold higher than the general population, yet remain largely absent from targeted prevention research. HIV vulnerability among this population is mediated through relationship and family systems that are restructured by migration, reorganizing household composition, gender norms, trust, and communication patterns through which prevention engagement occurs. Despite this, migration has rarely been examined as a force that transforms the relational contexts shaping engagement with HIV testing, HIV self-testing (HIVST), and pre-exposure prophylaxis (PrEP). Methods The MiST-Pathways Study will use a sequential mixed-methods, community-based pilot design among first-generation African immigrant adults (ages 18-50) residing in New York and Massachusetts. The study will proceed in three phases: Aim 1 will use semi-structured interviews (n = 15) and a structured survey (n = 75) to identify relationship typologies and migration-related relational mechanisms influencing HIV prevention engagement; Aim 2 will employ Palava Hut Conversations (PHC) (an African-centered deliberative method) with up to 30 participants to co-develop and prioritize relationship-tailored intervention components; and Aim 3 will conduct a proof-of-concept assessment of the prioritized component using a single-group pre-post design (n = 24), incorporating surveys and cognitive interviews to assess feasibility, acceptability, and preliminary evidence of mechanism activation. All activities will be conducted virtually via Zoom and WhatsApp, with eligibility screening administered through REDCap. The study has been approved by the University at Buffalo Institutional Review Board (STUDY00010347) and registered at ClinicalTrials.gov (NCT07565584). Discussion This protocol outlines the planned evaluation of a sequentially designed, community-engaged pilot study to examine how migration reshapes relational contexts that influence HIV prevention decision-making among African immigrants. Findings will inform the development of culturally grounded, relationship-tailored prevention strategies and the design of a future, larger-scale intervention study.

Pain in pancreatic ductal adenocarcinoma (PDAC) is associated with poor survival, but whether altered pain processing carries prognostic significance is unknown. We analyzed a prospective cohort of 143 patients with PDAC who underwent pancreatic quantitative sensory testing (PQST) after diagnosis. Patients were classified as having normal pain processing (n=84), segmental hyperalgesia (n=30), or widespread hyperalgesia (n=29). Survival was measured from the date of P-QST assessment. During follow-up, 70 deaths occurred. Widespread hyperalgesia was associated with increased mortality in unadjusted Cox analysis (HR 1.96, 95% CI 1.14,3.35) and after adjustment for age, sex, tumor stage, comorbidity, opioid treatment, and body mass index (adjusted HR 2.33, 95% CI 1.30,4.15). Segmental hyperalgesia was not associated with mortality. Kaplan Meier analysis demonstrated lower survival probability in the widespread hyperalgesia group (log rank p=0.025). These findings suggest that widespread hyperalgesia, reflecting altered central pain processing, identifies a subgroup of PDAC patients at increased risk of mortality independent of conventional clinical factors.

Atherosclerosis is a systemic vascular process linked to cardiovascular, cognitive and renal outcomes. DNA methylation (DNAm)-based scores of atherosclerosis may capture cumulative biological processes underlying vascular aging. Here, we examined associations of DNAm scores for coronary artery calcification (DNAm-CAC) and carotid plaque (DNAm-cPlaque), derived from a large study of imaging-based subclinical atherosclerosis, with prevalent and incident outcomes in two population-based cohorts of older adults: the Health and Retirement Study (HRS; n = 3,875) and The Irish Longitudinal Study on Ageing (TILDA; n = 487). Higher DNAm scores were associated with adverse cardiometabolic profiles and socioeconomic indicators. In HRS, higher DNAm-CAC was associated with prevalent cardiovascular disease (odds ratio per SD, 1.16; 95% confidence interval (CI), 1.07-1.26), lower cognitive function ({beta} = -0.50, 95% CI -0.68 to -0.32) and lower estimated glomerular filtration rate (eGFR; -1.7 ml min-1 1.73 m-2, 95% CI -2.6 to -0.8) in unadjusted models. After adjustment for demographic and clinical risk factors, DNAm-CAC ({beta} = -0.29, 95% CI -0.46 to -0.13) and DNAm-cPlaque ({beta} = -0.24, 95% CI -0.42 to -0.06) remained associated with lower cognitive function, and DNAm-cPlaque was associated with incident cognitive impairment or dementia (hazard ratio per SD, 1.16; 95% CI, 1.01-1.32). Associations were attenuated after further adjustment for race/ethnicity and socioeconomic indicators. In TILDA, higher DNAm-cPlaque was associated with worse cognitive performance (incidence rate ratio, 1.11; 95% CI, 1.01-1.21), increased risk of incident cardiovascular disease (hazard ratio, 1.18; 95% CI, 1.00-1.42) and lower eGFR, with consistent associations observed for DNAm-CAC. These findings suggest that DNAm-based scores of atherosclerosis capture systemic vascular processes linked to multiple age-related outcomes across populations. Further work is needed to clarify the biological pathways reflected by these scores and their relation to cumulative and socially patterned vascular risk.

Background and Aims: Steatotic liver disease (SLD) has high clinical and public health relevance. Robust population estimates of SLD and its subcategories are challenging due to the limitations of ultrasound measurements or non-invasive scores, particularly for low-grade steatosis. We aimed to quantify SLD prevalence using magnetic resonance imaging (MRI) in the population-based German National Cohort (NAKO). Methods: Hepatic multi-echo Dixon MRI was performed at 5 dedicated study sites with identical setup across Germany. Liver fat (proton density fat fraction, PDFF), R2* as proxy for liver iron, and liver volume were assessed. The resulting data of N = 29'842 individuals (age range 20-72 years) were weighted by survey weights for regional representativeness, resulting in a sample of 50% women and a mean age of 45.6 years. SLD was defined as PDFF [&ge;] 5.75%, and sex-specific prevalence according to age, BMI, socioeconomic status and geographic region was calculated. Results: Overall, SLD prevalence was 21.3% in women and 35.7% in men, and the majority were metabolic dysfunction-associated (MASLD, 89.3% of all SLD cases). Prevalence increased with age in a sex-specific pattern, suggesting potential menopausal effects in women. There was a relevant prevalence of SLD in individuals with normal weight (5.3% in women, 13.2% in men) and the age group <25 years (7.5% in women, 11.9% in women). Differences in prevalence between low and high socioeconomic status were more pronounced in women (37% vs 15.8%) compared to men (45.5% vs 30.3%). Conclusions: Data underscore the high public health relevance of SLD and its subcategory MASLD. The considerable prevalence in groups historically considered low-risk, such as younger or lean individuals, emphasizes the need for raising awareness early.

INTRODUCTION: Postmenopausal estrogen decline may contribute to Alzheimer's disease (AD) risk, but longitudinal evidence linking circulating estrogens to cerebrospinal fluid (CSF) biomarkers is lacking. METHODS: We analyzed 866 female participants from the European Prevention of AD Longitudinal Cohort Study with baseline serum estradiol and estrone measured by liquid chromatography tandem mass spectrometry and repeated CSF measurements of amyloid-beta (A{beta})42, phosphorylated (p) Tau181, and total (t) Tau. RESULTS: Neither estradiol nor estrone was associated with longitudinal A{beta}42. Higher estradiol was associated with lower baseline tau and slower tau increases over time. Baseline estradiol-tau associations were stronger in apolipoprotein E (APOE) {epsilon}4 carriers, though APOE{epsilon}4 did not modify longitudinal associations. Amyloid positivity did not moderate hormone-tau associations but was associated with steeper tau increases over time. Estrone showed no significant associations. DISCUSSION: These findings suggest a more consistent relationship between estradiol and tau-related rather than amyloid-related pathology.