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Evaluating Scoring and Weighting Methods of Global Cognition in a Harmonized United States and Korean Research Sample
No full textBackground:
Global cognitive metrics are useful for tracking cognitive aging, yet there is no consensus on how to best define and measure global cognition. The aim of this study was to compare scoring methods for global cognition against validity indicators.
Method:
Using harmonized factor scores of four cognitive domains (memory, executive function, language, visuospatial) in the United States and Korea (Table 1), we compared scoring methods for global cognition with validity indicators of cognition, functioning, and structural neuroimaging at baseline. Scoring approaches included combining cognitive domains with mean z‐scoring, congeneric confirmatory factor analysis (CFA; maximum likelihood robust estimation), principal component analysis (PCA), and weighting domains based on the Mini‐Mental Status Examination (MMSEComposite). Correlations (r) were used to compare composites against continuous validity indicators. The Clinical Dementia Rating Scale Sum of Boxes (CDR‐SB) and MMSE were used to measure cognition and functioning. Neuroimaging measures included brain volume relative to cerebrospinal fluid (BV/CSF) and intracranial volume‐normalized measures of brain volume (BV/ICV), ventricular volume (VV), frontal lobe volume (FL), and medial temporal lobe volume (MTL). Receiver operating characteristic (ROC) curves assessed the ability to detect cognitive impairment (CDR‐Global≥0.5).
Result:
Cognitive composites were highly intercorrelated (Figure; r range:0.94,1.00), correlated with CDR‐SB (r range:‐0.72,‐0.65) and MMSE (r range:0.75,0.77), and detected cognitive impairment in the good range (AUCs=0.84‐0.88). Cognitive composites were similarly correlated with neuroimaging metrics, with differences of at most r = 0.02 across comparisons, except for FL, where MMSEComposite had an r 0.04 lower than the others. Composites yielded stronger correlations with most neuroimaging metrics compared to standalone measures except for BV/ICV with CDR‐SB (r = ‐0.27). MTL and VV demonstrated the strongest associations with cognitive composites and other indicators of cognition/functioning.
Conclusion:
Regardless of scoring method, global cognitive composites were similarly related to validity indicators of cognition/functioning and structural neuroimaging in a harmonized sample. MMSEComposite showed the strongest relationships with CDR but was less strongly associated with frontal lobe volume. Composites demonstrated stronger relationships with structural neuroimaging compared to standalone measures. Future work aims to evaluate similarities and differences between cohorts and evaluate relationships longitudinally
Mechanical Wear of Degraded Articular Cartilage
No full textPurpose: To evaluate the mechanical wear of cartilage with different types of degradation.
Methods: Bovine osteochondral explants were treated with interleukin-1β (IL-1β) to mimic inflammatory conditions, with chondroitinase ABC (ChABC) to specifically remove glycosaminoglycans (GAGs), or with collagenase to degrade the collagen network during 5 days of culture. Viscoelastic properties of cartilage were characterized via indentation. Biochemical assays were performed to quantify the cartilage matrix loss to the media during culture and from an accelerated, ex vivo wear test. The coefficient of friction during the wear test was measured. Distribution of GAGs in the tissue was assessed histologically.
Results: All three degradative treatments decreased the cartilage modulus values and depleted GAGs in histological sections. However, wear was not uniform among the different treatments. Collagen loss from the tissue due to mechanical wear was only higher with IL-1β and collagenase treatment, while collagen loss due to wear with ChABC treatment was similar to untreated controls. In addition, less GAG was released due to mechanical wear in all degraded groups than the controls, likely because GAGs had already been depleted from these tissues during culture. As no significant differences in the coefficient of friction were observed between groups, changes in wear were attributed to altered tissue composition and structure rather than to changes in frictional forces.
Conclusions: Results suggest that cartilage with a degraded collagen network is more susceptible to mechanical wear, but that cartilage wear may be relatively unaffected by the loss of GAGs. Furthermore, exacerbated mechanical wear could be an additional mechanism by which inflammatory cytokines induce cartilage breakdown
Recommendations for Studying In Situ Extracellular Vesicles From Solid Tissue
No full textSolid tissue-derived extracellular vesicles (ST-EVs) are extracellular vesicles (EVs) separated directly from solid tissues of both vertebrates and invertebrates. ST-EVs provide a physiologically relevant snapshot of tissue-specific molecular dynamics and can be enriched directly in situ, from tissues in their natural state, preserving the native characteristics of ST-EVs. However, their enrichment presents unique technical challenges compared to EVs derived from biofluids or cell culture media. The need for transparent reporting in ST-EV research is crucial to enhance the reproducibility, comparability, and reliability of research findings. The Solid Tissue Task Force, part of the Scientific Reproducibility Subcommittee of International Society for Extracellular Vesicles, aims to recommend reporting parameters and identify outstanding questions related to the pre-analytical and analytical handling of solid tissues, as well as ST-EV separation and characterization. These steps are essential for advancing the understanding of the biological roles of ST-EVs and their potential clinical applications
Maturation of human cardiac organoids enables complex disease modeling and drug discovery
No full textMaturation of human pluripotent stem (hPS) cell-derived cardiomyocytes is critical for their use as a model system. Here we mimic human heart maturation pathways in the setting of hPS cell-derived cardiac organoids (hCOs). Specifically, transient activation of 5' AMP-activated protein kinase and estrogen-related receptor enhanced cardiomyocyte maturation, inducing expression of mature sarcomeric and oxidative phosphorylation proteins, and increasing metabolic capacity. hCOs generated using the directed maturation protocol (DM-hCOs) recapitulate cardiac drug responses and, when derived from calsequestrin 2 (CASQ2) and ryanodine receptor 2 (RYR2) mutant hPS cells exhibit a pro-arrhythmia phenotype. These DM-hCOs also comprise multiple cell types, which we characterize and benchmark to the human heart. Modeling of cardiomyopathy caused by a desmoplakin (DSP) mutation resulted in fibrosis and cardiac dysfunction and led to identifying the bromodomain and extra-terminal inhibitor INCB054329 as a drug mitigating the desmoplakin-related functional defect. These findings establish DM-hCOs as a versatile platform for applications in cardiac biology, disease and drug screening
Evaluating the likelihood of pediatric sacral nerve stimulator explantations due to cure or complications: a survival analysis of 13-year institutional cohort
No full textIntroduction: Sacral neuromodulation (SNM) is a treatment option for children with refractory bladder and bowel dysfunction. Prior investigations have shown children may achieve cure of their symptoms following SNM implants and subsequently have their devices explanted. Herein, we present a 13-year experience of pediatric SNM placements and evaluate the likelihood of SNM explantation for any cause, for symptom resolution or complications.
Methods: An institutional retrospective review of children who underwent a 2nd stage SNM placement between November 2012 and January 2025 was performed. Reasons for SNM explantation was categorized as a cure or complication. Competing-risk time-to-event analysis was used.
Results: There were 129 SNM placements at a median of 10 years old (IQR 8.1-12.7); 88 were females (68.2%) and 41 required SNM revision (31.8%). Median follow-up was 3.5 (IQR 2.0-5.3) years. Subsequently, 46 underwent SNM explantation (35.7%). On survival analysis, median time to explantation (50%) was 6.0 (IQR 4.6-7.3) years. Among explanted, 34 were due to symptom resolution (73.9%) and 13 due to complications (4 infections; 4 pain at site; 3 for MRI requirements; 1 clinically ineffective). On competing risks analysis, 72.5% of the explantations at 6 years were for cure and 27.5% for complications. The 6-year explantation risk was 36.3% for cure and 13.8% for complications. Among 17 children who provided data after device explanation following cure (response rate: 51.5%), 16 (94%) had sustained symptom resolution at a median of 3.8 years (IQR 1.3-5.3) after explantation.
Conclusion: Approximately quarter of children with SNM placement achieved cure with increasing probability with follow-up time. More than 70% of explantations are due to cure and less than 10% were due to infections. There is high likelihood of sustained symptom resolution following explantation for cure. SNM remains a safe and viable option for children with refractory BBD with potential for cure
Identification of Determinants that Mediate Chlamydia Muridarum Tissue Tropism
No full textIUIBacteria within the genus Chlamydia are obligate intracellular pathogens that
infect a wide variety of vertebrates. Despite having highly similar genomes, closely
related Chlamydia species can have different tissue tropisms. The human pathogen
Chlamydia trachomatis exemplifies this; strains in three genetically similar biovars
(trachoma, chlamydia, and lymphogranuloma venereum) target different human tissues
(ocular epithelia, urogenital epithelia, and the lymphatic system, respectively). Studies
using the mouse pathogen Chlamydia muridarum have suggested that tropism is heavily
influenced by evasion of host immune responses, particularly, responses mediated by the
cytokine interferon-gamma (IFNγ). My goal was to use an unbiased approach to
investigate how C. muridarum circumvents immunity. I conducted a tropism screen using
a mutagenized C. muridarum library and murine-derived cells from distinct tissues. This
screen identified mutants that have reduced ability to proliferate in specific cell types in
IFNγ-dependent and independent manners. Some of the mutants had complex phenotypes
that could not be linked to single mutations. However, I also identified two isolates
whose growth was restricted in murine rectal and oviduct epithelia in an IFNγ-
independent manner. Both of these isolates had the same missense mutation in the gene
tc0237. I determined that complementation of the mutants with wild type tc0237 was
sufficient to reverse their tropism phenotype. Blocking the ability of host cells to respond
to infection by treating them with a protein synthesis inhibitor revealed that the factors
responsible for restricting tc0237 mutants were cell-line specific rather than a shared characteristic of epithelial cells. Several attempts to localize TC0237 using different
approaches were unsuccessful, but bioinformatic analyses revealed that TC0237 likely
remains associated with chlamydial cells and could oligomerize. Overall, my findings
suggest that TC0237 plays a critical role in C. muridarum immune evasion and show that
chlamydial tropism is not solely defined by IFNγ
Whole-genome sequencing analyses suggest novel genetic factors associated with Alzheimer’s disease and a cumulative effects model for risk liability
No full textGenome-wide association studies (GWAS) on Alzheimer's disease (AD) have predominantly focused on identifying common variants in Europeans. Here, we performed whole-genome sequencing (WGS) of 1,559 individuals from a Korean AD cohort to identify various genetic variants and biomarkers associated with AD. Our GWAS analysis identified a previously unreported locus for common variants (APCDD1) associated with AD. Our WGS analysis was extended to explore the less-characterized genetic factors contributing to AD risk. We identified rare noncoding variants located in cis-regulatory elements specific to excitatory neurons associated with cognitive impairment. Moreover, structural variation analysis showed that short tandem repeat expansion was associated with an increased risk of AD, and copy number variant at the HPSE2 locus showed borderline statistical significance. APOE ε4 carriers with high polygenic burden or structural variants exhibited severe cognitive impairment and increased amyloid beta levels, suggesting a cumulative effects model of AD risk
Sex disparities in alcohol-associated liver disease and subtype differences in alcohol-attributable cancers in the United States
No full textBackground/aims: Harmful alcohol use is a substantial contributor to liver diseases, liver cancer, and extrahepatic neoplasms. Patterns of alcohol consumption have shifted over recent decades. This study evaluates trends in alcohol-associated liver disease (ALD) and alcohol-attributable cancers in the United States (US) from 2000 to 2021.
Methods: Using the methodological framework of the Global Burden of Disease Study 2021, we analyzed trends in incidence, prevalence, and mortality from ALD and alcohol-attributable cancers in the US.
Results: In 2021, there were 28,340 new cases of ALD, 227,730 prevalent cases, and 21,860 deaths attributed to ALD in the US. From 2000 to 2021, ALD incidence, prevalence, and mortality increased by 43%, 36%, and 79%, respectively. The age-standardized incidence and death rate of ALD rose disproportionately among females compared to males. For alcohol-attributable cancers, primary liver cancer, colorectal cancer, and esophageal cancer accounted for the largest share of deaths in 2021. Age-standardized death rates increased significantly for primary liver cancer (annual percent change [APC] 2.21%, 95% confidence interval [CI] 1.70-2.73%) and other pharyngeal cancer (APC 1.35%, 95% CI 1.08-1.62%).
Conclusion: The burden of ALD is substantial and continues to rise in the US, with a particularly notable increase among females. Mortality from alcohol-attributable cancers is also increasing, mainly driven by primary liver cancer and pharyngeal cancer. However, system-wise, gastrointestinal cancer had the highest death attributable to alcohol. These findings highlight the urgent need for public health strategies to tackle ALD, primary liver cancer, and alcoholattributable extrahepatic malignancies
Evaluating Multi-Cancer Early Detection (MCED) in Medicare: Cost-Effectiveness and Policy Pathways for Pancreatic Cancer
No full textIUIPancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers. Most patients enter the clinical pathway at an advanced stage, long after symptoms have appeared, which limits treatment options and survival. Multi-Cancer Early Detection (MCED) tests that examine methylation patterns in circulating cell-free DNA offer a possible route toward earlier, more actionable diagnoses. Even with that promise, questions remain about the true economic value of these tests and the feasibility of Medicare coverage for the populations that may need them most.
This dissertation used a convergent parallel mixed-methods design to examine these questions. The quantitative analysis relied on a patient-level microsimulation built from nine confirmed Stage II and III PDAC cases, each supported by real-world billing data. The model was expanded through 30,000 Monte Carlo replications to test stability and ranges of possible outcomes. The average cost per patient was 12.0 billion in national direct medical spending. Stage-weighted modeling showed that most of these costs come from distant-stage disease, which accounts for more than three-quarters of total spending. When adjusted to the share of Medicare beneficiaries, the estimated Medicare-attributable spending ranged from 9.6 billion each year.
The qualitative analysis examined eight elite interviews with congressional staff conducted between February and July 2025. By the eighth interview, thematic saturation had been reached, producing 21 themes across fiscal, clinical, and policy areas. Staff from both parties raised persistent concerns about Medicare solvency and emphasized the need for strong fiscal safeguards in any new coverage pathway. PDAC was viewed as a compelling application for MCED because of its severity, limited early detection options, and the high costs associated with late-stage care. Across offices, Coverage with Evidence Development (CED) emerged as a feasible policy pathway, supported by constituent stories and earlier precedents in colorectal screening tools.
Convergent integration of the two strands demonstrated how the cost modeling and policy perspectives align. Both strands identified Stage III PDAC as a major source of economic and clinical burden, and congressional staff viewed feasibility through the lens of Medicare solvency and patient access. CED appeared as a shared mechanism that could balance early innovation with careful fiscal oversight. Bringing together health economics and elite interviewing illustrated how policy feasibility can be assessed in a practical way. The findings suggest that MCED for PDAC may be both economically and politically feasible when directed toward high-risk populations within a Medicare CED pathway, creating an opportunity to support earlier detection in a cancer that remains one of the most urgent challenges
Integration of spatial protein imaging and transcriptomics in the human kidney tracks the regenerative potential of proximal tubules
No full textThe organizational principles of nephronal segments are based on anatomical and physiological attributes that are linked to the homeostatic functions of the kidney. Recent molecular approaches have uncovered layers of deeper signatures and states in tubular cells that arise at various time points on the disease trajectory. Here, we introduce an analytical pipeline of multiplexed spatial protein imaging integrated with RNA expression to characterize proximal tubular subpopulations and neighborhoods in human kidney tissue. We demonstrate that, in reference tissue, a large proportion of S1 proximal tubular epithelial cells expresses thymus antigen 1 (THY1), a mesenchymal stromal and stem cell marker that regulates differentiation. Kidney disease is associated with loss of THY1 and transition toward expression of prominin 1 (PROM1), another stem cell marker recently linked to failed repair. Our data support a model in which the interplay between THY1 and PROM1 expression in proximal tubules associates with their regenerative potential and marks the timeline of disease progression