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Operationalizing a research-oriented learning healthcare system across covered entities: cross-institutional strategies and innovations
Full text linkThe concept of a Learning Health System (LHS) has been widely discussed in academic literature, yet its practical implementation remains a challenge. This paper describes the institutional journey, leadership structure, data governance policies, and technical innovations that together support a scalable and sustainable Research-Oriented LHS. Additionally, we propose an expanded data vision that aligns with interdisciplinary and translational research needs. Supplementary materials provide technical details for those interested in implementing such a model
Midfoot “H-Plate” for operative fixation of posterior wall acetabular fractures: a technical trick and case series
Full text linkBackground: Acetabular fractures involving the posterior wall remain challenging to treat, with no gold standard fixation method established. We describe a novel technique using Synthes 2.7 mm non-locking plates originally designed for the midfoot.
Methods: Retrospective review of 120 patients with posterior wall acetabular fractures treated with H-plates at a Level-1 trauma center (2012-2021). Patient demographics, operative parameters, and outcomes were analyzed.
Results: The cohort was predominantly male (67.5%) with motor vehicle collisions as the primary mechanism (89.1%). Forty-seven patients (39.1%) received isolated H-plate fixation. Operative time was significantly shorter with isolated H-plates versus additional hardware (2.25 ± 0.60 vs 2.70 ± 0.91 h; p = 0.003). No patients required reoperation for fixation failure. Total hip arthroplasty was required in 9.2% of patients.
Conclusion: The H-plate offers a simplified approach to posterior wall fixation with promising preliminary results, though longer follow-up is needed
Gut bacterial dysbiosis in pediatric severe malaria associates with post-discharge mortality
Full text linkGut microbiota have been implicated in severe malaria in murine models, but their contribution to the pathogenesis of severe malaria in children is unknown. Here we show through analysis of gut bacteria in stool samples from two separate African studies enrolling children with severe malaria, and children from local communities, that children with severe malaria have gut bacteria dysbiosis. Among children with severe malaria, there is increased abundance of Enterobacteriaceae that associates with multiple clinical complications of severe malaria. Moreover, increased abundance of Escherichia coli was a predictor of post-discharge mortality. Metagenome analysis identify elevated metabolic pathways and genes supporting the utilization of host-derived molecules in children with severe malaria that have the potential to promote the survival and growth of Enterobacteriaceae. Treatments that target Enterobacteriaceae may have the potential to reduce post-discharge mortality in children with severe malaria
Prostaglandin E2 as a Mechanistic Biomarker of Chronic Pancreatitis
Full text linkIntroduction: Chronic pancreatitis (CP) is a disease associated with chronic inflammation, fibrosis, and pain. There is a lack of tools available that facilitate early diagnosis, when intervention could prevent irreversible damage. Pilot data suggested prostaglandin E2 (PGE2) as a candidate biomarker for early CP. PGE2 activates signaling pathways that promote inflammation, pain, and fibrosis.
Methods: We assessed PGE2, metabolites, and downstream targets in pancreatic fluid collected endoscopically 0-10 (n = 110) and 10-20 (n = 111) minutes after intravenous secretin administration. PGE2 and metabolites were measured in plasma (n = 75) and urine (n = 71) from the same subjects. Subjects were enrolled in the PROCEED study and classified symptomatic controls, acute/recurrent acute pancreatitis (AP/RAP), or CP.
Results: A significant main effect was detected in 10-20 minutes pancreas fluid ( P = 0.027) and plasma ( P = 0.046); post hoc testing showed PGE2 was lower in the AP/RAP group compared with symptomatic controls. There was also trend toward lower PGE2 in urine ( P = 0.062). To elucidate the active downstream pathways, calcitonin gene-related peptide, substance P, and matrix metalloproteinases (MMPs) 1, 2, 3, 7, 9, and 13 were measured in pancreas fluid. A significant difference between the 3 groups was detected for both MMP7 and MMP9. MMP7 was elevated in individuals with CP vs AP/RAP ( P = 0.012) for samples collected early but both time points for MMP9 ( P = 0.027, P = 0.002).
Discussion: While PGE2 is detectable in pancreas fluid, these data suggest that it may not be sensitive enough to distinguish between AP/RAP and CP. However, MMPs may distinguish between stages of pancreatitis and require further testing as potential diagnostic biomarkers
MON-406 Efficacy of 7 Versus 10 mm Thyroid Radiofrequency Ablation Active Tips
Full text linkRadiofrequency ablation (RFA) is an effective treatment for benign thyroid nodules. The procedure utilizes an internally cooled electrode with an active tip to deliver thermal energy, resulting in coagulative necrosis of the nodule tissue. The active tip length can vary, with 7 and 10 mm being the most common options, but the optimal length remains unclear. In this study, we compared the efficacy of 7 versus 10 mm active tips in terms of volume reduction rates (VRR), defined as the percentage decrease in nodule volume after RFA over 12 months. We conducted a retrospective chart review of adult patients at an academic institution in the US from December 2021 to November 2024 who underwent RFA by a single endocrinologist. We included patients who had confirmed benign thyroid nodules as per the recommended guidelines and excluded those who received ablation for thyroid cancer. We identified 35 patients, of whom 91.4% were female, with a mean age of 50.6±17.5 years, who underwent RFA using either 7 mm (n=22) or 10 mm (n=13) active tips. The initial nodule volumes were similarly distributed between groups (<10 mL: 45.7%, 10-20 mL: 25.7%, ≥20 mL: 28.6%). Volume measurements were performed at baseline and 1, 3, 6, and 12 months after the RFA. When comparing 7 versus 10 mm active tips, we found a statistically significant VRR at every follow-up: 1 month (47.1±24.7% vs. 27.3±28.8%, p=0.044), 3 months (74.1±20.1% vs. 52.0±20.0%, p=0.035), 6 months (74.6±19.0% vs. 54.6±13.6%, p=0.016), and 12 months (85.9±22.4% vs. 59.3±20.0%, p=0.031) respectively. Procedure duration was comparable between both groups (480±259.6 vs. 511.3±286.1 seconds, p=0.742), although the 7 mm tip delivered significantly less energy (10.2±5.0 vs. 22.5±15.6 kJ, p=0.002) compared to the 10mm tip. In conclusion, our study demonstrates that the 7 mm active tip achieved consistently and statistically greater volume reduction rates compared to the 10 mm tip across all thyroid nodule volumes at all follow-up time points while requiring less delivered energy. Notably, the superior efficacy of the 7 mm probe was maintained even in larger nodules (≥10mL), which comprised 54.5% of the 7 mm probe group. These findings suggest that the 7 mm probe may be the preferred option for radiofrequency ablation of benign thyroid nodules across all size categories
Unraveling High‐Risk Cell‐Cell Interactions in Alzheimer's Disease Using an Integrative Single Cell Analysis
Full text linkBackground:
Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by cognitive decline and disruptions in neurovascular integrity, inflammation, immune signaling, and synaptic connectivity. While single‐cell and bulk RNA‐seq have revealed cell‐type‐specific changes in AD, the intercellular communication networks driving these processes remain unclear. This study introduces a novel integrative pipeline to systematically identify and prioritize robust cell‐cell interactions contributing to AD pathology.
Method:
We developed an advanced computational pipeline (Figure 1) that, to our knowledge, is the first to integrate cell prioritization tools with cell‐cell interactions to identify AD‐associated interactions. To achieve this, we integrated RNA‐seq from the Mount Sinai Brain Bank (MSBB) and single‐cell RNA‐seq (scRNA‐seq) from Grubman, Mathys, and MIT datasets, totaling over 2.4 million cells. The pipeline combined Diagnostic Evidence GAuge of Single cells (DEGAS), a transfer learning framework for identifying AD‐associated cellular states, with CellChat, which infers intercellular communication networks by mapping ligand‐receptor interactions across cell types. To ensure robustness, correlation analysis validated ligand‐receptor co‐expression, while differential gene expression (DEG) and gene ontology (GO) analyses identified pathways linked to AD‐associated states. Consistent interactions across datasets will be experimentally validated via colocalization using immunofluorescence (IF) and binding via co‐immunoprecipitation (Co‐IP).
Result:
Our pipeline consistently identified cell‐cell interactions underlying AD pathology across datasets (Figure 2). FN1‐SDC4 interactions between endothelial cells and astrocytes were associated with blood‐brain barrier dysfunction (Figure 3). CADM1‐CADM1 interactions, observed between oligodendrocytes and oligodendrocyte progenitor cells (Figure 3), highlighted their role in synaptic organization and connectivity deficits. The BSG‐PPIA interaction, specific to endothelial cells, was linked to vascular inflammation (Figure 3). Additional interactions, JAM3‐JAM3 and PTPRM‐PTPRM, were consistently identified in control contexts, suggesting roles in synaptic maintenance and axonal guidance. Correlation analysis further validated ligand‐receptor co‐expression, while DEG and GO analyses highlighted enriched pathways, including extracellular matrix organization, cell adhesion, and synaptic signaling. These results are now being further validated via IF and Co‐IP.
Conclusion:
This study highlights the novelty of our pipeline in integrating RNA‐seq data to identify robust intercellular communication networks in AD. By prioritizing consistent interactions across datasets, we provide insights into AD pathology that inform experimental validation and therapeutic development
The Cognitive Change Index in the Alzheimer's Disease Research Center setting: Self‐ and informant‐ratings for perceived cognitive decline
No full textIntroduction: The Cognitive Change Index (CCI) is a brief questionnaire that assesses self and informant perceptions regarding cognitive function. We examined the ability of the CCI to distinguish between cognitively unimpaired (CU) older adults and those with mild cognitive impairment (MCI) or Alzheimer's disease (AD) dementia.
Methods: 485 individuals from the Indiana Alzheimer's Disease Research Center (IADRC) and their study partners completed 20-item self and informant versions of the CCI. Receiver operator characteristic (ROC) curves were analyzed to assess differentiation between CU and those with impairment.
Results: High area under the ROC curve (AUC) values were obtained when using the self and informant CCI forms to distinguish CU individuals from those with impairment, with AUC values of 0.803 (95% confidence interval [CI] = 0.761-0.844) and 0.914 (95% CI = 0.886-0.942) for the self and informant forms, respectively.
Discussion: The CCI can serve as a useful screening instrument in the context of a multimodal assessment strategy for MCI and dementia.
Highlights: Novel research that uses the Cognitive Change Index (CCI) for dementia screening. Our findings suggest that CCI can distinguish those with dementia compared to those without. These findings can be correlated to other screening instruments. Results could see the CCI play a role in early Alzheimer's disease (AD) screening and diagnosis
Treatment‐related amyloid clearance (TRAC): a framework to characterize patients in the era of anti‐amyloid therapies
Full text linkFollowing regulatory approval of anti-amyloid beta (Aβ) therapies, a better characterization of patients receiving these treatments is needed to guide clinical management and inclusion in future trials. This Alzheimer's Association-convened workgroup proposes a terminology, treatment-related amyloid clearance (TRAC), to reflect alterations in disease pathophysiology based on biomarker evidence for clearance of Aβ deposits. TRAC designates biomarker-defined pharmacodynamic changes, rather than direct neuropathological evidence, and applies to individuals with (1) pretreatment biomarker confirmation of cerebral Aβ deposition, (2) treatment with an Aβ-targeting therapy, and (3) a follow-up biomarker test indicative of partial or full clearance of Aβ deposits. The workgroup currently recommends defining TRAC using amyloid-positron emission tomography (PET) and emphasizes the role of quantitative measurements for defining the degree of clearance. This framework is expected to be adapted over time in response to rapidly evolving biomarker and clinical advances and with the accumulation of real-world data on patients receiving anti-Aβ therapies. Highlights TRAC identifies patients with biomarker evidence for clearance of amyloid deposits. TRAC is currently defined using amyloid-PET. Full TRAC means that PET levels dropped below predetermined positivity threshold. Partial TRAC means that PET levels dropped significantly but remain above threshold. This framework is meant to guide future research on patients receiving treatment
Group B streptococcal infections in pregnancy and early life
No full textBacterial infections with Group B Streptococcus (GBS) are an important cause of adverse outcomes in pregnant individuals, neonates, and infants. GBS is a common commensal in the genitourinary and gastrointestinal tracts and can be detected in the vagina of approximately 20% of women globally. GBS can infect the fetus either during pregnancy or vaginal delivery resulting in preterm birth, stillbirth, or early-onset neonatal disease (EOD) in the first week of life. The mother can also become infected with GBS leading to postpartum endometritis, and rarely, maternal sepsis. An invasive GBS infection of the neonate may present after the first week of life (late-onset disease, LOD) through transmission from caregivers, breast milk, and other sources. Invasive GBS infections in neonates can result in sepsis, pneumonia, meningitis, neurodevelopmental impairment, death, and lifelong disability. A policy of routine screening for GBS rectovaginal colonization in well-resourced countries can trigger the administration of intrapartum antibiotic prophylaxis (IAP) when prenatal testing is positive, which drastically reduces rates of EOD. However, many countries do not routinely screen pregnant women for GBS colonization but may administer IAP in cases with a high risk of EOD. IAP does not reduce rates of LOD. A global vaccination campaign is needed to reduce the significant burden of invasive GBS disease that remains among infants and pregnant individuals. In this narrative review, we provide a comprehensive overview of the global impact of GBS colonization and infection, virulence factors and pathogenesis, and current and future prophylactics and therapeutics