Citations

Abstract Patent foramen ovale (PFO) has a prevalence of approximately 25%. Its association with pyogenic brain abscess (PBA) is unclear. We reviewed adults with PBA and known PFO status from 1 January 2009 through 31 December 2021 at Mayo Clinic. High PFO prevalence (40.5%) was seen. PBA patients with PFO had distinct abscess characteristics but unchanged 1-year, all-cause mortality.

Abstract Background Cytomegalovirus (CMV) infection remains one of the most prevalent and important infections following solid organ transplant (SOT). Treatment is often challenging, especially when dealing with refractory and resistant CMV infections.Table 1:Univariable logistic regression analyses of associations with early refractory CMV infectionTable 2:Univariable logistic regression analyses of associations with resistant CMV infection Methods We performed a retrospective cohort study of SOT recipients with clinically significant CMV infection (csCMVi) at a tertiary transplant center in the US during 2010-2016. The primary outcome was early refractory CMV infection and secondary outcomes were drug resistance, CMV recurrence, and mortality. Kaplan-Meier estimation, univariable logistic regression analysis, and multivariable Cox regression were used for outcome analysis.Table 3:Multivariable Cox regression analysis of associations with recurrent CMV infection after primary treatment endedNote: Refractory CMV was not included in the model for recurrent CMV as no patients with refractory infection had recurrence. Results A total of 145 SOT recipients with csCMVi were included. Most patients were recipients of liver (49%), followed by kidney (22.1%), heart (6.9%), lung (5.5%), and pancreas (4.1%). Multiple organ transplants accounted for 12.4% of the cohort. Most common induction was an anti-IL-2 antibody (43.9%) followed by ATG (29.5%). 82 (56.5%) had CMV D+/R- mismatch. In total, 34 (23.4%) had CMV syndrome, 38 (26.2%) had tissue-invasive CMV disease, while the rest (50.3%) were asymptomatic. After the initial 3 weeks of antiviral therapy, 13 (8.9%) patients had probable refractory csCMVi; most of them (10 [76.9%]) were CMV D+/R- mismatch. Longer time after transplant had lower risk (OR 0.68; CI 0.48-0.95, p=0.029) while lower absolute lymphocyte count (ALC) was higher risk of early refractory csCMVi (OR 1.54; CI 1.01-2.44, p=0.048) (Table 1). Drug-resistant CMV occurred in 7 patients (4.8%); a high initial CMV DNA level was associated with resistant csCMVi (OR 2; CI 1.08-3.93, p=0.031) (Table 2). Of 144 patients with post-treatment follow-up, 25 (17.2%) experienced recurrent csCMVi within 6 months. Table 3 shows the associations with recurrence of csCMVi after initial treatment. 30 patients (20.7%) died during a median follow-up of 4 years, but refractory, resistant or recurrent CMV were not associated with mortality. Conclusion Refractory csCMVi is associated with low ALC and an earlier onset post-transplant. Resistant csCMVi is associated with high levels of initial CMV DNA. Recurrence of csCMVi is common and possibly associated with low ALC at the end of antiviral treatment. Disclosures All Authors: No reported disclosures

Abstract Background Despite effective therapy for methicillin-susceptible Staphylococcus aureus (MSSA) bacteremia with anti-staphylococcal penicillins (ASP; e.g., oxacillin, nafcillin) or cefazolin, persistent bacteremia is associated with poorer clinical outcomes and increased complications. Emerging strategies, such as combination therapy with an ASP or cefazolin and ertapenem, have demonstrated the potential to accelerate microbiologic clearance in persistent MSSA bacteremia. However, despite its increasing utilization in clinical practice, data on the effectiveness of this combination regimen remains limited. We sought to describe the clinical characteristics and outcomes of patients with MSSA bacteremia receiving combination therapy. Methods We performed a single-center, retrospective study of adult patients with MSSA bacteremia who received ASP or cefazolin and ertapenem combination therapy from 2019-2023. Time to blood culture clearance, in-hospital mortality, and 90-day relapse were examined. Results A total of 57 patients were included: median age of 65 years [IQR 53-73] with 75.4% male. MSSA bacteremia complicated by infective endocarditis and cardiac implantable electronic device infection occurred in 35.1% and 12.3%, respectively. The median length-of-stay was 16 days [IQR 12-28], and 57.9% required ICU admission. Forty (70.2%) patients underwent source control interventions such as valve replacement, device extraction or surgical debridement. The median duration of bacteremia prior to combination therapy initiation was 4 days [IQR 3-6]. Blood culture clearance occurred in a median of 1 day. The median duration of combination therapy was 4 days [IQR 3-6]. In-hospital mortality was 15.8%. None of the patients surviving the hospitalization experienced relapsed bacteremia within 90 days. Conclusion This study supports growing evidence that combination therapy may offer benefits in managing persistent MSSA bacteremia, specifically with regards to time to blood culture clearance. Further investigation is warranted to determine optimal timing of combination therapy and if known benefits of combination therapy translate into superior clinical outcomes as compared to monotherapy. Disclosures All Authors: No reported disclosures

Background Costosternal cartilages and the costal margin, collectively termed costal cartilage, are hyaline cartilage connecting ribs to the sternum and to adjacent ribs, respectively. Presence of intact costal cartilage is essential for elasticity of the chest wall. Anecdotally, costal cartilage injuries are underdiagnosed on trauma CT scan in patients with rib fractures. Our aim was to determine a baseline frequency of acute costal cartilage injury among patients presenting with rib fractures. Methods We performed a retrospective cohort study of injured adult patients admitted to Level I/II trauma centers with rib fractures from January 2020 to July 2024. CT images obtained at admission were manually reviewed by chest wall surgeons for presence of costal cartilage injury. Concordance with the original radiology report was obtained. Multivariable regression was used to analyze factors associated with costal cartilage injury and missed cartilage fractures. Results 1441 patients were identified; 197 (14%) had a costal cartilage fracture. A plurality of injuries included falls (n=667, 46%). Median ISS (Injury Severity Score) was 13 (IQR: 9 to 21), median Abbreviated Injury Scale thorax score was 3 (IQR: 3 to 3), and median number of fractured ribs was 3 (IQR: 3 to 7). 294 (21%) patients had radiographic flail segments, and 136 (9%) had sternal fractures. 172 (87%) patients had a costal cartilage fracture missed on initial trauma chest CT. On multivariable analysis, ISS (adjusted OR (aOR) 1.02 (95% CI 1.01 to 1.04), radiographic flail segment (aOR 1.6 (95% CI 1.10 to 2.31)) and presence of sternal fracture (aOR 1.85 (95% CI 1.19 to 2.89)) were associated with costal cartilage fractures. Only the total number of rib fractures was associated with a missed costal cartilage fracture on univariate analysis (OR 1.17 (95% CI 1.01 to 1.36)). Conclusions Costal cartilage injuries are common and frequently are not identified during interpretation of the initial trauma CT. A higher index of suspicion is warranted for costal cartilage fractures among patients with greater injury burden, radiographic flail segment, and sternal fractures. Level of evidence Level III.

Abstract Cutaneous squamous cell carcinoma (cSCC) poses significant clinical challenges due to its rising incidence and potential for metastasis. Histopathologic risk stratification is further limited by substantial inter-observer variability. Unsupervised AI approaches based on content-based image retrieval offer scalable and interpretable decision support for diagnostic pathology. The objective of this study was to evaluate the use of image retrieval within histopathology atlases to stratify cSCC tumor differentiation from whole-slide images (WSIs), while comparing different patch selection and feature extraction strategies. This retrospective study included 552 archived WSIs comprising 385 well-differentiated, 102 moderately differentiated, and 66 poorly differentiated cases collected across Mayo Clinic sites in Arizona, Florida, and Minnesota. Image atlases were constructed using multiple patch aggregation strategies (Mosaic, Collage, and Montage) and deep learning encoders (KimiaNet, PathDino, and H-Optimus-0). A leave-one-WSI-out evaluation framework was used to assess differentiation classification performance using accuracy, specificity, sensitivity, and F1 score. Mosaic combined with KimiaNet achieved the highest Top-1 accuracy (74.9%) and specificity (92.6%), while Mosaic with H-Optimus-0 yielded the best Top-5 accuracy (79.0%) and macro-F1 score (62.6%). Collage combined with KimiaNet produced the highest Top-5 specificity (99.5%). The generalizability of the evaluated AI models varied across hospitals, reflecting differences in imaging protocols, staining practices, and patient populations. Overall, unsupervised image search and retrieval provides effective, annotation-free support for cSCC differentiation and has the potential to enhance dermatopathology workflows when appropriate combinations of patch selection and feature ex-traction methods are employed.

Abstract Background Immunohistochemically detected phosphorylated α‐synuclein (p‐α‐syn) in cutaneous nerves has been found in >95% of patients meeting consensus criteria for dementia with Lewy bodies (DLB); however, its performance in prodromal stages (mild cognitive impairment‐Lewy body [MCI‐LB]) and clinical practice is unknown. Objective We evaluated skin biopsy for p‐α‐syn in a convenience cohort of patients with suspected MCI‐LB or DLB in a tertiary care setting. Methods 53 patients underwent commercially available skin biopsy for skin nerve p‐α‐syn as part of a clinical evaluation for suspected MCI‐LB/DLB. Consensus MCI‐LB/DLB criteria blinded to skin biopsy result were applied through retrospective chart review; those not definitively meeting criteria were considered questionable synucleinopathy (QS). Results Median age at skin biopsy was 70 years (range, 43–87 years) with 81% men. 36 patients (68%) had positive skin biopsies. 32/43 (74%) patients meeting clinical consensus criteria for DLB/MCI‐LB had a positive skin biopsy, with higher frequency in MCI‐LB (87%) compared with DLB (60%). 4/10 (40%) QS had positive biopsies. One patient with a positive skin biopsy had no evidence of central nervous system (CNS) α‐syn on autopsy. Conclusions Positive skin biopsy for p‐α‐syn occurs across the spectrum of cognitive presentations of Lewy body disease including prodromal DLB, albeit at a lower frequency in this retrospective review of atypical cases compared with typical clinical presentations. A positive skin biopsy may not reflect CNS synucleinopathy as the etiology for a patient's symptoms in some cases. Longitudinal studies of skin biopsies for p‐α‐syn in suspected MCI‐LB/DLB with autopsy confirmation are needed. © 2025 International Parkinson and Movement Disorder Society.

Abstract Background Most existing biomarkers for Alzheimer's disease (AD) inform on core AD pathologies in the central nervous system, namely amyloid, tau and neurodegeneration (ATN). However, molecular disease mechanisms underlying AD are complex and heterogeneous, highlighting the need for cost‐effective blood‐based biomarkers that reflect brain molecular changes in AD beyond ATN. Method Using peripheral blood transcriptome data from the Mayo Clinic Study of Aging(MCSA) and the Alzheimer's Disease Neuroimaging Initiative, we identified genes associated with AD or mild cognitive impairment (MCI) diagnosis, cognitive, and harmonized neuroimaging measures in two cohorts, followed by meta‐analysis. We identified consensus gene co‐expression modules in MCSA and ADNI using WGCNA and assessed the association between module eigengenes and aforementioned measures. Using seven bulk brain RNAseq cohorts, we confirmed the preservation of coexpression modules across blood and brain. Enrichment analyses of Gene Ontology (GO) terms and cell‐types were performed using significant and/or hub genes. The MCSA transcriptome was further deconvoluted to obtain cell‐type proportions and cell‐type specific expression. Result Blood transcriptome modules M5 and M8 are upregulated in AD/MCI and associate with worse cognition, whereas M1, M10, M13, M16, and M21 are downregulated in AD/MCI and associate with better cognition. M17 associates with more microhemorrhages. Cell‐type enrichment analysis revealed that M5 is enriched in basophils, monocytes, and neutrophils; M8 in monocytes and neutrophils; M13 in natural kills cells; M17 in megakaryocytes; M21 in B cells. GO analysis shows broad consistency with the cell‐type enrichment analysis. M1, 5, and 8 are preserved in the brain network modules. From these modules, we prioritized transcripts significantly associated with at least one AD‐related phenotype in both blood and brain. Cell‐type deconvolution analysis shows that prioritized transcripts in M1 associate with better cognition and higher metabolic activity in B cells. Conclusion We identified blood transcripts and modules associated with AD/MCI, cognition, or neuroimaging, with three preserved in brain networks. These three modules represent centrally linked peripheral molecular signatures that can reveal perturbed brain pathways and cell level transcriptional changes in AD/MCI. We aim to further investigate the prioritized transcripts in additional datasets to establish them as potential novel biomarkers and therapeutic targets.

Abstract Background Progressive supranuclear palsy (PSP) is a devastating neurodegenerative disorder with rapid progression to death. Multiple efforts to develop a disease‐modifying therapy for PSP have yet to succeed. We previously reported the discovery of three potential therapeutic targets for PSP. These three genes, DDR2, KANK2, and STOM, are consistently upregulated in the brains of PSP patients and mouse models of tauopathy. Reducing their expression in a drosophila model significantly rescued the tau‐induced eye degeneration and tau seeding activity. To translate these targets into the clinic, we are developing antisense oligonucleotides (ASO) as potential therapies. Method We screened candidate ASOs in neuroglioma cell line H4. ASO hits were validated for their potency and safety. We also used iPSC‐derived neurons from PSP patients to test the potency and potential toxicity of our ASOs. To investigate target engagement, therapeutic efficacy and preliminary pharmacodynamic properties, we treated iPSC‐derived midbrain organoids with the ASO leads. Lastly, we will assess the off‐target effects of the ASOs by investigating the levels of mRNA transcripts that share similar sequences as our targets using RNAseq. Result Our in vitro screening identified ASO leads that significantly reduce the target gene expressions at mRNA and protein levels in a dose‐dependent manner. The ASO hits also exhibit low cellular toxicity in the H4 cell line. Upon treating iPSC neurons with ASO hits, we were able to validate the dose‐dependent reduction of target mRNAs. Cell viability analysis indicated low toxicity, suggesting that these ASOs are potent and safe. In midbrain organoid model, DDR2‐targeting ASO showed time‐dependent target engagement and were prioritized for further development. Conclusion We developed candidate therapeutics for PSP using ASOs that silence novel therapeutic targets discovered in our systems based cross‐species screening. We showed that our ASOs have low toxicity and confirmed target engagement at both mRNA and protein levels in vitro. The results suggest a favorable preclinical profile of our ASO leads that warrants additional investigations. Importantly, PSP shares congruent pathophysiological changes with other tauopathies, such as Alzheimer’s disease. These common perturbed pathways indicate that our ASOs can be potentially repurposed for multiple neurodegenerative tauopathies.

Abstract Background More than 85% of Alzheimer's disease (AD) donor brains exhibit some degree of cerebral amyloid angiopathy (CAA), which is characterized predominantly by Aβ40 deposits in the brain vasculature and can cause blood brain barrier (BBB) leakage. CAA is associated with risk of infarcts, cerebral hemorrhages, and cognitive decline. Brain cell type‐specific mechanisms that influence CAA pathology, as well as related measures such as Aβ40 biochemical measures and tight junction proteins, an indicator of BBB integrity, are still elusive. Method We performed single‐nucleus RNA sequencing (snRNAseq) of temporal cortex tissue from 79 AD donors, with varying levels of CAA co‐pathology. Measurements of soluble, insoluble and membrane‐associated fractions of brain Aβ40 and tight junction protein (claudin‐5, occludin) levels were available for these donors. We correlated these measures with cell proportions. We also conducted differential gene expression and analyses for intercellular communications and regulatory networks. Result We identified 25 clusters and annotated them with major brain cell types. There were 3 oligodendrocyte, 7 excitatory and 7 inhibitory neuronal, 2 microglial, 2 astrocytic, and 1 each for endothelial, pericytic, fibroblast, and oligodendrocyte precursor cell clusters. We found that higher CAA and Aβ40 levels correlate with reduced neuronal and increased microglial, astrocytic and vascular cell proportions. Increased tight junction proteins correlate with increased inhibitory neuronal and reduced microglial, astrocytic and vascular cell proportions. Among all clusters, one microglial, both astrocytic and the pericytic clusters have greater number of genes significantly associated with CAA, Aβ40 and tight junction protein levels. Most significant genes have negative associations with CAA and membrane‐bound Aβ40 and positive with tight junction protein measures. Using these genes as input for intercellular communications analysis, we prioritized ligand‐target interactions from microglia or astrocytes to pericytes. Some of the prioritized targets are transcription factors in pericytes. Using regulon analysis, we identified genes downstream of these transcription factors that are also significantly associated with lower CAA and membrane‐bound Aβ40 and higher tight junction protein levels. Conclusion We revealed glia‐to‐pericytes intercellular interactions and pericytic gene regulatory networks that are potentially perturbed by CAA and BBB breakdown. Future directions include analyzing external snRNAseq datasets and performing functional validations.

Abstract Background Alzheimer's disease (AD) affects all brain cells and has complex genomic and immunological alterations. Previous research discovered missense AD risk or protective variants in microglial genes ABI3 and PLCG2, respectively. Expression levels of these genes are altered in AD and can influence microglial function. This study aims to uncover protective, and risk microglial molecular signatures associated with these variants to determine their role in microglial subtypes and states in AD by single cell expression and functional studies. Method We generated microglia‐enriched snRNAseq data from donors harboring either AD protective PLCG2 or AD risk ABI3 missense mutations, or neither mutation. After standard snRNAseq QC, we performed differential expressed gene (DEG) analysis of all microglial cells between variant carriers and non‐carriers using MAST. We defined protective signature as genes that are both down in ABI3 and up in PLCG2 mutation‐carriers. In contrast, risk signature genes are up in ABI3 and down in PLCG2 mutation‐carriers. We investigated the conservation of protective and risk signatures across multiple datasets, including scRNAseq data from iPSC‐derived microglia cells carrying PLCG2 protective variant, snRNAseq data from AD‐resilient donors, and data from AD and other diagnostic groups across multiple brain regions sourced from external datasets. Result We obtained snRNAseq profiles of 35,000 microglia from AD variant carriers. Our DEG analysis among all microglia cells provided 227 microglial protective and 293 risk signature genes defined by these variants. Using integrated analysis of multiple internal and external datasets, we further narrowed down these signatures. We determined that these high‐confidence protective signature genes are downregulated in early AD, upregulated in late AD brains and positively‐correlated with protective variant load in in vitro models. In contrast, risk signature genes are upregulated in early AD, downregulated in late AD and resilient donors. Risk signature expression is decreased with protective PLCG2 variant load, and altered with Aβ treatment in in vitro models. Conclusion Our study uncovers microglia specific protective and risk signatures associated with AD using sn/scRNAseq datasets from multiple sources and models. These findings nominate novel immune targets and pathways with implications for microglial function in health and disease, and ultimately therapeutic potential.