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ABSTRACT Background Multiple outpatient therapies have been developed for COVID‐19 in high‐risk individuals, but solid organ transplant (SOT) recipients were not well represented in controlled clinical trials. To date, few comparative studies have evaluated outcomes between outpatient therapies in this population. Methods We performed a retrospective cohort study using de‐identified administrative claims data from OptumLabs Data Warehouse. Patients were included if they were age ≥ 18 years, diagnosed with COVID‐19 between January 2022 and December 2023, and underwent SOT prior to COVID‐19. The primary outcome was 30‐day hospitalization. Stabilized inverse probability of treatment weighting was used to account for potential confounding variables. Results 4192 SOT recipients with COVID‐19 were identified. 1403 received an outpatient COVID‐19 therapy, including anti‐spike monoclonal antibodies ( N = 748, 53.3%), molnupiravir ( N = 327, 23.3%), ritonavir‐boosted nirmatrelvir ( N = 217, 15.5%), or remdesivir ( N = 141, 10.0%). In weighted analysis compared to no treatment, anti‐spike monoclonal antibodies (hazard ratio [HR] 0.39, 95% confidence interval [CI] 0.28–0.55; p < 0.001), molnupiravir (HR 0.56, 95% CI 0.36–0.89; p = 0.013), and nirmatrelvir (HR 0.47, 95% CI 0.25–0.89; p = 0.020) were associated with reduced hospitalization risk, while remdesivir (HR 1.00, 95% CI 0.50–1.98; p = 0.992) was not. Hospitalization rates were similar between the treatment agents, apart from remdesivir showing a higher risk compared to anti‐spike monoclonal antibodies. Conclusions Outpatient COVID‐19 therapies were largely associated with improved outcomes among SOT recipients. These treatment agents showed similar rates of 30‐day hospitalization, except for remdesivir. The choice of outpatient COVID‐19 therapy in SOT recipients should primarily account for patients’ individual circumstances and drug‐drug interactions rather than differential therapeutic efficacy. image

AbstractBackgroundAlzheimer's disease (AD) is the most prevalent neurodegenerative disease, yet our comprehension predominantly relies on studies within the non‐Hispanic White (NHW) population. To address this, Accelerating Medicines Partnership in AD (AMP‐AD) aimed to promote inclusivity in multi‐omics AD research, to unravel unique molecular signatures and pathways. The study aimed to provide comprehensive insights into the proteomic landscape of AD across diverse racial groups.MethodDorsolateral prefrontal cortex (DLPFC) and superior temporal gyrus (STG) brain tissues were donated from multiple centers (Mayo Clinic, Emory University, Rush University, Mt. Sinai School of Medicine) and were harmonized through neuropathological evaluation, specifically adhering to the Braak staging and CERAD criteria. Among 1105 DLPFC tissue samples (980 unique individuals), 322 were from African American donors, 214 from Latino Americans, 551 from NHW donors, and the rest were from a mixed or unknown racial background. Among 280 STG samples, 86 were African American, 76 Latino American, 116 NHW and the rest were mixed or unknown ethnicity. All tissues were uniformly homogenized and analyzed by tandem mass tag‐based mass spectrometry (TMT‐MS). Following quality control (QC), proteins with more than 50% missing values were removed and iterative principal component analysis was conducted to remove outliers within brain regions. Differential protein expression was conducted within and across races after adjusting for batch using regression‐analysis.ResultIn total, 9,180 proteins from the DLPFC, and 9,734 proteins from STG brain tissues were quantified by TMT‐MS. Further analysis identified approximately 3,000 differentially abundant proteins in AD brains compared to controls within race. The AD‐associated differentially abundant proteins were strongly correlated between DLPFC and STG regions and with CERAD and Braak. Protein levels of MAPT and APP demonstrated equivalent disease‐related elevations in both African American and NHW individuals with AD. Notably, after adjusting for AD, significant differences in protein levels were identified across race.ConclusionThe proteomics approach employed by AMP‐AD sheds light on the brain proteome in AD across diverse racial groups, emphasizing the importance of inclusive research in establishing robust and generalizable discoveries. The identified proteins here could underscore racial disparities beyond disease association, contributing to a more nuanced understanding of AD pathophysiology.

AbstractBackgroundTwo main risk factors of Alzheimer’s disease (AD) are aging and APOE‐ε4. However, some individuals remain cognitively normal despite having these risk factors. They are considered “cognitively resilient”. This study aimed to identify molecular factors that confer cognitive resilience in APOE‐ε4 carriers ≥ 80 years of age and may serve as biomarkers.MethodWe applied weighted gene co‐expression network analysis (WGCNA) to generate consensus co‐expression networks from blood of participants in two antemortem cohorts, the Mayo Clinic Study of Aging (MCSA, n=105), and the Alzheimer’s Disease Neuroimaging Initiative (ADNI, n=91), using RNA‐sequencing and microarray data, respectively. We associated these networks with resilience (resilient vs non‐resilient), cognitive endophenotypes and hippocampal volume. Preservation between consensus networks from blood and those derived from postmortem brain tissues of AD and control donors from AMP‐AD (n=1174) was evaluated. We validated the human findings in four AD mouse models. Finally, machine learning models were utilized to discriminate cases (AD+mild cognitive impairment (MCI)) from controls in MCSA, ADNI and ANMerge antemortem cohorts.ResultFour consensus networks were significantly correlated with a memory phenotype (logical memory delayed recall=LMDR) and hippocampal volume in both MCSA and ADNI. Among these, blood expression module M3 was most preserved with the brain transcriptome. M3 was enriched with NDUF hub genes that are involved in the mitochondrial respiratory chain. Expression levels of M3 and many blood NDUFs had significant associations with better LMDR and hippocampal volume. In brain, NDUFs were upregulated in controls compared to AD, and their expression levels were associated with better global cognition and decreased AD neuropathology. Many NDUFs were significantly downregulated in the hippocampus or cortex of AD mice compared to wild‐types. Lastly, models that included blood NDUFs improved diagnostic accuracy of AD+MCI compared to models that only included demographic and risk variables (age, sex, APOE‐ε4) in MCSA, ADNI and ANMerge. In MCSA and ADNI, adding NDUFs’ expression to models that included established blood biomarkers (Aβ42/40, ptau181, NFL) further improved diagnostic accuracy.ConclusionOur results suggest that mitochondrial NDUFs are centrally‐linked peripheral molecular signatures that may be resilience factors against AD and serve as both therapeutic targets and novel diagnostic biomarkers.

AbstractBackgroundAlzheimer’s disease (AD) patients have decline in cognitive domains including memory, language, visuospatial, and/or executive function and brain pathology including amyloid‐β and tau deposition, neurodegeneration, and frequent vascular co‐pathologies detectable by neuroimaging and/or cerebrospinal fluid biomarkers. However, molecular disease mechanisms are complex and heterogeneous. It is necessary to develop cost‐effective blood‐based biomarkers reflecting brain molecular perturbations in AD. We identified blood‐based gene and co‐expression network level changes associated with AD/mild cognitive impairment (MCI) diagnosis and AD‐related phenotypes.MethodWe performed differential gene expression and weighted gene co‐expression network analysis, followed by meta‐analysis, using blood transcriptome data of 391 participants from the Mayo Clinic Study of Aging and 654 participants from the Alzheimer's Disease Neuroimaging Initiative. The neuroimaging phenotypes include microhemorrhages, infarcts, amyloid burden, hippocampal volume, and white matter hyperintensities. The cognitive phenotypes include standardized cognitive subtest scores and composite scores for memory, language, visuospatial, and executive function.ResultFive out of 18 modules(M) are significantly associated with diagnosis or cognition (FDR‐adjusted p<0.05). M1 and M15 both positively associates with memory, M1 positively associated with language and M15 with visuospatial function. M1 and M15 are enriched in differentially expressed genes (DEGs) associated with language and executive function, respectively. M2 negatively associates with logical memory delayed recall scores(LMDR), memory, executive, and language functions and is enriched in DEGs for these phenotypes. M8 negatively associates with memory, language and executive functions and is enriched in DEGs for memory and language. M12 positively associates with LMDR. M1 and M15 are down‐regulated while M2 and M8 are up‐regulated in AD/MCI patients. Cell‐type enrichment analysis showed M2 is enriched in monocytes and neutrophils; M8 in monocytes; M15 in B cells (FDR <0.05). Gene ontology terms enriched in these modules indicated broad consistency with their cell types.ConclusionWe identified five modules significantly associated with AD/MCI or cognitive phenotypes using blood transcriptome data. These findings nominate blood transcriptome changes and their enriched biological processes as potential pathomechanisms in cognitive decline and AD/MCI development. We aim to investigate these blood transcripts as potential biomarkers for AD or AD‐related phenotypes and therapeutic targets through additional replication and experimental validation studies.

Abstract Multiplexed Immunofluorescence (MxIF) enables detailed immune cell phenotyping, providing critical insights into cell behavior within the tumor immune microenvironment (TIME). However, signal integrity can be compromised due to the complex cyclic staining processes inherent to MxIF. Hematoxylin and Eosin (H&E) staining, on the other hand, offers complementary information through its depiction of cell morphology and texture patterns and is often visually cross-referenced with MxIF in clinical settings. In this study, we proposed a novel framework to align H&E and MxIF images for precise cross-modal cell feature validation. Using cell detection outputs from each modality as anchors, we formulated the multimodal image registration problem as point set alignment. Coherent Point Drift (CPD) is employed for initial alignment, followed by Graph Matching (GM) for refinement. Evaluations on ovarian cancer tissue microarrays (TMAs) demonstrate that our method achieves high alignment accuracy, enabling reliable validation of cell-level features across modalities for both restained and serial sections. Our results indicate that restained H&E enhances confidence in findings derived from MxIF. Additionally, we demonstrated the feasibility of generating high-quality virtual H&E images from MxIF data when restained H&E is unavailable, offering a viable alternative for integrated multimodal analysis.

Background: Mismatch between osteochondral allograft (OCA) donor and recipient sex has been shown to negatively affect outcomes. This study accounts for additional donor variables and clinically relevant outcomes. Purpose: To evaluate whether donor sex, age, donor-recipient sex mismatch, and duration of graft storage affect clinical outcomes and failure rates after knee OCA transplantation. Study Design: Cohort study; Level of evidence, 3. Methods: Patients undergoing knee OCA transplantation between 2003 and 2018 were prospectively followed. Inclusion criteria consisted of primary OCA transplantation and minimum 2-year follow-up. Patient descriptive data and allograft donor sex, age, and graft storage time before implantation were collected. Patients were evaluated for reoperation, failure, and achievement of clinically significant outcomes for International Knee Documentation Committee scores. Reoperation was defined as subsequent surgical intervention of the transplanted allograft, including second-look arthroscopy for graft evaluation, debridement, and loose body removal. Failure was defined as revision of the primary OCA transplantation or conversion to arthroplasty. A Kaplan-Meier curve determined cumulative survivability of OCA transplantations, and log-rank testing was used to compare survivorship between groups. Stepwise regression analysis was utilized to evaluate associations between donor variables and achievement of clinically significant outcomes, reoperation, and failure. Results: A total of 372 patients undergoing OCA transplantation were included and followed for a mean 5.4 years (SD, 2.7; range, 2.0-16.3). Isolated OCA transplantation was performed in 45% of cases (169/372). A mismatch in donor and recipient sex was present for more female patients (90%) than male patients (10%; P < .001). Those who had a sex-mismatched graft more frequently underwent concomitant tibial tubercle osteotomy ( P = .034). When controlling for patient sex, no other differences were seen between groups matched and mismatched by sex. Univariable and multivariable analysis found no significant difference in survival free from reoperation or failure on the basis of donor-recipient sex mismatch, donor age, or graft storage time before implantation. Conclusion: In contrast to previous historical data, no donor variables were associated with inferior clinical outcomes in patients who underwent OCA transplantation. These data can help inform graft selection, expedient recipient selection, and outcome optimization after OCA transplantation.

Purpose To characterize variation in the value of hip arthroscopy for femoroacetabular impingement and explore associations between value and patient‐specific demographic characteristics, comorbidities, preoperative patient‐reported outcome measures (PROMs), and intraoperative variables. Methods We included all patients aged 18 years or older who underwent primary arthroscopic acetabular labral repair or debridement between 2015 and 2020 with minimum 2‐year follow‐up. The exclusion criteria were hip dysplasia, advanced hip osteoarthritis (TÖnnis grade >1), or unreconcilable documenting errors. Value was calculated by dividing 2‐year postoperative International Hip Outcome Tool 33 scores by time‐driven activity‐based costs. To protect the confidentiality of internal hospital cost data, the study average for value was normalized to 100. Multivariable linear mixed‐effects models were used to identify factors underlying variation in value. Results This study included 161 patients. There were 76 women (47.2%) and 85 men, with a mean age of 36.0 years (standard deviation [SD], 10.9 years) and mean body mass index (BMI) of 25.8 (SD, 4.3). Most patients were white (92.5%), were not Hispanic (93.8%), and were commercially insured (92.5%). Preoperatively, 57.1% of hips were classified as Tönnis grade 1 (57.1%) whereas the remainder were grade 0. The normalized value of hip arthroscopy ranged from 25.4 to 216.4 (mean ± SD, 100 ± 38.4), with a 3.0‐fold variation between patients in the 10th and 90th percentiles. Higher value was significantly associated with Tönnis grade 0 (12.2‐point increase, P = .025), no prior contralateral hip arthroscopy (17.3‐point increase, P = .039), higher preoperative PROMs (0.52‐point increase per 1‐unit increase, P < .001), and no bone marrow aspirate concentrate or microfracture (33.8‐point increase, P < .001). Value was also significantly associated with osteoplasty type and labral treatment technique ( P < .05 for both). In contrast, operative year, age, sex, BMI, race, ethnicity, Outerbridge grade, and American Society of Anesthesiologists score were not independently associated with value. A model incorporating these factors as fixed effects and the surgery center as a random effect explained 42.3% of the observed variation in value. Sensitivity analyses revealed that value drivers may vary slightly across PROMs. Conclusions This study revealed wide variation in the value of hip arthroscopy that was most strongly explained by osteoplasty type, labral management technique, and preoperative PROMs. In contrast, patient demographic characteristics such as age, sex, and BMI contributed minimal independent variability. Level of Evidence Level IV, economic and decision analysis.

AbstractBackgroundSystemic inflammation plays a pivotal role in many chronic diseases including Alzheimer’s disease (AD). Assessing the composition of immune pathways in neurodegenerative diseases can contribute to precision medicine. Using publicly available transcriptomic data, we sought to elucidate transcriptional networks pertinent to inflammatory pathways across brain regions and peripheral blood in AD/mild cognitive impairment (MCI) and peripheral blood in Parkinson’s disease (PD).MethodFor the AD/MCI vs. control dataset, we analyzed bulk‐RNAseq collected from 6 brain regions of donors from ROSMAP, Mayo Clinic, and Mount Sinai School of Medicine (MSSM) brain banks available from the AMP‐AD consortium. Ante‐mortem, blood RNAseq expression data was retrieved from the AMP‐AD Emory Vascular cohort and Mayo Clinic Study of Aging (MCSA). We also collected blood‐derived microarray expression data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). For the PD vs Control dataset, blood‐derived bulk‐RNAseq from the PDBP and PPMI cohorts were available through the AMP‐PD consortium. Following quality control, normalization, and residual generation to account for biological and technical variables, co‐expression network modules and their enriched pathways were identified using WGCNA within each dataset. Module/trait correlation tests for aging and diagnosis (cases [AD/MCI or PD] vs control) phenotypes were evaluated. Gene Ontology enrichment analyses were executed to identify enriched pathways and brain or blood cell types within the modules. Modules were tested for preservation across cohorts.ResultWe identified conserved immune signatures across brain regions and cohorts. Modules involved in immune response were preserved across all cohorts. Blood consensus modules involved in immune response were preserved in the brain and vice versa. Some immune modules were associated with AD/MCI, PD, and/or aging. Brain immune modules are significantly associated with aging and/or AD. Significant correlations (q<0.05) with PD diagnosis were present. In the MCSA and Emory vascular cohorts, there were no significant (q<0.05) associations between modules and diagnosis, while in ADNI there were nominal (p<0.05) associations.ConclusionPreserved transcriptional immune networks were identified across blood and brain and across two neurodegenerative diseases. Expanding gene co‐expression network analyses to other diseases and integrating additional omics measures and phenotypes can further strengthen these findings to unravel the immune signatures across complex diseases.

AbstractBackgroundA complex, multicellular disease with genetic and immunological elements, Alzheimer’s disease (AD) affects millions worldwide. There has been previous research linking AD to the missense variants ABI3‐rs616338‐T and PLCG2‐rs72824905‐G, and the altered expression of these genes has been shown to disrupt microglial function. In our understanding of AD risk and resilience, limited research has been conducted on how these variants affect microglial subtypes and states in AD.MethodsWe previously identified DOCK8 protein as a target for fluorescent activated nuclei sorting (FANS) to enrich microglia nuclei from frozen human brains. Using this enrichment strategy, we generated microglia enriched snRNAseq data from temporal cortex tissue of 30 donors harboring ABI3 or PLCG2 missense mutations, or neither mutation. We introduced PLCG2 variant in either homozygote, and heterozygote forms into an AD patient derived iPSC through CRISPR/Cas9 approach, differentiated these cells into microglia cells (IMGLs) following established protocols, and generated scRNAseq data after treatment with Amyloidβ. We applied standard alignment and quality control pipelines to the snRNAseq and scRNAseq datasets in parallel. Established markers of microglia states and subtypes were utilized to annotate the clusters; analyzed for their hub gene expression using comparisons between cluster differential profiling to determine signature pathways. Differential gene expression was assessed using pseudo bulk and MAST approaches.ResultsWe obtained single nuclei transcriptome profiles of 54,000 frozen human brain nuclei, of which 35,000 are microglia, through snRNAseq, and single cell profiles of 63,000 iMGLs through scRNAseq, using our standard alignment and quality control procedures. Our differential gene expression analysis identified novel genes and pathways which were identified as part of resilience or AD risk networks in microglia subtypes and states. These alterations were validated using orthogonal experimental methods and further explored for their conservation using in vivo external datasets. Pseudotime inference will be completed to probe microglia marker gene expression dynamics, treatment conditions, along with continuous cell‐state changes.ConclusionOur study uncovers microglia subtype specific resilience and risk factors provided by AD related genetic variants using snRNAseq from frozen human brain and scRNAseq from IPSC derived microglia cells. These findings nominate novel targets and pathways with therapeutic potential.

AbstractBackgroundAlzheimer’s disease (AD) is a devastating neurodegenerative disorder with few therapies to treat, mitigate or prevent its onset. Understanding of this disease is predominantly based on research in non‐Hispanic Whites (NHW) although AD disproportionately affects African Americans (AA) and Latin Americans (LA), underrepresented in AD research. To address this knowledge gap, the Accelerating Medicine Partnership for Alzheimer’s Disease (AMP‐AD) Diversity Working Group was launched to generate multi‐omics data from post‐mortem brain tissue from donors of predominantly AA and LA descent. Here, we focus on genomic and transcriptomics measures, made available through the AD Knowledge Portal (ADKP).MethodBrain tissue from dorsolateral prefrontal cortex (DLPFC), caudate nucleus (CN), superior temporal gyrus (STG) and temporal pole (TP) regions of AA (N = 299), LA (N = 344) and NHW (N = 532) donors was obtained through Mayo Clinic, Mt. Sinai School of Medicine, Emory, Columbia, Rush Alzheimer’s Disease Center, Banner Sun Health, and 1Florida. DNA extracted from DLPFC tissue samples (n = 641) was utilized for whole genome sequencing (WGS) at New York Genome Center (NYGC). RNAseq of 2,224 samples was conducted either at Mayo, Rush or NYGC. Sequencing reads were processed through GenomeGPS and MAPRseq pipelines for WGS and RNAseq data, respectively. Following quality control (QC), RNAseq data was normalized and assessed for sources of variation (SOV). Integration of WGS and RNAseq data to perform comparative eQTL analysis across multi‐ethnic populations and brain regions is ongoing.ResultWGS data for 621 donors, and RNAseq data generated at Mayo (n = 1,136 samples), Rush (n = 627), and NYGC (n = 779) sequencing centers, were deposited to the ADKP. Consensus processing of RNAseq data revealed site, sex, race/ethnicity, RIN, AD diagnosis, age at death and/or library batch as SOV across various sites and brain regions. Principal component analysis of gene expression measures revealed no major stratification by disease or brain region. Accompanying clinical metadata of donors have been distributed through ADKP.ConclusionThese multi‐omics data made available to the research community is expected to be an initial step towards bridging our data and knowledge gap to elucidate conserved and distinct AD related pathways across these underrepresented at‐risk populations.