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Abstract Background Recurrent Clostridioides difficile infection (rCDI) is common, with a prior CDI linked to a risk of up to 65% for subsequent recurrences. Fecal microbiota, live-jslm (RBL) is the first microbiota-based product approved in the US for the prevention of rCDI in adult patients following antibiotic treatment for rCDI. This study reports the characteristics and outcomes of patients with rCDI who were administered RBL in a real-world setting. Methods Adult patients with rCDI who received RBL either at home or a clinic from healthcare professionals affiliated with a home-care provider network were included. Patients were required to have at least 8 weeks of follow-up after RBL administration, with CDI recurrence status assessed at week 8. Patient demographics, clinical characteristics, administration setting, prior medication use, and prior healthcare resource utilization were collected. The primary outcome was CDI recurrence within 8 weeks post-RBL administration. All variables were summarized descriptively using median and interquartile range (IQR) for continuous outcomes and count and percentage for categorical variables. Results Between July 2023 and March 2024, 136 patients with rCDI received RBL, of whom 73 had at least 8-week follow up and reported CDI recurrence status at week 8. Patients had a median age of 63.0 years (IQR = 47.0, 76.0), 68.5% were female, most (74.0%) had ≥ 3 prior CDI recurrences, 5.5% had received fecal microbiota transplant, and 9.6% had received bezlotoxumab (Table). One third of patients (32.9%) had previously been hospitalized and 38.4% had prior emergency room visits due to CDI. Most patients were previously treated with antibiotics for rCDI: 39.7% with vancomycin only, 11.0% with fidaxomicin only, and 43.8% with both vancomycin and fidaxomicin. All patients, except for 4 with missing data, received RBL 24-72 hours post-antibiotics. Most patients (83.6%) received RBL at home. At week 8, the overall treatment success rate (no CDI recurrence) was 87.7% (87.3% [62/71] in RBL-naïve; 100% [2/2] in previously RBL-treated). Conclusion RBL was effective in preventing recurrence of CDI at 8 weeks in a real-world setting, where most patients received RBL at home. These results suggest that RBL is effective in managing rCDI, including in a home care setting. Disclosures Sahil Khanna, MBBS, MS, Ferring Pharmaceuticals, Inc.: Grant/Research Support|Finch: Grant/Research Support|Immuron: Advisor/Consultant|Niche: Advisor/Consultant|Pfizer: Grant/Research Support|Probio Tech, LLC: Advisor/Consultant|Seres Therapeutics: Grant/Research Support|Takeda: Advisor/Consultant|Vedanta: Grant/Research Support Sanghyuk Seo, PharmD, MS, Ferring Pharmaceuticals, Inc.: Employee Min Yang, MD, PhD, Analysis Group, Inc.: I am an employee of Analysis Group, Inc., which has received consulting fees from Ferring for the conduct of this study. Viviana García-Horton, PhD, Analysis Group, Inc.: I am an employee of Analysis Group, Inc., which has received consulting fees from Ferring for the conduct of this study. Yipeng Gao, PhD, Analysis Group, Inc.: I am an employee of Analysis Group, Inc., which has received consulting fees from Ferring for the conduct of this study. Hannah Kim, PhD, Analysis Group, Inc.: I am an employee of Analysis Group, Inc., which has received consulting fees from Ferring for the conduct of this study. Loren Ormenaj, n/a, Analysis Group, Inc.: I am an employee of Analysis Group, Inc., which has receivedconsulting fees from Ferring for the conduct of this study. Amy Guo, PhD, Ferring Pharmaceuticals, Inc.: Employee

Abstract Autoimmunity affects 10% of the population. Within this umbrella, autoantibody-mediated diseases targeting one autoantigen provide a unique opportunity to comprehensively understand the developmental pathway of disease-causing B cells and autoantibodies. While such autoreactivities are believed to be generated during germinal centre reactions, the roles of earlier immune checkpoints in autoantigen-specific B cell tolerance are poorly understood. We address this concept in patients with CASPR2-autoantibody encephalitis and healthy controls. In both groups, comparable and high (∼0.5%) frequencies of unmutated CASPR2-reactive naïve B cells were identified. By contrast, CASPR2-reactive memory B cells were exclusive to patients, and their B cell receptors demonstrated affinity-enhancing somatic mutations with heterogenous binding kinetics. These effector molecules possessed epitope-dependent pathogenic effects in vitro neuronal cultures and in vivo. The unmutated common ancestors of these memory B cells showed a distinctive balance between strong CASPR2 reactivity and very limited binding across the remaining human proteome. Our results are the first to propose mechanisms underlying autoantigen-specific tolerance in humans. We identify permissive central tolerance, defective peripheral tolerance and heterogenous autoantibody binding properties as sequential pathogenic steps which licence CASPR2-directed pathology. By leveraging the basic immunobiology, we rationally direct tolerance-restoring approaches in CASPR2-antibody diseases. This paradigm is applicable across autoimmune conditions.

Objectives: ImPACTS (Improving Acute Care Through Simulation) is a collaborative simulation-based program partnering pediatric specialty centers (“hubs”) with general emergency departments (GEDs) to improve pediatric acute care. Objective measurements of ImPACTS, such as evaluating Pediatric Readiness Score (PRS) and simulation-based outcome improvements, have been reported previously. Barriers to and facilitators of program involvement and the downstream effects of the program have not been previously described. This study explores these aspects and key drivers for successful collaboration. Methods: The authors performed open coding of semistructured interviews of hub team members and pediatric emergency care coordinators (PECCs) from community GED “spokes.” We then identified and explored themes within the categories of barriers to, facilitators of, and barrier mitigation strategies for successful partnerships from the perspectives of both groups. Results: Analysis generated 4 dominant themes: buy-in, communication, personnel, and logistics. Engagement, institutional support, and buy-in of site leaders and individual participants were crucial to successful implementation, without which the programs were not completed or never started. Hubs benefited from project involvement via increased local engagement in pediatric readiness, organizational support, and further buy-in from institutional leadership, allowing for the future continuation of ImPACTS and similar programs. Benefits experienced by GEDs impacted education, pediatric readiness, and clinical and financial partnerships across institutions. Additionally, spoke interviewees cited downstream effects of participation, including increased collaboration and improved relationships with hub sites as being the most impactful. Conclusion: Understanding the key drivers of all collaborators is instrumental in successfully implementing large-scale educational and quality initiatives like the ImPACTS program.

AbstractBackgroundThe residual approach has found wide application in researching cognitive resilience, a phenomenon conceptually understood as cognitive performance being better‐than‐typical for an individual, despite apparent AD pathology. The standard residual approach extracts information about an individual’s resilience from the residuals of a linear model predicting cognition. This approach is subject to several limiting assumptions. Here, we explore the implications of these assumptions and propose an alternative predictive modeling approach which circumvents them.MethodsOur alternative approach relies on training a machine learning model on a sample of participants who follow a “typical” clinical progression (Fig. 1A). Residuals are then extracted for a heterogeneous dataset that potentially includes resilient participants by comparing observed cognitive outcomes to those predicted by the “typical” model (Fig. 1B). Additionally, our estimate can be refined by effectively estimating and removing model error from the extracted residual by leveraging a second predictive model (Fig. 1C). Using simulated data, we explore the assumptions made by the standard approach and the consequences of their violation. We then contrast this against our approach.ResultsOur simulations demonstrated that the standard residual approach only extracted accurate resilience estimates if the predictors used in the model explained cognition sufficiently well, while being unrelated to resilience itself. That is, as the predictors explain more of the resilience, the residuals became increasingly determined by model error (Fig. 2). We found that residuals achieved with our approach are more precise and provide individualized estimates that are unaffected by the aforementioned trade‐off (Fig. 3).ConclusionsOur approach holds several advantages over the standard approach: The definition of resilience can be freely adjusted and enforced via different definitions of “typical”, it allows for incorporating complex, non‐linear models without removing relevant information from the residual, the error component of the residual can be estimated through cross‐validation, and all predictors that potentially explain cognition can be included into the model without losing resilience information from the residual. Our approach can be used to measure any phenomenon that can be operationalized as a deviation from a typical outcome and, thus, is also applicable for researching resistance to pathology.

AbstractBackgroundThere is a strong link between tau and progression of Alzheimer’s disease (AD), necessitating an understanding of tau spreading mechanisms. Prior research, predominantly in typical AD, suggested that tau propagates from epicenters (regions with earliest tau) to functionally connected regions. However, given the constrained spatial heterogeneity of tau in typical AD, validating this connectivity‐based tau spreading model in AD variants with distinct tau deposition patterns is crucial.MethodWe included 269 amyloid‐β‐positive (PET/CSF) individuals with clinically diagnosed atypical AD (113 posterior cortical atrophy, PCA‐AD; 83 logopenic variant primary progressive aphasia, lvPPA‐AD; 33 behavioural variant AD, bvAD; 40 corticobasal syndrome, CBS‐AD) and 68 with typical AD from 12 international cohorts, who underwent tau‐PET (54% [18F]AV1451/[18F]flortaucipir/Tauvid, 27% [18F]MK6240, 19% [18F]PI2620). Using Gaussian mixture modeling including amyloid‐β‐negative controls, cross‐sectional tau‐PET standardized uptake value ratios within Schaefer‐200 atlas regions were transformed to tau positivity probabilities. Tau epicenters were defined as the 5% regions with highest tau positivity probabilities. For each variant, the association between functional connectivity‐based distance (using the 30% strongest positive region‐to‐region connections of a group‐average connectivity matrix from ADNI elderly controls) and tau‐PET covariance (group‐average correlation per region pair) was assessed through linear regression, adjusting for age, sex, site, and Euclidean distance. Regions were categorized based on functional proximity to the epicenter (quartiles 1‐4) and tau positivity probabilities were assessed accordingly.ResultTau positivity probabilities matched clinical variants, with a posterior pattern in PCA‐AD, left‐hemispheric dominant pattern in lvPPA‐AD, widespread pattern in bvAD, sensorimotor cortex involvement in CBS‐AD, and temporo‐parietal predominance in typical AD (Figure 1). In line with this, tau epicenters were highly heterogeneous across variants (Figure 1). In all variants, greater tau‐PET covariance was associated with shorter functional connectivity‐based distance (Figure 2). We observed that regions in closer functional proximity to the epicenter exhibited higher tau positivity probabilities than regions functionally further away (p<0.05, Figure 3).ConclusionThis multi‐center study shows that the brain’s functional architecture serves as a universal predictor of tau spreading in AD. Since tau is a key driver of neurodegeneration and cognitive decline in AD, this finding holds potential for personalized medicine and defining participant‐specific endpoints in clinical trials.

AbstractBackgroundThere is a strong link between tau and progression of Alzheimer’s disease (AD), necessitating an understanding of tau spreading mechanisms. Prior research, predominantly in typical AD, suggested that tau propagates from epicenters (regions with earliest tau) to functionally connected regions. However, given the constrained spatial heterogeneity of tau in typical AD, validating this connectivity‐based tau spreading model in AD variants with distinct tau deposition patterns is crucial.MethodWe included 269 amyloid‐ß‐positive (PET/CSF) individuals with clinically diagnosed atypical AD (113 posterior cortical atrophy, PCA‐AD; 83 logopenic variant primary progressive aphasia, lvPPA‐AD; 33 behavioural variant AD, bvAD; 40 corticobasal syndrome, CBS‐AD) and 68 with typical AD from 12 international cohorts, who underwent tau‐PET (54% [18F]AV1451/[18F]flortaucipir/Tauvid, 27% [18F]MK6240, 19% [18F]PI2620). Using Gaussian mixture modeling including amyloid‐ß‐negative controls, cross‐sectional tau‐PET standardized uptake value ratios within Schaefer‐200 atlas regions were transformed to tau positivity probabilities. Tau epicenters were defined as the 5% regions with highest tau positivity probabilities. For each variant, the association between functional connectivity‐based distance (using the 30% strongest positive region‐to‐region connections of a group‐average connectivity matrix from ADNI elderly controls) and tau‐PET covariance (group‐average correlation per region pair) was assessed through linear regression, adjusting for age, sex, site, and Euclidean distance. Regions were categorized based on functional proximity to the epicenter (quartiles 1‐4) and tau positivity probabilities were assessed accordingly.ResultTau positivity probabilities matched clinical variants, with a posterior pattern in PCA‐AD, left‐hemispheric dominant pattern in lvPPA‐AD, widespread pattern in bvAD, sensorimotor cortex involvement in CBS‐AD, and temporo‐parietal predominance in typical AD (Fig.1). In line with this, tau epicenters were highly heterogeneous across variants (Fig.1). In all variants, greater tau‐PET covariance was associated with shorter functional connectivity‐based distance (Fig.2). We observed that regions in closer functional proximity to the epicenter exhibited higher tau positivity probabilities than regions functionally further away (p<0.05, Fig.3).ConclusionThis multi‐center study shows that the brain’s functional architecture serves as a universal predictor of tau spreading in AD. Since tau is a key driver of neurodegeneration and cognitive decline in AD, this finding holds potential for personalized medicine and defining participant‐specific endpoints in clinical trials.

Therapy dogs have been increasingly incorporated into a variety of medical treatment programs to improve patients’ treatment outcomes and wellbeing. However, research investigating the stress level of therapy dogs in this setting is limited. This is the first randomized–controlled and prospective study that investigated the wellbeing of therapy dogs in an inpatient stroke rehabilitation program. In this study, 14 therapy dog–handler pairs were embedded in an inpatient stroke rehabilitation program to provide animal-assisted treatment (AAT). These therapy dog–handler pairs actively participated in stroke rehabilitation by walking with the patient, playing fetch with the patient, and being petted/brushed by the patient, amongst various other AAT activities. To measure canine stress responses during the rehabilitation sessions, salivary cortisol and oxytocin concentrations, heart rate and heart rate variability, tympanic membrane temperature, and a behavioral evaluation were recorded before and after interactions with the patient. The results demonstrated that therapy dogs had significantly decreased heart rate and increased heart rate variability after the AAT session. Right tympanic temperature significantly increased after the session, but there was no significant difference in terms of salivary cortisol or oxytocin levels, nor in stress-related behavioral evaluations after the AAT session. Taken together, the results suggest that incorporating AAT into an inpatient stroke rehabilitation program did not induce stress in the therapy dogs, and that the therapy dogs may have been more relaxed after the session.