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Target Engagement and Cognitive Outcomes of Anti‐Amyloid Immunotherapies in Early‐Onset Alzheimer's Disease: First Report from the LEADS Study
No full textBackground:
In clinical trials, monoclonal antibodies targeting Aβ pathology have shown strong target engagement, resulting in rapid Aβ clearance and a deceleration in rate of clinical decline. Now that these treatments are approved and implemented in clinical practice, we could assess their effects in observational studies involving these patients.
Method:
We analyzed data from 20 participants with early‐onset Alzheimer's disease (EOAD) in the Longitudinal Early‐Onset Alzheimer's Disease Study (LEADS) cohort, treated with Aducanumab (n = 4), Lecanemab (n = 15), or both (one transitioning from Aducanumab to Lecanemab). All participants had MCI or mild dementia at baseline, longitudinal Aβ and tau PET, as well as cognitive assessments, with at least one observation before and after treatment initiation. We applied piecewise regression with a knot at the treatment start, to evaluate changes in Aβ and tau PET burden and Clinical Dementia Rating‐Sum of Boxes (CDR‐SB) scores. We compared the trajectories of treated participants with an untreated group (i.e., treated‐untreated comparison) from LEADS, matched for age, sex, APOE ε4 genotype, pretreatment Aβ and tau PET load, CDR‐SB, and follow‐up duration, using a 1:3 matching design.
Result:
The median treatment duration was 8 months (IQR=5‐10). In the piecewise regression model, the treated group showed significant decreases in Aβ burden post‐treatment (Δ=‐52 Centiloids/yr, p <0.001) with widespread neocortical involvement (Figure 1). However, no significant inflection in tau burden (Δ=0 SUVR/yr, p = 0.58) or CDR‐SB (Δ=0.3 units/yr, p = 0.57) trajectories was observed. In the treated‐untreated comparison, the treated group showed a trend toward slower increases in CDR‐SB scores post‐treatment (ΔT=‐1.8, p = 0.07) compared to the untreated group (Figure 2). Aβ levels significantly decreased in the treated group compared to the untreated group (ΔΤ=‐8.5, p <0.001). No significant differences in tau trajectories were observed between groups (ΔT=0.4, p = 0.68), with both showing increases in cortical regions of interest.
Conclusion:
We observed excellent target engagement, with piecewise regression models showing rates of Aβ clearance comparable to those seen in Phase 3 trials. The study was underpowered to detect cognitive benefits, which are limited over a short follow‐up interval. These findings underscore the utility of observational studies with biomarker data in evaluating treatment efficacy, offering insights that complement traditional randomized trials
The collaboration of surgical education fellows' (CoSEF) guide to designing, executing, and publishing surgical education research
No full textAcute blood biomarker responses to consensual sexual choking/strangulation in young adult women: a randomized crossover study
No full textIntroduction: Sexual strangulation, commonly referred to as "choking", has become increasingly common among young adults, yet its neurobiological consequences remain poorly understood. Preclinical and clinical evidence suggests strangulation may trigger axonal injury, neuroinflammation, and blood-brain barrier dysfunction. Blood biomarkers of neural injury and inflammation provide a sensitive means to detect subtle effects.
Aim: To examine whether consensual sexual choking/strangulation acutely alters blood biomarkers of neural injury and inflammation compared to non-choking sexual activity in young adult women.
Methods: In a randomized crossover study, 29 women (mean age 21.5 ± 2.7) completed three laboratory visits: baseline (≥24 h abstinence), post-choking sex, and post-non-choking sex. Blood was collected within 24 h of sexual events. Neural injury biomarkers (NfL, tau, GFAP, UCH-L1, S100B) and inflammatory markers (IL-1ra, TNF-R1, CCL-2, VEGF-A, VCAM-1) were analyzed using Quanterix and Luminex multiplex immunoassays. Mixed-effects regression models tested exposure-by-time interactions, adjusting for age and brain trauma history.
Results: Neurofilament light (NfL) significantly increased after choking-involved sex but remained unchanged after non-choking, which resulted in a statistically significant exposure-by-time interaction [β = -0.21, 95% CI (-0.38, -0.03), p = 0.021]. Other neural biomarkers did not differ by exposure. Among inflammatory markers, CCL-2 and VEGF-A demonstrated a similar pattern as NfL, with acute increases after choking-involved sex, but not following non-choking sex, yielding in exposure-by-time interaction effects (CCL-2: β = -14.60, 95% CI [-25.70, -3.43, p = 0.011; VEGF-A: β = -9.29 (-19.71, 1.13), p = 0.079]. IL-1ra, TNF-R1, and VCAM-1 remained stable.
Discussion: Consensual sexual strangulation elicited acute increases in NfL and CCL-2, with VEGF-A showing a similar pattern, suggesting transient axonal stress and hypoxia-related inflammatory signaling. These findings indicate that sexual choking/strangulation, even in consensual contexts, may have subtle, yet detectable cellular burden. Future studies with larger samples, refined temporal sampling, and multimodal outcomes are needed to clarify short- and long-term implications
221. Effectiveness of RSV Vaccines in Older Adults in the United States, VISION Network, 2023-2025
No full textBackground:
Respiratory syncytial virus (RSV) caused approximately 100,000-160,000 hospitalizations annually in adults aged ≥60 years in the United States (US) before RSV vaccine introduction. In 2023, two vaccines were recommended for prevention of severe RSV disease in adults aged ≥60 years using shared clinical decision making. In 2024, a third product was licensed, and all three available vaccines were recommended for all adults aged ≥75 years and for adults aged 60-74 years at increased risk of severe RSV disease. We assessed post-licensure vaccine effectiveness (VE) to inform future recommendations and public communications.
Methods:
VISION is a multi-site electronic health record-based study including >200 hospitals in the US. Adults aged ≥60 years hospitalized with RSV-like illness and tested for RSV were included. Cases had a positive molecular or antigen RSV test; controls had a negative molecular RSV test. Critical illness included admission to the intensive care unit or in-hospital death. VE against hospitalization and critical illness was calculated using a test negative design as (1-adjusted odds ratio) x 100% where the odds ratio compares odds of vaccination in cases and controls after adjusting for confounders. Results were stratified by time since RSV vaccination, age group, and immunocompromised status.
Results:
Among 83,652 hospitalizations during October 2023-March 2024 and October 2024-March 2025, VE was 62% (95% CI: 56-67%, Table) against RSV-associated hospitalization, median 279 days after RSV vaccination. VE was 83% (95% CI: 73-89%) at 14-59 days after vaccination and 42% (95% CI: 30-53%) at least 1 year after vaccination (median 429 days). VE against RSV-associated critical illness was 69% (95% CI: 55-78%), median 277 days after vaccination. VE was similar by age group and among those with and without immunocompromising conditions.
Conclusion:
RSV vaccines are effective at preventing severe RSV and have the potential to reduce the burden of RSV-associated hospitalizations among older adults, although waning protection was apparent during the second season after vaccination. Ongoing monitoring of RSV VE is warranted to ensure vaccines are working as expected, to understand duration of protection, and to inform policy decisions
EOAD‐Signature Atrophy Predicts Progression to Dementia in Patients with Early‐onset MCI due to Alzheimer's Disease
No full textBackground:
Prognostic risk stratification for patients at the mild cognitive impairment (MCI) stage of early‐onset Alzheimer's disease (EOAD) would allow professionals and loved ones to make better‐informed medical and life planning decisions. While research including our own (Bakkour, Morris, Dickerson, 2009) has demonstrated the prognostic value of MRI‐based measures of brain structure in late‐onset amnestic AD, its utility for predicting progression to dementia in EOAD remains unclear. Here, we measured the magnitude of cortical atrophy within our recently described EOAD signature regions (Touroutoglou et al. 2023) in patients with EOAD at the MCI stage (N = 130) recruited in LEADS. The main goal of the study was to evaluate the utility of this measure as a predictor of time to subsequent progression to dementia. Our second goal was to examine the independent or synergistic contributions of EOAD signature of atrophy and standard clinical severity measures used in clinical trials.
Method:
For each patient, we measured the time between baseline visit and subsequent visit at which progression to mild dementia was documented or last observation. Baseline cortical atrophy was measured as W‐scores (i.e., Z‐scores adjusted for age and sex relative to a sample of healthy controls) in the EOAD signature. Baseline clinical severity was quantified with the Clinical Dementia Rating Sum‐of‐Boxes scores (CDR‐SB). Simple and multivariable Cox regression models examined the relationship between atrophy in EOAD signature, baseline CDR‐SB, and the likelihood of progression to dementia.
Result:
Greater baseline atrophy in the EOAD signature predicted higher risk of progression to dementia (hazard ratio = 1.2, 95% CI 1.1‐1.3) and provided additive value to the CDR‐SB (hazard ratio: 2.1, 95% CI:1.7‐2.8) in predicting progression.
Conclusion:
These findings point to the role of EOAD MRI signature as an imaging biomarker to guide prognostication for patients with EOAD and their families and to inform the design of clinical trials
P-2113. Performance of a Commercial Metagenomic Microbial Cell-free DNA Sequencing Assay in Identifying Explanatory Pathogens of Pulmonary Nodules in a Multi-Center Pediatric Immunocompromised Population
No full textBackground:
Pulmonary nodules on radiography in setting of recent neutropenia or immune suppression for graft versus host disease (GVHD) are concerning for bacterial or invasive fungal disease (IFD). Determining etiology often requires invasive tests that may be inconclusive and pose risk. Non-invasive assays that detect pathogens may improve time to optimal therapy and outcomes. This study sought to evaluate the utility of a commercial metagenomic microbial cell-free DNA (mcfDNA) sequencing assay (Karius SpectrumTM) to identify causative pathogens in this setting.
Methods:
Subjects aged 120 days to 22 years with recent neutropenia or GVHD and with newly detected chest imaging findings meeting EORTC/MSGERC guidelines for possible IFD were enrolled at 27 North American hospitals from 2019 to 2024. Plasma was collected ≤144 hours after imaging and shipped frozen for mcfDNA testing by Karius Laboratories. Microbiology, radiology, pathology, and procedure reports were collected for 49 days post imaging. A three-physician Central Review Board (CRB) reviewed collected data to identify pathogen(s) explaining imaging findings; this served as the reference standard (RS). The CRB separately labeled mcfDNA resulted pathogens as explanatory or not of imaging findings. Operating characteristics (OC) of mcfDNA were relative to the RS; true positives concurred with at least one RS organism.
Results:
Analyses include 146 subjects enrolled through May 2023 with a valid mcfDNA result and complete CRB review. Clinical data review identified ≥1 pathogen that explained qualifying imaging for 67 (46%) subjects (33 fungus, 38 bacteria). OC of mcfDNA were: sensitivity, 44.8% (95% confidence interval, 32.9–56.7%); specificity, 77.2% (68.0–86.5%); positive predictive value, 62.5% (48.8–76.2%); negative predictive value (NPV), 62.2% (52.7–71.8%). 18 (12%) mcfDNA tests yielded an explanatory pathogen missed by RS. 7 (5%) subjects had discordant explanatory pathogens identified by the RS and mcfDNA.
Conclusion:
OC of mcfDNA assay limit it as a stand-alone test for detecting causative pathogens of pulmonary nodules in children with neutropenia or GVHD. NPV is too low to support using this assay to “rule out” infection. This assay offers adjunctive diagnostic utility alongside traditional testing
Effects of restorative materials, colors, and surface finishing on the scanning accuracy of an intraoral scanner
No full textBackground/purpose: When teeth are restored using dental materials, there is potential for these restorations to influence the accuracy of intraoral scans. Such variations in accuracy could subsequently affect the precision of the derived virtual cast, the registration of the maxillo-mandibular relationship, and the fabrication of prostheses. This study aimed to assess the effect of various restorative materials, prosthesis colors, and their surface finishes on the accuracy of intraoral scans performed with a TRIOS 4 scanner.
Materials and methods: Using a 4 × 2 × 2 factorial experimental design, the research analyzed how metal-ceramic, zirconia, lithium disilicate, and milled PMMA; shades B1 and A4; and surface finishes (either polishing or glazing) influence the trueness and precision of scans. The trueness and precision were quantified using root mean square (RMS) values.
Results: Significant differences in scan accuracy were observed, contingent on material, color, and finishing, along with notable interactions between these factors. Overall, PMMA exhibited the highest trueness and zirconia demonstrated the best precision. Polished lithium disilicate and PMMA showed better trueness for the A4 shade, whereas glazed lithium disilicate and PMMA performed better for the B1 shade. Metal-ceramic restorations showed an opposite trend. Zirconia restorations showed better trueness for A4 shade than B1 shade for both polished and glazed surfaces.
Conclusion: Significant interactions between materials, colors, and surface treatments were observed. Although clinicians may not be able to modify existing restorations' materials, color, or surface treatment, they need to be mindful that the intricate interaction of these factors will affect the accuracy of intraoral scans
3D printed collimators and dosimetry for spatially fractionated radiation therapy
No full textBackground: Spatially fractionated radiation therapy (SFRT) has shown incredible potential in sparing normal tissues and activating mechanisms of tumor control distinct from conventional radiotherapy. However, the optimal spatial configuration of SFRT as well as the optimal peak and valley dose values have not been established. This poses a barrier to widespread clinical implementation and efficacy.
Purpose: To facilitate greater SFRT optimization, this work establishes a simple, readily customizable, and cost-effective approach for fabricating SFRT collimators with different spatial configurations as well as peak and valley dose values.
Methods: The approach involves fabrication of custom SFRT collimators, each consisting of a 3D-printed plastic shell filled with tungsten. Once fabricated, the collimator dosimetry is characterized using a combination of Gafchromic film and ion chamber measurements. Monte Carlo simulations are used to verify SFRT dosimetry and assess positional uncertainties. The collimators are applied in preclinical mouse experiments demonstrating how they can be used to deliver SFRT.
Results: Five collimators were fabricated for use at kilovoltage energies and one collimator was fabricated for use at megavoltage energies. Across all collimators, the peak widths ranged from 1.2 to 10.1 mm and the valley widths ranged from 1.1 to 10.6 mm. For the kilovoltage collimators, the highest peak-to-valley dose ratio was 32.4 at the surface and this dropped to 29.5 at 10 mm depth. For the megavoltage collimator, at 95 cm SSD, the peak-to-valley dose ratio was 2.7 at 15 mm depth and this dropped to 2.2 at 100 mm depth. In the mouse experiments, out of multiple SFRT parameters, the mean tumor valley dose had the strongest correlation with change in tumor volume (p = 0.02). The Monte Carlo simulations indicated a 5 mm translation of the mouse tumor relative to the beam led to a 44.8% change in the mean tumor dose, underlying the importance of precise positioning for SFRT.
Conclusions: This work establishes a novel approach for custom 3D printing of SFRT collimators and their subsequent characterization. The developed collimators are capable of SFRT delivery at both kilovoltage and megavoltage photon beam energies. This approach facilitates patient specific customization as well as optimization of the peak and valley doses for more effective SFRT
Association Between Fragmentation of Care and Delivery of Adjuvant Chemotherapy in Patients Traveling to High-Volume Hospitals for Pancreatic Adenocarcinoma
No full textBackground: Surgical care for pancreatic ductal adenocarcinoma (PDAC) is increasingly centralized to high-volume hospitals (HVHs), prompting many patients to travel farther for resection. While surgery is centralized, adjuvant chemotherapy is often delivered locally, resulting in care fragmentation. The implications of this separation on chemotherapy receipt and survival are unclear. This study evaluated associations between travel distance, care fragmentation, and receipt of adjuvant chemotherapy in patients undergoing upfront PDAC resection at HVHs and assessed how these factors influenced overall survival.
Methods: Patients with non-metastatic PDAC who underwent upfront resection at HVHs (≥20 pancreatectomies/year) were identified from the National Cancer Database (2007-2021). The cohort was stratified by adjuvant chemotherapy receipt, travel distance (deciles D1-D10), and care fragmentation. Multivariable logistic regression assessed factors associated with chemotherapy receipt; Cox proportional hazards models evaluated survival.
Results: Among 17,807 patients treated at 97 HVHs, 10,200 (57%) received adjuvant chemotherapy. Patients traveling ≥14 miles (≥D4) were less likely to receive adjuvant chemotherapy (D4 odds ratio [OR] 0.85; 95% confidence interval [CI] 0.73-0.99; P=0.04). Patients experiencing care fragmentation were more likely to receive adjuvant therapy (64.3% vs. 54.4%, OR 1.51; 95% CI 1.35-1.69; P<0.001). Travel ≥20 miles (≥D5) was associated with higher mortality (hazards ratio [HR] 1.12; 95% CI 1.02-1.23; P=0.01). Conversely, receipt of adjuvant chemotherapy (HR 0.77; 95% CI 0.73-0.81; P<0.001) and fragmented care (HR 0.89; 95% CI 0.84-0.93; P<0.001) were associated with improved survival.
Conclusions: Longer travel distance was associated with lower chemotherapy receipt and worse survival. Care fragmentation was linked to improved treatment access and survival, underscoring the need for coordinated cross-institutional care
Indiana's EMTs and Paramedics 2025 Supply, Demand, and Projections
No full textThis brief summarizes 2025 supply, demand, and projection data for Indiana’s emergency medical technicians (EMTs) and paramedics based on Lightcast labor market estimates. Indiana has an estimated 2,280 actively practicing EMTs and 3,709 paramedics. Projected job growth for both professions from 2025 to 2035 is minimal and remains well below national averages, with EMT employment expected to grow by 0.2% and paramedic employment by 5.1%. Job openings are projected to decline for both professions, with paramedic openings estimated to fall by 16.3% and EMT openings by 10%, reflecting reduced growth and replacement needs. These trends highlight anticipated contraction in EMS labor demand across the coming decade