Citations

Abstract Background Spinal cord injury (SCI) induces complex secondary pathophysiological cascades, including microvascular disruption, glial activation, and chronic neuroinflammation. These vascular changes are dynamic and spatially heterogeneous across acute, subacute, and chronic phases. However, limitations in in vivo imaging resolution have impeded precise, longitudinal evaluation of spinal microcirculation. Objective To quantify post-SCI alterations in spinal cord vessel density, flow speed, and morphology over time using ultrasound localization microscopy (ULM), and to correlate these changes with chronic astrocytic reactivity assessed by GFAP expression. Methods Eleven Sprague-Dawley rats underwent T9–T11 laminectomy; nine received a standardized 200 kdyn contusion using the Infinite Horizons Impactor and were assigned to acute (24h), subacute (7d), and chronic (21d) groups (n = 3/group), while two served as uninjured controls. ULM was performed using a Vevo 3100 high-frequency ultrasound system with a 40 MHz transducer following intravenous Definity® microbubble injection. Vessel density (VD) and flow speed (FS) were quantified at the lesion epicenter and adjacent rostral/caudal regions. Arterial and venous compartments were distinguished by flow direction. Histological sections were stained for glial fibrillary acidic protein (GFAP), and %Area was quantified across phases. One-way ANOVA and Tukey’s test evaluated between-group differences; Pearson correlation identified phase-specific relationships between vascular metrics and chronic GFAP expression. Results ULM provided super-resolved imaging of spinal microvasculature at 5–10 µm resolution. Venous VD significantly declined from 0.92 ± 0.18 (acute) to 0.42 ± 0.23 (subacute) and 0.11 ± 0.07 (chronic, p < 0.001), particularly in dorsal regions. Arterial VD remained stable across timepoints (p > 0.05), while FS demonstrated transient reductions in both arterial and venous systems during the subacute phase. Chronic venous FS partially recovered by Day 21. GFAP-positive area increased significantly in the chronic group (3.3 ± 0.87%) compared to acute (1.52 ± 0.42%) and subacute (1.40 ± 0.05%) (p < 0.05), indicating delayed astrocyte reactivity. Correlation analysis revealed significant inverse associations between chronic GFAP %Area and early ventral venous density (r = − 1.0, p < 0.05), as well as positive correlations with chronic ventral arterial FS (r = 1.0, p < 0.01), suggesting early microvascular deficits may predict long-term gliosis. Conclusion This study demonstrates the feasibility and power of ULM to quantify dynamic microvascular remodeling in SCI with unprecedented resolution. Venous rarefaction precedes chronic astrocytosis, while arterial flow speed partially recovers over time. These findings highlight key spatiotemporal biomarkers of injury progression and support the use of ULM as a noninvasive platform for monitoring SCI pathophysiology and guiding therapeutic timing.

Abstract Introduction Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and glucagon-like peptide-1 receptor and glucose-dependent insulinotropic polypeptide dual receptor agonists (GLP-1/GIP RAs) have transformed the management of obesity and type 2 diabetes, both of which are prevalent in women of reproductive age and are closely linked to fertility concerns and adverse pregnancy outcomes [1,2]. Beyond their metabolic effects, emerging evidence suggests GLP-1 RAs and GLP-1/GIP RAs can positively influence ovulatory function, menstrual regularity, and conception, particularly in women with obesity or polycystic ovary syndrome (PCOS). However, the reproductive implications of GLP-1 RA and GLP-1/GIP RA use remain poorly understood [3]. This study seeks to address this critical gap by investigating self-reported changes in sexual activity, menstruation, and fertility among reproductive-aged women using GLP-1 RAs and GLP-1/GIP RAs within an institution. 1. Kong L, Nilsson IAK, Gissler M, Lavebratt C. Associations of Maternal Diabetes and Body Mass Index With Offspring Birth Weight and Prematurity. JAMA Pediatr. Apr 1 2019;173(4):371-378. doi:10.1001/jamapediatrics.2018.5541 2. Drummond RF, Seif KE, Reece EA. Glucagon-like peptide-1 receptor agonist use in pregnancy: a review. Am J Obstet Gynecol. Jan 2025;232(1):17-25. doi:10.1016/j.ajog.2024.08.024 3. Cesta CE, Rotem R, Bateman BT, et al. Safety of GLP-1 Receptor Agonists and Other Second-Line Antidiabetics in Early Pregnancy. JAMA Intern Med. Feb 1 2024;184(2):144-152. doi:10.1001/jamainternmed.2023.6663 Objective The primary objectives of this study are: 1) to explore how GLP-1 RAs and GLP-1/GIP RAs may influence reproductive health, specifically sexual activity, menstrual regularity, fertility and conception; 2) to understand the prevalence and patterns of contraceptive use and failure and clinician counseling among women taking GLP-1 RAs and GLP-1/GIP RAs during their reproductive years; and 3) to assess whether reproductive outcomes differ by specific GLP-1 RA and GLP-1/GIP RAs. Methods This descriptive, cross-sectional survey study will be conducted across multiple sites of a major academic institution. Eligible participants include women aged 18-55 who are currently prescribed a GLP-1 RA or GLP-1/GIP RAs, identify as female, report heterosexual relationships, are English-speaking, and are patient portal users. Exclusion criteria include postmenopausal women, non-English speakers, and those unable to complete the survey independently. Participants will receive an electronic questionnaire through the patient’s portal. The survey will collect demographic information, reproductive health history, menstrual patterns, sexual activity, and contraceptive use. QR code included with link to the survey. Responses will be de-identified and stored for analysis. Descriptive statistics and correlation tests will be used to evaluate associations between GLP-1 RA and GLP-1/GIP RA use and reproductive outcomes. Results Data collection and analysis are ongoing. Preliminary results will describe participant demographics, frequency of self-reported changes in menstruation, fertility, and sexual activity, as well as patterns of contraceptive use and potential failure using GLP-1 RAs and GLP-1/GIP RAs. Conclusions This study will provide insight into the reproductive health experiences of women taking GLP-1 RAs and GLP-1/GIP RAs. By identifying self-reported menstrual, fertility, and sexual health changes, findings may inform future clinical counseling, contraceptive recommendations, reproductive safety guidance, and interdisciplinary research on broader physiological effects of GLP-1 RAs and GLP-1/GIP RAs. Ultimately, this work aims to bridge the current gap between metabolic therapy and women’s health reproductive health outcomes. Disclosure No.

Abstract The B-cell maturation antigen (BCMA)–targeting bispecific T-cell engager pavurutamab (AMG 701) directs the cytotoxic T-cell response toward multiple myeloma (MM) cells. This phase 1/1b, open-label, dose-exploration and dose-expansion study evaluated the safety, tolerability, and efficacy of pavurutamab monotherapy in patients with triple-class relapsed/refractory MM (RRMM). Pavurutamab (5-18 000 μg) was administered IV weekly with step-up dosing in week 1. Overall, 172 patients received at least 1 dose of pavurutamab; 73 received the recommended phase 2 dose (RP2D; 18 000 μg), with 2 different step-up dosing regimens in phase 1b. Twelve patients had dose-limiting toxicities, which included cytokine release syndrome (CRS) and increased transaminases; none of which occurred at the RP2D. The most frequently reported treatment-emergent adverse events included CRS (74.4%), anemia (61.0%), neutropenia (47.1%), and hypophosphatemia (45.3%). Grade ≥3 infections were noted in 60 patients (34.9%). The overall response rate (ORR) was 46.5% among all patients and 65.8% (very good partial response [VGPR] or better, 60.3%) among 73 patients treated at the RP2D. At median follow-up of 17.2 months, median duration of response (DOR) was 36.6 months (95% confidence interval [CI], 22.3 to not estimable). Median progression-free survival (PFS) for all patients was 5.5 months (95% CI, 2.8-10.1) and 16.8 months (95% CI, 5.0 to not estimable) with the RP2D. Pavurutamab exposure generally increased in a dose-proportional manner, with high soluble BCMA levels correlating with lower exposure level. The acceptable safety profile, pharmacokinetics, and preliminary efficacy of pavurutamab supports anti-BCMA T-cell engager therapy in heavily pretreated patients with RRMM. This trial was registered at www.clinicaltrials.gov as NCT03287908.

Abstract INTRODUCTION Anti—amyloid‐β (Aβ) therapies are reshaping Alzheimer's disease (AD) management. Understanding changes in real‐world patterns of diagnostic testing and infusion chair usage is essential for optimizing access to care. METHODS Retrospective analysis of Mayo Clinic enterprise electronic health records (Jan 2019–Mar 2025) assessed trends in AD‐relevant brain imaging, fluid biomarkers, apolipoprotein E (APOE) testing, and lecanemab infusions. Rates of amyloid‐beta (Aβ) positivity by sex and age, APOE genotype frequencies, and lecanemab treatment initiation and discontinuation were evaluated. RESULTS Following national insurance coverage changes, lecanemab infusions grew by 110 infusions per quarter to 605 in Q1 2025. Aβ positron emission tomography scans increased (+22/quarter), cerebrospinal fluid biomarker orders declined (−25/quarter), and plasma p‐tau 217 orders rapidly increased (+238/quarter). Females were more likely to be Aβ positive ( p < 0.006). APOE ‐ε4 homozygotes were less likely to initiate lecanemab (HR = 0.11, p < 0.001). DISCUSSION The adoption of anti‐Aβ therapies coincided with a rapid shift in diagnostic workflows.

Abstract Intercellular communication between multiple myeloma (MM) cells and osteoclast precursor cells (pre-OCs) contributes extensively to the occurrence and development of myeloma-related bone destruction. However, key interacting modes and the exchanged substances involved in this communication remain unclear. In this study, we discover that tunneling nanotubes (TNTs) directly connect MM and pre-OCs. Using the stable isotope labeling with amino acids in cell culture assay and a positive-negative double selection strategy, we identify filamin A (FLNA) as a major protein transported from MM to pre-OCs. FLNA acts as a molecular clutch linking extracellular matrix–bound MAC1 to the cytoskeleton, activating Rho and MAPK signaling pathways and promoting F-actin polymerization, which subsequently enhances osteoclast differentiation by modulating cellular stiffness, traction force, and deformability. In addition, FLNA directly binds vinculin and promotes its recruitment to podosomes, thereby enhancing the functions of podosomes and the bone resorption capacity of osteoclasts. The conditional depletion of Flna in mice suppresses podosome activity and reduces stiffness, traction force, and deformability in pre-OCs, leading to significantly impaired osteoclast differentiation and increased bone mass. In the Vk∗MYC mouse model of myeloma, the administration of the TNT inhibitor latrunculin B disrupts FLNA transport to osteoclasts and alleviates osteolytic bone disease. These findings highlight the critical role of MM-transferred FLNA in osteoclastogenesis and suggest that targeting TNTs may represent a therapeutic strategy to limit pathological bone resorption associated with MM.

Introduction: Calibrated automated thrombogram assay parameters have been shown to assess hypercoagulation state and, therefore, may independently predict posttrauma, symptomatic venous thromboembolism (VTE). Yet, calibrated automated thrombogram lacks high throughput and standardization, limiting diagnostic potential. This study analyzed thrombin generation (TG) profiles in trauma patients using a high-throughput assay, processing up to 10 samples at once, providing batch testing capabilities. We hypothesized that trauma patients who developed VTE would show distinct TG profiles compared with those who did not. Methods: Trauma patients presenting to a Level I Trauma Center had samples collected within 12 hours postinjury prospectively. Follow-up was conducted to 90 days, time to symptomatic VTE diagnosis or death, confirmed via autopsy or imaging. TG profiles were measured from the ST Genesia assay. Data were presented as median (interquartile ranges) or n (%), with the Wilcoxon rank-sum or chi-squared test. Associations between TG parameters and clinical risk factors were assessed using Spearman correlation analysis or the Wilcoxon rank-sum test. Results: Two hundred and fifty-four trauma patients were analyzed [48.5 years (31.0, 62.0), 72.0% male]: 64 patients with VTE (25.2%) to 190 with non-VTE. VTE pts had a median time to VTE of 8 days, with 29 developing deep venous thrombosis, 24 with pulmonary embolism, and 11 with deep venous thrombosis/pulmonary embolism. No significant differences were found in age, sex, or body mass index; significantly more VTE patients underwent surgery and blood transfusions within 24 hours. TG profiles demonstrated accelerated TG in patients who developed VTE compared with non-VTE, with significant differences in peak height ( P = 0.001), time to peak ( P = 0.021), endogenous thrombin potential ( P < 0.001), and velocity index ( P = 0.001). Conclusion: TG profiles using ST Genesia can differentiate trauma patients at high risk of developing VTE. The platform suits clinical labs needing high throughput by providing batch testing capabilities. Study type: Prospective study with less than large effect and no negative criteria. Level of evidence: II.

ABSTRACT Intrinsic Acinetobacter -derived cephalosporinases (ADCs) in Acinetobacter baumannii are AmpC-type β-lactamases that confer resistance to β-lactam agents, typically through insertion sequence (IS) element-driven overexpression. However, the contribution of ADCs to resistance against advanced β-lactam agents has not been systematically investigated. Given the increasing clinical use of these agents, including cefiderocol, we analyzed the diversity and function of ADC variants in a global collection of carbapenem-resistant A. baumannii (CRAb) isolates. We identified 52 distinct ADC variants in a collection of 428 CRAb clinical isolates from the United States. Among these, variants carrying both a valine substitution at position 292 in the R2 loop and an alanine duplication (ADUP) in the Ω loop consistently conferred stable resistance to cefiderocol. Biochemical and crystallographic analyses demonstrated that ADC-227, which harbors a V292W substitution with an ADUP at position 218a in the Ω loop, exhibits enhanced catalytic efficiencies for ceftazidime and cefiderocol and moderately reduced inhibition by avibactam, leading to resistance not only to cefiderocol but also to ceftazidime–avibactam. Structural studies revealed conformational flexibility of the R2 loop, allowing dynamic accommodation of substrates. Collectively, the findings identify Val292, in combination with an ADUP in the Ω loop, as a mutational “hot spot” for ADCs evolution that may undermine the efficacy of newer β-lactams, including cefiderocol. These results underscore the need for ongoing molecular surveillance of A. baumannii isolates to detect and track the emergence of such variants in clinical settings. IMPORTANCE Carbapenem-resistant Acinetobacter baumannii (CRAb) has been designated as a critical priority pathogen by the World Health Organization (WHO). Cefiderocol has been introduced as a novel therapy against CRAb; however, recent clinical data highlight concerning treatment failures and excess mortality. Understanding resistance mechanisms is therefore essential to preserve the clinical utility of this agent. This study addresses a critical knowledge gap by investigating the role of intrinsic Acinetobacter -derived cephalosporinases (ADCs), which are ubiquitous in A. baumannii and diverse in sequence. By defining specific mutational patterns that endanger cefiderocol activity, this work highlights how chromosomally encoded enzymes can evolve to erode the effectiveness of newer β-lactams such as cefiderocol. These insights underscore the importance of integrating molecular surveillance into clinical practice and antimicrobial stewardship to ensure timely detection of emerging resistance in clinical A. baumannii isolates, ultimately informing treatment strategies and guiding future drug development.

ABSTRACT HLA‐A*02:1040:02 differs from HLA‐A*02:01:01:01 by a single nucleotide substitution in codon 283 (CCC>TCC) in exon 5.

Abstract Background Outpatient antibiotic stewardship programs (ASP) are recommended by the CDC and Joint Commission. We analyzed the impact of annual, focused syndrome-specific ASP interventions on trends in long-duration antibiotic prescribing (LDAP). Methods This was a retrospective, observational, multicenter cohort study from November 2020 through June 2025. All ambulatory encounters generating systemic antibiotic prescriptions within the healthcare enterprise were screened. Hospitalizations, emergency department visits, and infectious diseases encounters were excluded. Encounters generating ≥1 systemic antibiotic with &gt;7 days duration were categorized as long-duration. Targeted departments (primary and urgent care) received direct intervention (eg, education, peer-comparison reporting, data tracking). LDAP was modeled over time by month and compared by diagnosis group (ASP-priority diagnoses vs nonpriority) and provider specialty department (ASP-targeted vs nontargeted) using linear regression models. Results Of 642 579 encounters included, 42.2% were long duration. LDAP in ASP-targeted departments dropped from 46.8% to 34.8% (difference −12 percentage points [pp]), whereas nontargeted departments dropped from 45.5% to 39.1% (difference −6.4 pp). The estimated annual LDAP decrease was 3.4 pp in targeted versus 2.4 pp in nontargeted departments (difference 1.0 pp, P = .009). Within targeted departments, significant LDAP decreases were seen both in priority and nonpriority diagnoses, whereas nontargeted departments showed no change in LDAP in priority diagnoses. In a sensitivity analysis of nonpriority diagnoses, ASP-targeted departments had a larger estimated annual decrease in LDAP versus nontargeted (difference 1.4 pp, P &lt; .001). Conclusions Annual syndrome-specific ASP interventions correlated with improvements in LDAP, including outside of priority syndromes in targeted departments. LDAP is a viable metric for evaluating ambulatory ASPs.