Citations

Abstract SRD5A3-CDG is a rare autosomal recessive congenital disorder of glycosylation characterized by multisystemic dysfunction, including neurological, psychomotor, cognitive, and visual impairments. Approximately 60 cases have been reported, with treatment limited to symptomatic management. SRD5A3 encodes a polyprenal reductase enzyme essential for synthesizing dolichol, a lipid carrier of the oligosaccharide precursor in N-glycosylation. To address the lack of effective treatments and disease models suitable for high-throughput screening, we developed the first C. elegans model of SRD5A3-CDG, harboring the homozygous W19X nonsense mutation commonly observed in patients. This model recapitulates disease-relevant phenotypes, including developmental delays, neurological dysfunction, and mevalonate pathway dysregulation. Using this model, we conducted a high-throughput motility-based drug repurposing screen and identified atorvastatin, an FDA-approved HMG-CoA reductase inhibitor, as a repurposing candidate. Atorvastatin rescued disease-relevant phenotypes in the worm model and restored polyprenol-to-dolichol ratios in patient fibroblasts. These findings highlight atorvastatin as a promising drug repurposing candidate for SRD5A3-CDG.

476 Background: Outcomes remain poor for patients with advanced/metastatic CCA treated with first-line gemcitabine-cisplatin +/- anti-PD(L)1. Lirafugratinib is the first highly selective, irreversible FGFR2 inhibitor designed to target oncogenic FGFR2 driver alterations and resistance mutations. ReFocus (NCT04526106) is an open-label, multicenter phase 1/2 study in patients with advanced/metastatic CCA and other solid tumors with FGFRok2 alterations. Methods: Pivotal cohort of patients (n=116) with advanced/metastatic CCA harboring FGFR2 f/r previously treated with ≥1 systemic therapy and FGFR i-naive were treated with oral lirafugratinib 70 mg once daily until disease progression or unacceptable toxicity. The primary endpoint was confirmed ORR per RECIST v1.1 by independent review committee (IRC). Key secondary endpoint was duration of response (DOR); other secondary endpoints: disease control rate (DCR), progression-free survival (PFS), overall survival (OS), safety, and quality of life per EORTC QLC-C30. Results: As of 27SEP2024, the primary efficacy analysis of IRC-assessed data (n=114) and the secondary analysis of investigator-assessed data (n=116) set was done. The primary efficacy analysis excluded 2 patients as not available. Median age 57 years with 61.4% female. IRC-assessed ORR was 47%, and median DOR was 11.8 months (mos) (95% CI, 7.5-13.0), where 76.2% of responses lasted >6 mos. Median PFS was 11.3 mos (95% CI, 9.2, 14.8), with 12-month rate of 49.2%. Median OS was 22.8 mos (95% CI, 17.3-27.2), with 12-month rate of 74.6%. DCR was 96.5%. Common grade ≥3 on-target, off-tumor treatment-related adverse events (TRAEs) included palmar-plantar erythrodysesthesia (32.8%) and stomatitis (12.1%). TRAEs led to dose reductions of 75.9%, dose interruption of 82.8%, and treatment discontinuation of 4.3%. QoL was maintained. Conclusions: Lirafugratinib demonstrated clinically meaningful anti-tumor activity (ORR, DOR, and PFS), manageable and tolerable safety in CCA FGFR2 f/r patients. Clinical trial information: NCT04526106 . Best Overall Response, n (%) IRC c Investigator d Complete Response Partial Response Stable Disease Progression Disease Not Evaluable 3 (2.6)50 (43.9)57 (50.0)3 (2.6)1 (0.9) 061 (52.6)51 (44.0)3 (2.6)1 (0.9) ORR a , n (%)95% CI 53 (46.5)37.1, 56.1 61 (52.6)43.1, 61.9 DCR b , n (%)95% CI 110 (96.5)91.3, 99.0 112 (96.6)91.4, 99.1 a ORR defined as proportion achieving confirmed response of complete response or partial response per RECIST v1.1. b DCR defined as proportion with confirmed response of complete response, partial response, or stable disease per RECIST v1.1. c Primary Efficacy Analysis Set. d Secondary Efficacy Analysis Set. Percentages based on number of patients in the analysis set for each treatment arm. Exact Clopper-Pearson used for 95% CI. IRC and investigator assessments are based on different populations and cannot compare directly.

Abstract Background According to consensus guidelines, area under the concentration–time curve (AUC) is recommended for vancomycin dosing rather than trough-based monitoring, but transition to AUC-based dosing requires substantial staff education and resource allocation. We sought to evaluate the level of congruency between vancomycin total daily doses (TDD) determined using a trough concentration goal of 10-15 mcg/mL compared with an online Bayesian calculator targeting an AUC of 400-600 mg·h/L.Patient DemographicsInitial Dose Results Methods We performed a retrospective, multicenter cohort study of vancomycin therapeutic drug monitoring (TDM) in non–critically ill adults hospitalized from March 1, 2017-December 31, 2021. Patients were included if they received intravenous vancomycin for ≥72 hours with a documented trough target of 10 to 15 mg/L, had ≥1 serum vancomycin trough concentration assessed at steady state, and received ≥2 doses of vancomycin after serum assessment with or without dose adjustment. Using an online vancomycin calculator with Bayesian modeling, the study team input patients’ trough-based dosing data to retrospectively estimate the initial vancomycin AUC exposure achieved and the initial and post-trough TDD recommended for an AUC target of 400 to 600 mg⸱h/L. The initial and post-trough vancomycin total daily dose (TDD) derived by the online calculator were compared with the actual doses used for each patient when a trough concentration of 10 to 15 mg/L was targeted.Comparison of Trough-Based and AUC-Based Dosing of Vancomycin AUC indicates area under the concentration–time curve; TDD, total daily dose. Dashed line indicates where the 2 methods are equal; shading indicates where the 2 methods are within 20% of each other Results In total, 89 patients were included in the study. The actual vancomycin TDD with trough monitoring (target, 10-15 mg/L) was within 20% of the recommended AUC-based TDD for 62 patients (70%) with initial dosing and for 74 (83%) after the initial trough concentration. Nephrotoxicity was rarely observed (2%) and the median duration of vancomycin was 4 days. Conclusion Given the frequency of dosing similarity between 400-600 mg·h/L AUC and 10-15 mg/L trough-based dosing, vancomycin trough-based monitoring to a goal of 10-15 mg/L is an option warranting further exploration. Disclosures All Authors: No reported disclosures

Abstract Background Posaconazole immediate release (IR) suspension is the standard product for enteral feeding tube (EFT) administration but has erratic pharmacokinetic behavior and results in sub satisfactory concentrations. Limited evidence suggests that the posaconazole oral delayed-release (DR) tablets may be crushed. Methods This was a retrospective cohort study of hospitalized adults who received EFT administration of posaconazole IR suspension or crushed DR tablets between 2018 and 2024. Patients were eligible if they had at least one serum concentration drawn ≥5 days after posaconazole initiation. The primary outcome was the attainment of therapeutic (≥700ng/mL for prophylaxis, ≥1,000ng/mL for treatment) serum concentration within 30 days. Secondary outcomes included time to therapeutic serum concentration, adverse drug effects, and frequency of clogged EFT. Multivariable cox proportional hazards regression was used to assess the relationship between posaconazole formulation and attainment of therapeutic concentrations while adjusting for confounding variables. Results Of the included patients, 100 received DR tablets and 48 received IR suspension. There were no significant differences in baseline characteristics or severity of illness. Among DR tablet and IR suspension recipients, 59% and 23% achieved therapeutic concentrations, respectively (p < 0.001). After adjusting for age, sex, BMI, drug interactions, posaconazole indication, malabsorptive gastrointestinal conditions, IR suspension was significantly less likely than crushed DR tablets to achieve therapeutic posaconazole concentrations within 30-days (HR 0.37, 95% CI 0.20-0.71; p < 0.003). The crushed DR tablet group required less total daily posaconazole to achieve therapeutic concentrations (400 vs 600 mg/day, p = 0.003). Clogged EFTs were more frequent in the crushed DR tablet group (27% vs 10%, p = 0.022), while no differences were observed in the occurrence of hepatotoxicity or hypokalemia. Conclusion Administration of crushed posaconazole DR tablets via EFT is more likely to attain therapeutic concentrations compared to IR suspension. The optimal technique for administering crushed DR tablets to prevent EFT complications warrants investigation. Disclosures Patrick M. Wieruszewski, PharmD, FCCM, Wolters Kluwer/UpToDate: Advisor/Consultant

Abstract Background Antimicrobial stewardship programs (ASP) commonly employ formulary restriction and prospective audit with feedback; however, frontline prescribers and other unit-based clinicians may enhance core ASP tactics as ASP extenders. We hypothesized that unit-based pharmacists act as ASP extenders and sought to characterize ASP interventions in their routine work.Top individual antimicrobial classes intervened on by unit-based pharmacistsUnit-based pharmacist antimicrobial intervention types Methods Retrospective, observational study of ASP interventions by unit-based pharmacists from July 2017 - April 2025 across the Mayo Clinic Enterprise. ASP interventions recorded using a standardized pharmacist documentation tool (Epic iVents [Software]) were collected retrospectively. Interventions on hospitalized, adult patients categorized as ‘ASP’ or linked with an antimicrobial were included; interventions by ASP dedicated staff were excluded. Secondary outcomes included: intervention subtypes and outcomes, location, and associated antimicrobial(s). Frequencies and percentages were used to summarize categorical data. Results A total of 104,055 interventions were included from 59,106 unique patients at 26 hospitals with the majority performed at the three destination sites. On average, 1,107 interventions were completed monthly by unit-based pharmacists. Frequently targeted antimicrobial classes were vancomycin and derivatives, penicillins, and 3rd/4th-generation cephalosporins (e.g., ceftriaxone and cefepime) (Figure 1); 20,111 (19.3%) interventions were on ≥ 1 antimicrobial. Of the 66,827 interventions with a documented subtype, ASP was the most common (77.8%), with the remainder classified as dose (17.3%), medication (3%), or duration changes (1%) (Figure 2). A minority (2.2%) were documented as conducted under pharmacist collaborative practice agreements. Documented prescriber intervention rejections were uncommon (6.6%). Reported outcomes, when available, included therapy optimization, cost savings and avoidance of adverse drug events. Conclusion Unit-based pharmacists acted frequently as ASP extenders. These findings support unit-based pharmacist and ASP collaborative efforts. Disclosures All Authors: No reported disclosures

Abstract Background Methicillin-susceptible Staphylococcus aureus bacteremia (MS-SAB) is treated with antistaphylococcal penicillins (ASP) or cefazolin. Altered pharmacokinetics in the setting of hypoalbuminemia may reduce the likelihood of therapeutic success in patients receiving highly protein bound beta-lactams. ASPs and cefazolin are 94% and 80% protein bound, respectively. We assessed the impact of hypoalbuminemia (≤2.5 g/dL) on clinical outcomes in patients with MS-SAB treated with ASPs or cefazolin.Table 1:Unweighted and weighted analysis of full cohort by albumin statusTable 2:Weighted analysis of cefazolin and ASP cohorts by albumin status Methods This single center, retrospective study included adults (≥18 years) admitted with community-acquired MS-SAB between 1/1/2006 and 12/31/2019 who received ASPs or cefazolin and had a serum albumin obtained between the date of first culture positivity and 72 hours of definitive therapy. Exclusion criteria included receipt of ≥5 days of MSSA active empiric therapy prior to definitive, polymicrobial bacteremia, antibiotics for an indication other than MS-SAB, or central nervous system infection. The primary outcome was failure to clear blood cultures within 72 hours of definitive therapy initiation. Propensity score weighting was used to adjust for baseline differences between cohorts. Results 160 patients were included with 61 (38.1%) being hypoalbuminemic (Table 1). In the propensity score weighted analysis, the primary outcome occurred in 37% of patients with an albumin ≤2.5 g/dL vs. 10.2% with an albumin >2.5 g/dL (p< 0.001). This finding was consistent in both ASP and cefazolin subgroups (Table 2). Hospital length of stay was longer in hypoalbuminemic patients but did not represent a statistically significant difference in the weighted overall analysis (15.9 vs. 11.6 days, p=0.8). There was no difference in inpatient mortality in any of the cohorts analyzed. 90-day all-cause mortality was higher in hypoalbuminemic patients only in the cefazolin subgroup analysis (20.7% vs 4.9%, p=0.019). Conclusion The presence of hypoalbuminemia was associated with failure to clear blood cultures within 72 hours of definitive therapy initiation in patients with MS-SAB. While no significant difference in mortality was observed overall, the higher mortality in the cefazolin subgroup warrants further research on the impact of hypoalbuminemia on clinical outcomes in patients with MS-SAB. Disclosures Larry M. Baddour, MD, UpToDate, Inc.: Royalty payments (authorship duties).

Abstract Background The number of cancer survivors aged older than 65 years is rising rapidly. Current evidence‐based exercise guidelines lack specific guidance for older cancer survivors as a result of insufficient evidence. An expert panel was convened to develop consensus‐based recommendations for exercise in older cancer survivors. Methods The development of recommendations was guided by the Grading of Recommendations Assessment, Development, and Evaluation Evidence‐to‐Decision framework for good practice statements. The panel drew from the available literature, a Delphi survey of exercise and health professionals, other exercise guidelines, clinical and research expertise, and interest‐holder input provided by a community advisory board of older cancer survivors and caregivers ( n = 11). Recommendations had to be deemed accessible (i.e., no added barriers) to older cancer survivors and feasible to implement. The panel voted on the strength of the recommendation for or against each statement, with consensus set at 85% agreement. Results Consensus was reached on 11 recommendations covering the following areas: medical evaluation/clearance for exercise, pre‐exercise assessment, exercise prescription, exercise tolerance and safety, exercise delivery, and behavioral support. The recommendations aimed to promote engagement in and uptake of appropriately prescribed exercise programming by older cancer survivors, while keeping barriers and risks as low as possible. Conclusions Older cancer survivors can benefit from appropriately prescribed exercise, which should be an essential component of their cancer care. Exercise and health professionals need to consider the unique needs of older cancer survivors to ensure that exercise is safe and effective for this population, while also reducing barriers to reach as many people as possible.

Uncontrolled systemic inflammatory responses are a critical pathological feature of fatal Ebola virus (EBOV) infection. While some inflammatory responses may originate from mononuclear phagocytes (MNPs), nonimmune cells vastly outnumber MNPs and may be an important source of inflammation. Here, we demonstrated that highly virulent EBOV induced a high and sustained pro-inflammatory response compared to less virulent ebolaviruses in non-MNPs through TLR4-independent NF-κB activation. We identified the EBOV matrix protein VP40 as a potent activator of NF-κB in non-MNPs, whose intrinsic inflammatory activation ability is higher than VP40 proteins from less virulent ebolaviruses. This suggests that VP40 is a virulence determinant inducing distinct degrees of pro-inflammatory responses among ebolaviruses. Mechanistically, VP40 activated the NF-κB signaling pathway, primarily via TNFR1 using a ligand-independent mechanism. These findings reveal mechanisms that may drive systemic inflammation and promote EBOV pathogenesis, suggesting potential therapeutic strategies to mitigate immune dysregulation in severe EBOV infections.

Abstract Background Prior studies of Alzheimer's disease (AD) biomarker disclosure have answered important questions about individuals’ experiences learning amyloid results. In comparison, the experiences of individuals performing AD biomarker disclosure have been under characterized. The present study examines the clinician experience disclosing amyloid positron emission tomography (PET) results within the Alzheimer's Disease Neuroimaging Initiative's ADNI‐4 study. Methods The ADNI‐4 longitudinal cohort study includes a pragmatic process for amyloid PET disclosure for participants across the cognitive spectrum. Disclosing clinicians complete a short questionnaire after each disclosure session, reporting on the visit length, the clinician's rating of participant and study partner understanding and emotional reactions, topics discussed, challenges, assessment of the visit overall, and any feedback about the process. Results Across the first 100 disclosures (48 cognitively normal, 35 Mild Cognitive Impairment (MCI), 17 dementia) in ADNI‐4, visits lasted an average of 29.4 minutes (SD 13.9, range 10‐90). Most cognitively impaired participants had a loved one present at the disclosure visit (dementia 94%, MCI 80%) but the majority of cognitively normal participants (73%) did not. Clinicians rated understanding of the result as adequate for all study partners and the vast majority (94%) of participants. Clinicians reported feeling “very confident” in their ability to assess readiness to receive result (70%), disclose (73%), and answer questions (77%). Clinicians rated all visits as “good” or better, with two‐thirds (65%) rated as “excellent.” Frequently discussed topics included meaning of result (99%), other risk factors (72%), and emotional impact of result (49%). Stigma and discrimination were rarely discussed, coming up in 12% and 3% of disclosure sessions, respectively. Challenges were infrequent (7%) and primarily included desire for additional information and challenges related to the participant's impairment. Clinicians provided the study team feedback about the disclosure process for 25% of disclosure visits. Comments included the desire for additional information or resources, positive feedback, and the importance of the study partner. Conclusions Clinicians disclosing amyloid PET results in ADNI‐4 report high confidence, adequate participant and study partner understanding, and few challenges. These data from clinicians, in combination with participant data, will inform future disclosure practices in both research and care.