Faculty Bibliography

BACKGROUND AND OBJECTIVES/OBJECTIVE:This systematic review (SR) provides updated evidence-based conclusions regarding the use of pharmacologic migraine prevention in adults to inform a new joint American Academy of Neurology (AAN) and American Headache Society practice guideline. METHODS:A multidisciplinary panel conducted an SR following the 2017 AAN Clinical Practice Guideline Process Manual. Randomized controlled trials evaluating pharmacologic preventive treatments for adults with episodic or chronic migraine were included. Searches encompassed MEDLINE, Embase, and ClinicalTrials.gov from database inception through June 6, 2024. Studies were screened in duplicate, with dual independent risk-of-bias assessment. Outcomes included change in monthly headache days, ≥50% responder rate, and validated patient-reported quality of life (QOL) measures. Raw mean differences, standardized mean differences, and risk ratios were calculated. A modified Grading of Recommendations Assessment, Development, and Evaluation process was used to classify certainty of evidence. RESULTS:A total of 217 studies met inclusion criteria. For episodic migraine, high-confidence evidence showed that galcanezumab and erenumab are more effective than placebo in reducing headache frequency. Moderate-confidence evidence supported benefit from atogepant, eptinezumab, fremanezumab, propranolol, topiramate, and valproate. Several additional oral agents including amitriptyline, bisoprolol, flunarizine, fluoxetine, levetiracetam, metoprolol, nifedipine, pizotifen, and telmisartan had low-confidence evidence suggesting possible benefit. For chronic migraine, high-confidence evidence supported reductions in headache frequency with fremanezumab, galcanezumab, and onabotulinumtoxinA. Moderate-confidence evidence supported benefit from atogepant, eptinezumab, erenumab, topiramate and valproate. Across both episodic and chronic migraine populations, erenumab, fremanezumab, galcanezumab, eptinezumab, rimegepant, atogepant, topiramate and onabotulinumtoxinA demonstrated improvements in patient-reported QOL outcomes on validated instruments. Evidence comparing active treatments was limited and generally of low or very low confidence, restricting conclusions about comparative effectiveness. DISCUSSION/CONCLUSIONS:This SR provides a comprehensive synthesis of evidence on pharmacologic migraine prevention in adults. High- and moderate-confidence findings confirm the efficacy of several established and newer preventive therapies and demonstrate improvements in patient-reported outcomes across multiple validated measures. These conclusions informed the development of evidence-based recommendations, presented in a companion publication, to guide clinicians in selecting preventive medications for adults with episodic and chronic migraine.

Parkinson's disease (PD) is a neurodegenerative disorder involving a neuroinflammatory response, the cause of which remains unclear. Transposable elements (TEs) have been linked to inflammation, but their potential role in PD remains unexplored. Using bulk- and single-nuclei RNA-seq of postmortem brain tissue from four brain regions, we studied TE transcription and its correlation with PD neuroinflammation. Over a thousand TEs, including LINE-1 s and ERVs, were expressed in a cell type- and region-specific manner in the human brain. Increased TE expression was found in microglia and neurons in the substantia nigra and putamen of PD brains, but not amygdala or prefrontal cortex, compared to controls. This TE activation correlated with an innate immune response in the same brain regions. The link between an interferon response and TE activation was mechanistically confirmed using human pluripotent stem cell-derived microglia and neurons. Our findings provide insights into TE transcription in the PD brain and suggest that TEs may contribute to neuroinflammation and pathological progression in PD.

BACKGROUND/UNASSIGNED:There are limited results about total ankle arthroplasty (TAA) in the setting of severe malalignment. The aim of this study was to compare midterm patient-reported and radiographic outcomes in patients with severe varus or valgus tibiotalar deformity treated with primary transfibular TAA at a minimum of 5-year follow-up. METHODS/UNASSIGNED:Retrospective review was performed of all primary transfibular TAA by a single surgeon from October 2012 to January 2020 and grouped based on preoperative coronal talar tilt angle. Severe preoperative deformity included cases with ≥10° of varus (n = 36) or valgus (n = 33), while cases within 5° of neutral coronal alignment (n = 140) served as a control group. PROMs included 12-item Short-Form Health Survey physical and mental component scores, Ankle Osteoarthritis Scale, and Visual Analog Scale. Alignment and periprosthetic cysts (>2 mm) were assessed on postoperative radiographs. Adverse events and reoperations were reported using the Canadian Orthopaedic Foot and Ankle Society Reoperation Coding System. RESULTS/UNASSIGNED:Aside from age (Neutral vs. Valgus, 58.1 vs. 64.2 years; p = 0.01), there were no significant differences in demographics, preoperative, or postoperative PROMs among the 3 groups. The median preoperative talar tilt was -15.1° (interquartile range [IQR], -17.8° to -13.1°) in the Varus and 16.0° (IQR, 12.0° to 19.5°) in the Valgus groups; there were no significant differences in median tibiotalar alignment between the 3 groups postoperatively. In the Neutral group, 1 patient had postoperative varus, and 2 patients had postoperative valgus deformity. In the Varus group, 1 patient had recurrent varus, and 1 patient progressed to valgus. Seven ankles had periprosthetic cysts. Overall reoperation rates were similar (Neutral, 34%; Varus, 33%; Valgus, 36%) with no implant revisions. CONCLUSION/UNASSIGNED:Transfibular TAA is capable of correcting severe coronal tibiotalar malalignment in the primary treatment of end-stage ankle arthritis. Patients with ≥10° varus or valgus deformity demonstrated postoperative patient-reported and radiographic outcomes similar to those with neutral ankle alignment at midterm follow-up, without an increased risk of reoperations. LEVEL OF EVIDENCE/UNASSIGNED:Level III. See Instructions for Authors for a complete description of levels of evidence.

PURPOSE/UNASSIGNED:This study describes the patient-centered approach to hearing technology selection and fitting of the participants randomized to a best practice hearing intervention as part of the Aging and Cognitive Health Evaluation in Elders (ACHIEVE) study (ClinicalTrials.gov identifier NCT03243422). We evaluated associations between hearing technology with daily hours of hearing aid use and listening and communication goal achievement. METHOD/UNASSIGNED:technology levels, and offered at least one hearing-assistive technology (HAT). The Client-Oriented Scale of Improvement (COSI) was used to identify listening needs that guided intervention delivery and was used to assess attainment of hearing-related goals following ~10-week intervention period. Hearing aid datalogging was used to measure hours of daily wear. We estimated the association between hearing aid technology level, HATs, hours of wear, and COSI goal attainment using an ordered logistic model adjusting for auditory and sociodemographic characteristics. Proportionality odds assumption was checked for all models. RESULTS/UNASSIGNED:= 9.3 hr across all participants) and did not differ between hearing technology (levels or HATs). Participant COSI goals, which included categories such as conversation in noise and in quiet or attending church and/or meetings, improved and were not dependent on technology used. Participants benefited from patient-centered hearing intervention, and there were no statistically significant associations among hearing aid technology level, HATs, hours of use, and change in COSI goals. CONCLUSIONS/UNASSIGNED:The patient-centered selection of hearing technology used in the ACHIEVE study resulted in high levels of hearing aid and HAT usage, along with positive COSI listening goal attainment for the majority of participants. Carefully assessed and selected technology is needed to meet individual auditory rehabilitation needs. SUPPLEMENTAL MATERIAL/UNASSIGNED:https://doi.org/10.23641/asha.32069253.

IntroductionBleeding and thrombosis are major causes of morbidity and mortality in pediatric extracorporeal membrane oxygenation (ECMO), yet their evolving, time-dependent risks remain poorly defined. This study evaluated clinical predictors of bleeding and thrombotic events using time-to-event analysis.MethodsA retrospective cohort study was conducted using the Pediatric ECMO Outcomes Registry (PEDECOR) from October 2011 to September 2024. Patients aged ≤18 years undergoing their first ECMO run were included. Two time-varying Cox proportional hazards models assessed associations between prior complications and time to first bleed or thrombosis, adjusting for clinical and ECMO-related variables.ResultsAmong 1444 patients, median age was 0.4 years (IQR: 0.0-4.4), and 53.6% were male. Bleeding occurred in 65% and thrombosis in 28%. Time to first bleeding events had a median of 2 days (IQR: 0-4) while time to first thrombosis had a median of 3 days (IQR: 2-6). Prior thrombosis was associated with lower early bleeding risk (HR: 0.39, 95% CI: 0.25-0.62, p < 0.001), which reversed over time (interaction HR: 1.44, 95% CI: 1.08-1.92, p = 0.013; crossover at 12.4 days). Similarly, prior bleeding was associated with reduced early thrombosis risk (HR: 0.49, 95% CI: 0.34-0.71, p < 0.001), but reversed over time (interaction HR: 1.63, 95% CI: 1.26-2.11, p < 0.001; crossover at 4.3 days). Central cannulation, cardiac surgery, and non-pulmonary indications were associated with bleeding; sepsis was associated with thrombosis. Anticoagulant type and sex were not significant.ConclusionsBleeding and thrombosis are common and time-dependent in pediatric ECMO. These findings support dynamic anticoagulation strategies tailored to evolving risk.

OBJECTIVES/OBJECTIVE:To evaluate the effect of a proprietary motion artifact correction algorithm on CBCT spatial resolution using an in vitro phantom model. STUDY DESIGN/METHODS:Fifty CBCT scans were acquired with a ProMax 3D unit using a point spread function phantom mounted on a motorized turntable. Ten protocols were tested, including no motion and induced motion up to 9 degrees, with and without activation of the correction algorithm. Spatial resolution was assessed using full width at half maximum (FWHM), surface plots, fast Fourier transforms, pairwise comparisons, and Bland-Altman analysis. RESULTS:Motion increased FWHM values and distorted the point spread function, with greater irregularity as motion magnitude increased. The correction algorithm produced partial improvement in selected motion protocols, particularly at lower motion magnitudes, but the effect was inconsistent across all motion conditions and measurement directions. In the no-motion protocol, activation of the algorithm introduced slight unsharpness and increased heterogeneity in the high-frequency domain. CONCLUSION/CONCLUSIONS:Patient motion degrades CBCT spatial resolution. The proprietary correction algorithm may provide partial improvement under selected conditions, particularly at lower motion magnitudes, but it does not replace the need for careful patient stabilization during image acquisition and should be used cautiously when motion is unlikely.

OBJECTIVES/OBJECTIVE:Generative artificial intelligence (AI) holds promise for creating patient education materials (PEM). However, AI-produced content is often difficult to read. Prompts for AI to write at a lower reading level either fail to meet recommended targets (≤6th grade) or demonstrate inconsistent results. We aimed to determine whether a new AI prompt for plain language would create PEMs that are easier to read, understand, and act upon. METHODS:We analyzed PEMs from two websites (HealthyChildren.org, UpToDate) and two generative AI programs (ChatGPT, Gemini). For each AI program, we used a basic prompt and an advanced prompt to generate separate documents. From these sources, we collected six sets of PEMs about five acute pediatric conditions, evaluated them using a panel of readability indices, and used ANOVA to compare average readability scores between sources. Two pediatricians assessed understandability and actionability using the Patient Education Materials Assessment Tool (PEMAT). We calculated mean PEMAT scores, with values > 70% considered understandable/actionable. RESULTS:ChatGPT (advanced prompt) created PEM with the lowest mean grade reading level (5.8; SD 0.84) and highest PEMAT scores (91% understandable, 84% actionable). Documents from generative AI using the advanced prompt and UpToDate had mean readability scores ≤ 6th grade, with significantly better readability than AI-generated documents using the basic prompt or HealthyChildren.org. All sources except HealthyChildren.org had mean understandability > 70%; AIs using the advanced prompt and UpToDate exceeded the actionability threshold. CONCLUSIONS:A plain-language prompt for generative AI created PEMs that were readable, understandable, and actionable, with comparable results across two AI programs. PRACTICE IMPLICATIONS/CONCLUSIONS:Healthcare providers can use this new plain-language prompt for generative AI programs to quickly create free, patient-friendly PEM about acute healthcare topics. As these AI programs were not trained to provide medical guidance, medical professionals should continue to review PEM prior to sharing with patients.

In the contemporary era of minimally invasive surgery, injectable biomaterial scaffolds have demonstrated significant potential in bone tissue engineering (BTE). Completely injectable hydrogel substratum with microscale bone graft particulates delivered through a needle-shaped orifice shifts a new paradigm for surgical interventions in clinical settings. Despite growing interest in biopolymer-based BTE systems, clinically applicable delivery platforms and a mechanistic understanding of cell-material interactions remain limited. This study developed a dual-syringe auto-mix system capable of generating an in situ cross-linking hydrogel-mineral construct composed of gelatin-hydroxyphenyl propionic acid, hyaluronic acid-tyramine, horseradish peroxidase, hydrogen peroxide, and calcium phosphate particles of varying sizes. Material distribution, rheological and mechanical properties, and swelling were characterized. Goat bone marrow-derived mesenchymal stem cells served as the basis for examining how the composite affected cell viability, morphology, proliferation, contractility, osteogenic differentiation, mineralization, and chemotactic behavior. To determine whether these biological findings were supported mechanically, an ex vivo cone-beam computed tomography model was used to evaluate volumetric stability and resistance to deformation at the graft-host interface. Cross-linking established a stable internal microarchitecture while remaining compatible with cell viability and nutrient-dependent survival. Formation of the gelatin-hyaluronan (GH) network significantly increased the storage modulus relative to gelatin (G) alone, whereas subsequent calcium phosphate incorporation (GH-CP) preserved this mechanical competence while attenuating the volumetric expansion of GH. These physical characteristics were accompanied by more organized cell morphology, enhanced osteogenic differentiation, and mineral deposition throughout a larger portion of the matrix. Heterogeneous interpenetrating gap striation (HIGS) appeared in regions of cellular aggregation and matrix deposition, and a new conceptualization of the osteogenic phenomenon, termed cling osteogenesis, has been proposed. These outcomes support an intricate relationship between early mechanical stabilization, mechanotransduction, and osteogenesis in injectable hydrogel-mineral systems.

Critical-sized bone defects remain a significant clinical challenge, and dipyridamole (DIPY)-coated 3D-tricalcium phosphate (β-TCP) scaffolds have shown promising osteogenic efficacy in preclinical models. However, the literature on the systematic physicochemical characterization of this scaffold system, including optimization of DIPY loading parameters, release kinetics, and surface properties, is lacking. This study addresses these gaps by characterizing DIPY-loaded 3D-printed β-TCP scaffolds across solid and porous architectures, three coating concentrations (10, 100, and 1000 µM), and three coating volumes (250, 500, and 1000 µL). Under static PBS conditions, drug release over 21 days was quantifiable only at 1000 µM, and release-kinetics modeling (zero-order, Higuchi, and Korsmeyer-Peppas) was therefore restricted to this highest concentration. At 1000 µM, both scaffold types showed biphasic release profiles, with standard empirical models reasonably approximating the overall kinetics, while not fully capturing the biphasic behavior over the entire duration. Porous scaffolds showed significant volume-dependent release (p = 0.002, η