Faculty Bibliography

OBJECTIVES/OBJECTIVE:Background parenchymal enhancement (BPE) and mammographic density (MD) are imaging biomarkers derived from contrast-enhanced mammography (CEM). However, unlike MD, the consistency of BPE across consecutive examinations in pre- and postmenopausal women has remained unexplored. MATERIALS AND METHODS/METHODS:A computational search was conducted for all screening CEM exams performed at our facility between December-2012 and January-2024 to identify patients with at least five consecutive negative annual screenings. BPE grades and MD categories were extracted from the official radiology reports, and their variability parameters were statistically compared both between these factors and across age groups. RESULTS:Forty-five eligible patients at premenopausal age-group were identified (mean age at first scan 38.2 ± 3.4 years, range: 27-42) and a matched postmenopausal age-group was assembled (mean age at first scan 63.7 ± 3.8 years, range: 60-74), resulting in 450 CEMs analyzed. BPE demonstrated greater variability than MD, including fluctuations of at least one category on the scale (71.1-91.1 %), two-category changes (17.8-22.2 %), and transitions between low and high binary categories (17.8-27.7 %) (P < 0.01 for all). Similar rates of two-category BPE transitions (P = 0.65) and shifts between low and high binary categories (P = 0.32) were observed in pre- and postmenopausal women; however, the latter group had a significantly smaller proportion of cases with five consistent grades (P = 0.02). CONCLUSION/CONCLUSIONS:BPE on CEM demonstrates greater longitudinal variability than MD across all age groups and is not more pronounced in premenopausal compared to postmenopausal women. This highlights its dynamic nature and underscores the need for caution when considering BPE in clinical decision-making or as a biomarker, while also suggesting that strict menstrual cycle phase targeting may be less critical.

BACKGROUND/UNASSIGNED:While extremes of body mass index (BMI) are known to influence surgical risks, their distinct impacts on short- and long-term outcomes following hip fracture remain poorly defined. This study compared outcomes in severely underweight, normal weight, and obese elderly patients. METHODS/UNASSIGNED:A retrospective cohort study was conducted using a prospectively collected hip fracture database (2014-2024) at a single academic medical center. Patients with BMI ≤16.5 (severely underweight) or ≥35 (class 2+ obesity) were compared to a randomly selected cohort of normal-weight controls (BMI 18.5-25.0). Outcomes included complications, discharge disposition, mortality, and functional recovery. RESULTS/UNASSIGNED:A total of 282 patients were included. Obese patients had significantly higher odds of intensive care unit (ICU) admission compared to normal weight patients (OR 5.75 [2.00-16.39], p = .001) and were less likely to be discharged home (OR 0.31 [0.14-0.66], p = .003). In contrast, underweight status was significantly associated with increased six-month mortality compared to normal weight (OR 4.95 [1.34-18.18], p = .016). No significant differences were found in healing or functionality across groups. CONCLUSION/UNASSIGNED:Obese patients were more likely to require ICU admission but did not face increased long-term mortality. Severely underweight patients demonstrated the opposite pattern, with minimal short-term morbidity but significantly higher risk of death at six months. These findings suggest that short- and long-term risks after hip fracture diverge at the extremes of BMI and highlight the need for tailored perioperative strategies based on metabolic status.

The narrowest biological tubes are comprised of cells that hollow to form an intracellular lumen. Here, we examine early lumenogenesis of the C. elegans excretory cell, which branches to form an H-shaped intracellular tube spanning the length of the worm. Using genetically paralyzed embryos to freeze movement, we describe lumen initiation and branching for the first time using time-lapse fluorescence microscopy. We show that the excretory cell lumen forms through a plasma membrane invasion mechanism when a nascent lumen grows from the plasma membrane into the cytoplasm. The lumen subsequently extends along the left-right axis before branching to form anterior-posterior projections. Through a genetic screen, we identify mutations in ina-1/⍺-integrin and pat-3/β-integrin that block lumenogenesis at the anterior-posterior branching step, and we show that integrin function is required within the excretory cell. Finally, we find that the excretory cell crosses the epidermal basement membrane where anterior-posterior branches form and demonstrate that basement membrane crossing fails in integrin mutant embryos. Our findings reveal how an intracellular lumen initiates and branches and identify integrins and basement membrane as key branching regulators.

Therapeutic targeting of mutant KRAS pathways driving cancers is being actively investigated to identify feedback mechanisms responsible for the development of adaptive resistance to mutant KRAS inhibitors undergoing clinical trials. Here we report RASH3D19 as a mediator of RAS pathway activation through a positive feedback loop involving the KRAS-microRNA signalling axis. KRAS-induced miR-222 represses ETS1 expression and downstream transactivation of miR-301a leading to elevation of its target RASH3D19. RASH3D19 facilitates activation of RAS pathways by promoting dimerization and interaction of EGFR with the SOS2, GRB2, SHP2 and GAB1 complex. Genetic deletion of RASH3D19 in mutant KRAS-expressing cancer cells exhibits growth retardation in vitro, in vivo and sensitized pancreatic ductal adenocarcinoma and colorectal cancer cells, organoids and xenografts to mutant KRAS inhibitors, suppressing feedback reactivation of RAS pathways. Therapeutic targeting of RASH3D19 is expected to lead to tumour debulking and alleviating resistance to KRAS inhibitors in mutant KRAS-expressing cancers.

Hepatic encephalopathy (HE) is a common complication of decompensated cirrhosis that can be reversed with treatment. Frequent episodes of recurrence are common, impacting patients, caregivers and healthcare systems, increasing morbidity and mortality statistics and resulting in grave financial consequences. Uptake and adherence to formal recommendations for HE diagnosis and management are low. There is an unmet need to advocate for the use of these recommendations in a more pragmatic form. Clinicians from multiple disciplines, dedicated to raising liver disease awareness, convened in a roundtable format to review and discuss the latest HE guidelines and relevant peer-reviewed literature on HE. The result was this clinical care publication on the screening, diagnosis and management of HE which seeks to facilitate clinicians' recognition and diagnosis of HE, apply a pathway of care for HE that addresses steps for initial management, long-term maintenance and prevention; it also addresses practical recommendations concerning situations encountered in HE. Resources are provided to address the different needs of the three key players in HE: patients, caregivers, and healthcare professionals.

OBJECTIVE:To update the 2016 American Headache Society (AHS) guideline on parenteral pharmacologic therapies for the management of migraine attacks in the emergency department (ED). METHODS:We conducted a systematic review and meta-analysis using the same methodology as the 2016 guideline. The original search strategy was repeated and expanded to include studies of nerve blocks and sphenopalatine ganglion (SPG) blocks. We searched Medline, Embase, Cochrane, clinicaltrials.gov, and the World Health Organization (WHO) International Clinical Trials Registry Platform through February 10, 2025. Eligible studies were randomized controlled trials (RCTs) involving adults diagnosed with migraine, treated in the ED with intravenous (IV), intramuscular (IM), subcutaneous (SC), or nerve block (including SPG block) interventions. Two reviewers independently screened titles/abstracts and full texts; a third reviewer resolved disagreements. Data were extracted using a standardized form and verified by a second reviewer. Risk of bias was assessed using the American Academy of Neurology (AAN) criteria. Where applicable, meta-analyses were performed. Efficacy was categorized as highly likely, likely, or possibly effective or ineffective. Clinical recommendations were developed using the AAN guideline development process. RESULTS:The search identified 26 new RCTs evaluating 20 injectable treatments. Of these, 12 were rated class I (low risk of bias), 9 class II, and 4 class III. Prochlorperazine IV, dexketoprofen IV, sumatriptan SC, and greater occipital nerve blocks (GONB) were considered highly likely to be effective based on multiple class I studies. Chlorpromazine IV, metoclopramide IV, eptinezumab IV, ketorolac IV, and supraorbital nerve blocks (SONB) were considered likely effective based on one class I or multiple class II studies. Hydromorphone IV, propofol IV, and paracetamol IV were considered likely ineffective based on class I or multiple class II studies. After review of the evidence and a consensus process, recommendations were made for each intervention. CONCLUSIONS:Prochlorperazine IV and GONB must be offered to eligible adults presenting to the ED with a migraine attack for treatment of headache requiring parenteral therapy (level A - must offer) in those without contraindications, while hydromorphone IV must not be offered (level A - must not offer). Treatments that should be offered when appropriate (level B - should offer) include dexketoprofen IV, ketorolac IV, metoclopramide IV, sumatriptan SC, and SONB. Chlorpromazine IV, dexamethasone IV, and valproate IV may be offered (level C - may offer). Paracetamol IV may not be offered (level C - should not offer). Eptinezumab should be offered (level B) only for patients matching the clinical trial population but is rated level U - no recommendation for an ED-specific population. Additional evidence is needed for caffeine, granisetron, ibuprofen, ketamine, lidocaine, normal saline, propofol, and SPG blocks, all currently rated level U - no recommendation.

BACKGROUND:Bariatric surgery has long been established as an effective treatment option for obesity and diabetes [Kalainov et al. in J Am Acad Orthop Surg [32(10):427-438, 2025] and Ogden et al. in JAMA 311(8):806-806, 2025. 10.1001/jama.2014.732]. Recently, GLP-1 Receptor Agonists' (GLP-1RAs) use has expanded as an alternative therapy for weight loss and diabetes management. While GLP1RAs are known to be safe and effective, few have compared long term outcomes of GLP-1RAs versus the "gold standard" of bariatric surgery among Medicare/Medicaid patients, who make up the largest payer group in the U.S. [Kalainov et al. in J Am Acad Orthop Surg [32(10):427-438, 2025]. METHODS:This was a retrospective, multicenter study of obese, type-2 diabetic patients (T2D) ≥ 18 years old, who initiated weekly injectable semaglutide or tirzepatide or underwent bariatric surgery between January 1st, 2018 to July 31st, 2024. Patients with a baseline BMI ≤ 35, those with prior GLP1-RA use, or any prior bariatric procedure were excluded from analysis. The primary outcome of interest was % total body weight loss 3 months to 3 years post intervention among bariatrics surgery patients vs. GLP1-RA patients (any GLP1-RA prescription and 12 months continuous GLP1-RA prescription). RESULTS:7667 patients were included for analysis (7200 GLP1-RA, 467 bariatric surgery). Bariatric surgery patients were younger (median (IQR): 43 (34, 53) vs. 65 (54, 72); p < 0.001) and more likely to be female (67.5% vs. 60.8%; p < 0.01) and Hispanic (58.7% vs. 19.4%; p < 0.001) while GLP1-RA users were more likely to be white (58.5% vs. 10.7%; p < 0.001). In models adjusting for demographic and clinical characteristics, bariatric surgery was associated with a 22.9% total weight loss 3 years following surgery compared to 2.3% for patients with any GLP1-RA use, and 15.9% vs 2.4% for patients with 12 months consecutive GLP1-RA use (22.9 [21.0-24.8] vs 2.3 [0.5-4.1], 15.9 [6.9-24.9] vs. 2.4 [6.7-11.5]. CONCLUSIONS:Among obese, T2D, publicly insured patients, bariatric surgery was associated with greater weight loss than GLP1-RAs at all measured periods from 3 months to 3 years post op.

OBJECTIVES/UNASSIGNED:To examine how structural factors, such as child protective services (CPS) involvement, prehospital interactions with police or emergency medical services (EMS), and clinical factors, such as autism diagnosis, contribute to physical restraint use among pediatric patients presenting to the emergency department (ED) for behavioral health concerns. METHODS/UNASSIGNED:In this retrospective cohort study, we reviewed pediatric ED encounters from January 1, 2021, to October 31, 2023, at a tertiary care children's hospital. Multivariable logistic regression was used to assess associations among autism diagnosis, CPS involvement, and arrival mode (police/EMS) and physical restraint use, adjusted for demographic variables. RESULTS/UNASSIGNED:Among 6288 behavioral health encounters, physical restraints were used in 124 (1.97%; 95% CI, 1.69, 2.58) encounters. Children arriving by police or EMS were 3 times more likely to be restrained than those arriving by car or walk-in (adjusted odds ratio, aOR = 3.07, 95% CI, 2.01-4.69). Children with CPS involvement were almost twice as likely to be restrained (aOR = 1.91; 95% CI, 1.26-2.88). Children diagnosed with autism were 7 times more likely to be restrained (aOR = 7.25, 95% CI, 3.61-14.55). Black children were more likely to be restrained than White children (aOR = 1.78, 95% CI, 1.12-2.84). CONCLUSION/UNASSIGNED:CPS involvement, transport by police or EMS, autism diagnosis, and Black race were independently associated with increased physical restraint use in pediatric ED patients. These findings emphasize the role of both structural and child-level factors in contributing to physical restraint in emergency behavioral health care, highlighting the need for a multifactorial approach to reduce restraint use.