Citations

Background: Cell-penetrating peptides cross cell membrane barriers while carrying cargoes in a functional form. Our work identified two novel lung-targeting peptides, S7A and R11A. Here, we present studies on biodistribution, the cell types targeted, and an in vitro proof of application. Methods: Studies were performed in human bronchial epithelial cells (HBECs) with and without various endocytic inhibitors, and coincubation with fluorescently labeled transferrin or endocytic markers. Cyclic R11A (cR11A) was conjugated to siRNA duplexes and anti-viral activity against SARS-CoV-2 was tested. Biodistribution studies were performed by injecting wild-type mice with fluorescently labeled peptides, and various circulation times were allowed for, as well as cross-staining of lung sections or isolated single cells with various cellular markers, followed by fluorescence-activated cell sorting or confocal microscopy. Results: cR11A showed peak uptake in 15 min, with the highest uptake in airway epithelial type II (ATII) cells, followed by p63+ basal cells and ionocytes. Cyclization increased transduction efficiencies ~100-fold. Endocytosis studies showed a decrease in peptide uptake by pre-treatment with Pitstop2 but not Amiloride or Nystatin. Endocytic marker Lamp1 showed colocalization at the earliest time point, with the escape of the peptide from endocytic vesicles later. cR11A conjugated to ant-spike and anti-envelop proteins showed anti-viral effects with an EC90 of 0.6 μM and 1.0 µM, respectively. Conclusions: We have identified a novel peptide, cR11A, that targets ATII, basal cells, and ionocytes, the cyclization of which increased transduction efficiency in vitro and in vivo. The uptake mechanism appears to be via clathrin-mediated endocytosis with escape from endocytic vesicles. cR11A can act as a vector to deliver anti-viral siRNA to epithelial cells.

Summary Dupilumab, the first biologic approved for eosinophilic esophagitis treatment (EoE-tx) in 2022, demonstrated favorable safety in phase-III clinical trials. However, real-world dupilumab-associated adverse reactions (DARs) for EoE-tx are unknown. This study aims to evaluate DAR for EoE-tx using the FDA Adverse Event Reporting System. FDA Adverse Event Reporting System was queried for DAR between 2022Q1 and 2023Q4. Individual DARs (iDARs) were categorized and compared between treatment groups: EoE, asthma, atopic dermatitis, and chronic rhinosinusitis with nasal polyps. Logistic regression was used to predict serious DAR and outcomes, and zero-truncated negative binomial regression was used to predict the number of iDAR. There were 51,000 DAR observations; 1459 for EoE-tx with 103 (7.1%) serious reactions and 44 (3.0%) serious outcomes including 3 deaths. For EoE-tx, the mean iDAR was 3.68 [3.51, 3.85], and the iDAR incidence rate ratio among men receiving EoE-tx was 0.73 [0.65, 0.83]. EoE-tx average iDAR primarily included general (0.75 [0.70, 0.80]), injection-site (0.69 [0.63, 0.74]), dermatologic (0.51 [0.46, 0.55]), and gastrointestinal (0.24 [0.21, 0.27]) reactions. Adults ≥50 years had 1.97 [1.28, 2.99] higher odds for serious DAR compared to younger adults in EoE-tx. Overall, dupilumab demonstrated a favorable safety profile across all indications, with low rates of serious adverse events. For EoE-tx specifically, higher total iDAR rates were observed, driven largely by increased injection-site and gastrointestinal reactions compared to other indications. Additionally, women exhibited higher iDAR rates than men across all indications.

Background/Objectives: Spinoplastic surgery is an emerging multidisciplinary field developed to address and reduce the complication of pseudoarthrosis following complex spinal reconstructions. While the number of spinal fusion procedures continues to rise every year, fusion failure rates remain as high as 40%. Although pseudoarthrosis may not always manifest clinically, it remains a leading cause of persistent pain and need for subsequent revision surgeries. The multidisciplinary collaboration between spine and plastic surgeons in spinoplastic surgery has therefore emerged as a proactive strategy aimed at preventing complications, particularly in patients identified as high-risk for pseudoarthrosis. As the patient population expands and spinoplastic surgery continues to evolve, refining patient selection criteria becomes essential for achieving optimal surgical outcomes. This review aims to provide a comprehensive overview of recent advancements in spinoplastic surgery, highlighting current indications, surgical techniques, recent case reports, and strategies for identifying suitable candidates. Methods: We performed a narrative review of English language literature through April 2025. Spinoplastic case reports and case series published within the last 20 years were included in the review. Results: Indications for use of a spinoplastic approach clustered into prior fusion failure, extensive oncologic resection, severe spinal deformity, procedures requiring extensive spinal involvement, and/or patients at risk for impaired bone healing. Succesful radiographic union and improvement of symptoms were widely reported across all 9 case reports/series. Conclusions: Although evidence is presently limited, spinoplastic surgery appears to achieve high bone graft fusion rates with acceptable morbidity and functional improvement in a carefully selected group of high-risk spinal reconstruction patients. Still, larger prospective studies are warranted to refine patient selection and validate functional benefit.

OBJECTIVE Idiopathic normal pressure hydrocephalus (iNPH) is characterized by gait deterioration, cognitive disturbances, and urinary incontinence. Gait deficits pose safety hazards due to frequent falls, yet objective investigations of gait improvement following ventriculoperitoneal shunt (VPS) placement are limited. Therefore, the aim of this study was to assess objective improvement in gait parameters for patients with iNPH after VPS placement. METHODS All patients treated with a VPS for iNPH by the senior author at a single tertiary care center from December 2017 to January 2023 were retrospectively reviewed. Patients who underwent detailed motion analysis testing before surgery with > 1 follow-up assessment were included. Analyzed parameters included gait velocity, gait cadence, stride length, stride width, gait stability ratio, total support, and single support. Time-dependent linear mixed-effects models and generalized additive mixed-effects models (GAMMs) were used to model short-term and longitudinal gait parameter changes, respectively. RESULTS A total of 212 patients (137 male, median age was 75.2 years) who underwent VPS placement for iNPH were included, with a total of 747 gait analyses performed at a median last-gait analysis follow-up duration of 12.0 months. Statistically significant changes in all gait parameter values were seen between the preoperative time point and first postoperative follow-up (within 3 months) time point (paired Wilcoxon p < 0.001), with a statistically significant majority of patients experiencing improvement (binominal p < 0.0001). Longitudinal analyses using a GAMM showed increased gait velocity, single support, and stride length, with decreased stability ratio, step width, and total support at early time points, while a plateau was achieved around 6 months. CONCLUSIONS A detailed gait analysis demonstrated significant improvements in objective ambulation metrics, particularly in the gait velocity, stride length, and gait stability ratio, following VPS placement in patients with iNPH. Most patients maintained marked improvement from baseline to the last follow-up assessment, although a plateau of the benefit was experienced over longer follow-up.

Lymphoscintigraphy, which is commonly used for sentinel lymph node mapping, can help diagnose lymphedema, lymphatic leakage, and lymphatic malformations and provides valuable information for surgical planning and treatment.

The translation of AI-generated brain metastases (BM) segmentation into clinical practice relies heavily on diverse, high-quality annotated medical imaging datasets. The BraTS-METS 2023 challenge has gained momentum for testing and benchmarking algorithms using rigorously annotated internationally compiled real-world datasets. This study presents the results of the segmentation challenge and characterizes the challenging cases that impacted the performance of the winning algorithms. Untreated brain metastases on standard anatomic MRI sequences (T1, T2, FLAIR, T1PG) from eight contributed international datasets were annotated in stepwise method: published UNET algorithms, student, neuroradiologist, final approver neuroradiologist. Segmentations were ranked based on lesion-wise Dice and Hausdorff distance (HD95) scores. False positives (FP) and false negatives (FN) were rigorously penalized, receiving a score of 0 for Dice and a fixed penalty of 374 for HD95. The mean scores for the teams were calculated. Eight datasets comprising 1303 studies were annotated, with 402 studies (3076 lesions) released on Synapse as publicly available datasets to challenge competitors. Additionally, 31 studies (139 lesions) were held out for validation, and 59 studies (218 lesions) were used for testing. Segmentation accuracy was measured as rank across subjects, with the winning team achieving a LesionWise mean score of 7.9. The Dice score for the winning team was 0.65 ± 0.25. Common errors among the leading teams included false negatives for small lesions and misregistration of masks in space. The Dice scores and lesion detection rates of all algorithms diminished with decreasing tumor size, particularly for tumors smaller than 100 mm3. In conclusion, algorithms for BM segmentation require further refinement to balance high sensitivity in lesion detection with the minimization of false positives and negatives. The BraTS-METS 2023 challenge successfully curated well- annotated, diverse datasets and identified common errors, facilitating the translation of BM segmentation across varied environments and providing the tools for future development of personalized volumetric reports to patients undergoing BM treatment.

AbstractINTRODUCTIONWe investigated the usefulness of plasma neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) for capturing vascular cognitive impairment (VCI) in the context of amyloidosis.METHODSUsing two independent cohorts (n = 1810), we assessed the relationship of plasma NfL and GFAP with (1) vascular brain indices; (2) diagnostic states using the following definitions: vascular versus not (white matter hyperintensity/total intracranial volume ≥ 1.3%), and cognitively impaired (CI) versus cognitively unimpaired (CU) using Clinical Dementia Rating ([CDR] scale ≥ 0.5); and (3) their upstream predictors using structural equation models (SEMs).RESULTSPlasma NfL and GFAP were associated with vascular brain damage and differed across states (VCI > vascular CU > non‐vascular CI > non‐vascular CU). In a population‐based sample, these biomarkers distinguished vascular CU and VCI from non‐vascular CU groups with greater separation in amyloid negative participants. Pathway analyses showed NfL was primarily influenced by systemic/brain vascular health, whereas amyloid contributed to GFAP variability.DISCUSSIONPlasma biomarkers, particularly NfL, capture vascular brain changes and show promise for VCI identification.Highlights Plasma NfL and glial fibrillary acidic protein (GFAP) were associated with vascular brain indices. Plasma biomarkers differed across diagnostic states (VCI > vascular CU > non‐vascular CI > non‐vascular CU). Plasma markers discriminated vascular from non‐vascular states with greater separation in Aβ− participants. NfL was linked to vascular health, while amyloid influenced GFAP variability in the population‐based sample. Future longitudinal frameworks should consider systemic inflammation markers along with these plasma markers to better understand VCID‐related brain changes and cognitive decline.