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A live attenuated cold-adapted parainfluenza virus type 3 (PIV-3) vaccine is being developed to prevent the serious lower respiratory tract disease caused by this virus in infants and young children. This cold-passaged mutant (cp45) was evaluated in seronegative chimpanzees and found to be highly attenuated in both the upper and lower respiratory tracts compared to its wild-type parent. Animals immunized with cp45 were also highly resistant to wild-type PIV-3 challenge. Stability of the attenuation phenotype was demonstrated by the administration to 2 additional chimpanzees of an isolate of cp45 obtained after 10 days of replication in a chimpanzee. It was attenuated in both the upper and lower respiratory tracts. The cp45 virus present in the respiratory tract secretions of chimpanzees retained the temperature-sensitive (ts) phenotype, but some loss of ts property was observed in the isolates. These results provide a basis on which to proceed to clinical trials in seronegative human infants and children.

Immune cells congregate at specific loci to fight infections during inflammatory responses, a process that must be transient and self-resolving. Cell dispersal promotes resolution, but it remains unclear how transition from clustering to dispersal is regulated. Here we show, using quantitative live imaging in zebrafish, that differential ligand-induced trafficking of chemokine receptors such as Cxcr1 and Cxcr2 orchestrates the state of neutrophil congregation at sites of tissue damage. Through receptor mutagenesis and biosensors, we show that Cxcr1 promotes clustering at wound sites, but is promptly desensitized and internalized, which prevents excess congregation. By contrast, Cxcr2 promotes bidirectional motility and is sustained at the plasma membrane. Persistent plasma membrane residence of Cxcr2 prolongs downstream signaling and is required for sustained exploratory motion conducive to dispersal. Thus, differential trafficking of two chemokine receptors allows coordination of antagonistic cell behaviors, promoting a self-resolving migratory response. Inflammatory responses must be induced and resolved timely to serve protection from pathogens without inducing excessive tissue damage. Here the authors use live imaging in zebrafish to show that the intracellular trafficking of two chemokine receptors, Cxcr1 and Cxcr2, is differentially regulated on activated neutrophils to control their clustering and dispersal, respectively.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Objectives/Goals: The timing of neurosurgery is highly variable for post-hemorrhagic hydrocephalus (PHH) of prematurity. We sought to utilize microvascular imaging (MVI) in ultrasound (US) to identify biomarkers to discern the opportune time for intervention and to analyze the cerebrospinal fluid (CSF) characteristics as they pertain to neurosurgical outcome. Methods/Study Population: The inclusion criteria for the study are admission to the neonatal intensive care unit (NICU) with a diagnosis of Papile grade III or IV. Exclusion criteria are congenital hydrocephalus and hydrocephalus secondary to myelomeningocele/brain tumor/vascular malformation. We are a level IV tertiary referral center. Our current clinical care pathway utilizes brain US at admission and at weekly intervals. Patients who meet certain clinical and radiographic parameters undergo temporary or permanent CSF diversion. Results/Anticipated Results: NEL was implemented at our institution for PHH of prematurity in fall 2022. To date, we have had 20 patients who were diagnosed with grade III or IV IVH, of which 12 qualified for NEL. Our preliminary safety and feasibility results as well as the innovative bedside technique pioneered at our institution are currently in revision stages for publication. Preliminary results of the MVI data have yielded that hyperemia may confer venous congestion in the germinal matrix, which should then alert the neurosurgeon to delay any intervention to avoid progression of intraventricular blood. With regard to CSF characteristics, we anticipate that protein, cell count, hemoglobin, iron, and ferritin will decrease with NEL. Discussion/Significance of Impact: The timing of PHH of prematurity is highly variable. We expect that MVI will offer radiographic biomarkers to guide optimal timing of neurosurgical intervention. A better understanding of CSF characteristics could potentially educate the neurosurgeon with regard to optimal timing of permanent CSF diversion based on specific CSF parameters.

Abstract BACKGROUND A simple, reliable grading scale to better characterize nonfunctioning pituitary adenomas (NFPAs) preoperatively has potential for research and clinical applications. OBJECTIVE To develop a grading scale from a prospective multicenter cohort of patients that accurately and reliably predicts the likelihood of gross total resection (GTR) after transsphenoidal NFPA surgery. METHODS Extent-of-resection (EOR) data from a prospective multicenter study in transsphenoidal NFPA surgery were analyzed (TRANSSPHER study; ClinicalTrials.gov NCT02357498). Sixteen preoperative radiographic magnetic resonance imaging (MRI) tumor characteristics (eg, tumor size, invasion measures, tumor signal characteristics, and parameters impacting surgical access) were evaluated to determine EOR predictors, to calculate receiver-operating characteristic curves, and to develop a grading scale. A separate validation cohort (n = 165) was examined to assess the scale's performance and inter-rater reliability. RESULTS Data for 222 patients from 7 centers treated by 15 surgeons were analyzed. Approximately one-fifth of patients (18.5%; 41 of 222) underwent subtotal resection (STR). Maximum tumor diameter > 40 mm; nodular tumor extension through the diaphragma into the frontal lobe, temporal lobe, posterior fossa, or ventricle; and Knosp grades 3 to 4 were identified as independent STR predictors. A grading scale (TRANSSPHER grade) based on a combination of these 3 features outperformed individual variables in predicting GTR (AUC, 0.732). In a validation cohort, the scale exhibited high sensitivity and specificity (AUC, 0.779) and strong inter-rater reliability (kappa coefficient, 0.617). CONCLUSION This simple, reliable grading scale based on preoperative MRI characteristics can be used to better characterize NFPAs for clinical and research purposes and to predict the likelihood of achieving GTR.

Purpose The incidence of metabolic bone diseases in pediatric neurosurgical patients is rare. We examined our institutional experience of metabolic bone diseases along with a review of the literature in an effort to understand management for this rare entity. Methods Retrospective review of the electronic medical record database was performed to identify patients with primary metabolic bone disorders who underwent craniosynostosis surgery between 2011 and 2022 at a quaternary referral pediatric hospital. Literature review was conducted for primary metabolic bone disorders associated with craniosynostosis. Results Ten patients were identified, 6 of whom were male. The most common bone disorders were hypophosphatemic rickets ( n  = 2) and pseudohypoparathyroidism ( n  = 2). The median age at diagnosis of metabolic bone disorder was 2.02 years (IQR: 0.11–4.26), 2.52 years (IQR: 1.24–3.14) at craniosynostosis diagnosis, and 2.65 years (IQR: 0.91–3.58) at the time of surgery. Sagittal suture was most commonly fused ( n  = 4), followed by multi-suture craniosynostosis ( n  = 3). Other imaging findings included Chiari ( n  = 1), hydrocephalus ( n  = 1), and concurrent Chiari and hydrocephalus ( n  = 1). All patients underwent surgery for craniosynostosis, with the most common operation being bifronto-orbital advancement ( n  = 4). A total of 5 patients underwent reoperation, 3 of which were planned second-stage surgeries and 2 of whom had craniosynostosis recurrence. Conclusions We advocate screening for suture abnormalities in children with primary metabolic bone disorders. While cranial vault remodeling is not associated with a high rate of postoperative complications in this patient cohort, craniosynostosis recurrences may occur, and parental counseling is recommended.

Abstract BACKGROUND The influence of the surgeon's preoperative goal regarding the extent of tumor resection on patient outcomes has not been carefully studied among patients with nonfunctioning pituitary adenomas. OBJECTIVE To analyze the relationship between surgical tumor removal goal and patient outcomes in a prospective multicenter study. METHODS Centrally adjudicated extent of tumor resection (gross total resection [GTR] and subtotal resection [STR]) data were analyzed using standard univariate and multivariable analyses. RESULTS GTR was accomplished in 148 of 171 (86.5%) patients with planned GTR and 32 of 50 (64.0%) patients with planned STR (P = .001). Sensitivity, specificity, positive predictive value, and negative predictive value of GTR goal were 82.2, 43.9, 86.5, and 36.0%, respectively. Knosp grade 0-2, first surgery, and being an experienced surgeon were associated with surgeons choosing GTR as the goal (P < .01). There was no association between surgical goal and presence of pituitary deficiency at 6 mo (P = .31). Tumor Knosp grade (P = .004) and size (P = .001) were stronger predictors of GTR than was surgical goal (P = .014). The most common site of residual tumor was the cavernous sinus (29 of 41 patients; 70.1%). CONCLUSION This is the first pituitary surgery study to examine surgical goal regarding extent of tumor resection and associated patient outcomes. Surgical goal is a poor predictor of actual tumor resection. A more aggressive surgical goal does not correlate with pituitary gland dysfunction. A better understanding of the ability of surgeons to meet their expectations and of the factors associated with surgical result should improve prognostication and preoperative counseling.