PATH-38. ROSETTE-FORMING GLIONEURONAL TUMOR IS DEFINED BY FGFR1 ACTIVATING ALTERATIONS WITH FREQUENT ACCOMPANYING PI3K AND MAPK PATHWAY MUTATIONS

Abstract BACKGROUND Rosette-forming glioneuronal tumor (RGNT) is an uncommon CNS tumor originally described in the fourth ventricle characterized by a low-grade glial neoplasm admixed with a rosette-forming neurocytic component. METHODS We reviewed clinicopathologic features of 42 patients with RGNT. Targeted next-generation sequencing was performed, and genome-wide methylation profiling is underway. RESULTS The 20 male and 22 female patients had a mean age of 25 years (range 3–47) at time of diagnosis. Tumors were located within or adjacent to the lateral ventricle (n=16), fourth ventricle (15), third ventricle (9), and spinal cord (2). All 31 tumors assessed to date contained FGFR1 activating alterations, either in-frame gene fusion, kinase domain tandem duplication, or hotspot missense mutation in the kinase domain (p.N546 or p.K656). While 7 of these 31 tumors harbored FGFR1 alterations as the solitary pathogenic event, 24 contained additional pathogenic alterations within PI3-kinase or MAP kinase pathway genes: 5 with additional PIK3CA and NF1 mutations, 4 with PIK3CA mutation, 3 with PIK3R1 mutation (one of which also contained focal RAF1 amplification), 5 with PTPN11 mutation (one with additional PIK3R1 mutation), and 2 with NF1 deletion. The other 5 cases demonstrated anaplastic features including hypercellularity and increased mitotic activity. Among these anaplastic cases, 3 harbored inactivating ATRX mutations and two harbored CDKN2A homozygous deletion, in addition to the FGFR1 alterations plus other PI3-kinase and MAP kinase gene mutations seen in those RGNT without anaplasia. CONCLUSION Independent of ventricular location, RGNT is defined by FGFR1 activating mutations or rearrangements, which are frequently accompanied by mutations involving PIK3CA, PIK3R1, PTPN11, NF1, and KRAS. Whereas pilocytic astrocytoma and ganglioglioma are characterized by solitary activating MAP kinase pathway alterations (e.g. BRAF fusion or mutation), RGNT are genetically more complex with dual PI3K-Akt-mTOR and Ras-Raf-MAPK pathway activation. Rare anaplastic examples may show additional ATRX and/or CDKN2A inactivation

Population Pharmacokinetic Modeling of Dolutegravir to Optimize Pediatric Dosing in HIV-1-Infected Infants, Children, and Adolescents

Background and Objective: HIV treatment options remain limited in children. Dolutegravir is a potent and well-tolerated, once-daily HIV-1 integrase inhibitor recommended for HIV-1 infection in both adults and children down to 4 weeks of age. To support pediatric dosing of dolutegravir in children, we used a population pharmacokinetic model with dolutegravir data from the P1093 and ODYSSEY clinical trials. The relationship between dolutegravir exposure and selected safety endpoints was also evaluated. // Methods: A population pharmacokinetic model was developed with data from P1093 and ODYSSEY to characterize the pharmacokinetics and associated variability and to evaluate the impact of pharmacokinetic covariates. The final population pharmacokinetic model simulated exposures across weight bands, doses, and formulations that were compared with established adult reference data. Exploratory exposure–safety analyses evaluated the relationship between dolutegravir pharmacokinetic parameters and selected clinical laboratory parameters and adverse events. // Results: A total of N = 239 participants were included, baseline age ranged from 0.1 to 17.5 years, weight ranged from 3.9 to 91 kg, 50% were male, and 80% were black. The final population pharmacokinetic model was a one-compartment model with first-order absorption and elimination, enabling predictions of dolutegravir concentrations in the pediatric population across weight bands and doses/formulations. The predicted geometric mean trough concentration was comparable to the adult value following a 50-mg daily dose of dolutegravir for all weight bands at recommended doses. Body weight, age, and formulation were significant predictors of dolutegravir pharmacokinetics in pediatrics. Additionally, during an exploratory exposure–safety analysis, no correlation was found between dolutegravir exposure and selected safety endpoints or adverse events. // Conclusions: The dolutegravir dosing in children ≥ 4 weeks of age on an age/weight-band basis provides comparable exposures to those historically observed in adults. Observed pharmacokinetic variability was higher in this pediatric population and no additional safety concerns were observed. These results support the weight-banded dosing of dolutegravir in pediatric participants currently recommended by the World Health Organization

Breastfeeding and Protein Intake Influence Body Mass Index from 2 Months to 22 Years in the Cebu Longitudinal Health and Nutrition Survey

BACKGROUND: Protein intake (PI) may alter adiposity but few studies have explored the age-specific associations of PI with body mass index (BMI). OBJECTIVE: We analyzed how PI and breastfeeding relate to BMI in the CLHNS (Cebu Longitudinal Health and Nutrition Survey), an observational Filipino birth cohort (1983-2005). METHODS: Random-effects longitudinal regression models estimated the association of daily breastfeeding frequency and energy-adjusted PI residuals with concurrent BMI z scores (zBMI) measured bimonthly from 2 to 24 mo (n = 2899), and the association of breastfeeding history and PI residuals with concurrent BMI using 5 surveys from 2 to 22 y (n = 2435). Models included statistical interactions between PI, breastfeeding, age, and energy intake and adjusted for potential confounders. RESULTS: Breastfeeding was associated with higher predicted zBMI at 6 mo (β: 0.491 SD; 95% CI: 0.422, 0.560) and at 18 mo (β: 0.114 SD; 95% CI: 0.032, 0.197). Daily breastfeeding frequency contributed to higher predicted zBMI in younger infants and lower predicted zBMI in later infancy. Those with longer breastfeeding history (19 mo) were significantly smaller at age 11 y (in kg/m2; β: -0.220; 95% CI: -0.342, -0.097) than those with a shorter (4 mo) breastfeeding duration. Total complementary PI was positively associated with predicted zBMI. Complementary animal PI was positively associated with predicted zBMI in nonbreastfed infants. Plant PI was inversely associated with predicted zBMI of nonbreastfed infants at 6 mo. At 22 y contrasts between high (75th percentile) and low (25th percentile) PIs showed that animal PI was associated with higher predicted BMI (β: 0.187; 95% CI: 0.045, 0.329), and total PI was inversely related to predicted BMI (β: -0.008; 95% CI: -0.015, -0.001). CONCLUSION: Breastfeeding frequency, breastfeeding history, and PI contribute to BMI from infancy to young adulthood in the CLHNS

Sequences of Regressions Distinguish Nonmechanical from Mechanical Associations between Metabolic Factors, Body Composition, and Bone in Healthy Postmenopausal Women

Background: There is increasing recognition of complex interrelations between the endocrine functions of bone and fat tissues or organs.  Objective: The objective was to describe nonmechanical and mechanical links between metabolic factors, body composition, and bone with the use of graphical Markov models.  Methods: Seventy postmenopausal women with a mean ± SD age of 62.3 ± 3.7 y and body mass index (in kg/m2) of 24.9 ± 3.8 were recruited. Bone outcomes were peripheral quantitative computed tomography measures of the distal and diaphyseal tibia, cross-sectional area (CSA), volumetric bone mineral density (vBMD), and cortical CSA. Biomarkers of osteoblast and adipocyte function were plasma concentrations of leptin, adiponectin, osteocalcin, undercarboxylated osteocalcin (UCOC), and phylloquinone. Body composition measurements were lean and percent fat mass, which were derived with the use of a 4-compartment model. Sequences of Regressions, a subclass of graphical Markov models, were used to describe the direct (nonmechanical) and indirect (mechanical) interrelations between metabolic factors and bone by simultaneously modeling multiple bone outcomes and their relation with biomarker outcomes with lean mass, percent fat mass, and height as intermediate explanatory variables.  Results: The graphical Markov models showed both direct and indirect associations linking plasma leptin and adiponectin concentrations with CSA and vBMD. At the distal tibia, lean mass, height, and adiponectin-UCOC interaction were directly explanatory of CSA (R2 = 0.45); at the diaphysis, lean mass, percent fat mass, leptin, osteocalcin, and age-adiponectin interaction were directly explanatory of CSA (R2 = 0.49). The regression models exploring direct associations for vBMD were much weaker, with R2 = 0.15 and 0.18 at the distal and diaphyseal sites, respectively. Lean mass and UCOC were associated, and the global Markov property of the graph indicated that this association was explained by osteocalcin.  Conclusions: This study, to our knowledge, offers a novel approach to the description of the complex physiological interrelations between adiponectin, leptin, and osteocalcin and the musculoskeletal system. There may be benefits to jointly targeting both systems to improve bone health

A modest start, but a steady rise in research use: a longitudinal study of nurses during the first five years in professional life

<p>Abstract</p> <p>Background</p> <p>Newly graduated nurses are faced with a challenging work environment that may impede their ability to provide evidence-based practice. However, little is known about the trajectory of registered nurses' use of research during the first years of professional life. Thus, the aim of the current study was to prospectively examine the extent of nurses' use of research during the first five years after undergraduate education and specifically assess changes over time.</p> <p>Method</p> <p>Survey data from a prospective cohort of 1,501 Swedish newly graduated nurses within the national LANE study (Longitudinal Analyses of Nursing Education and Entry in Worklife) were used to investigate perceived use of research over the first five years as a nurse. The dependent variables consisted of three single items assessing instrumental, conceptual, and persuasive research use, where the nurses rated their use on a five-point scale, from 'never' (1) to 'on almost every shift' (5). These data were collected annually and analyzed both descriptively and by longitudinal growth curve analysis.</p> <p>Results</p> <p>Instrumental use of research was most frequently reported, closely followed by conceptual use, with persuasive use occurring to a considerably lower extent. The development over time showed a substantial general upward trend, which was most apparent for conceptual use, increasing from a mean of 2.6 at year one to 3.6 at year five (unstandardized slope +0.25). However, the descriptive findings indicated that the increase started only after the second year. Instrumental use had a year one mean of 2.8 and a year five mean of 3.5 (unstandardized slope +0.19), and persuasive use showed a year one mean of 1.7 and a year five mean of 2.0 (unstandardized slope +0.09).</p> <p>Conclusion</p> <p>There was a clear trend of increasing research use by nurses during their first five years of practice. The level of the initial ratings also indicated the level of research use in subsequent years. However, it took more than two years of professional development before this increase 'kicked in.' These findings support previous research claiming that newly graduated nurses go through a 'transition shock,' reducing their ability to use research findings in clinical work.</p

Het archeologisch onderzoek in Raversijde (Oostende) in de periode 1992-2005

Raversijde - sinds 1970 deel van de stad Oostende, voordien Middelkerke - gaat terug tot een laatmiddeleeuwse vissersnederzetting met de naam Walraversijde. Deze vissersnederzetting was gesitueerd nabij de huidige grens Middelkerke/Oostende in een zone die zich grotendeels binnen het huidige provinciedomein Raversijde bevindt, maar zich ook nog in belangrijke mate uitstrekt tot op het strand ter hoogte van dit domein.In deze publicatie over archeologisch onderzoek in Raversijde komen de opgravingscampagnes op het grondgebied van het provinciedomein Raversijde uit de periode 1992-1998 uitvoerig aan bod. Daarnaast worden een aantal markante opgravingsresultaten van na 1998 belicht: het muntdepot dat op het einde van 1999 werd aangetroffen, de in 2003 aangesneden zone met begravingen en de in 2005 geïdentificeerde Romeinse dijk.Dit 8ste deel van de Relicta Monografieën behandelt chronologisch de resten en sporen uit de prehistorie, de Romeinse periode, de late middeleeuwen en de vroeg-moderne tijden. Deze publicatie is in de eerste plaats een opgravingsverslag: ze beschrijft, analyseert en interpreteert de belangrijkste sporen samen met een selectie van de aangetroffen mobiele resten en de resultaten van natuurwetenschappelijk onderzoek