Application of Physiologically-Based Pharmacokinetic Modeling to Characterize CYP3A-Mediated Drug-Drug Interactions in the Pediatric Population

Children are at risk for experiencing life-threatening drug-drug interactions (DDIs) because they often receive multiple medications throughout hospitalization. Although DDIs frequently occur in pediatric patients, dedicated DDI studies are rarely conducted in infants and children for ethical and practical reasons. Therefore, we typically rely on adult DDI studies although changes in metabolic pathways during development may lead to differences in DDI potential between adults and children. For example, cytochrome P450 (CYP) 3A7 is the predominant CYP3A isoform expressed in neonates and it has lower catalytic activity compared to CYP3A4, the predominant CYP3A isoform expressed in adults. Physiologically-based pharmacokinetic (PBPK) modeling can potentially overcome these challenges by predicting pediatric DDI potential when pediatric data are sparse or unavailable. In this dissertation we leveraged PBPK modeling to develop a systematic approach to provide dosing recommendations in pediatric patients experiencing CYP3A mediated DDIs spanning a variety of interaction mechanisms across the pediatric age continuum. First, we evaluated the DDI between the reversible CYP3A inhibitor, fluconazole, and the CYP3A substrate, sildenafil, administered to neonates for the co-treatment of invasive candidiasis and pulmonary hypertension. This study highlighted the feasibility of leveraging PBPK modeling to predict DDIs in infants and the need to include CYP3A7 parameters in neonates. Second, we evaluated the complex DDI between lopinavir/ritonavir (LPV/RTV) plus rifampicin involving mixed CYP3A time-dependent and competitive inhibition plus induction in pediatric patients co-infected with human immunodeficiency virus (HIV) and tuberculosis (TB). Despite the complexity of this interaction, we were able to capture the observed magnitude of the DDI in pediatric patients receiving boosted LPV/RTV plus rifampicin. Finally, this systematic approach was applied to predict DDI potential and to optimize dosing in pediatric patients receiving a novel antibiotic and time-dependent inhibitor (solithromycin) in combination with the CYP3A substrate, midazolam, and the strong CYP3A inhibitor, ketoconazole. In this study, minor age-related differences in inhibitor concentration resulted in slight differences in the magnitude of the DDI between pediatric patients ≥ 2 months of age and adults. This systematic approach can be applied to other clinically relevant metabolic and transporter mediated DDIs when pediatric DDI data are sparse or unavailable.Doctor of Philosoph

Clinical Pharmacology Studies in Critically Ill Children

Developmental and physiological changes in children contribute to variation in drug disposition with age. Additionally, critically ill children suffer from various life-threatening conditions that can lead to pathophysiological alterations that further affect pharmacokinetics (PK). Some factors that can alter PK in this patient population include variability in tissue distribution caused by protein binding changes and fluid shifts, altered drug elimination due to organ dysfunction, and use of medical interventions that can affect drug disposition (e.g., extracorporeal membrane oxygenation and continuous renal replacement therapy). Performing clinical studies in critically ill children is challenging because there is large inter-subject variability in the severity and time course of organ dysfunction; some critical illnesses are rare, which can affect subject enrollment; and critically ill children usually have multiple organ failure, necessitating careful selection of a study design. As a result, drug dosing in critically ill children is often based on extrapolations from adults or non-critically ill children. Dedicated clinical studies in critically ill children are urgently needed to identify optimal dosing of drugs in this population. This review will summarize the effect of critical illness on pediatric PK, the challenges associated with performing studies in this vulnerable subpopulation, and the clinical PK studies performed to date for commonly used drugs

A psychological intervention based on cognitive-behavioural therapy reduces psychopathological symptoms that indirectly influence the heart rate via cortisol in hypertensive patients: Preliminary results of a pilot study

ObjectiveThis study aimed at assessing the effectiveness of cognitive-behavioural therapy (CBT) integrated with psychoeducation in a group of hypertensive patients with clinically significant psychopathological symptoms.MethodsOne hundred hypertensive patients completed the Symptom Checklist-90-Revised. Of them, 17 scored above the clinical range (cut-off = 0.75) on the Global Severity Index and were included in the study. Psychological distress was assessed again after the intervention (T1) and 6 months after the end of treatment (T2). In addition, the cortisol dosage and the heart rate (HR) measurement were collected at both T0 and T2. Then, mediation analyses were carried out to calculate whether psychopathological distress might predict HR through elevated serum cortisol levels, at both T0 and T2.ResultsThe psychological intervention (CBT integrated with psychoeducation) reduced most of the psychopathological symptoms (anxiety, depression, somatisations, obsessions and compulsions, hostility, interpersonal sensitivity and paranoid ideation) but not cortisol dosage and HR measurement. However, psychological distress indirectly predicted HR via cortisol at T0 but not at T2.ConclusionThese results suggest and encourage the replicability of data in larger sample sizes and the comparison with a control group. Nevertheless, these results highlight a need for a multidimensional assessment of disorders affecting the mental and physical spheres of patients to support their overall well-being

Intensive monitoring of conventional and surrogate quality parameters in a highly urbanized river affected by multiple combined sewer overflows

Abstract The paper reports results of four intensive campaigns carried out on the Seveso River (Milan metropolitan area, Italy) between 2014 and 2016, during intense precipitation events. Laboratory analyses were coupled with on-site, continuous measurements to assess the impact of pollutants on water quality based on both conventional and surrogate parameters. Laboratory data included total suspended solids, caffeine, total phosphorus and nitrogen, and their dissolved forms. Screening of trace metals (Cr, Cu, Pb, Ni, Cd) and PBDEs (polybromodiphenylethers) was carried out. Continuous measurements included water level, physico-chemical variables and turbidity. Nutrient concentrations were generally high (e.g. average total phosphorus > 1,000 μg/L) indicating strong sewage contributions. Among monitored pollutants Cr, Cu, Pb, and Cd concentrations were well correlated to TSS, turbidity and discharge, being bound mostly to suspended particulate matter. A different behavior was found for Ni, that showed an early peak occurring before the flow peak, as a result of first flush events. PBDEs correlated well to nutrient concentrations, showing the highest peaks soon after activation of the combined sewer overflows, likely because of its accumulation in sewers. In addition to showing the existing correlations between quality parameters, the paper highlights the importance of surrogate parameters as indicators of anthropic pollution inputs

Miradas sobre la literatura en lengua francesa : Hospitalidad, extranjería, revolución y diálogos culturales. XXX Jornadas de Literatura Francesa y Francófona

Las XXX Jornadas de Literatura Francesa y Francófona desarrolladas en mayo de 2017, tuvieron lugar, como en 2000 y 2007, en la Facultad de Humanidades y Ciencias de la Educación de la Universidad Nacional de La Plata. En una prolongada tradición cultural, la Asociación Argentina de Literatura Francesa y Francófona (AALFF) propone cada año estos encuentros, que se disponen en conjunto con distintas universidades del país y del extranjero. En esta oportunidad, la organización del evento estuvo a cargo de profesoras de las cátedras de Literatura Francesa, Traducción Literaria y Cultura y Civilización Francesas de los Departamentos de Letras y de Lenguas Modernas de la Facultad de Humanidades y Ciencias de la Educación. Esta confluencia dio cuenta de la voluntad de fortalecer, a partir de la Lengua y la Literatura Francesas, no sólo los estudios, la traducción y la investigación conjunta, sino los lazos existentes entre docentes, investigadores e investigadoras de áreas afines, objetivos que felizmente se lograron y que permitieron tejer un entramado de amistad y de mutuo enriquecimiento académico. Los tres días de intercambios en que se desarrollaron las Jornadas, reunieron cerca de 80 investigadores, docentes y estudiantes de grado y posgrado de diferentes universidades de nuestro país, de Uruguay (Universidad de la República, Udelar) y de Canadá (Universidad de Sherbrooke).Facultad de Humanidades y Ciencias de la Educació

Miradas sobre la literatura en lengua francesa : Hospitalidad, extranjería, revolución y diálogos culturales. XXX Jornadas de Literatura Francesa y Francófona

Las XXX Jornadas de Literatura Francesa y Francófona desarrolladas en mayo de 2017, tuvieron lugar, como en 2000 y 2007, en la Facultad de Humanidades y Ciencias de la Educación de la Universidad Nacional de La Plata. En una prolongada tradición cultural, la Asociación Argentina de Literatura Francesa y Francófona (AALFF) propone cada año estos encuentros, que se disponen en conjunto con distintas universidades del país y del extranjero. En esta oportunidad, la organización del evento estuvo a cargo de profesoras de las cátedras de Literatura Francesa, Traducción Literaria y Cultura y Civilización Francesas de los Departamentos de Letras y de Lenguas Modernas de la Facultad de Humanidades y Ciencias de la Educación. Esta confluencia dio cuenta de la voluntad de fortalecer, a partir de la Lengua y la Literatura Francesas, no sólo los estudios, la traducción y la investigación conjunta, sino los lazos existentes entre docentes, investigadores e investigadoras de áreas afines, objetivos que felizmente se lograron y que permitieron tejer un entramado de amistad y de mutuo enriquecimiento académico. Los tres días de intercambios en que se desarrollaron las Jornadas, reunieron cerca de 80 investigadores, docentes y estudiantes de grado y posgrado de diferentes universidades de nuestro país, de Uruguay (Universidad de la República, Udelar) y de Canadá (Universidad de Sherbrooke).Facultad de Humanidades y Ciencias de la Educació

Miradas sobre la literatura en lengua francesa : Hospitalidad, extranjería, revolución y diálogos culturales. XXX Jornadas de Literatura Francesa y Francófona

Las XXX Jornadas de Literatura Francesa y Francófona desarrolladas en mayo de 2017, tuvieron lugar, como en 2000 y 2007, en la Facultad de Humanidades y Ciencias de la Educación de la Universidad Nacional de La Plata. En una prolongada tradición cultural, la Asociación Argentina de Literatura Francesa y Francófona (AALFF) propone cada año estos encuentros, que se disponen en conjunto con distintas universidades del país y del extranjero. En esta oportunidad, la organización del evento estuvo a cargo de profesoras de las cátedras de Literatura Francesa, Traducción Literaria y Cultura y Civilización Francesas de los Departamentos de Letras y de Lenguas Modernas de la Facultad de Humanidades y Ciencias de la Educación. Esta confluencia dio cuenta de la voluntad de fortalecer, a partir de la Lengua y la Literatura Francesas, no sólo los estudios, la traducción y la investigación conjunta, sino los lazos existentes entre docentes, investigadores e investigadoras de áreas afines, objetivos que felizmente se lograron y que permitieron tejer un entramado de amistad y de mutuo enriquecimiento académico. Los tres días de intercambios en que se desarrollaron las Jornadas, reunieron cerca de 80 investigadores, docentes y estudiantes de grado y posgrado de diferentes universidades de nuestro país, de Uruguay (Universidad de la República, Udelar) y de Canadá (Universidad de Sherbrooke).Facultad de Humanidades y Ciencias de la Educació

Severe cardiomyopathy in a young patient with complete deficiency of adipose triglyceride lipase due to a novel mutation in PNPLA2 gene

We report the case of a 26 year-old male patient affected by neutral lipid storage myopathy with severe cardiac involvement. Patient parents were first cousins; a brother died at 3 years of age, during surgery. They referred that the child had always walked on toes, but he never presented weakness or difficulties in physical activity, compared to peers. The patient was first evaluated when he was 11 years-old and was reported to walk on toes, with difficulty to walk on heels, and to have mild calves hypertrophy and reduced tendon reflexes. Blood test revealed high values of CK (1657 U/L), while total and free carnitine levels were normal. Electromyography was normal; an effort test revealed excessive increase in lactic acid levels. He underwent a muscle biopsy that showed abnormal lipid storage. He was diagnosed to suffer from a lipid storage myopathy and therapy with riboflavin was started with some benefit to the patient. A neutral lipid storage myopathy was hypothesized and molecular analysis of the PNPLA2 gene revealed a homozygous novel deletion of seven nucleotides in exon 2 (c.41_47delGCTGCGG)

Challenging Hazards Amidst Observational Simulation in the Emergency Department: Advancing Gamification in Simulation Education Through a Novel Resident-led Skills Competition.

Medical simulation competitions have become an increasingly popular method to provide a hands-on gamified approach to education and training in the health professions. The most well-known competition, SimWars, consists of well-coordinated teams that are tasked with completing a series of mind-bending clinical scenarios in front of a live audience through \u27bracket-style\u27 elimination rounds. Similarly, challenging hazards amidst observational simulation (CHAOS) in the emergency department (ED) is another novel approach to gamification in both its structure and feel. Conducted at the Council of Emergency Medicine Resident Directors (CORD) 2018 National Assembly in San Antonio, Texas, instead of assigning premeditated teams, it placed random Emergency Medicine (EM) faculty, residents, and medical students together in teams to test them on a variety of fundamental EM content areas. Additionally, the event incorporated multiple levels within each round, allowing the inclusion of additional information to be shared with participants to support switching gears, as is typical for teams working in the ED and augmenting the perceived level of chaos. To assess this pilot project, formal quantitative and qualitative feedback was solicited at the end of the session. Quantitative evaluation of the intervention was obtained through an eight-item questionnaire using a five-point Likert-type scale from 19 of the 20 enrolled participants (95% response rate). Responses were generally positive with an overall course rating score of 4.45 out of 5 (SD +/- 0.62). Qualitative feedback revealed that learners enjoyed performing procedures and networking with their EM colleagues. The majority of residents (95%) recommend the activity be integrated into subsequent conferences. Areas for improvement included shorter cases and minimizing technical malfunctions. CHAOS in the ED was a successful pilot study that incorporated gamification as a means to deploy simulation-based training at a national emergency medicine conference in a community of simulation educators. Future studies should focus on incorporating learners\u27 feedback into subsequent CHAOS iterations and reducing overhead costs to increase its adoption by both regional and national audiences