Clinical Trial Simulation to Evaluate Population Pharmacokinetics and Food Effect: Capturing Abiraterone and Nilotinib Exposures

The objectives of this study were to determine (1) the accuracy with which individual patient level exposure can be determined and (2) whether a known food effect can be identified in a trial simulation of a typical population pharmacokinetic trial. Clinical trial simulations were undertaken using NONMEM VII to assess a typical oncology pharmacokinetic trial design. Nine virtual trials for each compound were performed for combinations of different level of between-occasion variability, number of patients in the trial and magnitude of a food covariate on oral clearance. Less than 5% and 20% bias and precision were obtained in individual clearance estimated for both abiraterone and nilotinib using this design. This design resulted biased and imprecise population clearance estimates for abiraterone. The between-occasion variability in most trials was captured with less than 30% of percent bias and precision. The food effect was detectable as a statistically significant covariate on oral clearance for abiraterone and nilotinib with percent bias and precision of the food covariate less than 20%. These results demonstrate that clinical trial simulation can be used to explore the ability of specific trial designs to evaluate the power to identify individual and population level exposures,covariate and variability effects

Electronic structure of epitaxial graphene layers on SiC: effect of the substrate

Recent transport measurements on thin graphite films grown on SiC show large coherence lengths and anomalous integer quantum Hall effects expected for isolated graphene sheets. This is the case eventhough the layer-substrate epitaxy of these films implies a strong interface bond that should induce perturbations in the graphene electronic structure. Our DFT calculations confirm this strong substrate-graphite bond in the first adsorbed carbon layer that prevents any graphitic electronic properties for this layer. However, the graphitic nature of the film is recovered by the second and third absorbed layers. This effect is seen in both the (0001)and $(000\bar{1})$ 4H SiC surfaces. We also present evidence of a charge transfer that depends on the interface geometry. It causes the graphene to be doped and gives rise to a gap opening at the Dirac point after 3 carbon layers are deposited in agreement with recent ARPES experiments (T.Ohta et al, Science {\bf 313} (2006) 951)

Baseline T cell dysfunction by single cell network profiling in metastatic breast cancer patients.

BackgroundWe previously reported the results of a multicentric prospective randomized trial of chemo-refractory metastatic breast cancer patients testing the efficacy of two doses of TGFβ blockade during radiotherapy. Despite a lack of objective responses to the combination, patients who received a higher dose of TGFβ blocking antibody fresolimumab had a better overall survival when compared to those assigned to lower dose (hazard ratio of 2.73, p = 0.039). They also demonstrated an improved peripheral blood mononuclear cell (PBMC) counts and increase in the CD8 central memory pool. We performed additional analysis on residual PBMC using single cell network profiling (SCNP).MethodsThe original trial randomized metastatic breast cancer patients to either 1 or 10 mg/kg of fresolimumab, every 3 weeks for 5 cycles, combined with radiotherapy to a metastatic site at week 1 and 7 (22.5 Gy given in 3 doses of 7.5 Gy). Trial immune monitoring results were previously reported. In 15 patients with available residual blood samples, additional functional studies were performed, and compared with data obtained in parallel from seven healthy female donors (HD): SCNP was applied to analyze T cell receptor (TCR) modulated signaling via CD3 and CD28 crosslinking and measurement of evoked phosphorylation of AKT and ERK in CD4 and CD8 T cell subsets defined by PD-1 expression.ResultsAt baseline, a significantly higher level of expression (p < 0.05) of PD-L1 was identified in patient monocytes compared to HD. TCR modulation revealed dysfunction of circulating T-cells in patient baseline samples as compared to HD, and this was more pronounced in PD-1+ cells. Treatment with radiotherapy and fresolimumab did not resolve this dyfunctional signaling. However, in vitro PD-1 blockade enhanced TCR signaling in patient PD-1+ T cells and not in PD-1- T cells or in PD-1+ T cells from HD.ConclusionsFunctional T cell analysis suggests that baseline T cell functionality is hampered in metastatic breast cancer patients, at least in part mediated by the PD-1 signaling pathway. These preliminary data support the rationale for investigating the possible beneficial effects of adding PD-1 blockade to improve responses to TGFβ blockade and radiotherapy.Trial registrationNCT01401062

Six-Month Prevalence of Mental Disorders and Service Contacts among Children and Youth in Ontario: Evidence from the 2014 Ontario Child Health Study

© The Author(s) 2019. Objectives: To present the 6-month prevalence and sociodemographic correlates of mental disorders and mental health–related service contacts in a sample of children (4 to 11 years) and youth (12 to 17 years) in Ontario. Methods: The 2014 Ontario Child Health Study is a provincially representative survey of 6537 families with children aged 4 to 17 years in Ontario. DSM-IV-TR mental disorders were assessed using the Mini International Neuropsychiatric Interview for Children and Adolescents (MINI-KID) and included mood (major depressive episode), anxiety (generalized anxiety, separation anxiety, social phobia, specific phobia), and behaviour disorders (attention-deficit/hyperactivity disorder, oppositional-defiant disorder, conduct disorder).The MINI-KID was administered independently to the primary caregiver and youth aged 12 to 17 years in the family’s home. Results: Past 6-month prevalence of any mental disorder ranged from 18.2% to 21.8% depending on age and informant. Behaviour disorders were the most common among children, and anxiety disorders were the most common among youth. Among children and youth with a parent-identified mental disorder, 25.6% of children and 33.7% of youth had contact with a mental health provider. However, 60% had contact with one or more of the providers or service settings assessed, most often through schools. Conclusions: Between 18% and 22% of children and youth in Ontario met criteria for a mental disorder but less than one-third had contact with a mental health provider. These findings provide support for strengthening prevention and early intervention efforts and enhancing service capacity to meet the mental health needs of children and youth in Ontario

Poverty, Neighbourhood Antisocial Behaviour, and Children’s Mental Health Problems: Findings from the 2014 Ontario Child Health Study

© The Author(s) 2019. Objectives: To determine if levels of neighbourhood poverty and neighbourhood antisocial behaviour modify associations between household poverty and child and youth mental health problems. Methods: Data come from the 2014 Ontario Child Health Study—a provincially representative survey of 6537 families with 10,802 four- to 17-year-olds. Multivariate multilevel modelling was used to test if neighbourhood poverty and antisocial behaviour interact with household poverty to modify associations with children’s externalizing and internalizing problems based on parent assessments of children (4- to 17-year-olds) and self-assessments of youth (12- to 17-year-olds). Results: Based on parent assessments, neighbourhood poverty, and antisocial behaviour modified associations between household poverty and children’s mental health problems. Among children living in households below the poverty line, levels of mental health problems were 1) lower when living in neighbourhoods with higher concentrations of poverty and 2) higher when living in neighbourhoods with more antisocial behaviour. These associations were stronger for externalizing versus internalizing problems when conditional on antisocial behaviour and generalized only to youth-assessed externalizing problems. Conclusion: The lower levels of externalizing problems reported among children living in poor households in low-income neighbourhoods identify potential challenges with integrating poorer households into more affluent neighbourhoods. More important, children living in poor households located in neighbourhoods exhibiting more antisocial behaviour are at dramatically higher risk for mental health problems. Reducing levels of neighbourhood antisocial behaviour could have large mental health benefits, particularly among poor children

The 2014 Ontario Child Health Study—Methodology

© The Author(s) 2019. Objective: To describe the methodology of the 2014 Ontario Child Health Study (OCHS): a province-wide, cross-sectional, epidemiologic study of child health and mental disorder among 4- to 17-year-olds living in household dwellings. Method: Implemented by Statistics Canada, the 2014 OCHS was led by academic researchers at the Offord Centre for Child Studies (McMaster University). Eligible households included families with children aged 4 to 17 years, who were listed on the 2014 Canadian Child Tax Benefit File. The survey design included area and household stratification by income and 3-stage cluster sampling of areas and households to yield a probability sample of families. Results: The 2014 OCHS included 6,537 responding households (50.8%) with 10,802 children aged 4 to 17 years. Lower income families living in low-income neighbourhoods were less likely to participate. In addition to measures of childhood mental disorder assessed by the Mini International Neuropsychiatric Interview for Children and Adolescents (MINI-KID) and OCHS Emotional Behavioural Scales (OCHS-EBS), the survey contains measures of neighbourhoods, schools, families and children, and includes administrative data held by the Ministries of Education and Health and Long-Term Care. Conclusions: The complex survey design and differential non-response of the 2014 OCHS required the use of sampling weights and adjustment for design effects. The study is available throughout Canada in the Statistics Canada Research Data Centres (RDCs). We urge external investigators to access the study through the RDCs or to contact us directly to collaborate on future secondary analysis studies based on the OCHS

Immunosuppressive role of fibrinogen-like protein 2 (FGL2) in CD8+regulatory T cells-mediated long-term graft survival

International audienc

Prediction of brain clozapine and norclozapine concentrations in humans from a scaled pharmacokinetic model for rat brain and plasma pharmacokinetics

BACKGROUND: Clozapine is highly effective in treatment-resistant schizophrenia, although, there remains significant variability in the response to this drug. To better understand this variability, the objective of this study was to predict brain extracellular fluid (ECF) concentrations and receptor occupancy of clozapine and norclozapine in human central nervous system by translating plasma and brain ECF pharmacokinetic (PK) relationships in the rat and coupling these with known human disposition of clozapine in the plasma. METHODS: Unbound concentrations of clozapine and norclozapine were measured in rat brain ECF using quantitative microdialysis after subcutaneous administration of a 10 mg/kg single dose of clozapine or norclozapine. These data were linked with plasma concentrations obtained in the same rats to develop a plasma-brain ECF compartmental model. Parameters describing brain ECF disposition were then allometrically scaled and linked with published human plasma PK to predict human ECF concentrations. Subsequently, prediction of human receptor occupancy at several CNS receptors was based on an effect model that related the predicted ECF concentrations to published concentration-driven receptor occupancy parameters. RESULTS: A one compartment model with first order absorption and elimination best described clozapine and norclozapine plasma concentrations in rats. A delay in the transfer of clozapine and norclozapine from plasma to the brain ECF compartment was captured using a transit compartment model approach. Human clozapine and norclozapine concentrations in brain ECF were simulated, and from these the median percentage of receptor occupancy of dopamine-2, serotonin-2A, muscarinic-1, alpha-1 adrenergic, alpha-2 adrenergic and histamine-1 for clozapine, and dopamine-2 for norclozapine were consistent with values reported in the literature. CONCLUSIONS: A PK model that relates clozapine and norclozapine disposition in rat plasma and brain, including blood-brain barrier transport, was developed. Using allometry and published human plasma PK, the model was successfully translated to predict clozapine and norclozapine concentrations and accordant receptor occupancy of both agents in human brain. These predicted exposure and occupancy measures at several receptors that bind clozapine may be employed to extend our understanding of clozapine's complex behavioral effects in humans

Regulator of G Protein Signaling Protein 12 (Rgs12) Controls Mouse Osteoblast Differentiation via Calcium Channel/Oscillation and Gαi-ERK Signaling

Bone homeostasis intimately relies on the balance between osteoblasts (OBs) and osteoclasts (OCs). Our previous studies have revealed that regulator of G protein signaling protein 12 (Rgs12), the largest protein in the Rgs super family, is essential for osteoclastogenesis from hematopoietic cells and OC precursors. However, how Rgs12 regulates OB differentiation and function is still unknown. To understand that, we generated an OB-targeted Rgs12 conditional knockout (CKO) mice model by crossing Rgs12 fl/fl mice with Osterix (Osx)-Cre transgenic mice. We found that Rgs12 was highly expressed in both OB precursor cells (OPCs) and OBs of wild-type (WT) mice, and gradually increased during OB differentiation, whereas Rgs12-CKO mice (Osx Cre/+ ; Rgs12 fl/fl ) exhibited a dramatic decrease in both trabecular and cortical bone mass, with reduced numbers of OBs and increased apoptotic cell population. Loss of Rgs12 in OPCs in vitro significantly inhibited OB differentiation and the expression of OB marker genes, resulting in suppression of OB maturation and mineralization. Further mechanism study showed that deletion of Rgs12 in OPCs significantly inhibited guanosine triphosphatase (GTPase) activity and cyclic adenosine monophosphate (cAMP) level, and impaired Calcium (Ca 2+ ) oscillations via restraints of major Ca 2+ entry sources (extracellular Ca 2+ influx and intracellular Ca 2+ release from endoplasmic reticulum), partially contributed by the blockage of L-type Ca 2+ channel mediated Ca 2+ influx. Downstream mediator extracellular signal-related protein kinase (ERK) was found inactive in OBs of Osx Cre/+ ; Rgs12 fl/fl mice and in OPCs after Rgs12 deletion, whereas application of pertussis toxin (PTX) or overexpression of Rgs12 could rescue the defective OB differentiation via restoration of ERK phosphorylation. Our findings reveal that Rgs12 is an important regulator during osteogenesis and highlight Rgs12 as a potential therapeutic target for bone disorders. © 2018 American Society for Bone and Mineral Research. © 2018 American Society for Bone and Mineral Researc