Initial Clinical Guidelines for Co-Occurring Autism Spectrum Disorder and Gender Dysphoria or Incongruence in Adolescents

Evidence indicates an overrepresentation of youth with co-occurring autism spectrum disorders (ASD) and gender dysphoria (GD). The clinical assessment and treatment of adolescents with this co-occurrence is often complex, related to the developmental aspects of ASD. There are no guidelines for clinical care when ASD and GD co-occur; however, there are clinicians and researchers experienced in this co-occurrence. This study develops initial clinical consensus guidelines for the assessment and care of adolescents with co-occurring ASD and GD, from the best clinical practices of current experts in the field. Expert participants were identified through a comprehensive international search process and invited to participate in a two-stage Delphi procedure to form clinical consensus statements. The Delphi Method is a well-studied research methodology for obtaining consensus among experts to define appropriate clinical care. Of 30 potential experts identified, 22 met criteria as expert in co-occurring ASD and GD youth and participated. Textual data divided into the following data nodes: guidelines for assessment; guidelines for treatment; six primary clinical/psychosocial challenges: social functioning, medical treatments and medical safety, risk of victimization/safety, school, and transition to adulthood issues (i.e., employment and romantic relationships). With a cutoff of 75% consensus for inclusion, identified experts produced a set of initial guidelines for clinical care. Primary themes include the importance of assessment for GD in ASD, and vice versa, as well as an extended diagnostic period, often with overlap/blurring of treatment and assessment.     

Development of a Real-Time Smartphone Solution for the Management of Women With or at High Risk of Gestational Diabetes

Gestational diabetes mellitus (GDM) is defined as new onset or recognition of glucose intolerance in pregnancy. Evidence supports tight blood glucose regulation to prevent adverse maternal and fetal outcomes. Finger-prick blood glucose (BG) testing with frequent clinic review remains the most common method of managing diabetes in pregnancy. The prevalence of GDM is rising globally, pressuring resource-limited services. We have developed an intuitive, interactive, reliable, and accurate management system to record BG measurements and deliver management of GDM remotely. Following an initial scoping phase, a prototype software application was developed using an Android smartphone with BG meter linkage via Bluetooth. A custom website was built for clinician review of the data transmitted by the smartphone. After system refinement, further evaluation was undertaken for usability and reliability in a 48-patient service development project. Women used the system for an average of 13.1 weeks. In all, 19 686 BG measures were transmitted, 98.6% of which had a meal tag. A total of 466 text messages were transmitted. A mean of 30 BG readings per woman per week were transmitted, and 85% of women submitted the minimum requirement of 18 readings per week. We have developed a novel, real-time, smartphone-based BG monitoring management system that allows clinician review of real-time patient-annotated BG results. Results indicate high usage and excellent compliance by women. Robust clinical, economic, and satisfaction evaluations are required. To address these requirements, we are currently conducting a randomized controlled pilot trial.     

The Effect of Moving Point of Contact Stimulation on Chondrocyte Gene Expression and Localization in Tissue Engineered Constructs

Tissue engineering is a promising approach for articular cartilage repair. However, using current technologies, the developed engineered constructs generally do not possess an organized superficial layer, which contributes to the tissue’s durability and unique mechanical properties. In this study, we investigated the efficacy of applying a moving point of contract-type stimulation (MPS) to stimulate the production of a superficial-like layer in the engineered constructs. MPS was applied to chondrocyte-agarose hydrogels at a frequency of 0.5, 1 or 2 Hz, under a constant compressive load of 10 mN for durations between 5 and 60 min over 3 consecutive days. Expression and localization of superficial zone constituents was conducted by qRT-PCR and in situ hybridization. Finite element modeling was also constructed to gain insight into the relationship between the applied stimulus and superficial zone constituent expression. Gene expression of superficial zone markers were affected in a frequency dependent manner with a physiologic frequency of 1 Hz producing maximal expression of PRG4, biglycan, decorin and collagen II. In situ hybridization revealed that localization of these markers predominantly occurred at 500–1000 μm below the construct surface which correlated to sub-surface strains between 10 and 25% as determined by finite element modeling. These results indicate that while mechanical stimuli can be used to enhance the expression of superficial zone constituents in engineered cartilage constructs, the resultant subsurface loading is a critical factor for localizing expression. Future studies will investigate altering the applied stimulus to further localize superficial zone constituent expression at the construct surface.     

Emotion regulation ability varies in relation to intrinsic functional brain architecture

This study investigated the neural basis of individual variation in emotion regulation, specifically the ability to reappraise negative stimuli so as to down-regulate negative affect. Brain functions in young adults were measured with functional Magnetic Resonance Imaging during three conditions: (i) attending to neutral pictures; (ii) attending to negative pictures and (iii) reappraising negative pictures. Resting-state functional connectivity was measured with amygdala and dorsolateral prefrontal cortical (DLPFC) seed regions frequently associated with emotion regulation. Participants reported more negative affect after attending to negative than neutral pictures, and less negative affect following reappraisal. Both attending to negative vs neutral pictures and reappraising vs attending to negative pictures yielded widespread activations that were significantly right-lateralized for attending to negative pictures and left-lateralized for reappraising negative pictures. Across participants, more successful reappraisal correlated with less trait anxiety and more positive daily emotion, greater activation in medial and lateral prefrontal regions, and lesser resting-state functional connectivity between (a) right amygdala and both medial prefrontal and posterior cingulate cortices, and (b) bilateral DLPFC and posterior visual cortices. The ability to regulate emotion, a source of resilience or of risk for distress, appears to vary in relation to differences in intrinsic functional brain architecture.     

CYP3A4 drug interactions: correlation of 10 in vitro probe substrates

AIMS: Many substrates of cytochrome P450 (CYP) 3A4 are used for in vitro investigations of drug metabolism and potential drug-drug interactions. The aim of the present study was to determine the relationship between 10 commonly used CYP3A4 probes using modifiers with a range of inhibitory potency. METHODS: The effects of 34 compounds on CYP3A4-mediated metabolism were investigated in a recombinant CYP3A4 expression system. Inhibition of erythromycin, dextromethorphan and diazepam N-demethylation, testosterone 6beta-hydroxylation, midazolam 1-hydroxylation, triazolam 4-hydroxylation, nifedipine oxidation, cyclosporin oxidation, terfenadine C-hydroxylation and N-dealkylation and benzyloxyresorufin O-dealkylation was evaluated at the apparent Km or S50 (for substrates showing sigmoidicity) value for each substrate and at an inhibitor concentration of 30 microM. RESULTS: While all CYP3A4 probe substrates demonstrate some degree of similarity, examination of the coefficients of determination, together with difference and cluster analysis highlighted that seven substrates can be categorized into two distinct substrate groups. Erythromycin, cyclosporin and testosterone form the most closely related group and dextromethorphan, diazepam, midazolam and triazolam form a second group. Terfenadine can be equally well placed in either group, while nifedipine shows a distinctly different relationship. Benzyloxyresorufin shows the weakest correlation with all the other CYP3A4 probes. Modifiers that caused negligible inhibition or potent inhibition are generally comparable in all assays, however, the greatest variability is apparent with compounds causing, on average, intermediate inhibition. Modifiers of this type may cause substantial inhibition, no effect or even activation depending on the substrate employed. CONCLUSIONS: It is recommended that multiple CYP3A4 probes, representing each substrate group, are used for the in vitro assessment of CYP3A4-mediated drug interactions.     

Executive Function in the Real World: BRIEF lessons from Mark Ylvisaker

It is well established that brain injuries adversely affect the executive functions and their development. Mark Ylvisaker had a substantial impact on how we assess and treat children and adolescents with disrupted executive functions secondary to traumatic brain injury. He articulated core principles for effective assessment and intervention that emphasized the importance of real-world meaning and application. He taught us that assessment that captures a child's everyday functioning in the context of real-world demands is often more informative than traditional neuropsychological measures alone and that interventions that improve functioning in the real-world environment are most useful. His pragmatic model influenced our own efforts to measure executive function and to develop intervention systems for children with executive function deficits. This article reviews the development of the Behavior Rating Inventory for Executive Function as an approach to ecological assessment of children and adolescents with traumatic brain injury. As we take what we learned from Mark Ylvisaker, it becomes increasingly apparent that our assessment and intervention methods, especially as related to the executive functions, demand an everyday, real-world context.