Bird's-eye view of GnRH analog use in a pediatric endocrinology referral center

OBJECTIVE: Gonadotropin-releasing hormone analogs (GnRHa) are standard of care for the treatment of central precocious puberty (CPP). GnRHa have also been prescribed in other clinical settings with the hope of increasing adult stature, although evidence to support this practice is lacking. The degree to which GnRHa are being prescribed for indications other than CPP in routine clinical care has not been described. We sought to systematically examine GnRHa prescribing practices among the pediatric endocrinologists at our academic medical center. METHODS: We reviewed medical records of children treated with GnRHa during a 6-year interval. Variables analyzed included gender, age at start of treatment, indication for therapy, and use of growth hormone as adjunctive treatment. Nonparametric analyses were utilized to compare treatment characteristics of those with CPP versus those without. RESULTS: A total of 260 patients (82% female) aged 8.06 ± 2.68 years were identified. Of these, 191 (73.5%) were treated for CPP, whereas 69 (26.5%) were treated for normally timed puberty in the context of idiopathic short stature/poor predicted height (n = 37), growth hormone deficiency (n = 17), congenital adrenal hyperplasia (n = 10), primary hypothyroidism (n = 4), and developmental delay (n = 1). Of the 161 girls with CPP, GnRHa therapy was initiated at ≥8 years of age in 62 (39%). CONCLUSION: Whereas most patients were treated for CPP, ~27% were treated for other indications. Of girls with CPP, 39% were treated at an age when benefit in terms of height is unlikely. This highlights the need for rigorous studies of GnRHa use for indications beyond CPP

Deterministic Parallel Global Parameter Estimation for a Model of the Budding Yeast Cell Cycle

Two parallel deterministic direct search algorithms are used to find improved parameters for a system of differential equations designed to simulate the cell cycle of budding yeast. Comparing the model simulation results to experimental data is difficult because most of the experimental data is qualitative rather than quantitative. An algorithm to convert simulation results to mutant phenotypes is presented. Vectors of parameters defining the differential equation model are rated by a discontinuous objective function. Parallel results on a 2200 processor supercomputer are presented for a global optimization algorithm, DIRECT, a local optimization algorithm, MADS, and a hybrid of the two

Structural insights into the mechanism of negative regulation of single-box high mobility group proteins by the acidic tail domain.

The Drosophila and plant (maize) functional counterparts of the abundant vertebrate chromosomal protein HMGB1 (HMG-D and ZmHMGB1, respectively) differ from HMGB1 in having a single HMG box, as well as basic and acidic flanking regions that vary greatly in length and charge. We show that despite these variations, HMG-D and ZmHMGB1 exist in dynamic assemblies in which the basic HMG boxes and linkers associate with their intrinsically disordered, predominantly acidic, tails in a manner analogous to that observed previously for HMGB1. The DNA-binding surfaces of the boxes and linkers are occluded in "auto-inhibited" forms of the protein, which are in equilibrium with transient, more open structures that are "binding-competent." This strongly suggests that the mechanism of auto-inhibition may be a general one. HMG-D and ZmHMGB1 differ from HMGB1 in having phosphorylation sites in their tail and linker regions. In both cases, in vitro phosphorylation of serine residues within the acidic tail stabilizes the assembled form, suggesting another level of regulation for interaction with DNA, chromatin, and other proteins that is not possible for the uniformly acidic (hence unphosphorylatable) tail of HMGB1.This work was supported by the Biotechnology and Biological Sciences Research Council through the award of Grant BB/D002257/1 (to J. O. T.) and a grant from the Deutsche Forschungsgemeinschaft (DFG) (to K. D. G.).This is the final published version. It first appeared at http://www.jbc.org/content/289/43/29817.long

Motion Corrected Cadence CPS Ultrasound for Quantifying Response to Vasoactive Drugs in a Rat Kidney Model

To establish the ability of contrast enhanced motion corrected Cadence Pulse Sequencing (CPS) to detect changes in renal blood flow induced by vasoactive substances in rats

The Social context of motorcycle riding and the key determinants influencing rider behavior: A qualitative investigation

Objective: Given the increasing popularity of motorcycle riding and heightened risk of injury or death associated with being a rider, this study explored rider behaviour as a determinant of rider safety and, in particular, key beliefs and motivations which influence such behaviour. To enhance the effectiveness of future education and training interventions, it is important to understand riders’ own views about what influences how they ride. Specifically, this study sought to identify key determinants of riders’ behaviour in relation to the social context of riding including social and identity-related influences relating to the group (group norms and group identity) as well as the self (moral/personal norm and self-identity). ----- ----- Method: Qualitative research was undertaken via group discussions with motorcycle riders (n = 41). Results: The findings revealed that those in the group with which one rides represent an important source of social influence. Also, the motorcyclist (group) identity was associated with a range of beliefs, expectations, and behaviours considered to be normative. Exploration of the construct of personal norm revealed that riders were most cognizant of the “wrong things to do” when riding; among those issues raised was the importance of protective clothing (albeit for the protection of others and, in particular, pillion passengers). Finally, self-identity as a motorcyclist appeared to be important to a rider’s self-concept and was likely to influence their on-road behaviour. ----- ----- Conclusion: Overall, the insight provided by the current study may facilitate the development of interventions including rider training as well as public education and mass media messages. The findings suggest that these interventions should incorporate factors associated with the social nature of riding in order to best align it with some of the key beliefs and motivations underpinning riders’ on-road behaviours

Transcutaneous vagus nerve stimulation (t-VNS): A novel effective treatment for temper outbursts in adults with Prader-Willi Syndrome indicated by results from a non-blind study.

Temper outbursts are a severe problem for people with Prader-Willi Syndrome (PWS). Previous reports indicate that vagus nerve stimulation (VNS) may reduce maladaptive behaviour in neurodevelopmental disorders, including PWS. We systematically investigated the effectiveness of transcutaneous VNS (t-VNS) in PWS. Using a non-blind single case repeat measures modified ABA design, with participants as their own controls, t-VNS was evaluated in five individuals with PWS [three males; age 22-41 (M = 26.8)]. After a baseline phase, participants received four-hours of t-VNS daily for 12 months, followed by one month of daily t-VNS for two-hours. The primary outcome measure was the mean number of behavioural outbursts per day. Secondary outcomes included findings from behavioural questionnaires and both qualitative and goal attainment interviews. Four of the five participants who completed the study exhibited a statistically significant reduction in number and severity of temper outbursts after approximately nine months of daily four-hour t-VNS. Subsequent two-hour daily t-VNS was associated with increased outbursts for all participants, two reaching significance. Questionnaire and interview data supported these findings, the latter indicating potential mechanisms of action. No serious safety issues were reported. t-VNS is an effective, novel and safe intervention for chronic temper outbursts in PWS. We propose these changes are mediated through vagal projections and their effects both centrally and on the functioning of the parasympathetic nervous system. These findings challenge our present biopsychosocial understanding of such behaviours suggesting that there is a single major mechanism that is modifiable using t-VNS. This intervention is potentially generalizable across other clinical groups. Future research should address the lack of a sham condition in this study along with the prevalence of high drop out rates, and the potential effects of different stimulation intensities, frequencies and pulse widths

Implementing a Health Care Professional-Supported Digital Intervention for Survivors of Cancer in Primary Care:Qualitative Process Evaluation of the Renewed Intervention

Background: Primary care has an important role in supporting cancer survivors, yet support is limited because of practitioners’ perceived lack of expertise and time. A digital intervention for cancer survivors could provide an efficient way for primary care staff to support cancer survivors without the need to accumulate expertise and skills to help patients make behaviour changes, providing very brief support alongside this could maximise adherence to the digital interventions. Renewed is a digital intervention combining online behaviour change advice with brief healthcare practitioner support from a nurse or healthcare assistant. Knowledge about the views and experiences of primary care staff providing support alongside a digital intervention for cancer survivors is sparse, limiting understanding of the acceptability and feasibility of this type of intervention. Objective: To explore Supporters’ experiences of providing support to cancer survivors using Renewed, to understand potential barriers and facilitators to implementation of Renewed in practice, and investigate strengths and weaknesses of the intervention from the perspective of healthcare professionals.Methods: This was a qualitative process evaluation, nested within a large trial evaluating Renewed. Twenty-eight semi-structured telephone interviews were conducted with nurses and healthcare assistants. Data were analysed using inductive thematic analysis.Results: Four themes were developed during analysis which reflected factors that Supporters identified as hindering or enabling them to provide support alongside Renewed Online (Themes: Renewed Online as an acceptable digital tool with some improvements; confidence to enact the Supporter role; practicalities of delivering support alongside a digital intervention; and managing a patient-led approach). The analysis suggests that Supporters perceived that a digital intervention such as Renewed would be beneficial to support cancer survivors in primary care, and fit within current practices. However, barriers to providing support alongside a digital intervention were also identified, including concerns about how to facilitate rapport building and, in a minority, concerns about employing a non-directive approach, in which the majority of advice and support is provided through a digital intervention, with brief additional support provided by primary care staff. Conclusion: These findings add to the literature about how best to provide support alongside digital interventions, suggesting that whilst most practitioners cope well with a non-directive approach, a minority require more training to feel confident implementing this. This study suggests that barriers to providing formal support to cancer survivors in primary care could be successfully overcome with an approach like Renewed, where a digital intervention provides most of the support and expertise, and healthcare practitioners provide the additional brief human support to maximise engagement. Strategies to maximise the chances of successful implementation for this type of intervention are discussed. <br/

Visuospatial Functioning In The Primary Progressive Aphasias

Objectives: The aim of this study was to identify whether the three main primary progressive aphasia (PPA) variants would show differential profiles on measures of visuospatial cognition. We hypothesized that the logopenic variant would have the most difficulty across tasks requiring visuospatial and visual memory abilities. Methods: PPA patients (n = 156), diagnosed using current criteria, and controls were tested on a battery of tests tapping different aspects of visuospatial cognition. We compared the groups on an overall visuospatial factor; construction, immediate recall, delayed recall, and executive functioning composites; and on individual tests. Cross-sectional and longitudinal comparisons were made, adjusted for disease severity, age, and education. Results: The logopenic variant had significantly lower scores on the visuospatial factor and the most impaired scores on all composites. The nonfluent variant had significant difficulty on all visuospatial composites except the delayed recall, which differentiated them from the logopenic variant. In contrast, the semantic variants performed poorly only on delayed recall of visual information. The logopenic and nonfluent variants showed decline in figure copying performance over time, whereas in the semantic variant, this skill was remarkably preserved. Conclusions: This extensive examination of performance on visuospatial tasks in the PPA variants solidifies some previous findings, for example, delayed recall of visual stimuli adds value in differential diagnosis between logopenic variant PPA and nonfluent variant PPA variants, and illuminates the possibility of common mechanisms that underlie both linguistic and non-linguistic deficits in the variants. Furthermore, this is the first study that has investigated visuospatial functioning over time in the PPA variants

Consistency in Polyclonal T-cell Responses to Gluten between Children and Adults with Celiac Disease

BACKGROUND & AIMS: Developing antigen-specific approaches for diagnosis and treatment of celiac disease requires a detailed understanding of the specificity of T cells for gluten. The existing paradigm is that T-cell lines and clones from children differ from those of adults in the hierarchy and diversity of peptide recognition. We aimed to characterize the T-cell response to gluten in children vs adults with celiac disease. METHODS: Forty-one children with biopsy-proven celiac disease (median age, 9 years old; 17 male), who had been on strict gluten-free diets for at least 3 months, were given a 3-day challenge with wheat; blood samples were collected and gluten-specific T cells were measured. We analyzed responses of T cells from these children and from 4 adults with celiac disease to a peptide library and measured T-cell receptor bias. We isolated T-cell clones that recognized dominant peptides and assessed whether gluten peptide recognition was similar between T-cell clones from children and adults. RESULTS: We detected gluten-specific responses by T cells from 30 of the children with celiac disease (73%). T cells from the children recognized the same peptides that were immunogenic to adults with celiac disease; deamidation of peptides increased these responses. Age and time since diagnosis did not affect the magnitude of T-cell responses to dominant peptides. T-cell clones specific for dominant α- or ω-gliadin peptides from children with celiac disease had comparable levels of reactivity to wheat, rye, and barley peptides as T-cell clones from adults with celiac disease. The α-gliadin-specific T cells from children had biases in T-cell receptor usage similar to those in adults. CONCLUSIONS: T cells from children with celiac disease recognize similar gluten peptides as T cells from adults with celiac disease. The findings indicate that peptide-based diagnostics and therapeutics for adults may also be used for children. Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved

Photoelectrocatalytic Surfactant Pollutant Degradation and Simultaneous Green Hydrogen Generation

For the first time, we demonstrate a photoelectrocatalysis technique for simultaneous surfactant pollutant degradation and green hydrogen generation using mesoporous WO$_3$/BiVO$_4$ photoanode under simulated sunlight irradiation. The materials properties such as morphology, crystallite structure, chemical environment, optical absorbance, and bandgap energy of the WO$_3$/BiVO$_4$ films are examined and discussed. We have tested the anionic type (sodium 2-naphthalenesulfonate (S2NS)) and cationic type surfactants (benzyl alkyl dimethylammonium compounds (BAC-C12)) as model pollutants. A complete removal of S2NS and BAC-C12 surfactants at 60 and 90 min, respectively, by applying 1.75 V applied potential vs RHE to the circuit, under 1 sun was achieved. An interesting competitive phenomenon for photohole utilization was observed between surfactants and adsorbed water. This led to the formation of H$_2$O$_2$ from water alongside surfactant degradation (anode) and hydrogen evolution (cathode). No byproducts were observed after the direct photohole mediated degradation of surfactants, implying its advantage over other AOPs and biological processes. In the cathode compartment, 82.51 μmol/cm$^2$ and 71.81 μmol/cm$^2$ of hydrogen gas were generated during the BAC-C12 and S2NS surfactant degradation process, respectively, at 1.75 V RHE applied potential