Stability of the Gross Motor Function Classification System, Manual Ability Classification System, and Communication Function Classification System.

AIM: To determine the stability of the Gross Motor Function Classification System (GMFCS), Manual Ability Classification System (MACS), and Communication Function Classification System (CFCS) over 1-year and 2-year intervals using a process for consensus classification between parents and therapists. METHOD: Participants were 664 children with cerebral palsy (CP), 18 months to 12 years of age, one of their parents, and 90 therapists. Consensus between parents and therapists on level of function was ≥92% for the GMFCS, MACS, and CFCS. A linearly weighted kappa coefficient of ≥0.75 was the criterion for stability. RESULTS: Kappa coefficients varied from 0.76 to 0.88 for the GMFCS, 0.59 to 0.73 for the MACS, and 0.57 to 0.77 for the CFCS. For children younger than 4 years of age, level of function did not change for 58.2% on the GMFCS, 30.3% on the MACS, and 39.3% on the CFCS. For children 4 years of age or older, level of function did not change for 72.3% on the GMFCS, 49.1% on the MACS, and 55% on the CFCS. INTERPRETATION: The findings support repeated classification of children over time. The kappa coefficients for the GMFCS are attributed to descriptions of levels for each age band. Consensus classification facilitates discussion between parents and professionals that has implications for shared decision-making. WHAT THIS PAPER ADDS: The findings support repeated classification of children over time. Stability was higher for the Gross Motor Function Classification System than the Manual Ability Classification System and Communication Function Classification System. The function of younger children was more likely to be reclassified. Percentage agreement between parents and therapists using consensus classification varied from 92% to 97%. The intraclass correlation coefficient overestimated stability compared with the weighted kappa coefficient

A Collaborative Approach to Decision Making Through Developmental Monitoring to Provide Individualized Services for Children With Cerebral Palsy.

In this Perspective, we suggest a process to improve physical and occupational therapists’ and families’ collaboration to provide appropriate, efficient, and effective evidence-based services to improve motor function, self-care performance, and participation in family and recreation activities for children with cerebral palsy (CP). This process is informed by 2 multisite prospective cohort studies (Move & PLAY and On Track). The heterogeneity of children with CP is described, limiting the utility of evidence from randomized controlled trials and systematic reviews to inform service planning for children with CP. An evidence-based alternative using prospective cohort studies that produce knowledge of determinants of outcomes important to children and families and methods for developmental monitoring using longitudinal developmental and reference percentile curves to inform individualized care is suggested. Guiding questions are provided to explore how knowledge of determinants and developmental monitoring can inform family-centered, collaborative, strengths-based, and focused service programs to support early development and function. Although this perspective paper is focused on children with CP, the research approach described for collection of useful information and the clinical method of data use may be helpful for people with other heterogeneous chronic health conditions in which physical and occupational therapists face similar challenges

Seagrass meadows

List of excluded full-text articles and the primary reason for exclusion. (DOCX 45 kb

Tolerability of subcutaneous immunoglobulin 20%, Ig20Gly, in pediatric patients with primary immunodeficiencies

Aim: To assess Ig20Gly tolerability in pediatric patients with primary immunodeficiencies. Patients & methods: Infusion parameters and tolerability were analyzed in pediatric patients (aged 2-5 years [n=6], 6-11 years [n=22] and 12-17 years [n=22]) receiving Ig20Gly in two Phase II/III trials. Results: Of 2624 Ig20Gly infusions, >99% did not require any rate reduction, interruption or discontinuation due to adverse events (AEs). Median maximum infusion rates and volumes/site were higher in patients 12-17 years of age (30ml/h/site; 30ml/site) versus 6-11 years (20ml/h/site; 15ml/site) and 2-5 years (18ml/h/site; 14ml/site). Rates of causally related systemic and local AEs (0.009 and 0.063 AEs/infusion) were low. Conclusion: Ig20Gly infused at relatively high rates and volumes was well tolerated in children

Population pharmacokinetic modeling and simulation of immunoglobulin exposure with varying dosing intervals of subcutaneous immunoglobulin 20% (Ig20Gly) in patients with primary immunodeficiency diseases

Background Immunoglobulin (IG) replacement therapy in patients with primary immunodeficiency diseases (PID) can be administered daily to every 2 weeks subcutaneously (SCIG) or every 3 or 4 weeks intravenously (IVIG). Objectives Develop a population pharmacokinetic (PK) model simulating IG exposure with Ig20Gly, a 20% SCIG; determine the dose adjustment factor for Ig20Gly relative to IVIG. Methods Data from patients with PID treated with Ig20Gly and IVIG 10% were used to characterize IG population PK by nonlinear mixed-effects modeling and validated using data splitting and a visual predictive check. IG profiles were simulated for 1000 patients/interval treated with Ig20Gly (daily, every 2 days, every 3 days, twice weekly, weekly, every 2 weeks). An Ig20Gly adjustment factor of 130% was used to simulate Ig20Gly to IVIG AUC ratios for weekly or every 2 weeks Ig20Gly dosing intervals and a monthly IVIG dosing interval. Results A 1-compartment model, using weight as a covariate on clearance, derived from an index modeling dataset (n = 81) demonstrated predictability for a validation dataset (n = 21). The model estimate of bioavailability was 73.9%. Simulations for 6 dosing intervals showed similar mean profiles with overlapping prediction intervals. Mean AUC ratios of Ig20Gly to IVIG with a dose adjustment factor of 1.30:1 were 98.7% for weekly and 97.7% for twice-weekly administration demonstrating comparable exposure. Conclusion Ig20Gly exposures from daily to up to every 2 weeks appeared equivalent. A 1.30 conversion factor provided coverage comparable to IVIG when Ig20Gly is administered daily to every 2 weeks

Hotspot autoimmune T cell receptor binding underlies pathogen and insulin peptide cross-reactivity

The cross-reactivity of T cells with pathogen- and self-derived peptides has been implicated as a pathway involved in the development of autoimmunity. However, the mechanisms that allow the clonal T cell antigen receptor (TCR) to functionally engage multiple peptide–major histocompatibility complexes (pMHC) are unclear. Here, we studied multiligand discrimination by a human, preproinsulin reactive, MHC class-I–restricted CD8+ T cell clone (1E6) that can recognize over 1 million different peptides. We generated high-resolution structures of the 1E6 TCR bound to 7 altered peptide ligands, including a pathogen-derived peptide that was an order of magnitude more potent than the natural self-peptide. Evaluation of these structures demonstrated that binding was stabilized through a conserved lock-and-key–like minimal binding footprint that enables 1E6 TCR to tolerate vast numbers of substitutions outside of this so-called hotspot. Highly potent antigens of the 1E6 TCR engaged with a strong antipathogen-like binding affinity; this engagement was governed though an energetic switch from an enthalpically to entropically driven interaction compared with the natural autoimmune ligand. Together, these data highlight how T cell cross-reactivity with pathogen-derived antigens might break self-tolerance to induce autoimmune disease

Geochemical properties of rocks and soils in Gusev Crater, Mars: Results of the Alpha Particle X-Ray Spectrometer from Cumberland Ridge to Home Plate

Geochemical diversity of rocks and soils has been discovered by the Alpha Particle X-Ray Spectrometer (APXS) during Spirit’s journey over Husband Hill and down into the Inner Basin from sol 470 to 1368. The APXS continues to operate nominally with no changes in calibration or spectral degradation over the course of the mission. Germanium has been added to the Spirit APXS data set with the confirmation that it occurs at elevated levels in many rocks and soils around Home Plate. Twelve new rock classes and two new soil classes have been identified at the Spirit landing site since sol 470 on the basis of the diversity in APXS geochemistry. The new rock classes are Irvine (alkaline basalt), Independence (low Fe outcrop), Descartes (outcrop similar to Independence with higher Fe and Mn), Algonquin (mafic-ultramafic igneous sequence), Barnhill (volcaniclastic sediments enriched in Zn, Cl, and Ge), Fuzzy Smith (high Si and Ti rock), Elizabeth Mahon (high Si, Ni, and Zn outcrop and rock), Halley (hematite-rich outcrop and rock), Montalva (high K, hematite-rich rock), Everett (high Mg, magnetite-rich rock), Good Question (high Si, low Mn rock), and Torquas (high K, Zn, and Ni magnetite-rich rock). New soil classes are Gertrude Weise (very high Si soil) and Eileen Dean (high Mg, magnetite-rich soil). Aqueous processes have played a major role in the formation and alteration of rocks and soils on Husband Hill and in the Inner Basin

Public involvement in the governance of population-level biomedical research: unresolved questions and future directions.

Population-level biomedical research offers new opportunities to improve population health, but also raises new challenges to traditional systems of research governance and ethical oversight. Partly in response to these challenges, various models of public involvement in research are being introduced. Yet, the ways in which public involvement should meet governance challenges are not well understood. We conducted a qualitative study with 36 experts and stakeholders using the World Café method to identify key governance challenges and explore how public involvement can meet these challenges. This brief report discusses four cross-cutting themes from the study: the need to move beyond individual consent; issues in benefit and data sharing; the challenge of delineating and understanding publics; and the goal of clarifying justifications for public involvement. The report aims to provide a starting point for making sense of the relationship between public involvement and the governance of population-level biomedical research, showing connections, potential solutions and issues arising at their intersection. We suggest that, in population-level biomedical research, there is a pressing need for a shift away from conventional governance frameworks focused on the individual and towards a focus on collectives, as well as to foreground ethical issues around social justice and develop ways to address cultural diversity, value pluralism and competing stakeholder interests. There are many unresolved questions around how this shift could be realised, but these unresolved questions should form the basis for developing justificatory accounts and frameworks for suitable collective models of public involvement in population-level biomedical research governance