Phase 1 trial supports safety and mechanism of action of peptide immunotherapy for peanut allergy.

BACKGROUND: Food allergy is a leading cause of anaphylaxis worldwide. Allergen-specific immunotherapy is the only treatment shown to modify the natural history of allergic disease, but application to food allergy has been hindered by risk of severe allergic reactions and short-lived efficacy. Allergen-derived peptides could provide a solution. PVX108 comprises seven short peptides representing immunodominant T-cell epitopes of major peanut allergens for treatment of peanut allergy. METHODS: Pre-clinical safety of PVX108 was assessed using ex vivo basophil activation tests (n = 185). Clinical safety and tolerability of single and repeat PVX108 doses were evaluated in a first-in-human, randomized, double-blind, placebo-controlled trial in peanut-allergic adults (46 active, 21 placebo). The repeat-dose cohort received six doses over 16 weeks with safety monitored to 21 weeks. Exploratory immunological analyses were performed at pre-dose, Week 21 and Month 18 after treatment. RESULTS: PVX108 induced negligible activation of peanut-sensitised basophils. PVX108 was safe and well tolerated in peanut-allergic adults. There were no treatment-related hypersensitivity events or AEs of clinical concern. The only events occurring more frequently in active than placebo were mild injection site reactions. Exploratory immunological analyses revealed a decrease in the ratio of ST2+ Th2A:CCR6+ Th17-like cells within the peanut-reactive Th pool which strengthened following treatment. CONCLUSION: This study supports the concept that PVX108 could provide a safe alternative to whole peanut immunotherapies and provides evidence of durable peanut-specific T-cell modulation. Translation of these findings to clinical efficacy in ongoing Phase 2 trials would provide important proof-of-concept for using peptides to treat food allergy.

Therapist perceptions of barriers to telehealth uptake in children's occupational therapy.

INTRODUCTION: The COVID-19 pandemic resulted in a rapid shift to telehealth implementation across paediatric occupational therapy services. Although telehealth can be an appealing option, access is conditional, and the delivery of a telehealth service differs from face-to-face. If telehealth is to be a viable and equitable option for families, insight is needed into why the service might be declined. The purpose of our study was to explore barriers to paediatric occupational therapy telehealth services from client and therapist perspectives in a Greater Sydney local health district. METHOD: A mixed method approach was used, including (i) retrospective review of clinical records for 250 clients seeking occupational therapy who declined the service and (ii) a focus group with four therapists providing the service. Client demographic information was summarised using descriptive statistics. Open-text responses about reasons for declining telehealth were analysed using qualitative content analysis, whereas thematic analysis was used to explore focus group data. FINDINGS: Key findings from the mixed methods analysis identified barriers and issues to consider when working to ensure equitable access to telehealth for children and families. These issues included child engagement, family complexity, the nature of assessments, interventions, and overarching service characteristics as well as the family's digital inclusion. Digital inclusion comprises affordable access to the internet, data, and devices and the capacity of a child and/or family to engage online. CONCLUSION: Our findings suggest that telehealth is not a panacea when face-to-face services are not available. Multiple barriers confounded uptake of telehealth prompting a call to action to ensure equitable access to occupational therapy services for all children.

The Influence of Heavier Football Helmet Faceguards on Head Impact Location and Severity.

OBJECTIVE: To determine whether players with heavier faceguards have increased odds of sustaining top of the head impacts and head impacts of higher severity. DESIGN: Cohort study. SETTING: On-field. PARTICIPANTS: Thirty-five division I collegiate football players. INTERVENTIONS: Faceguard mass was measured. Head impact location and severity (linear acceleration [gravity], rotational acceleration [radian per square second], and Head Impact Technology severity profile [unitless]) were captured for 19 379 total head impacts at practices using the Head Impact Telemetry System. MAIN OUTCOME MEASURES: Players' faceguards were categorized as either heavier (>480 g) or lighter (≤480 g) using a median split. Odds ratios (ORs) and 95% confidence intervals (CIs) were computed for sustaining top of the head impacts between faceguard groups using a random intercepts generalized logit model. We compared head impact severity between groups using random intercepts general linear models (α = 0.05). Player position was included in all models. RESULTS: Overall, the 4 head impact locations were equally distributed across faceguard groups (F(3,26) = 2.16, P = 0.117). Football players with heavier faceguards sustained a higher proportion impacts to the top of the head (24.7% vs 17.5%) and had slightly increased odds of sustaining top (OR, 1.72; 95% CI, 1.01-2.94) head impacts rather than front of the head impacts. CONCLUSIONS: Football players wearing heavier faceguards might be slightly more prone to sustaining a higher proportion of top of the head impacts, suggesting that greater faceguard mass may make players more likely to lower their head before collision. Individuals involved with equipment selection should consider the potential influence of faceguard design on head impact biomechanics when recommending the use of a heavier faceguard.

Secretion and proteolysis of heterologous proteins fused to the Escherichia coli maltose binding protein in Pichia pastoris.

The Escherichia coli maltose binding protein (MBP) has been utilized as a translational fusion partner to improve the expression of foreign proteins made in E. coli. When located N-terminal to its cargo protein, MBP increases the solubility of intracellular proteins and improves the export of secreted proteins in bacterial systems. We initially explored whether MBP would have the same effect in the methylotrophic yeast Pichia pastoris, a popular eukaryotic host for heterologous protein expression. When MBP was fused as an N-terminal partner to several C-terminal cargo proteins expressed in this yeast, proteolysis occurred between the two peptides, and MBP reached the extracellular region unattached to its cargo. However, in two of three instances, the cargo protein reached the extracellular region as well, and its initial attachment to MBP enhanced its secretion from the cell. Extensive mutagenesis of the spacer region between MBP and its C-terminal cargo protein could not inhibit the cleavage although it did cause changes in the protease target sites in the fusion proteins, as determined by mass spectrometry. Taken together, these results suggested that an uncharacterized P. pastoris protease attacked at different locations in the region C-terminal of the MBP domain, including the spacer and cargo regions, but the MBP domain could still act to enhance the secretion of certain cargo proteins.