Activity

No Abstract available.

Crohn’s disease (CD) patients who previously failed anti-tumor necrosis factor (TNF) therapy are at higher risk of treatment failure with subsequent biologics. This study aims to determine the effectiveness and safety of higher maintenance dose regimens of adalimumab compared with standard doses in CD patients who failed anti-TNF.

In this retrospective observational study, CD patients who failed anti-TNF and received adalimumab were categorized according to their post-induction maintenance regimen; 40mg subcutaneous (sc) weekly or 80mg sc every other week were defined as a high-dose (HD) maintenance regimen, and 40mg sc every other week was defined as a standard-dose (SD) maintenance regimen. The primary outcome was time to treatment failure. Cox proportional hazards regression was used to adjust for confounders. Sensitivity analysis was conducted using propensity scores to create a cohort of matched participants with similar distribution of baseline covariates.

Forty patients started on HD regimens following induction, and 77 patients received the SD regimen. The median time to failure in the HD group was 6.6years (interquartile range [IQR] 4.0-9.6) and 3.0years (IQR 0.9-9.4) in the SD group (log-rank test P=0.006). Patients on HD adalimumab had a lower hazard rate of treatment failure (hazard ratio 0.27; 95% confidence interval [0.12, 0.62]; P=0.002) compared with SD patients. No difference in adverse events was identified between groups (30% vs 31.2%, P=1.0). Results were similar in the propensity score-matched cohort.

High-dose maintenance regimens were associated with longer time-to-failure as compared with SD regimens in CD patient who failed anti-TNF.

High-dose maintenance regimens were associated with longer time-to-failure as compared with SD regimens in CD patient who failed anti-TNF.

To explore the safety, tolerability, pharmacokinetics and pharmacodynamics (PD) of GSK2646264 using skin challenge models.

Healthy volunteers (HV) with a positive allergen skin prick test received GSK2646264 (0.5% or 1% ww) and placebo creams on up to 10% body surface area (BSA). Cold (ColdU) or chronic spontaneous (CSU) urticaria patients received 1% GSK2646264 or placebo on up to 10% BSA. PD assessments included weal characteristics after skin allergen challenge, critical temperature threshold (CTT) in ColdU patients and defined area urticaria activity score in CSU patients.

Thirty-four patients were randomised (17 HV, 12 ColdU, 5 CSU). Topical application of GSK2646264 and placebo was well tolerated. Systemic pharmacokinetics (AUC [0-24] h*ng/mL) was similar between HVs (Geomean 97.9 [%CV 37]) and ColdU patients (Geomean 68.2 [%CV 14; 3.5% BSA] or 167 [%CV 120; 10% BSA]). Whilst in HVs a similar reduction in skin allergen challenge weal area was observed following 3 applications of GSK2646264 and placebo, a trend towards a greater reduction was seen in ColdU with GSK2646264 compared to placebo. A clinically meaningful reduction in CTT, in ColdU patients treated with GSK2646264, was observed in 4 of 9 patients, who demonstrated either a complete inhibition of ColdU to ≤4°C (n =2) or partial response (reduction by >4°C, n =2). Due to the small number of CSU patients recruited, no meaningful conclusions could be drawn from the defined area urticaria activity score PD endpoint.

This Phase 1/1b study confirms that GSK2646264 cream applied topically penetrates the skin and some reduction in CTT was observed. (NCT02424799).

This Phase 1/1b study confirms that GSK2646264 cream applied topically penetrates the skin and some reduction in CTT was observed. (NCT02424799).This study synthesized current research on the relationships between type of insurance and emergency department usage for children with asthma in the United States. Thematic analysis is in the context of the Affordable Care Act (ACA). A systematic mapping review yielded 20 articles published in the last 10 years on topics of insurance, emergency department usage, and pediatric asthma. Analysis indicates continued trends of increased emergency department use among asthmatic children since enactment of the ACA, running counter to the goal of fiscal efficiency for the healthcare system and reduction of health inequities. Barriers to care persist, particularly among communities of color, despite provisions to improve access to primary and preventive care. Inadequate access to primary care is associated with poor adherence among asthmatic children with public insurance. Those with health insurance through their parents’ employer experience barriers due to cost-sharing expenses. This leads to increased asthma severity and low medication adherence, resulting in the need for emergency care. A disconnect between increased health insurance coverage and utilization of primary care in some populations implies unmet service needs that warrant further investigation. Findings inform policymakers and public health leaders of persistent health inequities resulting in preventable emergency department usage.Translational repression is a conserved mechanism in microRNA (miRNA)-guided gene silencing. In Arabidopsis, ARGONAUTE1 (AGO1), the major miRNA effector, localizes in the cytoplasm for mRNA cleavage and at the endoplasmic reticulum (ER) for translational repression of target genes. However, the mechanism underlying miRNA-mediated translational repression is poorly understood. In particular, how the subcellular partitioning of AGO1 is regulated is largely unexplored. Here, we show that the plant hormone brassinosteroids (BRs) inhibit miRNA-mediated translational repression by negatively regulating the distribution of AGO1 at the ER in Arabidopsis thaliana. We show that the protein levels rather than the transcript levels of miRNA target genes were reduced in BR-deficient mutants but increased under BR treatments. The localization of AGO1 at the ER was significantly decreased under BR treatments while it was increased in the BR-deficient mutants. Moreover, ROTUNDIFOLIA3 (ROT3), an enzyme involved in BR biosynthesis, co-localizes with AGO1 at the ER and interacts with AGO1 in a GW motif-dependent manner. Complementation analysis showed that the AGO1-ROT3 interaction is necessary for the function of ROT3. GSK2110183 Our findings provide new clues to understand how miRNA-mediated gene silencing is regulated by plant endogenous hormones.