Search

Chronic urticaria (CU) is characterized by weals (hives) angio-oedema (or both) that last for ≥ 6 weeks, with chronic spontaneous urticaria (CSU) being the most common subtype. Patients with omalizumab-refractory CSU represent an unmet clinical need. In this study, we aimed to assess the prevalence and predictors of omalizumab failure in a large cohort of patients with CU and assess the effectiveness of dupilumab for omalizumab-refractory CU. Of 338 patients with CU, 33 received omalizumab; 69.7% (n = 23) were responders and 30.3% (n = 10) were nonresponders. Bivariate regression demonstrated that female sex [adjusted odds ratio (aOR) 1.53, 95% confidence interval (CI) 1.14-2.06], higher baseline weekly urticaria activity score (aOR 1.05, 95% CI 1.01-1.09) and older age (controlling for sex) (aOR 1.00, 95% CI 1.00-1.01) were associated with omalizumab failure. Of 10 patients with omalizumab-refractory CU, 3 were well controlled with ciclosporin (all children), whereas the 7 adults failed a mean [standard deviation (SD)] of 5.6 (2.6) treatments, including ciclosporin. All seven achieved a complete response with dupilumab, with time to response varying between 1 and 6 months. While our results suggest a favourable efficacy of dupilumab in patients with omalizumab-refractory CU, future confirmatory studies are required., Competing Interests: Conflicts of interest EN has been a speaker or consultant, or has received investigator-initiated research funding from AbbVie, Arcutis, Bausch Health, Boehringer Ingelheim International, Bristol Myers Squibb, Galderma, Janssen, LEO Pharma, Medexus, Novartis Pharmaceuticals, Pfizer, Sanofi Genzyme, Sun Pharmaceuticals, Eli Lilly and UCB. EN is the founder of Montreal Derm FilEZ website, which is a non-profit educational resource. M.B.-S. is a consultant for Novartis and Sanofi. The other authors declare no conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Association of Dermatologists.)

Objective: Implementation of machine learning (ML) may be limited by patients' right to "meaningful information about the logic involved" when ML influences healthcare decisions. Given the complexity of healthcare decisions, it is likely that ML outputs will need to be understood and trusted by physicians, and then explained to patients. We therefore investigated the association between physician understanding of ML outputs, their ability to explain these to patients, and their willingness to trust the ML outputs, using various ML explainability methods., Materials and Methods: We designed a survey for physicians with a diagnostic dilemma that could be resolved by an ML risk calculator. Physicians were asked to rate their understanding, explainability, and trust in response to 3 different ML outputs. One ML output had no explanation of its logic (the control) and 2 ML outputs used different model-agnostic explainability methods. The relationships among understanding, explainability, and trust were assessed using Cochran-Mantel-Haenszel tests of association., Results: The survey was sent to 1315 physicians, and 170 (13%) provided completed surveys. There were significant associations between physician understanding and explainability (P < .001), between physician understanding and trust (P < .001), and between explainability and trust (P < .001). ML outputs that used model-agnostic explainability methods were preferred by 88% of physicians when compared with the control condition; however, no particular ML explainability method had a greater influence on intended physician behavior., Conclusions: Physician understanding, explainability, and trust in ML risk calculators are related. Physicians preferred ML outputs accompanied by model-agnostic explanations but the explainability method did not alter intended physician behavior., (© The Author(s) 2020. Published by Oxford University Press on behalf of the American Medical Informatics Association. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

The development of significant mechanisms of resistance to beta-lactam antibiotics in Pseudomonas aeruginosa in cystic fibrosis (CF) patients have been studied in ten CF patients during a two week course of anti-pseudomonal beta-lactam antibiotic therapy. Sputum samples were collected on days 1, 7 and 15. Entire homogenized sputum samples were examined directly for the number of bacteria resistant to different levels of antibiotics. This allowed the detection of pre-existing resistant subpopulations of bacteria as well as following the changes in beta-lactam antibiotic susceptibility during treatment. P. aeruginosa isolates were characterized by means of sero-grouping, phage- and pyocin-typing. Outer membrane proteins of paired sensitive and resistant strains were characterized. Sonicated extracts of cells were assayed for basal and induced beta-lactamase activity. Beta-lactamase activity was further characterized by isoelectric focusing and inhibition profiles. Our observations were in accordance with the hypothesis that the sensitive inducible population was overrun by the pre-existing resistant subpopulation, during treatment. The resistant in-vivo selected P. aeruginosa population exhibited stable partially derepression but the beta-lactamase inhibitor tazobactam restored beta-lactam antibiotic activity.

Pseudomonas aeruginosa strain PA01, which is normally sensitive to 10 units/ml of polymyxin, was adapted in eight successive steps to be resistant to polymyxin at 6000 units/ml. The polymyxin-resistant variant was very sensitive to all other antibiotics with which it was challenged, including hydrophobic antibiotics such as erythromycin. This increased sensitivity implies that the acquired polymyxin resistance had disrupted the permeability barrier of the outer membrane. Changes in the outer membrane protein profile of PA01 were studied at each adaption step using sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE). At the third step (resistant to 80 units/ml) protein H1 was absent. At succeeding steps up to 6000 units/ml of polymyxin, protein H1 was still absent and the levels of OM proteins D, E, F (major porin) and G were all considerably reduced compared with the wild type. Overproduction of protein H1 by wild type P. aeruginosa under conditions of magnesium depletion has been proposed as a mechanism to explain polymyxin resistance. However, protein H1 remained absent from the outer membrane of the polymyxin-resistant variants even under magnesium depletion. Furthermore, protein H1 could not be induced by magnesium depletion when the resistant variant was repeatedly grown in concentrations of polymyxin as low as 10 units/ml yet, at this low concentration, the variant retained its resistance to 6000 units/ml. These observations make it unlikely that induction of protein H1 alone is a mechanism of polymyxin resistance in P. aeruginosa.