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Abstract Obesity over‐activates the classical arm of the renin‐angiotensin system (RAS), impairing skeletal muscle remodeling. We aimed to compare the effect of exercise training and enalapril, an angiotensin‐converting enzyme inhibitor, on RAS modulation in the skeletal muscle of obese animals. Thus, we divided C57BL/6 mice into two groups: standard chow (SC) and high‐fat (HF) diet for 16 weeks. At the eighth week, the HF‐fed animals were divided into four subgroups—sedentary (HF), treated with enalapril (HF‐E), exercise training protocol (HF‐T), and combined interventions (HF‐ET). After 8 weeks of treatment, we evaluated body mass and index (BMI), body composition, exercise capacity, muscle morphology, and skeletal muscle molecular markers. All interventions resulted in lower BMI and attenuation of overactivation in the classical arm, while favoring the B2R in the bradykinin receptors profile. This was associated with reduced apoptosis markers in obese skeletal muscles. The HF‐T group showed an increase in muscle mass and expression of biosynthesis markers and a reduction in expression of degradation markers and muscle fiber atrophy due to obesity. These findings suggest that the combination intervention did not have a synergistic effect against obesity‐induced muscle remodeling. Additionally, the use of enalapril impaired muscle's physiological adaptations to exercise training.

Abstract Background Determination of control level in recurrent angioedema (RAE) is necessary to guide management. Here, we validated a Turkish version of the angioedema control test (AECT) for 4‐week (AECT‐4wk) and for 3‐month (AECT‐3mth) and assessed their utility in monitoring RAE. Method The recommended structured translation process for patient‐reported outcome measures was completed. The final versions were administered to 51 patients with mast cell‐mediated angioedema (MMAE) and 38 patients with hereditary angioedema, and the minimal clinically important difference (MCID) was determined. Additionally, anchor surveys comprising angioedema activity score for 28 days (AAS‐28 day), visual analog score for angioedema control, Likert scale for the control level from the patient's perspective (LS‐AEC), angioedema quality of life, short form‐12 (SF‐12) and patients' assessment of treatment sufficiency were applied. Results The Turkish AECT versions showed good convergent validity with a substantial correlation with anchor tools and known‐group validity. Excellent internal consistency and reproducibility were observed. Equal or more than 10 of 16 points scored with the AECT‐4wk and AECT‐3mth identified patients with well‐controlled disease. The disease activity, control and burden parameters were consistent with the disease control level defined depending on the cut‐off point 10 of AECT. Three‐point changes in AECT‐4wk and ‐3 mt could detect MCID in disease control in all patients. Conclusions Turkish AECT versions are valid and reliable tools for assessing and monitoring disease control in patients with RAE. The use of the Turkish versions of the AECT in routine patient care, clinical trials and angioedema research is recommended.

Abstract Background Although there have been significant advances in the treatment of chronic spontaneous urticaria (CSU) in recent years, there remains a lack of clear guidance on when and how to step down treatment in responders. This study aims to investigate stepping down approaches of different steps of CSU treatment from a global perspective. Methods “Stepping down chronic spontaneous urticaria treatment” (SDown‐CSU) is an international, multicenter, observational, cross‐sectional, survey‐based study of the Urticaria Centers of Reference and Excellence (UCARE) network. The questionnaire included 48 questions completed by physicians in the UCARE network. Results Surveys completed by 103 physicians from 81 UCAREs and 34 countries were analyzed. Seventy‐eight percent of the participants responded that they had a national urticaria management guideline written by their professional societies and 28% responded that they had to operate under a regulatory guideline proposed by central health funding organizations. Seventy‐two and 58.7% of these national recommendations do not contain any detailed information on when and/or how CSU treatment should be discontinued. There was a lack of detailed information on antihistamines and cyclosporine in particular. A predefined maximum duration was generally not applicable to omalizumab and cyclosporine (81% and 82%, respectively). Nearly all UCAREs step down omalizumab within 6 months from the first controlled status and 42% discontinue cyclosporine after 6 months regardless of the control status. Conclusions The findings from the SDown‐CSU study clearly highlight a global need for guidance on the process of stepping down treatment in CSU. Additionally, the study offers a step‐down algorithm applicable to all stages of CSU treatment.

Abstract Background Colorectal cancer (CRC) screening can help to reduce its incidence and mortality. Noninvasive strategies, such as plasma analysis of epigenetic alterations, can constitute important biomarkers of CRC detection. Objective This study aimed to evaluate the plasma methylation status of SEPT9 and BMP3 promoters as biomarkers for detection of CRC and its precursor lesions in a Brazilian population. Methods Plasma samples from 262 participants of the CRC screening program of Barretos Cancer Hospital who had a positive fecal occult blood test and underwent colonoscopy and cancer patients were analyzed. Participants were grouped according to the worst lesion detected in the colonoscopy. Cell‐free circulating DNA (cfDNA) was bisulfite treated followed by the analysis of SEPT9 and BMP3 methylation status using a droplet digital PCR system (ddPCR). The best methylation cutoff value for group discrimination was calculated by receiver operating characteristic (ROC) curve analysis. Results Among the 262 participants, 38 were diagnosed with CRC, 46 with advanced adenomas 119 with nonadvanced adenomas, three with sessile serrated lesions, and 13 with hyperplastic polyps. In 43 participants, no lesion was detected in the colonoscopy and were used as controls. The CRC group showed the highest cfDNA concentration (10.4 ng/mL). For the SEPT9 gene, a cutoff of 2.5% (AUC = 0.681) that discriminates between CRC and the control group resulted in CRC sensitivity and specificity of 50% and 90%, respectively. Concerning the BMP3 gene, a cutoff of 2.3% (AUC = 0.576) showed 40% and 90% of sensitivity and specificity for CRC detection, respectively. Combining SEPT9, BMP3 status, and age over 60 years resulted in a better performance for detecting CRC (AUC = 0.845) than the individual gene models, yielding 80% and 81% of sensitivity and specificity, respectively. Conclusion The present study suggests that a combination of SEPT9 and BMP3 plasma methylation, along with age over 60 years, showed the highest performance in detecting CRC in a Brazilian population. These noninvasive biomarkers can potentially serve as useful tools for CRC screening programs.

Traditionally, the treatment of inflammatory conditions has focused on the inhibition of inflammatory mediator production; however, many conditions are refractory to this classical approach. Recently, an alternative has been presented by researchers to solve this problem: The immunomodulation of cells closely related to inflammation. Hence, macrophages, a critical key in both innate and acquired immunity, have been presented as an alternative target for the development of new medicines. In this work, we tested the fluorophenyl-imidazole for its anti-inflammatory activity and possible immunomodulatory effect on RAW 264.7 macrophages. We also evaluated the anti-inflammatory effect of the compound, and the macrophage repolarization to M2 was confirmed by the ability of the compound to reduce the M1 markers TNF-α, IL-6, MCP-1, IL-12p70, IFN-γ, and TLR4, the high levels of p65 phosphorylated, iNOS and COX-2 mRNA expression, and the fact that the compound was not able to induce the production of M1 markers when used in macrophages without lipopolysaccharide (LPS) stimulation. Moreover, fluorophenyl-imidazole had the ability to increase the M2 markers IL-4, IL-13, CD206, apoptosis and phagocytosis levels, arginase-1, and FIZZ-1 mRNA expression before LPS stimulation. Similarly, it was also able to induce the production of these same M2 markers in macrophages without being induced with LPS. These results reinforce the affirmation that the fluorophenyl-imidazole has an important anti-inflammatory effect and demonstrates that this effect is due to immunomodulatory activity, having the ability to trigger a repolarization of macrophages from M1 to M2a. These facts suggest that this molecule could be used as an alternative scaffold for the development of a new medicine to treat inflammatory conditions, where the anti-inflammatory and proregenerative properties of M2a macrophages are desired.

Abstract Background Urticarial vasculitis (UV) should be differentiated from chronic spontaneous urticaria (CSU) in patients initially presenting with recurrent wheals, although criteria for differential diagnosis remain ill‐defined. Objectives To set the goals, define criteria and unmet needs in UV diagnosis and differential diagnosis with CSU, and explore the possibility of coexistence of both diseases. Methods Thirteen experts experienced in UV research participated in a Delphi survey of European Academy of Allergy and Clinical Immunology taskforce. This Delphi survey involved three rounds of anonymous responses to n = 32 questions with the aim to aggregate the experts' opinions and to achieve consensus. Urticaria specialists (n = 130, most from Urticaria Centers of Reference and Excellence) evaluated the consensus statements and recommendations in the fourth and final round. Results The panel agreed that essential criteria to guide a skin biopsy in patients with recurrent wheals should include at least one of the following features: wheal duration >24 h, bruising/postinflammatory hyperpigmentation, and systemic symptoms. Leukocytoclasia and fibrin deposits were identified as a minimum set of UV histological criteria. As agreed by the panel members, CSU and normocomplementemic UV (NUV) may coexist in some patients. Conclusions The use of established criteria for the diagnosis and differential diagnosis of UV in patients with recurrent wheals can help guide the diagnostic approach and prompt earlier treatment. Further studies should investigate whether CSU and NUV are different entities or part of a disease spectrum.

Abstract Background The Angioedema Control Test (AECT) is a patient‐reported outcome measure developed and validated for the assessment of disease control in patients with recurrent angioedema. Its sensitivity to change and minimal clinically important difference (MCID) have hitherto not been established. Methods Patients with recurrent angioedema due to chronic spontaneous urticaria, hereditary angioedema, or acquired C1‐inhibitor deficiency were repeatedly asked to complete the AECT along with the Angioedema Quality of Life Questionnaire (AE‐QoL), Dermatology Life Quality Index (DLQI), and anchors for disease control and whether treatment was sufficient during routine care visits. The sensitivity to the change of the AECT was determined by correlating changes in its scores over time with changes in the applied anchors. The MCID was determined using anchor‐based and distributional criterion‐based approaches. Results Eighty‐six cases were used for this analysis. Changes in AECT scores correlated well with AE‐QoL changes (but less with changes in the DLQI) as well as other applied anchors, demonstrating its sensitivity to change. The MCID was found to be three points for improvement of angioedema control. The available number of cases with meaningful deterioration in our dataset was too low to reach a definite conclusion on the MCID for deterioration of angioedema control. Conclusion The AECT is a valuable tool to assess changes in disease control in patients with recurrent angioedema over time. The lowest AECT score change that reflects a meaningful improvement of disease control to patients (MCID) is three points.

Abstract Background Hereditary angioedema (HAE) with C1‐inhibitor deficiency (HAE‐C1‐INH) is characterized by recurrent, debilitating episodes of swelling. Sebetralstat, an investigational oral plasma kallikrein inhibitor, demonstrated promising efficacy for on‐demand treatment of HAE‐C1‐INH in a phase 2 trial. We describe the multipronged approach informing the design of KONFIDENT, a phase 3 randomized, placebo‐controlled, three‐way crossover trial evaluating the efficacy and safety of sebetralstat in patients aged ≥12 years with HAE‐C1‐INH. Methods To determine an optimal endpoint to measure the beginning of symptom relief in KONFIDENT, we engaged patients with HAE on clinical outcome measures and subsequently conducted analyses of phase 2 outcomes. Sample size was determined via a simulation‐based approach using phase 2 data. Results Patient interviews revealed a strong preference (71%) for the Patient Global Impression of Change (PGI‐C) over other measures and indicated a rating of “A Little Better” as a clinically meaningful milestone. In phase 2, a rating of “A Little Better” demonstrated agreement with attack severity improvement and resolution on the Patient Global Impression of Severity and had better sensitivity than “Better.” Simulations indicated that 84 patients completing treatment would ensure at least 90% power for assessing the primary endpoint of time to beginning of symptom relief defined as a PGI‐C rating of at least “A Little Better” for two time points in a row. Conclusions Patient feedback and phase 2 data support PGI‐C as the primary outcome measure in the phase 3 KONFIDENT trial evaluating sebetralstat, which has the potential to be the first oral on‐demand treatment for HAE‐C1‐INH attacks.

Abstract Background The coronavirus disease pandemic and its containing measures have caused concerns for patients with hereditary angioedema (HAE) and their treating physicians. Both faced challenges surrounding interaction, and communication had to adapt to facilitate appropriate management. Specifically, the pandemic resulted in reduced in‐person contact in clinics. Where possible, telemedicine appointments were offered and treatment outside the hospital setting was encouraged. Body The pandemic markedly affected patient‐physician communication, which is essential to maintain partnerships and optimize care. Although patients with HAE are often experts in their condition, guidance by their physicians is essential, especially with the recent shift toward patient‐centered management for rare diseases and shared decision‐making (SDM). SDM enables patients to take control of their disease and allows the risks and benefits of treatment to be discussed with their physicians. This review explores perspectives from patients and physicians in the HAE clinical setting, particularly regarding their experiences with communication throughout the pandemic. We discuss the importance of SDM in rare diseases such as HAE, factors that impact effective communication, and potential solutions. Conclusion Since patient‐centered care and SDM have particular relevance in rare diseases in general, we believe our findings could be transferrable and applicable in the management of other rare diseases.

Abstract Background Chronic spontaneous urticaria (CSU) is a common and disabling disease. Assessments of IgE and C‐reactive protein (CRP) are recommended in the diagnostic work‐up, but the role and clinical relevance of these biomarkers are not well characterized. Moreover, it remains unknown if elevated levels of IgE or CRP are linked to CSU microRNA (miRNA) signatures or interleukin 31 (IL‐31). Methods We measured IgE and CRP serum levels in 47 CSU patients (and 45 healthy controls) and determined CSU disease activity using the urticaria activity score (UAS7). Expression levels of miR‐155 and miR‐221 were assessed by RT‐PCR, and IL‐31 levels were determined by ELISA. Results Total IgE and CRP levels were independently increased in CSU patients. IgE and CRP levels were highest and lowest in patients with high and mild disease activity. IgE levels correlated with miR‐155 levels, whereas CRP levels correlated with miR‐221 levels. miR‐155 and miR‐221 were significantly overexpressed in CSU patients. ROC analyses linked miRNA‐155 and CSU with a sensitivity of 79% and specificity of 87%, and miRNA‐221 and CSU with a sensitivity of 75% and specificity of 91%. High CRP and miR‐221 expression levels were linked to elevated levels of IgG anti‐TPO and IL‐31. Conclusion IgE and CRP are useful biomarkers for disease activity in CSU, with distinct miRNA profiles. High CRP and miR‐221 levels may point to autoimmune CSU and a role for IL‐31.

Abstract In an urban built city environment, the performance of electromagnetic (EM) wave propagation through building materials poses a new set of challenges to radio frequency engineers in the prediction of the 5G‐network coverage planning. We propose the prospects on the use of composite building materials enhanced with different volumetric fractions of iron (III) oxide (Fe2O3) inclusions as a reddish‐brown colouring admixture in modern‐day concrete. Using a non‐destructive microwave measurement technique, a two‐factor 6 × 10 factorial experiment and a randomized controlled statistical study from 3.40 to 3.60 GHz is conducted on 15‐cm thick building material prototypes enhanced with 2‐wt% to 10‐wt% micro‐sized Fe2O3 inclusions to evaluate their efficacy on EM wave propagation. Transmission coefficients (S21) data are analysed statistically between treatment and control groups, yielding up to 2.28 dB mean S21 improvement in performance and a fractional bandwidth of 100% by the 2‐wt% Fe2O3 treatment group. Electromagnetic characterisations of the fabricated mortar samples with different Fe2O3 inclusions are performed using Nicholson‐Ross‐Weir model followed by the evaluation of dielectric and propagation losses. Our findings support the use of 2‐wt% Fe2O3 as the optimal volumetric fraction which improves the microwave transparency, thus creating potential EM benefits for the fifth‐generation (5G) wireless communication systems.

Abstract Background Cold urticaria (ColdU) is characterized by pruritic wheals following exposure of the skin to cold. Many patients show insufficient response to antihistamines, the first line treatment. Based on the high efficacy of interleukin‐1(IL‐1)‐inhibition in cold‐induced urticarial autoinflammatory diseases, we assessed the effects of rilonacept, an IL‐1 inhibitor, in ColdU patients unresponsive to standard treatment. Methods In this randomized, double‐blind, placebo‐controlled two‐center study, we included 20 patients with ColdU. In the first part, patients received 320 mg rilonacept or placebo (1:1) followed by weekly doses of 160 mg rilonacept or placebo for 6 weeks. In the second part, all patients received weekly 160 mg or 320 mg rilonacept for 6 weeks, open‐label. The primary endpoint was change in critical temperature threshold (CTT). Secondary endpoints included changes in quality of life impairment (Dermatology Life Quality Index, DLQI), differences of inflammatory mediators upon cold provocation and safety assessment over the study period. Results Baseline mean CTTs were 20.2°C (placebo) and 17.3°C (rilonacept). Mean CTTs did not change significantly during the 6‐week double‐blind treatment (placebo – 0.45°C; rilonacept +0.89°C). IL‐6, IL‐18 and HSP‐70 blood levels showed interindividual variability without significant changes during hand cold water bath provocation in placebo‐ or rilonacept‐treated patients. In contrast, DLQI significantly improved in the rilonacept (mean DLQI reduction of 3.8; p = 0.002) but not in the placebo group (mean DLQI reduction of 0). Comparing baseline with the rilonacept open‐label treatment, there were no changes in CTTs or DLQI scores. Conclusion IL‐1 inhibition with rilonacept did not improve ColdU, but demonstrated a good safety profile. Clinical Trial Registration EudraCT number: 2012‐005726‐30. ClinicalTrials.gov identifier: NCT02171416.

Abstract Background IgE‐mediated food allergy is the result of an aberrant immune response involving the interaction of a food allergen with its specific IgE bound to FcɛRI, the high affinity IgE receptor, on mast cells. Allergen‐specific IgE also binds to soluble binding factors, but, their expression and role in food allergy is not well characterized. Here, we assess the prevalence and relevance of soluble IgE binding factors in food allergy and tolerance. Methods We measured serum levels of four IgE binding factors, that is, galectin‐3, galectin‐9, soluble FcɛRI (sFcεRI) and soluble CD23 (sCD23) in 67 adults sensitized to peanut or hazelnut and sFcɛRI in 29 children sensitized to hen's egg. Adults without food allergen sensitization (n = 17) served as healthy controls. We compared serum levels of patients and controls and assessed them, in the former, for links to clinical features including allergy and tolerance. Results Serum levels of sFcɛRI and sCD23, but not galectin‐3 and galectin‐9, significantly differ in food‐sensitized patients as compared to healthy controls. A subgroup (28%) of peanut and hazelnut allergic patients had elevated sFcεRI levels, that were associated with higher total and specific IgE levels. Furthermore, sFcεRI levels were significantly higher in tolerant subjects compared to allergics. Among hazelnut allergic patients, those with high sFcεRI levels tolerated the highest protein amounts in the oral food challenge. Conclusion sFcɛRI but not sCD23, galectin‐3 and galectin‐9 might play a role in the pathophysiology of food allergy. Its functional role or use as biomarker should be assessed in further studies.

Abstract MASK‐air®, a validated mHealth app (Medical Device regulation Class IIa) has enabled large observational implementation studies in over 58,000 people with allergic rhinitis and/or asthma. It can help to address unmet patient needs in rhinitis and asthma care. MASK‐air® is a Good Practice of DG Santé on digitally‐enabled, patient‐centred care. It is also a candidate Good Practice of OECD (Organisation for Economic Co‐operation and Development). MASK‐air® data has enabled novel phenotype discovery and characterisation, as well as novel insights into the management of allergic rhinitis. MASK‐air® data show that most rhinitis patients (i) are not adherent and do not follow guidelines, (ii) use as‐needed treatment, (iii) do not take medication when they are well, (iv) increase their treatment based on symptoms and (v) do not use the recommended treatment. The data also show that control (symptoms, work productivity, educational performance) is not always improved by medications. A combined symptom‐medication score (ARIA‐EAACI‐CSMS) has been validated for clinical practice and trials. The implications of the novel MASK‐air® results should lead to change management in rhinitis and asthma.

Abstract Background CT‐P39 is being developed as a biosimilar of reference omalizumab. This study aimed to assess the pharmacokinetic equivalence of CT‐P39 to European Union‐approved and United States‐licensed reference omalizumab (EU‐ and US‐omalizumab, respectively). Methods This two‐part, randomised, parallel‐group, double‐blind Phase 1 trial (NCT04018313) was conducted in healthy individuals with a total immunoglobulin E (IgE) level ≤100 international units (IU)/ml at screening. In part 2, described herein, participants were randomised (1:1:1) to receive a single 150 mg subcutaneous dose of CT‐P39, EU‐omalizumab, or US‐omalizumab. The primary endpoint was pharmacokinetic equivalence in terms of area under the concentration–time curve (AUC) from time zero to the last quantifiable concentration (AUC0–last), AUC from time zero to infinity (AUC0‐inf), and maximum serum concentration (Cmax). Equivalence was concluded if 90% confidence intervals (CIs) of the geometric least‐squares means ratios were contained within the predefined 80%–125% equivalence margin. Additional pharmacokinetic parameters, pharmacodynamics, safety, and immunogenicity were also evaluated. Results Overall, 146 participants were randomised (CT‐P39, N = 47; EU‐omalizumab, N = 49; US‐omalizumab, N = 50). For all primary pharmacokinetic parameters, 90% CIs for pairwise treatment comparisons were within the 80%–125% equivalence margin, demonstrating pharmacokinetic equivalence. Decreases in free IgE and increases in total IgE serum concentrations were comparable across groups. CT‐P39 was well tolerated. Safety endpoints were comparable across groups: there were no treatment‐related serious adverse events, deaths, or discontinuations due to treatment‐emergent adverse events. Conclusions CT‐P39 was well tolerated and demonstrated pharmacokinetic equivalence with EU‐omalizumab and US‐omalizumab following administration of a single dose in healthy individuals.

Abstract Background Urticaria is a common condition presenting both as acute and chronic disease within primary care. To those without specialist training it is poorly understood from the points of view of diagnosis and management. It causes a considerable disease burden to sufferers with marked impact on quality of life. Purpose of this review The recent publication of the EAACI/GA²LEN/EuroGuiDerm/APAAACI Guideline for the Definition, Classification, Diagnosis and Management of Urticaria guideline prompted us to take this excellent resource and re‐configure its findings and recommendations to a non‐specialist audience with particular reference to the needs of the primary care team.

Abstract Background Chronic spontaneous urticaria (CSU) negatively impacts patients' sleep, thereby reducing health‐related quality of life (HRQoL). Half of patients with inadequately controlled CSU report sleep interference often or every night, which can lead to depression, anxiety, social, and work‐related problems. Methods This randomized, double‐blind, placebo‐controlled Phase 2b core study (NCT02477332) included adult patients ≥18 years with moderate to severe CSU inadequately controlled with H1‐antihistamines. The current analysis includes patients randomized to receive ligelizumab 72 or 240 mg, omalizumab 300 mg or placebo every 4 weeks (q4w) for five injections over 20 weeks with treatment‐free follow‐up for 24 weeks. Patients could enter the open‐label extension study (NCT02649218) from Week 32 onwards if their weekly urticaria activity score was ≥12, which included an open‐label treatment (52 weeks of ligelizumab 240 mg q4w) and a 48‐week post‐treatment follow‐up. Weekly Sleep Interference Scores (SIS7, range 0 [no interference]–21 [substantial interference]), Weekly Activity Interference Score (AIS7), Dermatology Life Quality Index (DLQI) scores, and Overall Work Impairment were assessed. Results Mean baseline SIS7 scores were balanced between the treatment arms for ligelizumab 72 mg (n = 84) and 240 mg (n = 85), omalizumab 300 mg (n = 85), and placebo (n = 43). By Week 12, patients experienced large improvements in sleep interference, with least square mean (standard error) changes from baseline (CFB) in SIS7 of −7.84 (0.58), −7.55 (0.61), −6.98 (0.60), and −5.85 (0.81), respectively. By Week 12, CFB in AIS7 were −8.25 (0.57), −8.25 (0.59), −7.30 (0.60), and −5.62 (0.79), DLQI scores were −9.79 (0.77), −9.93 (0.81), −8.35 (0.79), and −6.99 (1.11), and Overall Work Impairment scores were −28.96 (3.73), −30.76 (3.71), −25.74 (3.91), and −20.13 (5.10) for ligelizumab 72 and 240 mg, omalizumab 300 mg and placebo, respectively. Improvements in each patient‐reported outcome were sustained with ligelizumab 240 mg treatment during the extension study. Conclusions Ligelizumab showed effective and sustained responses in managing sleep interference in patients with CSU, and numerically higher responses than with omalizumab and placebo. Treating the symptoms of CSU with ligelizumab improved disease burden, HRQoL, and markedly improved sleep quality.

Abstract Background Cholinergic urticaria (CholU) is a common type of chronic inducible urticaria, characterized by small itchy wheals that appear upon physical exercise or passive warming. Malassezia globosa, a skin resident fungus, has been identified as an antigen that induces mast cell/basophil degranulation and wheal formation through specific IgE, in Japanese patients with atopic dermatitis and CholU. In this study we aimed in assessing the rate of IgE sensitizations against skin resident fungi in European CholU patients. Methods We assessed serum IgE levels to Malassezia furfur, Candida albicans and Trichophyton mentagrophytes using routine lab testing and Malassezia globosa using a newly established ELISA. We correlated the results to wheal formation and other clinical features. Results Four patients (of 30 tested) had elevated levels of IgE against Malassezia furfur and Candida albicans and two had elevated levels of IgE against Trichophyton mentagrophytes. Four sera (of 25 tested) had elevated levels of IgE to the Malassezia globosa antigen supMGL_1304. Sensitization to one skin fungus was highly correlated with sensitization to the other tested fungi. We saw highly significant correlations of sensitization to supMGL_1304 with wheal size in the autologous sweat skin test (rs = 0.7, P = 0.002, n = 19), the Erlangen atopy score (rs = 0.5, P = 0.03, n = 19), total IgE serum levels (rs = 0.5, P = 0.04, n = 19) and a positive screen for IgE against common airborne/inhalant allergens s (sx1; rs = 0.54, P = 0.02, n = 19). Conclusions Sensitization to skin resident fungi including Malassezia globosa is uncommon in European CholU patients, but is associated with atopy and pronounced wheal formation upon dermal contact with their own sweat. Trial registration German Clinical Trials Registry DRKS-ID: DRKS00004277

Abstract Background Information/communication technologies such as mobile phone applications (apps) would enable chronic urticaria (CU) patients to self‐evaluate their disease activity and control. Yet, recently Antó et al (2021) reported a global paucity of such apps for patients with CU. In this analysis, we assessed patient interest in using apps to monitor CU disease activity and control using questions from the chronic urticaria information and communication technologies (CURICT) study. Methods The methodology for CURICT has been reported. Briefly, a 23‐item questionnaire was completed by 1841 CU patients from 17 UCAREs across 17 countries. Here, we analyzed patient responses to the CURICT questions on the use of apps for urticaria‐related purposes. Results As previously published, the majority of respondents had chronic spontaneous urticaria (CSU; 63%; 18% chronic inducible urticaria (CIndU) [CIndu]; 19% with both), were female (70%) and in urban areas (75%). Over half of patients were very/extremely interested in an app to monitor disease activity (51%) and control (53%), while only ∼1/10 were not. Patients with both urticaria types versus those with CSU only (odds ratio [OR], 1.36 [1.03–1.79]) and females versus males (OR [95% CI], 1.47 [1.17–1.85]) were more likely to be very to extremely interested in an app to assess disease control. Conclusions Overall, half of the patients with CU were very to extremely interested in using an app to assess their disease activity and control. Development of well‐designed apps, specific to disease types (CSU, CIndU, CSU + CIndU, etc), validated by experts across platforms would help improve the management and possibly outcomes of CU treatment while providing important patient information to be used in future research.

Abstract Background The pathogenesis of contact dermatitis, a common inflammatory skin disease with limited treatment options, is held to be driven by inflammasome activation induced by allergens and irritants. We here aim to identify inflammasome‐targeting treatment strategies for irritant contact dermatitis. Methods A high content screen with 41,184 small molecules was performed using fluorescent Apoptosis associated speck‐like protein containing a CARD (ASC) speck formation as a readout for inflammasome activation. Hit compounds were validated for inhibition of interleukin (IL)‐1β secretion. Of these, the approved thiuramdisulfide derivative disulfiram was selected and tested in a patch test model of irritant contact dermatitis in 25 healthy volunteers. Topical application of disulfiram, mometasone or vehicle was followed by application of sodiumdodecylsulfate (SDS) for 24 h each. Eczema induction was quantified by mexameter and laser speckle imaging. Corneocyte sampling of lesional skin was performed to assess inflammasome‐mediated cytokines IL‐1β and IL‐18. Results Disulfiram induced a dose‐dependent inhibition of ASC speck formation and IL‐1β release in cellular assays in vitro. In vivo, treatment with disulfiram, but not with vehicle and less mometasone, inhibited SDS‐induced eczema. This was demonstrated by significantly lower erythema and total perfusion values assessed by mexameter and laser speckle imaging for disulfiram compared to vehicle (p

Abstract Background Berotralstat (BCX7353) is an oral, once‐daily inhibitor of plasma kallikrein recently approved for prevention of angioedema attacks in adults and adolescents with hereditary angioedema (HAE). The objective of this report is to summarize results from an interim analysis of an ongoing long‐term safety study of berotralstat in patients with HAE. Methods APeX‐S is an ongoing, phase 2, open‐label study conducted in 22 countries (ClinicalTrials.gov, NCT03472040). Eligible patients with a clinical diagnosis of HAE due to C1 inhibitor deficiency (HAE‐C1‐INH) were centrally allocated to receive berotralstat 150 or 110 mg once daily. The primary objective was to determine long‐term safety and the secondary objective was to evaluate effectiveness. Results Enrolled patients (N = 227) received berotralstat 150 mg (n = 127) or 110 mg (n = 100) once daily. The median (range) duration of exposure was 342 (11–540) and 307 (14–429) days for the 150‐mg and 110‐mg groups, respectively. Treatment‐emergent adverse events (TEAEs) occurred in 91% (n = 206) of patients. The most common TEAEs across treatment groups were upper respiratory tract infection (n = 91, 40%), abdominal pain (n = 57, 25%), headache (n = 40, 18%), and diarrhea (n = 31, 14%) and were mostly mild to moderate. Fifty percent (n = 113) of patients had at least one drug‐related adverse event (AE; 150 mg, n = 57 [45%]; 110 mg, n = 56 [56%]), and discontinuations due to AEs occurred in 19 (8%) patients (150 mg, n = 13 [10%]; 110 mg, n = 6 [6%]). Three (1.3%) patients experienced a drug‐related serious TEAE. Among patients who received berotralstat through 48 weeks (150 mg, n = 73; 110 mg, n = 30), median HAE attack rates were low in month 1 (150 mg, 1.0 attacks/month; 110 mg, 0.5 attacks/month) and remained low through 12 months (0 attacks/month in both dose groups). Mean HAE attack rates followed a similar trend, and no evidence for patient tolerance to berotralstat emerged. In both dose groups, angioedema quality of life scores showed clinically meaningful changes from baseline. Conclusions In this analysis, both berotralstat doses, 150 and 110 mg once daily, were generally well tolerated. Effectiveness results support the durability and robustness of berotralstat as prophylactic therapy in patients with HAE. Trial registration The study is registered with ClinicalTrials.gov (NCT03472040).

Abstract Background Hereditary angioedema with C1 inhibitor deficiency (C1-INH-HAE) is characterized by recurrent swelling in subcutaneous or submucosal tissues. Symptoms often begin by age 5–11 years and worsen during puberty, but attacks can occur at any age and recur throughout life. Disease course in elderly patients is rarely reported. Methods The Icatibant Outcome Survey (IOS) is an observational study evaluating the safety, tolerability, and efficacy of icatibant. We conducted descriptive analyses in younger (age

Abstract Skin microdialysis (SMD) is a versatile sampling technique that can be used to recover soluble endogenous and exogenous molecules from the extracellular compartment of human skin. Due to its minimally invasive character, SMD can be applied in both clinical and preclinical settings. Despite being available since the 1990s, the technique has still not reached its full potential use as a tool to explore pathophysiological mechanisms of allergic and inflammatory reactions in the skin. Therefore, an EAACI Task Force on SMD was formed to disseminate knowledge about the technique and its many applications. This position paper from the task force provides an overview of the current use of SMD in the investigation of the pathogenesis of chronic inflammatory skin diseases, such as atopic dermatitis, chronic urticaria, psoriasis, and in studies of cutaneous events during type 1 hypersensitivity reactions. Furthermore, this paper covers drug hypersensitivity, UVB-induced- and neurogenic inflammation, and drug penetration investigated by SMD. The aim of this paper is to encourage the use of SMD and to make the technique easily accessible by providing an overview of methodology and applications, supported by standardized operating procedures for SMD in vivo and ex vivo.

Abstract Background Urticarial vasculitis (UV) is defined by long‐lasting urticarial lesions combined with the histopathologic findings of leukocytoclastic vasculitis. As one of the major unmet needs in UV, diagnostic criteria are rather vague and not standardized. Moreover, there seems to be considerable overlap with chronic spontaneous urticaria (CSU), particularly for the normocomplementemic variant of UV. Therefore, this study aimed to develop a diagnostic scoring system that improves the histopathologic discrimination between UV and CSU. Methods Lesional skin sections of patients with clinical and histopathologic diagnosis of UV (n = 46) and CSU (n = 51) were analyzed (blinded to the diagnosis) for the following pre‐defined criteria: presence of leukocytoclasia, erythrocyte extravasation, fibrin deposits, endothelial cell swelling, ectatic vessels, blurred vessel borders, dermal edema, intravascular neutrophil, and eosinophil numbers and numbers of dermal neutrophils, macrophages and mast cells. Results The greatest differences between UV and CSU samples were observed for leukocytoclasia (present in 76% of UV vs. 3.9% of CSU samples; p

Abstract The objective of this analysis was to evaluate the change over time in age at first symptoms, age at diagnosis, and delay in diagnosis using data from the Icatibant Outcome Survey (IOS). Patients with a diagnosis of C1-INH-HAE who were born before the year 1990 and who were diagnosed before they reached 25 years of age were included in the analysis. Both age at diagnosis and delay in diagnosis of C1-INH-HAE appear to decline with later decade of birth, despite wide variation across the countries assessed, suggesting that improved disease awareness causes increased rates of earlier diagnosis over time. Our findings demonstrate that some patients are still experiencing long delays to diagnosis, indicating an ongoing need for improved disease awareness.

Abstract Background Icatibant is a bradykinin B2-receptor antagonist used for the treatment of hereditary angioedema attacks resulting from C1-inhibitor deficiency. Treatment is not adjusted by body weight however the impact of body mass index (BMI) on the effectiveness of icatibant is not documented in the literature. We examined disease characteristics and icatibant treatment effectiveness in patients stratified by BMI in the Icatibant Outcome Survey, an ongoing, international, observational study monitoring the real-world safety and effectiveness of icatibant. Methods Attack and treatment characteristics as well as outcomes following treatment with icatibant were compared among patients with underweight, normal, overweight, and obese BMI. Results Data from 2697 icatibant-treated attacks in 342 patients (3.5, 44.7, 34.8, and 17.0% patients of underweight, normal, overweight, and obese BMI, respectively) were analyzed. There was no significant difference in the frequency and severity of attacks across BMI groups, although obese patients tended to have more attacks of high severity. There was no impact of BMI on the frequency of laryngeal attacks, but patients with normal BMI had fewer cutaneous attacks and more abdominal attacks. Most attacks (71.9–83.8%) were treated with a single icatibant injection without the need for rescue with plasma-derived C1-inhibitor (pdC1-INH), regardless of BMI. Patients with obese BMI used pdC1-INH as rescue treatment more often (P

A genuine microbiota resides in the lungs which emanates from the colonization by the oropharyngeal microbiota. Changes in the oropharyngeal microbiota might be the source of dysbiosis observed in the lower airways in patients suffering from asthma or cystic fibrosis (CF). To examine this hypothesis, we compared the throat microbiota from healthy children (n=62) and that from children with asthma (n=27) and CF (n=57) aged 6 to 12 years using 16S rRNA amplicon sequencing. Our results show high levels of similarities between healthy controls and children with asthma and CF revealing the existence of a core microbiome represented by Prevotella, Streptococcus, Neisseria, Veillonella, and Haemophilus. However, in CF, the global diversity, the bacterial load, and abundances of 53 OTUs were significantly reduced, whereas abundances of 6 OTUs representing opportunistic pathogens such as Pseudomonas, Staphylococcus, and Streptococcus were increased compared to those in healthy controls controls and asthmatics. Our data reveal a core microbiome in the throat of healthy children that persists in asthma and CF indicating shared host regulation favoring growth of commensals. Furthermore, we provide evidence for dysbiosis with a decrease in diversity and biomass associated with the presence of known pathogens consistent with impaired host defense in children with CF.

BackgroundSympathetic and parasympathetic influences on heart rate (HR), which are governed by baroreflex mechanisms, are integrated at the cardiac sinus node through hyperpolarization‐activated cyclic nucleotide–gated channels (HCN4). We hypothesized that HCN4 blockade with ivabradine selectively attenuates HR and baroreflex HR regulation, leaving baroreflex control of muscle sympathetic nerve activity intact. Methods and ResultsWe treated 21 healthy men with 2×7.5 mg ivabradine or placebo in a randomized crossover fashion. We recorded electrocardiogram, blood pressure, and muscle sympathetic nerve activity at rest and during pharmacological baroreflex testing. Ivabradine reduced normalized HR from 65.9±8.1 to 58.4±6.2 beats per minute (P

Purpose. Neutrophil-dominated airway inflammation is a key feature of progressive lung damage in cystic fibrosis (CF). Thus, reducing airway inflammation is a major goal to prevent lung damage in CF. However, current anti-inflammatory drugs have shown several limits. PI3Kγ plays a pivotal role in leukocyte recruitment and activation; in the present study we determined the effects of genetic deletion and pharmacologic inhibition of PI3Kγ on airway inflammation and structural lung damage in a mouse model of CF lung disease. Methods. βENaC overexpressing mice (βENaC-Tg) were backcrossed with PI3Kγ-deficient (PI3KγKO) mice. Tissue damage was assessed by histology and morphometry and inflammatory cell number was evaluated in bronchoalveolar lavage fluid (BALF). Furthermore, we assessed the effect of a specific PI3Kγ inhibitor (AS-605240) on inflammatory cell number in BALF. Results. Genetic deletion of PI3Kγ decreased neutrophil numbers in BALF of PI3KγKO/βENaC-Tg mice, and this was associated with reduced emphysematous changes. Treatment with the PI3Kγ inhibitor AS-605240 decreased the number of neutrophils in BALF of βENaC-Tg mice, reproducing the effect observed with genetic deletion of the enzyme. Conclusions. These results demonstrate the biological efficacy of both genetic deletion and pharmacological inhibition of PI3Kγ in reducing chronic neutrophilic inflammation in CF-like lung disease in vivo.

Electrical myotonia is known to occur in a number of inherited and acquired disorders including myotonic dystrophies, channelopathies, and metabolic, toxic, and inflammatory myopathies. Yet, electrical myotonia in myasthenia gravis associated with antibodies against muscle-specific tyrosine kinase (MuSK) has not been previously reported. We describe two such patients, both of whom had a typical presentation of proximal muscle weakness with respiratory failure in the context of a significant electrodecrement in repetitive nerve stimulation. In both cases, concentric needle examination revealed electrical myotonia combined with myopathic motor unit morphology and early recruitment. These findings suggest that MuSK myasthenia should be included within the differential diagnosis of disorders with electrical myotonia.

Microbially mediated reductive immobilization of chromium is a possible remediation technique for sites contaminated with Cr(VI). This study is part of a broader effort investigating the biogeochemical mechanisms for Cr(VI) reduction in Hanford 100H aquifer sediments using flow-through laboratory columns. It had previously been shown that reduced chromium in the solid phase was in the form of freshly precipitated mixed-phase Cr(III)-Fe(III) (hydr)oxides, irrespective of the biogeochemical conditions in the columns. In this study, the reduced Cr phases in the columns were investigated further using spectroscopy to understand the structure and mechanisms involved in the formation of the end products. Several samples representing potential processes that could be occurring in the columns were synthesized in the laboratory and characterized using X-ray absorption near edge structure (XANES) and X-ray scattering. The XANES of Cr(III) particles in the columns most closely resembled those from synthetic samples produced by the abiotic reaction of Cr(VI) with microbially reduced Fe(II). Microbially mediated Cr-Fe reduction products were distinct from abiotic Cr-Fe (hydr)oxides [CrFe(OH)] and organically complexed Cr(III) sorbed onto the surface of a mixed ferrihydrite-goethite mineral phase. Furthermore, analyses of the abiotically synthesized samples revealed that even the end products of purely abiotic, iron-mediated reduction of Cr(VI) are affected by factors such as the presence of excess aqueous Fe(II) and cellular matter. These results suggest that CrFe(OH) phases made under realistic subsurface conditions or in biotic cultures are structurally different from pure Cr(OH) or laboratory-synthesized CrFe(OH). The observed structural differences imply that the reactivity and stability of biogenic CrFe(OH) could potentially be different from that of abiotic CrFe(OH)., (Copyright © by the American Society of Agronomy, Crop Science Society of America, and Soil Science Society of America, Inc.)

Premise of the Study: Are there dimensions of symbiotic root interactions that are overlooked because plant mineral nutrition is the foundation and, perhaps too often, the sole explanation through which we view these relationships? In this paper we investigate how the root nodule symbiosis in selenium (Se) hyperaccumulator and nonaccumulator Astragalus species influences plant selenium (Se) accumulation., Methods: In greenhouse studies, Se was added to nodulated and nonnodulated hyperaccumulator and nonaccumulator Astragalus plants, followed by investigation of nitrogen (N)-Se relationships. Selenium speciation was also investigated, using x-ray microprobe analysis and liquid chromatography-mass spectrometry (LC-MS)., Key Results: Nodulation enhanced biomass production and Se to S ratio in both hyperaccumulator and nonaccumulator plants. The hyperaccumulator contained more Se when nodulated, while the nonaccumulator contained less S when nodulated. Shoot [Se] was positively correlated with shoot N in Se-hyperaccumulator species, but not in nonhyperaccumulator species. The x-ray microprobe analysis showed that hyperaccumulators contain significantly higher amounts of organic Se than nonhyperaccumulators. LC-MS of A. bisulcatus leaves revealed that nodulated plants contained more γ-glutamyl-methylselenocysteine (γ-Glu-MeSeCys) than nonnodulated plants, while MeSeCys levels were similar., Conclusions: Root nodule mutualism positively affects Se hyperaccumulation in Astragalus. The microbial N supply particularly appears to contribute glutamate for the formation of γ-Glu-MeSeCys. Our results provide insight into the significance of symbiotic interactions in plant adaptation to edaphic conditions. Specifically, our findings illustrate that the importance of these relationships are not limited to alleviating macronutrient deficiencies., (© 2014 Botanical Society of America, Inc.)

Background and Purpose: While remifentanil can be used either during labour or fetal surgery, more should be known about the transplacental transfer of this opioid. The aim of this study was to investigate the placental transfer and haemodynamic effects of remifentanil after i.v. administration to pregnant ewes., Experimental Approach: Seven pregnant ewes received a continuous infusion of remifentanil (0.33 µg·kg⁻¹·min⁻¹) for 1 h, and maternal and fetal arterial blood samples were drawn at regular intervals during and up to 1 h after the discontinuation of the infusion. Haemodynamic parameters were monitored continuously. Blood gas samples were drawn at baseline and once during the infusion., Key Results: Peak maternal remifentanil plasma levels of 4.0 ± 0.9 ng·mL⁻¹ (mean ± SD) and peak fetal plasma levels of 0.4 ± 0.3 ng·mL⁻¹ were obtained. Remifentanil plasma levels dropped rapidly after the discontinuation of the infusion. The continuous infusion of remifentanil did not result in significant maternal or fetal haemodynamic changes., Conclusions and Implications: Remifentanil rapidly passes through the placenta of pregnant ewes and although remifentanil concentrations stay significantly lower in the fetus compared with those in the mother, remifentanil can be detected in significant amounts in the fetus.