Search

BackgroundAimsMethods & ProceduresOutcomes & ResultsSemantic variant of primary progressive aphasia (svPPA) is a form of dementia leading to progressive language comprehension and production difficulties.We investigated whether a phonological approach combined with transcranial direct current stimulation (tDCS) would improve naming skills in semantic-based word finding difficulties due to svPPA.A 58-year-old female with svPPA was treated with phonological components analysis (PCA) combined with anodal transcranial direct current simulation (atDCS) of the left anterior temporal lobe. She completed four structured therapy blocks, each lasting two weeks and separated by a minimum two-week break including two interim tests. Before and after the intervention, we additionally assessed the participant’s general cognitive and language skills.Logistic regression showed that the participant’s ability to name trained and untrained items improved significantly. Furthermore, her overall cognitive and language abilities seemed to stagnate over the eight months, which seems surprising given the underlying progressive svPPA. We therefore concluded that phonological approaches combined with tDCS can enhance naming abilities even though the difficulties are mainly semantically driven. [ABSTRACT FROM AUTHOR]

Background: Baricitinib treatment in adults with moderate‐to‐severe atopic dermatitis (AD) has demonstrated rapid improvements in itch as well as AD sign severity and affected body surface area as assessed by the Eczema Area and Severity Index (EASI) total score, whether administered as monotherapy or in combination with topical corticosteroids (TCS). As EASI clinical signs differ in time course and associated antecedents, the effects of baricitinib on each individual clinical sign are of interest. Objectives: In this post hoc analysis, we aimed to investigate the effects of baricitinib on individual EASI subscores, namely excoriation, oedema/papulation, erythema and lichenification, in both monotherapy and TCS combination therapy trials. Methods: We analysed the percent change from baseline in individual EASI subscores from three phase‐III, double‐blind, 16‐week trials of baricitinib in monotherapy (BREEZE‐AD1/BREEZE‐AD2) and TCS combination therapy (BREEZE‐AD7) cohorts via mixed model repeated measures (MMRM). Results: Baricitinib 4 mg showed rapid and sustained improvements in all four clinical signs in both cohorts. Significant effects emerged at week 1 for excoriation, oedema/papulation and erythema scores in monotherapy (p < 0.001) and TCS combination therapy (p < 0.001, p < 0.01, p < 0.001), plateaued at week 4, and remained significant versus placebo through week 16. The effect on lichenification scores also emerged early, at week 1 in monotherapy (p < 0.05) and week 2 in combination therapy (p < 0.001), with scores continuously improving without a clear plateau. Effect magnitude was highest in excoriation scores, exhibiting near‐maximal reduction in week 1 of monotherapy and remaining highest across all timepoints in combination therapy. Conclusions: Rapid and sustained improvements were observed across clinical signs of inflammation and particularly on excoriation following baricitinib treatment. Our findings suggest that selective inhibition of janus kinases 1 and 2 leads to rapid and sustained control of skin inflammation, and that rapid reductions in itch translate into early disruption of the itch‐scratch cycle. [ABSTRACT FROM AUTHOR]

In this paper, we propose a new cooperative method that improves the accuracy of Turn Movement Count (TMC) under challenging conditions by introducing contextual observations from the surrounding areas. The proposed method focuses on the correct identification of the movements in conditions where current methods have difficulties. Existing vision-based TMC systems are limited under heavy traffic conditions. The main problems for most existing methods are occlusions between vehicles that prevent the correct detection and tracking of the vehicles through the entire intersection and the assessment of the vehicle's entry and exit points, incorrectly assigning the movement. The proposed method intends to overcome this incapability by sharing information with other observation systems located at neighboring intersections. Shared information is used in a cooperative scheme to infer the missing data, thereby improving the assessment that would otherwise not be counted or miscounted. Experimental evaluation of the system shows a clear improvement over related reference methods. [ABSTRACT FROM AUTHOR]

In 1999, Alberta Transportation and Economic Corridors (TEC) implemented the Geohazard Risk Management Program (GRMP) to identify, assess, monitor, and prioritize the mitigation of risk resulting from geohazard events at specific sites along the provincial highway network. The GRMP was developed to address a variety of geohazard types including rockfall hazards that occur at natural and constructed (cut) highway backslopes. An evaluation of various methods for the condition assessment of rockfall geohazards, including TEC's current GRMP risk rating system, has been completed with the intent of better understanding the suitability of each method as TEC transitions to a formalized GAM program. The GRMP risk rating values for selected rockfall geohazard sites along highway corridors in Alberta were compared to values developed from the results of five established rock mass and rock slope rating systems. The results of this study demonstrate that TEC's current GRMP risk rating system is a viable tool for the condition assessment and performance monitoring of rockfall geohazards, which could be utilized within a formalized GAM program, further benefitting from years of recorded application in Alberta. Of the other rating systems tested, the rockfall hazard rating system (RHRS) showed a strong correlation with the GRMP risk rating while Q-Slope, the Geological Strength Index (GSI) and Rock Mass Rating (RMR) correlation were marginal but displayed a potential for use as condition assessment tools. The work presented in this paper provides the first evaluation of rock slope rating systems for rockfall hazards along corridors in Alberta, directly comparing them to the slope performance as observed by TEC in a quantitative manner. [ABSTRACT FROM AUTHOR]

Encorafenib is a novel kinase inhibitor of BRAF V600E as well as wild‐type BRAF and CRAF and has received approval, in combination with binimetinib, to treat BRAF V600E or V600K mutation‐positive unresectable or metastatic melanoma or in combination with cetuximab to treat BRAF V600E mutation‐positive colorectal cancer. The absorption, distribution, metabolism and excretion (ADME) of encorafenib was studied by administering [14C] encorafenib (100 mg containing 90 μCi of radiolabeled material) to 4 healthy male subjects (NCT01436656). Following a single oral 100‐mg dose of [14C] encorafenib to healthy male subjects, the overall recovery of radioactivity in the excreta was ≥93.9% in all four subjects, indicating that good mass balance was achieved. An equal mean of 47.2% for the radioactivity dose was eliminated in the feces and urine. The percentage of the dose eliminated in the feces (5.0%) and urine (1.8%) as unchanged encorafenib was minor. Metabolism was found to be the major clearance pathway (~88% of the recovered radioactive dose) for encorafenib in humans and is predominantly mediated through N‐dealkylation of the isopropyl carbamic acid methyl ester to form the primary phase 1 direct metabolite M42.5 (LHY746). Oral absorption was estimated from the radioactive dose recovered in the urine (47.2%) and the total radioactive dose recovered in the feces as metabolites (39%). Based on these values and the assumptions that encorafenib and its metabolites are stable in feces, the fraction of oral absorption was estimated to be at least ~86%. [ABSTRACT FROM AUTHOR]

Background: Oral Janus kinase inhibitors (JAKi) have been approved for the treatment of several chronic inflammatory conditions, including rheumatoid arthritis (RA) and atopic dermatitis (AD). Prompted by new evidence, the Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency (EMA) recently reassessed the benefit–risk balance of oral JAKi. The PRAC recommended that oral JAKi should be used only if no suitable alternatives are available in patients ≥65 years of age, or who have a history of atherosclerotic cardiovascular (CV) disease, other CV risk factors (e.g. history of long‐term smoking) or have malignancy risk factors, and used with caution in patients at risk of pulmonary embolism or deep vein thrombosis. The European Commission's final decision was issued in March 2023. Objectives: Our goal was to highlight the PRAC recommendations, especially in the context of oral JAKi use in AD. Methods: Authors summarized the PRAC recommendations, the new clinical evidence on oral JAKi safety and key differences between patients with RA and AD. Results: Risk of developing adverse events of special interest (e.g. cardiovascular events, malignancy) is higher in patients with RA than in patients with AD, because of the higher prevalence of the underlying risk factors. Conclusions: The benefit–risk profile of JAKi approved for AD remains favourable, including use as first‐line systemic therapy for patients with AD <65 years of age and without CV or malignancy risk factors. [ABSTRACT FROM AUTHOR]

Purpose: With the increasing adoption of artificial intelligence (AI) in various domains, including healthcare, there is growing acceptance and interest in consulting AI models to provide medical information and advice. This study aimed to evaluate the accuracy of ChatGPT's responses to practice quiz questions designed for otolaryngology board certification and decipher potential performance disparities across different otolaryngology subspecialties. Methods: A dataset covering 15 otolaryngology subspecialties was collected from an online learning platform funded by the German Society of Oto-Rhino-Laryngology, Head and Neck Surgery, designed for board certification examination preparation. These questions were entered into ChatGPT, with its responses being analyzed for accuracy and variance in performance. Results: The dataset included 2576 questions (479 multiple-choice and 2097 single-choice), of which 57% (n = 1475) were answered correctly by ChatGPT. An in-depth analysis of question style revealed that single-choice questions were associated with a significantly higher rate (p < 0.001) of correct responses (n = 1313; 63%) compared to multiple-choice questions (n = 162; 34%). Stratified by question categories, ChatGPT yielded the highest rate of correct responses (n = 151; 72%) in the field of allergology, whereas 7 out of 10 questions (n = 65; 71%) on legal otolaryngology aspects were answered incorrectly. Conclusion: The study reveals ChatGPT's potential as a supplementary tool for otolaryngology board certification preparation. However, its propensity for errors in certain otolaryngology areas calls for further refinement. Future research should address these limitations to improve ChatGPT's educational use. An approach, with expert collaboration, is recommended for the reliable and accurate integration of such AI models. [ABSTRACT FROM AUTHOR]

This article discusses the implementation of ex vivo confocal microscopy (EVCM) during Mohs surgery for basal cell carcinoma (BCC). EVCM is a technique that provides high-resolution images of tumors and resection margins, allowing for the detection of residual BCC. The study evaluated the impact of EVCM on medical quality, patient experience, workflow, and financial sustainability. The results showed a decrease in discrepancy rates between EVCM and traditional methods, a reduction in surgery time, and improved patient outcomes. The integration of EVCM in routine surgery was found to be beneficial for patients, physicians, and the healthcare system. [Extracted from the article]

Reoviruses are used as oncolytic viruses to destroy tumor cells. The concomitant induction of anti-tumor immune responses enhances the efficacy of therapy in tumors with low amounts of immune infiltrates before treatment. The reoviruses should provoke immunogenic cell death (ICD) to stimulate a tumor cell-directed immune response. Necroptosis is considered a major form of ICD, and involves receptor-interacting protein kinase 1 (RIPK1), RIPK3 and phosphorylation of mixed-lineage kinase domain-like protein (MLKL). This leads to cell membrane disintegration and the release of damage-associated molecular patterns that can activate immune responses. Reovirus Type 3 Dearing (T3D) can induce necroptosis in mouse L929 fibroblast cells and mouse embryonic fibroblasts. Most human tumor cell lines have a defect in RIPK3 expression and consequently fail to induce necroptosis as measured by MLKL phosphorylation. We used the human colorectal adenocarcinoma HT29 cell line as a model to study necroptosis in human cells since this cell line has frequently been described in necroptosis-related studies. To stimulate MLKL phosphorylation and induce necroptosis, HT29 cells were treated with a cocktail consisting of TNFα, the SMAC mimetic BV6, and the caspase inhibitor Z-VAD-FMK. While this treatment induced necroptosis, three different reovirus T3D variants, i.e., the plasmid-based reverse genetics generated virus (T3DK), the wild-type reovirus T3D isolate R124, and the junction adhesion molecule-A-independent reovirus mutant (jin-1) failed to induce necroptosis in HT29 cells. In contrast, these viruses induced MLKL phosphorylation in murine L929 cells, albeit with varying efficiencies. Our study shows that while reoviruses efficiently induce necroptosis in L929 cells, this is not a common phenotype in human cell lines. This study emphasizes the difficulties of translating the results of ICD studies from murine cells to human cells. [ABSTRACT FROM AUTHOR]

The evidence‐ and consensus‐based guideline on atopic eczema was developed in accordance with the EuroGuiDerm Guideline and Consensus Statement Development Manual. Four consensus conferences were held between December 2020 and July 2021. Twenty‐nine experts (including clinicians and patient representatives) from 12 European countries participated. This second part of the guideline includes recommendations and detailed information on basic therapy with emollients and moisturizers, topical anti‐inflammatory treatment, antimicrobial and antipruritic treatment and UV phototherapy. Furthermore, this part of the guideline covers techniques for avoiding provocation factors, as well as dietary interventions, immunotherapy, complementary medicine and educational interventions for patients with atopic eczema and deals with occupational and psychodermatological aspects of the disease. It also contains guidance on treatment for paediatric and adolescent patients and pregnant or breastfeeding women, as well as considerations for patients who want to have a child. A chapter on the patient perspective is also provided. The first part of the guideline, published separately, contains recommendations and guidance on systemic treatment with conventional immunosuppressive drugs, biologics and janus kinase (JAK) inhibitors, as well as information on the scope and purpose of the guideline, and a section on guideline methodology. [ABSTRACT FROM AUTHOR]

"What Is Life? Five Great Ideas in Biology" by Paul Nurse is a book that explores the concept of life from a biological perspective. The author discusses various definitions of life put forth by different scholars throughout history, including Aristotle, Darwin, JBS Haldane, and Carl Woese. Nurse presents his own indicators of life, such as the ability to evolve through natural selection and having a hereditary system. The book delves into five key ideas in biology: the cell, the gene, evolution by natural selection, life as chemistry, and life as information. Nurse also highlights the connections between science and the humanities, and expresses his moral views on topics like the fragility of nature and the importance of universal healthcare. However, the book has been criticized for its treatment of religion, as the author presents a perspective that leans towards atheism and dismisses religious beliefs as "creationist myths." [Extracted from the article]

Introduction Atopic dermatitis (AD) is a chronic, inflammatory disease that can affect multiple regions of the body, but can be particularly burdensome on exposed areas of skin, such as the head and neck (H&N). Tralokinumab, a high-affinity monoclonal antibody that specifically neutralizes interleukin-13, is approved in multiple countries for adults with moderate-to-severe AD. Phase 3 trials showed tralokinumab provided significant improvements in AD severity and was well-tolerated up to 52 weeks of treatment. The ongoing open-label, 5-year extension trial, ECZTEND (NCT03587805), assesses the safety and efficacy of tralokinumab after the completion of parent trials (PT). Objective To assess tralokinumab efficacy in the head and neck region. Methods: This post hoc analysis included adult patients with moderate-to-severe AD initially randomized to tralokinumab 300mg Q2W in the phase 3 PTs ECZTRA 1 (NCT03131648) or ECZTRA 2 (NCT03160885). Patients on active tralokinumab treatment were followed for up to 52 weeks in PTs and for up to 152 weeks in ECZTEND as of data cutoff April 30, 2022. Patients re-randomized to placebo at Week (Wk) 16 were not included beyond that timepoint. For this analysis, overall EASI and H&N regional EASI (H&N EASI) were evaluated. H&N EASI (0-7.2) was calculated based on the severity of erythema, induration/papulation, excoriation, lichenification and area of involvement. All data were analyzed and presented as observed. Results: At baseline, 87.8% (1047/1192) of patients had H&N involvement (H&N EASI>1), and 49.9% (591/1192) of patients exhibited severe AD (IGA 4). Baseline median H&N EASI for the pooled PTs was 3.0 (IQR 1.8; 4.5). In the pooled PTs, 48.2% (542/1125) and 71.2% (558/784) of patients achieved H&N EASI=1, at Wk16 and Wk52, respectively. After 3 years additional treatment (Wk152 in ECZTEND), the proportion of patients with H&N EASI=1 was 87.2% (232/266) and the median H&N EASI was 0.2 (IQR 0.0; 0.5). In the subgroup of patients (n=301) with severe AD (IGA 4) and high H&N involvement (H&N EASI=4), median H&N EASI improved from 5.4 at baseline to 2.4 and 0.8 at Wk16 and Wk52, respectively, and 0.4 at Wk152. Improvements in H&N region were comparable to overall EASI improvement. Conclusions: Tralokinumab provided sustained improvements in the H&N regions in patients with moderate-to-severe AD for up to 4 years. Sustained improvements were also seen in patients with severe disease and substantial H&N involvement at baseline. [ABSTRACT FROM AUTHOR]

Background Atopic dermatitis (AD) is associated with substantial impairment in quality of life, including sleep disturbances, anxiety, and depression, which may increase the risk of cardiovascular disease (CVD). However, the association between CVD and AD is not well established. Objectives: To evaluate incidence rates (IRs) of venous thromboembolism (VTE), deep vein thrombosis (DVT), and pulmonary embolism (PE) in patients with and without AD in a population-based cohort study in Denmark, and to assess IRs of malignancies, major adverse cardiovascular events (MACE), VTE, and the distribution of Atherosclerotic Cardiovascular Disease (ASCVD) risk factors in patients with AD and rheumatoid arthritis (RA) in a nested cohort analysis. Methods: Data from all individuals aged =12 years (=18 years in the nested cohort analysis) between January 1, 2000, and December 31, 2018, were extracted from the Danish National Patient Registry. Patients with =1 AD diagnosis during the study period were matched on sex and age with 10 individuals from the general population. The nested cohort analysis included patients diagnosed with RA as an additional comparison population. In the overall cohort, IRs of VTE, DVT, and PE were assessed; the nested cohort analysis evaluated the distribution of ASCVD risk factors and incidence of malignancies, MACE, and VTE in patients with and without ASCVD risk factors (age =65 years, and history of smoking, coronary artery disease, stroke, DVT, PE, and malignancy). The follow-up period was from the first diagnosis during the study period until the occurrence of death or an endpoint, the first instance of migration, or December 31, 2018. IRs are shown per 100 patient-years (PY) of exposure with 95% confidence intervals. Results: The population-based cohort comprised 190,751 patients, including 17,341 patients with AD and 173,410 age- and sex-matched controls. The IR/100 PY of VTE was similar between the AD cohort (0.14 [95% CI, 0.12-0.16]) and the general population (0.11 [0.11-0.12]). The IR/100 PY for VTE was higher in patients with AD aged =65 years (0.71 [0.56-0.90]) than the age-matched general population (0.50 [0.46-0.54]) and lower in the younger AD cohorts (12 to <18 years, 0.02 [0.00-0.08]; 18 to <65 years, 0.12 [0.09-0.13]). The IRs/100 PY of DVT and PE were comparable between the AD cohort (DVT, 0.08 [0.06-0.09]; PE, 0.06 [0.05-0.08]) and the general population (DVT, 0.06 [0.06-0.07]; PE, 0.05 [0.05-0.05]).a The nested cohort analysis comprised 195,807 patients, including 13,432 with AD, 48,055 with RA, and 134,320 age- and sex-matched controls. Distribution of risk factors for malignancies (excluding nonmelanoma skin cancer [NMSC]), MACE, and VTE was comparable in the AD cohort and general population, but higher in patients with RA. The IR/100 PY for malignancies (excluding NMSC) was higher in patients with AD with a history of malignancy (11.41 [9.83-13.25]) than those without (0.44 [0.40-0.48]), and in those aged =65 years (3.09 [2.75-3.48]) versus <65 years (0.36 [0.33-0.40]). Similarly, the IR/100 PY for MACE was higher in patients with AD aged =65 years (2.30 [2.01- 2.63]) versus <65 years (0.15 [0.13-0.17]), and patients with a history of ASCVD (5.02 [4.37-5.76]) versus without (0.15 [0.13-0.18]). Patients with AD with a history of VTE (including DVT/PE) and inherited thrombophilia had a greater risk of VTE than patients without these risk factors. Conclusions: In these 2 large cohort studies of adults and adolescents with AD, IRs of VTE, DVT, and PE were comparable with the general Danish population. The risk of VTE, malignancy, and MACE was higher in patients with AD with a history of risk factors for ASCVD. This underscores the need for appropriate monitoring and reporting of cardiovascular events in patients with AD, and active management of risk factors with early and effective therapeutic intervention. [ABSTRACT FROM AUTHOR]

Introduction Integrated safety data for lebrikizumab (LEB) treatment in moderate-to-severe atopic dermatitis (AD) has been previously published. Conjunctivitis and keratitis were identified as adverse events (AEs) of special interest in the AD program. Objectives: Further characterize patient-reported conjunctivitis and keratitis AEs in LEB clinical trials for AD. Methods: Data from adult and adolescent patients were analyzed in 2 groups: a) LEB 250mg every 2 weeks (LEBQ2W, N=783) vs placebo (PBO, N=404), weeks 0-16 (PC 0-16wk) from 4 clinical trials (ADvocate1, ADvocate2, ADhere, Phase 2b study); and b) patients who received at least one dose of LEB (ALL-LEB, N=1720) from 8 clinical trials (ADvocate1, ADvocate2, ADhere, ADore, ADjoin (ongoing), ARBAN, TREBLE, Phase 2b study). Conjunctivitis and keratitis refer to cluster definitions defined by MedDRA preferred terms conjunctivitis, allergic conjunctivitis, bacterial conjunctivitis, viral conjunctivitis, giant papillary conjunctivitis; and keratitis, atopic keratoconjunctivitis, allergic keratitis, ulcerative keratitis, vernal keratoconjunctivitis, respectively. Exposure adjusted incidence rates (IR) are provided as per 100 patientyears. Results: In PC 0-16wk, at baseline, similar proportions of LEB (21.5%) and PBO (19.3%) patients had medical history (MH) of conjunctivitis. Of ALL-LEB, 22.2% had MH of conjunctivitis; of those with conjunctivitis or keratitis AE, 40% had MH of conjunctivitis. In PC 0-16wk, conjunctivitis cluster was reported by 8.5% (IR:30.6) LEBQ2W vs 2.5% (IR:8.9) PBO; keratitis cluster was reported by 0.6% (IR:2.2) and 0.3% (IR:0.9) of patients, respectively. All conjunctivitis and keratitis events in PC 0-16wk were mild or moderate in severity; 5 events (3 conjunctivitis, 2 keratitis) led to treatment discontinuation (LEBQ2W) vs 1 conjunctivitis event (PBO). ALL-LEB treatment duration ranged from 1 dose to 100 weeks. In ALL-LEB, conjunctivitis cluster was reported by 10.6% (IR:12.2), with the majority being mild or moderate (10.3%) and 0.3% severe. Keratitis was reported by 0.5% (IR:0.6), with 1 severe event of vernal keratoconjunctivitis. Conjunctivitis and keratitis events resulted in 17 (1.0%) and 3 (0.2%) treatment discontinuations, respectively. Similar proportions of adult (11.3%; 0.6%) and adolescent (8.3%; 0.3%) patients reported conjunctivitis and keratitis events. The majority were reported within first 16 weeks of treatment. Conclusions: Conjunctivitis is an AE reported by LEB-treated patients. Patients with MH of conjunctivitis may have higher risk of developing treatment-emergent conjunctivitis or keratitis. Most events were mild or moderate in severity, did not lead to treatment discontinuation, were reported within first 16 weeks of treatment, and IR did not increase with longer duration of exposure. [ABSTRACT FROM AUTHOR]

Food systems (FSs) emit ~ 20 GtCO2e/y (~ 35% of global greenhouse gas emissions). This level tends to raise given the expected increases in food demands, which may threaten global climate targets. Through a rapid assessment, evaluating 60+ scenarios based on existing low-emission and carbon sequestration practices, we estimate that intensifying FSs could reduce its emissions from 21.4 to − 2.0 GtCO2e/y and address increasing food demands without relying on carbon offsets (e.g., related to afforestation and reforestation programs). However, given historical trends and regional contexts, a more diverse portfolio of practices, including diet shifts and new-horizon technologies, will be needed to increase the feasibility of achieving net-zero FSs. One likely pathway consists of implementing practices that shift food production to the 30th-percentile of least emission-intensive FSs (~ 45% emissions reduction), sequester carbon at 50% of its potential (~ 5 GtCO2e/y) and adopt diet shifts and new-horizon technologies (~ 6 GtCO2e/y). For a successful transition to happen, the global FSs would, in the next decade (2020s), need to implement cost-effective mitigation practices and technologies, supported by improvements in countries' governance and technical assistance, innovative financial mechanisms and research focused on making affordable technologies in the following two decades (2030–2050). This work provides options and a vision to guide global FSs to achieving net-zero by 2050. [ABSTRACT FROM AUTHOR]

The evidence‐ and consensus‐based guideline on atopic eczema was developed in accordance with the EuroGuiDerm Guideline and Consensus Statement Development Manual. Four consensus conferences were held between December 2020 and July 2021. Twenty‐nine experts (including clinicians and patient representatives) from 12 European countries participated. This first part of the guideline includes general information on its scope and purpose, the health questions covered, target users and a methods section. It also provides guidance on which patients should be treated with systemic therapies, as well as recommendations and detailed information on each systemic drug. The systemic treatment options discussed in the guideline comprise conventional immunosuppressive drugs (azathioprine, ciclosporin, glucocorticosteroids, methotrexate and mycophenolate mofetil), biologics (dupilumab, lebrikizumab, nemolizumab, omalizumab and tralokinumab) and janus kinase inhibitors (abrocitinib, baricitinib and upadacitinib). Part two of the guideline will address avoidance of provocation factors, dietary interventions, immunotherapy, complementary medicine, educational interventions, occupational and psychodermatological aspects, patient perspective and considerations for paediatric, adolescent, pregnant and breastfeeding patients. [ABSTRACT FROM AUTHOR]

Although 2-phosphonobutane-1,2,4,-tricarboxylic acid, PBTC, has manifold industrial applications, relevant and reliable data on the protonation of PBTC are poor. However, these data are critical parameters for ascertaining PBTC speciation, especially with regard to a sound structural and thermodynamic characterization of its metal ion complexes. A rigorous evaluation of pH-dependent 1H, 13C, and 31P chemical shifts along with accessible scalar spin–spin coupling constants (J) was performed in order to determine the pKa values of PBTC in 0.5 molal NaCl aqueous solution by means of nuclear magnetic resonance (NMR) spectroscopy. The phosphonate group revealed pKa values of 0.90 ± 0.02 and 9.79 ± 0.02, and the pKa values associated with the carboxylic groups are 3.92 ± 0.02, 4.76 ± 0.03, and 6.13 ± 0.03. Supported by DFT-calculated structures revealing strong intramolecular hydrogen bonding, the sequence of deprotonation could be unambiguously determined. [ABSTRACT FROM AUTHOR]

Understanding the genomic basis of adaptation to different abiotic environments is important in the context of climate change and resulting short‐term environmental fluctuations.Using functional and comparative genomics approaches, we here investigated whether signatures of genomic adaptation to a set of environmental parameters are concentrated in specific subsets of genes and functions in lacertid lizards and other vertebrates.We first identify 200 genes with signatures of positive diversifying selection from transcriptomes of 24 species of lacertid lizards and demonstrate their involvement in physiological and morphological adaptations to climate. To understand how functionally similar these genes are to previously predicted candidate functions for climate adaptation and to compare them with other vertebrate species, we then performed a meta‐analysis of 1,100 genes under selection obtained from ‐omics studies in vertebrate species adapted to different abiotic factors.We found that the vertebrate gene set formed a tightly connected interactome, which was to 23% enriched in previously predicted functions of adaptation to climate, and to a large part (18%) involved in organismal stress response. We found a much higher degree of identical genes being repeatedly selected among different animal groups (43.6%), and of functional similarity and post‐translational modifications than expected by chance, and no clear functional division between genes used for ectotherm and endotherm physiological strategies. In total, 171 out of 200 genes of Lacertidae were part of this network.These results highlight an important role of a comparatively small set of genes and their functions in environmental adaptation and narrow the set of candidate pathways and markers to be used in future research on adaptation and stress response related to climate change. [ABSTRACT FROM AUTHOR]

[Display omitted] Lipases are widely used in the detergent industry and must withstand harsh conditions involving both anionic and zwitterionic surfactants at alkaline pH. Thermomyces lanuginosus lipase (TlL) is often used and stays active at high concentrations of the anionic surfactant sodium dodecyl sulfate (SDS) at pH 8.0, but is sensitive to SDS at pH 6.0 and below. We propose that enhanced stability at pH 8.0 results from a structurally distinct complex formation with SDS. We use small-angle X-ray scattering (SAXS) to elucidate structures of TlL:SDS at pH 4.0, 6.0, and 8.0 and further investigate the complexes at pH 8.0 using hydrogen/deuterium exchange mass spectrometry (HDX-MS). At pH 4.0, large dense aggregates are formed at low [SDS], which become gradually less dense at higher [SDS], resulting in a core–shell structure. At pH 6.0, SDS induces a TlL dimer and forms a hemi-micelle along the side of the dimer. At higher [SDS], TlL adopts a core–shell structure. At pH 8.0, TlL forms a dimer with a SDS hemi-micelle but avoids a core–shell structure and maintains activity. Three helices are identified as SDS anchor points. This study provides important structural insight into the stability of TlL towards SDS under alkaline conditions. [ABSTRACT FROM AUTHOR]

The article reports the spread of the Cistercian Order in a part of what was then the kingdom of Denmark, which is now in Northern Germany. Topic discussed includes Cistercians working directly in parishes, or being directly involved in education and remaining true in Western Europe. Also when Cistercians began to make foundations in Scandinavia & Northern Germany, most of the inhabitants were new converts to the Christian religion, and there were still pockets of unconverted pagan populations.

Summary: Background: Tralokinumab, a fully human IgG4 monoclonal antibody that specifically binds with high affinity to interleukin‐13, effectively reduces moderate‐to‐severe atopic dermatitis (AD) when given every 2 weeks. The incidence of conjunctivitis is elevated vs. placebo, but severity and aetiology have not been examined. Objective: To analyse conjunctivitis data recorded in five randomized, placebo‐controlled trials of tralokinumab in adult patients with moderate‐to‐severe AD. Methods: Overall, 2285 adults with AD were studied up to 16 weeks. Cochran–Mantel–Haenszel weights were applied to calculate the adjusted incidence of adverse events. Results: The incidence of conjunctivitis was higher (7·5%) with tralokinumab than with placebo (3·2%). Most events were mild or moderate in severity, and 78·6% and 73·9% of events resolved during the trial in the tralokinumab and placebo groups, respectively. Two (1·4%) events led to the permanent discontinuation of tralokinumab. An increased incidence of conjunctivitis, regardless of treatment group, was associated with more severe baseline AD, and history of allergic conjunctivitis/atopic keratoconjunctivitis, as well as the number of atopic comorbidities. Limitations: This analysis reports events up to week 16 only, with limited confirmation of conjunctivitis and its aetiology by an ophthalmologist, and insufficient reporting of ophthalmic treatments. Conclusions: Treatment with tralokinumab was associated with an increased incidence of conjunctivitis vs. placebo, but these cases were mostly mild and transient. Whatis already known about this topic? Ocular disorders, including conjunctivitis, occur more frequently in patients with atopic dermatitis (AD).When using the interleukin (IL)‐4 and IL‐13 receptor blocking biologic dupilumab, patients with AD in clinical trials and real‐world practice experience higher rates of conjunctivitis, which increases with baseline AD severity.Tralokinumab, a fully human monoclonal antibody, binds specifically to IL‐13 with high affinity.Various rates of conjunctivitis have been observed in different clinical trials of tralokinumab. Whatdoes this study add? This is the first investigation of conjunctivitis in phase III studies of a biological drug specifically targeting IL‐13, in contrast to dupilumab, which targets the IL‐4 and IL‐13 receptorsThe incidence of conjunctivitis was higher with tralokinumab (7·5%) vs. placebo (3·2%); most cases were mild and resolved, or were resolving during study treatment.Risk factors included high AD severity, history of conjunctivitis, disease biomarker levels, and number and type of atopic comorbiditiesThis is the first study to show that some atopic comorbidities have a greater influence on the risk of conjunctivitis than others. Linked Comment: R. Nguyen. Br J Dermatol 2022; 186:391–392. [ABSTRACT FROM AUTHOR]

Dupilumab, a first-in-class therapy targeting the two key cytokines involved in the persistent underlying inflammatory pathway in atopic dermatitis (AD), is approved for treatment of moderate-to-severe AD in Europe, USA, Japan and several other countries. To assess dupilumab effects on SCORing Atopic Dermatitis (SCORAD) and component scores (objective and subjective SCORAD) over time in adults with moderate-to-severe AD. This post hoc analysis included 2,444 patients in four placebo-controlled, double-blind, randomized, phase 3 trials. SOLO 1 and 2 (NCT02277743; NCT02277769) evaluated 16 weeks of dupilumab monotherapy against placebo. CAFÉ (NCT02755649) and CHRONOS (NCT02260986) evaluated dupilumab with concomitant topical corticosteroids (TCS) against TCS alone for 16 and 52 weeks, respectively. 2,444 patients randomized to treatment in SOLO 1 and 2 (N = 1,379), CAFÉ (N = 325) and CHRONOS (N = 740) were analyzed. Dupilumab treatment significantly improved overall SCORAD and individual components as early as Week 1 or 2, with significant and clinically meaningful differences vs. control through end of treatment (p <.0001). These results occurred irrespective of dupilumab regimen, 300 mg subcutaneously weekly or every 2 weeks. In four large phase 3 trials in adults with moderate-to-severe AD, dupilumab treatment with or without concomitant TCS resulted in rapid and sustained improvements in all SCORAD outcomes vs. placebo or TCS alone. [ABSTRACT FROM AUTHOR]

Voluntary attentional control is the ability to selectively focus on a subset of visual information in the presence of other competing stimuli–a marker of cognitive control enabling flexible, goal-driven behavior. To test its robustness, we contrasted attentional control with the most common source of attentional orienting in daily life: attention shifts prior to goal-directed eye and hand movements. In a multi-tasking paradigm, human participants attended at a location while planning eye or hand movements elsewhere. Voluntary attentional control suffered with every simultaneous action plan, even under reduced task difficulty and memory load–factors known to interfere with attentional control. Furthermore, the performance cost was limited to voluntary attention: We observed simultaneous attention benefits at two movement targets without attentional competition between them. This demonstrates that the visual system allows for the concurrent representation of multiple attentional foci. Since attentional control is extremely fragile and dominated by premotor attention shifts, we propose that action-driven selection plays the superordinate role for visual selection. [ABSTRACT FROM AUTHOR]

This post hoc analysis examined SCORing Atopic Dermatitis (SCORAD) outcomes in 471 paediatric patients (children age 6-<12 years, n = 304; adolescents age 12-<18 years, n = 167) with atopic dermatitis treated with dupilumab, ± topical corticosteroids, in two 16-week phase 3 randomized controlled trials and a 1-year interim data cut of a subsequent open-label extension study. Paediatric patients treated with dupilumab (± topical corticosteroids) had significantly lower SCORAD, objective SCORAD (o-SCORAD), and individual SCORAD components from week 3 to 16 compared with placebo (± topical corticosteroids) in the randomized controlled trials. The results were sustained or continuously improved over 1 year of open-label treatment with dupilumab ± topical corticosteroids. SCORAD-50 was achieved in almost all patients (91.3-91.8%) by week 52 with continued dupilumab treatment across age groups. Almost all (> 86%) patients achieved mild or absent pruritus and sleep loss at week 52. In conclusion, dupilumab ± topical corticosteroids resulted in rapid and significant improvements in all aspects of SCORAD analysed, and the results were sustained over 1 year. [ABSTRACT FROM AUTHOR]

Oncolytic viruses are promising agents for cancer therapy because they selectively infect and kill tumor cells, and because they trigger immune responses that can boost anticancer immunity. Key to the latter process is the production of type I interferons (IFN-Is) that can turn noninflamed "cold" tumors into "hot" ones. Besides this desired anticancer effect, IFN-Is are antiviral and successful oncolytic virotherapy thus relies on tightly controlled IFN-I levels. This requires a profound understanding of when and how tumor cells induce IFN-I in response to specific viruses. In this study, we uncovered two key factors that augment IFN-I production in transformed human myeloid cells infected with a tumor-selective reovirus. Viral replication and IFN-α/β receptor (IFNAR) signaling progressively reinforced the levels of IFN-I expressed by infected cells. Mechanistically, both augmented the activation of interferon regulatory factor 3, a key transcription factor for IFNβ expression. Our findings imply that reovirus-permissive tumor cells themselves are a major source of IFN-I expression. As tumors can perturb the IFNAR pathway for their own survival, reovirus-exposed IFNAR-unresponsive tumors may need additional therapeutic intervention to promote the secretion of sufficient IFN-I into the tumor microenvironment. Our increased understanding of the parameters that affect reovirus-induced IFN-I levels could aid in the design of tailored virus-based cancer therapies. [ABSTRACT FROM AUTHOR]

Soil carbon is the major active pool of terrestrial carbon, and as such, soil organic carbon (SOC) targets, policies and measures will be pivotal to achieving global climate targets. SOC sequestration may reduce the net annual greenhouse gas emissions from Agriculture, Forestry and Other Land Use by between 3% and 71%, while simultaneously supporting various ecosystem services. Accurate SOC accounting and monitoring, however, is constrained by various technical challenges related to indicators, rates of SOC change, measuring the impact of management practices on SOC, and the long-term persistence of sequestered SOC. We assessed countries' pledges to the Paris Agreement for SOC in agriculture to better understand the level, transparency, and specificity of commitments. Reviewing 184 countries' initial Nationally Determined Contributions (NDCs), we considered whether SOC was included, what was pledged, the level of ambition promised and the specificity of mitigation targets. Twenty-eight countries referred to SOC in their NDCs, citing quantified or unquantified mitigation targets, national policies or programs, and actions and measures to be implemented in agricultural lands (14), peatlands (6) or wetlands (14). Countries' reasons for not including SOC in NDCs included the need to prioritize goals of sustainable development and food security above climate mitigation, a lack of incentives for farmers to improve management practices, and the difficulty of accurately monitoring changes in SOC. Including SOC targets in NDCs can improve NDCs' comprehensiveness and transparency to track and compare policy progress across NDCs; it can also leverage SOC-related climate finance, technical support, and capacity building. Key policy insights Many NDCs specify practices known to have the potential to achieve SOC sequestration or protection without explicitly mentioning SOC. The SOC-related mitigation potential of these practices can be quantified in future NDCs. NDCs are not presently a good indicator of countries' interest or commitment to SOC action at national level. To improve this, countries with existing SOC policies, programs, and actions can specify their SOC-related commitments in future NDCs. Increased collaboration between countries with experience managing SOC and countries needing support to develop SOC-related targets, policies, measures and incentives for land users and farmers would facilitate the provision of such needed support. To increase country commitments and attention to managing SOC, there is a need for improved SOC measurement and monitoring, for better evidence on the impacts of management practices on SOC, and for incentives for farmers to change practices and overcome barriers. [ABSTRACT FROM AUTHOR]

Background: Previous studies of dupilumab in adolescents and adults with moderate-to-severe atopic dermatitis (AD) showed no clinically meaningful adverse changes in laboratory parameters. Objective: The aim of this study was to assess laboratory outcomes in children aged 6–11 years with severe AD in a randomized, placebo-controlled, phase III trial of dupilumab. Methods: Children aged 6–11 years with severe AD were randomized 1:1:1 to 16 weeks of dupilumab 300 mg every 4 weeks, 100 or 200 mg every 2 weeks, or matching placebo, all with concomitant topical corticosteroids (TCS). Blood samples were collected at baseline and Weeks 4, 8, and 16; urine samples were collected at baseline and Weeks 4 and 16. Results: Of 367 patients enrolled in the study, 362 were included in the safety analysis, 351 completed study treatment, and 4 withdrew due to treatment-emergent adverse events not related to laboratory abnormalities. Both dupilumab + TCS groups showed overall trends toward increases in mean blood levels of eosinophils and alkaline phosphatase, and decreases in mean blood levels of platelets, neutrophils, and lactate dehydrogenase levels, without corresponding mean changes in the placebo + TCS group. None of these changes were associated with symptoms or clinically meaningful adverse outcomes, and none led to treatment modification. No clinically significant changes or trends were observed for other measured laboratory parameters. Conclusion: There were no clinically meaningful adverse changes in routine laboratory parameters attributable to treatment with dupilumab + TCS. Changes in platelet counts and lactate dehydrogenase levels likely reflect reduced inflammation. These results confirm similar findings in adults and adolescents, and suggest that there is no need for routine laboratory monitoring of children aged 6–11 years treated with dupilumab + TCS for severe AD. Trial Registration: ClinicalTrials.gov Identifier: NCT03345914. 4bTSAzFaRmrELnrwsHf1S6 Does treatment with dupilumab require routine laboratory monitoring in 6- to 11-year-old children with severe atopic dermatitis? (MP4 180482 kb) [ABSTRACT FROM AUTHOR]

Background: Baricitinib is an oral, selective, reversible Janus kinase 1/2 inhibitor approved in the European Union and Japan and under investigation in the United States for treatment of atopic dermatitis (AD). Objectives: To evaluate the impact of baricitinib plus background topical corticosteroids (TCS) on health‐related quality of life (HRQoL), how AD symptoms impact work productivity and life functioning, and treatment benefit using patient‐reported outcome (PRO) assessments in patients with moderate‐to‐severe AD previously experiencing inadequate response to TCS. Methods: Adult patients with AD in BREEZE‐AD7, a Phase 3, multicentre, double‐blind trial, were randomised 1 : 1 : 1 to daily oral placebo (control) or baricitinib 4‐ or 2‐mg plus TCS. PROs reported Week 1 through Week 16: Dermatology Life Quality Index (DLQI), Work Productivity and Activity Impairment‐AD (WPAI‐AD); Patient‐Reported Outcomes Measurement Information System (PROMIS) Itch and Sleep measures, and Patient Benefit Index (PBI). Data were analysed using logistic regression (categorical) and mixed model repeated measures (continuous). PBI scores were analysed using analysis of variance. Results: A total of 329 patients were randomised. Treatment with baricitinib 4‐mg (N = 111) or 2 mg (N = 109) plus TCS led to rapid, statistically significant improvements [vs. TCS plus placebo (N = 109)] in DLQI ≥4‐point improvement starting at Week 2 (4‐mg plus TCS, P ≤ 0.001; 2‐mg plus TCS P ≤ 0.05), change from baseline in WPAI‐AD presenteeism at Week 1 (4‐mg plus TCS, P ≤ 0.01; 2‐mg plus TCS P ≤ 0.05) and PROMIS itch interference at Week 2 (4‐mg plus TCS P ≤ 0.01). Improvements were sustained through Week 16 for baricitinib 4‐mg. Statistically significant improvements were observed at Week 16 for PBI global score (4‐mg plus TCS, P ≤ 0.001; 2‐mg plus TCS P ≤ 0.05). Conclusions: Baricitinib plus TCS vs. placebo plus TCS showed significant improvements in treatment benefit at Week 16 and rapid significant improvements in HRQoL and impact of AD symptoms on work productivity and functioning through 16 weeks. [ABSTRACT FROM AUTHOR]

The number of females participating in college sports in the U.S. has increased in last two decades. While female college athletes might be at a high risk, research examining disordered eating in this population is limited and difficult to summarize due to differences in methodologies. Factors contributing to disordered eating in female college athletes are not well established, but emotional regulation may be a potential correlate. The main purpose of this study was to examine the prevalence of disordered eating and explore potential differences between weight-sensitive and less weight-sensitive sports in a sample of female college athletes. The second purpose was to examine emotional regulation, body dissatisfaction, sport type, a family history of eating disorder, and BMI as potential predictors of disordered eating. The Eating Attitudes Test-26 and the Minnesota Eating Behavior Survey were used to estimate disordered eating prevalence in a sample of 151 athletes. Emotion regulation was assessed by the Difficulties in Emotion Regulation Scale. The prevalence of disordered eating was 6.6% and 10.6%, respectively, with no differences by sport type. The multiple regression model explained 11% of the EAT-26 variance, F(5, 150) = 3.74, p < .01. Greater emotional regulation difficulties (β = .174, t = 2.191, p = .03) and body dissatisfaction (β = .276, t = 2.878, p = .005) were significant predictors of disordered eating. Further examination of emotional regulation and body dissatisfaction in relation to disordered eating in female college athletes is warranted. [ABSTRACT FROM AUTHOR]

Sensitive skin is clinically defined by characteristic sensory perceptions including tightness, abnormal stinging, burning, tingling, pain and pruritus. Facial erythema may occur, and other body areas can be involved. Sensitive skin affects extremely the quality of life. According with the International Forum for the Study of Itch (IFSI), sensitive skin is defined as a syndrome. The unpleasant sensations described are in response to stimuli that normally should not provoke such sensations. Moreover, these unpleasant sensations cannot be explained by any skin disease. Sensitive skin is always considered when any new consumer health, cosmetic or household product is introduced in the market. Once sensitive skin is recognized, it is mandatory to identify specific triggers that commonly induce symptoms and even cutaneous visible signs. Sensitive skin syndrome can be exacerbated by an allergic setting and environmental factors (cold, hot, dryness, pollution, wind, chemicals...), a source of intolerance and unpleasant sensations. Cosmetics are the main triggering factors of sensitive skin according to patient's reports. The presence of potentially irritant substances in their composition increases the clinical expression of symptoms. As sensitive skin is frequent, and it is increasing based on the current development of cosmetic use worldwide, there is a need to develop better skin care products. The continuous research of active and safe skin care products to prevent and treat sensitive skin is extremely welcome. [ABSTRACT FROM AUTHOR]

Background and Objectives: Encorafenib is a kinase inhibitor indicated for the treatment of patients with unresectable or metastatic melanoma or metastatic colorectal cancer, respectively, with selected BRAF V600 mutations. A clinical drug–drug interaction (DDI) study was designed to evaluate the effect of encorafenib on rosuvastatin, a sensitive substrate of OATP1B1/3 and breast cancer resistance protein (BCRP), and bupropion, a sensitive CYP2B6 substrate. Coproporphyrin I (CP-I), an endogenous substrate for OATP1B1, was measured in a separate study to deconvolute the mechanism of transporter DDI. Methods: DDI study participants received a single oral dose of rosuvastatin (10 mg) and bupropion (75 mg) on days − 7, 1, and 14 and continuous doses of encorafenib (450 mg QD) and binimetinib (45 mg BID) starting on day 1. The CP-I data were collected from participants in a phase 3 study who received encorafenib (300 mg QD) and cetuximab (400 mg/m2 initial dose, then 250 mg/m2 QW). Pharmacokinetic and pharmacodynamic analysis was performed using noncompartmental and compartmental methods. Results: Bupropion exposure was not increased, whereas rosuvastatin Cmax and area under the receiver operating characteristic curve (AUC) increased approximately 2.7 and 1.6-fold, respectively, following repeated doses of encorafenib and binimetinib. Increase in CP-I was minimal, suggesting that the primary effect of encorafenib on rosuvastatin is through BCRP. Categorization of statins on the basis of their metabolic and transporter profile suggests pravastatin would have the least potential for interaction when coadministered with encorafenib. Conclusion: The results from these clinical studies suggest that encorafenib does not cause clinically relevant CYP2B6 induction or inhibition but is an inhibitor of BCRP and may also inhibit OATP1B1/3 to a lesser extent. Based on these results, it may be necessary to consider switching statins or reducing statin dosage accordingly for coadministration with encorafenib. Clinical Trial Registration: ClinicalTrials.gov NCT03864042, registered 6 March 2019. [ABSTRACT FROM AUTHOR]

Summary: Background: Tralokinumab, a fully human monoclonal antibody, specifically neutralizes interleukin‐13, a key cytokine driving peripheral inflammation in atopic dermatitis (AD). In phase II studies, tralokinumab combined with topical corticosteroids provided early and sustained improvements in AD signs and symptoms. Objectives: To evaluate the efficacy and safety of tralokinumab monotherapy in adults with moderate‐to‐severe AD who had an inadequate response to topical treatments. Methods: In two 52‐week, randomized, double‐blind, placebo‐controlled, phase III trials, ECZTRA 1 and ECZTRA 2, adults with moderate‐to‐severe AD were randomized (3 : 1) to subcutaneous tralokinumab 300 mg every 2 weeks (Q2W) or placebo. Primary endpoints were Investigator's Global Assessment (IGA) score of 0 or 1 at week 16 and ≥ 75% improvement in Eczema Area and Severity Index (EASI 75) at week 16. Patients achieving an IGA score of 0 or 1 and/or EASI 75 with tralokinumab at week 16 were rerandomized to tralokinumab Q2W or every 4 weeks or placebo, for 36 weeks. The trials were registered with ClinicalTrials.gov: NCT03131648 and NCT03160885. Results: At week 16, more patients who received tralokinumab vs. placebo achieved an IGA score of 0 or 1: 15·8% vs. 7·1% in ECZTRA 1 [difference 8·6%, 95% confidence interval (CI) 4·1–13·1; P = 0·002] and 22·2% vs. 10·9% in ECZTRA 2 (11·1%, 95% CI 5·8–16·4; P < 0·001) and EASI 75: 25·0% vs. 12·7% (12·1%, 95% CI 6·5–17·7; P < 0·001) and 33·2% vs. 11·4% (21·6%, 95% CI 15·8–27·3; P < 0·001). Early improvements in pruritus, sleep interference, Dermatology Life Quality Index, SCORing Atopic Dermatitis and Patient‐Oriented Eczema Measure were observed from the first postbaseline measurements. The majority of week 16 tralokinumab responders maintained response at week 52 with continued tralokinumab treatment without any rescue medication (including topical corticosteroids). Adverse events were reported in 76·4% and 61·5% of patients receiving tralokinumab in ECZTRA 1 and ECZTRA 2, respectively, and in 77·0% and 66·0% of patients receiving placebo in ECZTRA 1 and ECZTRA 2, respectively, in the 16‐week initial period. Conclusions: Tralokinumab monotherapy was superior to placebo at 16 weeks of treatment and was well tolerated up to 52 weeks of treatment. What is already known about this topic?Atopic dermatitis (AD) is a chronic interleukin (IL)‐13‐mediated disease.There is a need for safe and effective long‐term treatment options for AD.Tralokinumab is a fully human monoclonal antibody that binds specifically to IL‐13 with high affinity, thereby preventing receptor interaction and subsequent downstream signalling.Tralokinumab combined with topical corticosteroids showed early and sustained efficacy and safety in a 12‐week, phase IIb trial in moderate‐to‐severe AD. What does this study add?These are the first pivotal phase III trials demonstrating that by specifically targeting IL‐13 alone, patients can achieve significant improvements in AD signs and symptoms and quality of life, and maintain these improvements over time without the requirement for topical corticosteroids.These trials provide evidence that tralokinumab offers a long‐term, well‐tolerated treatment option for patients with moderate‐to‐severe AD. Linked Comment: Morra and Drucker. Br J Dermatol 2021; 184:386–387. Plain language summary available online [ABSTRACT FROM AUTHOR]

Atopic dermatitis (AD) is a highly pruritic, chronic inflammatory skin disease. The diagnosis is made using evaluated clinical criteria. Disease activity and burden are best measured with a composite score, assessing both objective and subjective symptoms, such as SCORing Atopic Dermatitis (SCORAD). AD management must take into account clinical and pathogenic variabilities, the patient's age and also target flare prevention. Basic therapy includes hydrating and barrier‐stabilizing topical treatment universally applied, as well as avoiding specific and unspecific provocation factors. Visible skin lesions are treated with anti‐inflammatory topical agents such as corticosteroids and calcineurin inhibitors (tacrolimus and pimecrolimus), which are preferred in sensitive locations. Topical tacrolimus and some mid‐potency corticosteroids are proven agents for proactive therapy, which is defined as the long‐term intermittent anti‐inflammatory therapy of frequently relapsing skin areas. Systemic anti‐inflammatory or immunosuppressive treatment is a rapidly changing field requiring monitoring. Oral corticosteroids have a largely unfavourable benefit–risk ratio. The IL‐4R‐blocker dupilumab is a safe, effective and licensed, but expensive, treatment option with potential ocular side‐effects. Other biologicals targeting key pathways in the atopic immune response, as well as different Janus kinase inhibitors, are among emerging treatment options. Dysbalanced microbial colonization and infection may induce disease exacerbation and can justify additional antimicrobial treatment. Systemic antihistamines (H1R‐blockers) only have limited effects on AD‐related itch and eczema lesions. Adjuvant therapy includes UV irradiation, preferably narrowband UVB or UVA1. Coal tar may be useful for atopic hand and foot eczema. Dietary recommendations should be patient‐specific, and elimination diets should only be advised in case of proven food allergy. Allergen‐specific immunotherapy to aeroallergens may be useful in selected cases. Psychosomatic counselling is recommended to address stress‐induced exacerbations. Efficacy‐proven 'Eczema school' educational programmes and therapeutic patient education are recommended for both children and adults. [ABSTRACT FROM AUTHOR]

Hot briquetting tests with mixtures of direct reduced iron (DRI) pellets and residues of the Midrex direct reduction process are conducted on a hydraulic piston press with a closed die. The trials seek to test the feasibility of recycling these residues by introducing them directly into hot briquetted iron (HBI). The inclusion of residues is possible if a high pressure of 350 MPa and a high briquetting temperature of 800 °C are applied. It is ascertained that up to 20 wt% of the HBI can consist of residues and still meet the quality requirements for the safe transportation to the steel plant if the mixture contains sufficient HBI screened fines and HBI classifier dust. Under such conditions, the HBI briquettes have a compressive strength of >300 MPa, an abrasion resistance of >80%, and, most importantly, an apparent density of >5 g cm−3. It is further shown that the hot briquetting of Midrex residues is also possible without DRI pellets so that they can be reused as educt in the Midrex direct reduction process. [ABSTRACT FROM AUTHOR]

Lebrikizumab is a monoclonal antibody that binds with high affinity and slow off-rate to interleukin (IL)-13, thereby blocking the downstream effects of IL-13 with high potency. ADvocate1 (NCT04146363) and ADvocate2 (NCT04178967) are identically designed phase 3, randomized, double-blinded, placebo-controlled trials evaluating lebrikizumab for the treatment of moderate-to-severe atopic dermatitis (AD). At Week 16 of both studies, lebrikizumab 250 mg every 2 weeks (Q2W) showed statistically significant improvements in measures of skin clearance and patient reported outcomes. Patients treated with lebrikizumab achieved clinically meaningful improvements in the signs and symptoms of AD with fewer AD flares across multiple definitions than patients treated with placebo. In patients who met the protocol-defined criteria for response to lebrikizumab at Week 16, most patients treated with lebrikizumab Q2W and lebrikizumab every 4 weeks (Q4W) maintained an Investigator's Global Assessment (IGA) 0/1 response (71% and 77%, respectively) and a 75% improvement in the Eczema and Severity Index from baseline (EASI 75; 78% and 82%, respectively) up to Week 52. The objective of this analysis is to determine the proportion and the individual efficacy trajectory of lebrikizumab-treated patients who exhibited a stable response with no or minimal fluctuations of efficacy from Week 16 to Week 52 in Week 16 responders. Patients who responded to lebrikizumab at the end of the 16-week induction period were rerandomized 2 : 2 : 1 to receive lebrikizumab Q2W, lebrikizumab Q4W or placebo Q2W (withdrawal) for 36 additional weeks. Week 16 responders were defined as those achieving an EASI 75 or IGA 0/1 with a ≥2-point improvement and without rescue medication use. We defined no or minimal fluctuations as maintaining EASI 75 for at least 80% of the 10 study visits from Week 16 to Week 52. Separately, we analysed EASI 90 with the same criteria. We also analysed the proportion of patients who achieved each endpoint at all 10 maintenance period study visits. ADvocate2 analyses were performed on a modified population, excluding 17 patients who entered the maintenance period (from a single study site) and whose eligibility could not be confirmed. Therefore, analyses were performed on the modified pooled population of ADvocate1 and ADvocate2 patients. All analyses were performed post hoc. If patients used rescue medication, discontinued treatment or transferred to the escape arm, data collected at or after the event was imputed as nonresponse. In ADvocate1 and ADvocate2, 291 patients met the criteria for response at Week 16 (EASI 75 or IGA 0/1 with a ≥2-point improvement and without rescue medication use) and were rerandomized to receive lebrikizumab Q2W (n = 113), lebrikizumab Q4W, (n = 118) or withdrawal (n = 60) from Week 16 to Week 52. The proportions of patients who maintained EASI 75 for at least 80% of the maintenance period were 71% (lebrikizumab Q2W), 71% (lebrikizumab Q4W) and 60% (withdrawal). The proportions of patients who maintained EASI 75 at all study visits were 53% (lebrikizumab Q2W), 55% (lebrikizumab Q4W) and 38% (withdrawal). The proportions of patients to achieve and maintain the more stringent response of EASI 90 for at least 80% of study visits were 45% (lebrikizumab Q2W), 51% (lebrikizumab Q4W) and 35% (withdrawal). In ADvocate1 and ADvocate2, approximately 7 out of 10 of patients who continued treatment with lebrikizumab maintained at least an EASI 75 response with no or minimal fluctuations. These individual patient data show that most patients treated with monotherapy lebrikizumab Q2W and Q4W maintain a stable response with no or minimal fluctuations of efficacy up to Week 52. [ABSTRACT FROM AUTHOR]

Filamentous fungi belonging to the genus Fusarium are notorious plant-pathogens that infect, damage and contaminate a wide variety of important crops. Phenamacril is the first member of a novel class of single-site acting cyanoacrylate fungicides which has proven highly effective against important members of the genus Fusarium. However, the recent emergence of field-resistant strains exhibiting qualitative resistance poses a major obstacle for the continued use of phenamacril. In this study, we synthesized novel cyanoacrylate compounds based on the phenamacril-scaffold to test their growth-inhibitory potential against wild-type Fusarium and phenamacril-resistant strains. Our findings show that most chemical modifications to the phenamacril-scaffold are associated with almost complete loss of fungicidal activity and in vitro inhibition of myosin motor domain ATPase activity. [ABSTRACT FROM AUTHOR]

Background: Functional constraint through genomic architecture is suggested to be an important dimension of genome evolution, but quantitative evidence for this idea is rare. In this contribution, existing evidence and discussions on genomic architecture as constraint for convergent evolution, rapid adaptation, and genic adaptation are summarized into alternative, testable hypotheses. Network architecture statistics from protein-protein interaction networks are then used to calculate differences in evolutionary outcomes on the example of genomic evolution in yeast, and the results are used to evaluate statistical support for these longstanding hypotheses. Results: A discriminant function analysis lent statistical support to classifying the yeast interactome into hub, intermediate and peripheral nodes based on network neighborhood connectivity, betweenness centrality, and average shortest path length. Quantitative support for the existence of genomic architecture as a mechanistic basis for evolutionary constraint is then revealed through utilizing these statistical parameters of the protein-protein interaction network in combination with estimators of protein evolution. Conclusions: As functional genetic networks are becoming increasingly available, it will now be possible to evaluate functional genetic network constraint against variables describing complex phenotypes and environments, for better understanding of commonly observed deterministic patterns of evolution in non-model organisms. The hypothesis framework and methodological approach outlined herein may help to quantify the extrinsic versus intrinsic dimensions of evolutionary constraint, and result in a better understanding of how fast, effectively, or deterministically organisms adapt. [ABSTRACT FROM AUTHOR]

Summary: Background: Dupilumab [a monoclonal antibody blocking the shared receptor subunit for interleukin (IL)‐4 and IL‐13] is approved for patients aged ≥ 12 years with inadequately controlled, moderate‐to‐severe atopic dermatitis (AD). Dupilumab trials of up to 52 weeks demonstrated efficacy and a favourable safety profile in patients with moderate‐to‐severe AD inadequately controlled with topical medications. Objectives: To further characterize the safety of dupilumab by evaluating clinical laboratory findings from three randomized, double‐blinded, placebo‐controlled phase III trials (LIBERTY AD SOLO 1 & 2 and LIBERTY AD CHRONOS). Methods: Patients were randomized 1 : 1 : 1 (SOLO 1 & 2) or 3 : 1 : 3 (CHRONOS) for 16 and 52 weeks, respectively, to dupilumab weekly, every 2 weeks or placebo. CHRONOS patients received a standardized concomitant topical corticosteroid regimen. Laboratory outcomes were summarized descriptively in 1376 patients from SOLO 1 & 2 and 740 from CHRONOS. Results: Treatment groups had similar results in baseline laboratory parameters. Platelets and neutrophils showed mild decreases from baseline in dupilumab vs. placebo groups. Some dupilumab‐treated patients had small transient increases in eosinophils. Grade 3 eosinophilia was reported in < 1% of dupilumab‐treated and placebo‐treated patients; no adverse events were associated with eosinophilia. Lactate dehydrogenase levels decreased from baseline during dupilumab treatment in all trials. No clinically meaningful changes were observed between treatment groups in other haematology, chemistry or urinalysis parameters. Conclusions: There were no clinically important changes in routine laboratory parameters that could be attributed to dupilumab. This study supports the use of dupilumab as a systemic treatment for moderate‐to‐severe AD that does not require laboratory monitoring. What's already known about this topic? Long‐term treatment of atopic dermatitis (AD) with conventional immunosuppressive agents is limited by the risk of significant side‐effects and a need for repeated tests to monitor haematological and/or organ (e.g. liver, kidney) toxicities.Dupilumab [a monoclonal antibody blocking the shared receptor subunit for interleukin (IL)‐4 and IL‐13] is approved for the treatment of patients with inadequately controlled, moderate‐to‐severe AD.In 16‐week and 52‐week studies, dupilumab demonstrated a positive risk/benefit profile in moderate‐to‐severe AD. What does this study add? This study is the first comprehensive analysis of dupilumab laboratory safety data of the 16‐week SOLO 1 & 2 (pooled N = 1376) and 52‐week CHRONOS (N = 740) trials, demonstrating an absence of clinically important changes in haematology, serum chemistry and urinalysis parameters in patients with moderate‐to‐severe AD treated with dupilumab.Our data support the use of dupilumab as a systemic treatment for the long‐term management of moderate‐to‐severe AD without routine laboratory monitoring in clinical practice. Respond to this article [ABSTRACT FROM AUTHOR]

Background: Recurrence of drug-resistant tuberculosis (DR-TB) after treatment occurs through relapse of the initial infection or reinfection by a new drug-resistant strain. Outbreaks of DR-TB in high burden regions present unique challenges in determining recurrence status for effective disease management and treatment. In the Republic of Moldova the burden of DR-TB is exceptionally high, with many cases presenting as recurrent.Methods: We performed a retrospective analysis of Mycobacterium tuberculosis from Moldova to better understand the genomic basis of drug resistance and its effect on the determination of recurrence status in a high DR-burden environment. To do this we analyzed genomes from 278 isolates collected from 189 patients, including 87 patients with longitudinal samples. These pathogen genomes were sequenced using Illumina technology, and SNP panels were generated for each sample for use in phylogenetic and network analysis. Discordance between genomic resistance profiles and clinical drug-resistance test results was examined in detail to assess the possibility of mixed infection.Results: There were clusters of multiple patients with 10 or fewer differences among DR-TB samples, which is evidence of person-to-person transmission of DR-TB. Analysis of longitudinally collected isolates revealed that many infections exhibited little change over time, though 35 patients demonstrated reinfection by divergent (number of differences > 10) lineages. Additionally, several same-lineage sample pairs were found to be more divergent than expected for a relapsed infection. Network analysis of the H3/4.2.1 clade found very close relationships among 61 of these samples, making differentiation of reactivation and reinfection difficult. There was discordance between genomic profile and clinical drug sensitivity test results in twelve samples, and four of these had low level (but not statistically significant) variation at DR SNPs suggesting low-level mixed infections.Conclusions: Whole-genome sequencing provided a detailed view of the genealogical structure of the DR-TB epidemic in Moldova, showing that reinfection may be more prevalent than currently recognized. We also found increased evidence of mixed infection, which could be more robustly characterized with deeper levels of genomic sequencing. [ABSTRACT FROM AUTHOR]

Purpose: The superior soft‐tissue contrast offered by the integrated magnetic resonance imaging (MRI) of the Unity MR‐linac compared to the x‐ray‐based image guidance on conventional linacs potentially allows for liver stereotactic body radiation therapy (SBRT) without the need for implanted markers or other surrogates. On conventional linacs, liver SBRT patients are typically positioned with their arms above their heads (arms‐up) to minimize exposure to healthy tissue. However, the spatial confinement of the MRI‐bore and increased treatment delivery times can make the arms‐up position straining. Therefore, we assessed the plan quality for MR‐linac treatment plans with the patient in the arms‐up and in the arms‐down position. Additionally, we compared the MR‐linac plans with clinically used arms‐up treatment plans made for a conventional linac. Methods: Fifteen consecutively treated patients with oligometastatic liver disease were included in this retrospective study. For each patient, a planning computed tomography (CT) with delineations, a diagnostic MRI, and a 3 × 20 Gy dual‐arc volumetric modulated arc therapy (VMAT) plan, which was used to treat the patient in an arms‐up position on the conventional linac, were available. For the MR‐linac, 15‐beam step‐and‐shoot intensity‐modulated radiation therapy (IMRT) plans were created for four patient positioning scenarios: arms‐up, mimicking current clinical practice; arms‐down, with treatment beams avoiding the arms on the entrance side; arms‐through, arms are down but not avoided, and right‐arm‐up; only the right arm is up and the left arm is avoided on the entrance side. Resulting treatment plans were compared. Bonferroni‐corrected two‐sided Wilcoxon signed‐ranks tests were used to assess statistical significance (P < 0.05). Results: No significant differences were found in gross tumour volume (GTV) coverage (D2%, D50%, and D98%) or liver sparing (liver‐GTV V<15Gy) between the clinical plans and any of the MR‐linac plans. The median target conformity [exterior V40%/planning target volume (PTV)] was significantly better in the clinical plans (5.8) than in the MR‐linac scenarios (arms‐down: 6.6, arms‐up/right‐arm‐up: 6.2, arms‐through: 6.3). No MR‐linac plan violated any additional organ‐at‐risk (OAR) constraint that was not already violated in the clinical plans. In the arms‐down scenario a significantly increased median spinal cord D1% (14.5 Gy) was detected compared to the clinical setup (7.2 Gy). For the arms‐down (arms‐through) scenario, the median left arm D1% was 1.5 (2.7) Gy, the median right arm D1% was 5.8 (22.7) Gy, and the median right arm V20Gy was 0.0 (14.7) cc. These differences were statistically significant. For the right‐arm‐up scenario, the median left arm D1% (2.3 Gy) and V5Gy (0.0) were not significantly different compared to the arms‐down scenario. Conclusions: Mimicking the current clinical practice by treating patients in the arms‐up/right‐arm‐up position on the MR‐linac leads to plans which are dosimetrically very similar to the conventional linac plans. Treating in the arms‐down position is expected to increase patient comfort at the cost of a small reduction in OAR sparing for individual patients. Treating through the arms is not encouraged due to substantial dose deposition in the arms. [ABSTRACT FROM AUTHOR]

The article focuses on studies devoted to dimensions of Cisterian Order lead to passages in the Regula Benedicti, the Carta Caritatis, the Consuetudines, and the Statutes of the General Chapter. Topics discussed include decline of monasteries and institutions, success of the White Monks and Nuns and economic activities practiced in the monasteries.

Atopic dermatitis (AD) is a common inflammatory skin disease that affects both children and adults, including a large number of adults of reproductive age. Several guidelines for the treatment of AD exist, yet specific recommendations for the treatment of pregnant or lactating women and for adults planning to have a child are often lacking. This position paper from the European Task force on Atopic Dermatitis (ETFAD) is based on up‐to‐date scientific literature on treating pregnant and lactating women as wells as adults with AD planning to have a child. It is based on the expert opinions of members of the ETFAD and on existing safety data on the proposed treatments, many of which are derived from patients with other inflammatory diseases or from transplantation medicine. For treating future parents, as well as pregnant and lactating women with AD, the use of topical treatments including moisturizers, topical corticosteroids, tacrolimus, antiseptics such as chlorhexidine, octenidine, potassium permanganate and sodium hypochlorite (bleach) is deemed to be safe. Ultraviolet (UV) therapy may also be used. Systemic treatment should be prescribed only after careful consideration. According to the opinion of the ETFAD, treatment should be restricted to systemic corticosteroids and cyclosporine A, and, in selected cases, azathioprine. [ABSTRACT FROM AUTHOR]

Atopic dermatitis (AD) is a chronic inflammatory skin disease presenting with recurrent eczematous lesions and intense pruritus. It is common and affects both children and adults, often beginning in infancy. Due to the unpredictable disease course, its visible skin lesions, itching and scratching followed by sleeplessness, other associated atopic diseases, and behavioral and psychiatric disorders, AD is an immense burden for patients and caregivers. AD is determined by a genetic predisposition characterized by an impaired skin barrier and a T-helper-2-predominant inflammation. Restoration of the skin barrier is the main approach for treating and preventing AD. In order to cope with acute flares, usually topical corticosteroids (TCS) are applied, while topical calcineurin inhibitors (TCI) are used mainly for maintenance therapy. There is a small group of patients who are refractory to TCS and TCI and require systemic immunosuppressive drugs such as ciclosporin. Novel, targeted therapies are under clinical investigation, among which an anti-IL-4/IL-13 receptor antibody has recently been approved in several countries. As we learn to understand the pathomechanisms of AD, the characteristics of the different patient subgroups, and the effectiveness of various targeted therapies, a personalized treatment ensuring the best efficacy and safety and, probably, a disease-modifying effect will result. [ABSTRACT FROM AUTHOR]

Many systemic therapies used for moderate-to-severe atopic dermatitis (AD) have immunosuppressive properties and necessitate laboratory screening and monitoring, adding to the treatment burden. Previous dupilumab studies in adults, adolescents and children aged 6–11 years with moderate-to-severe AD showed no clinically meaningful adverse changes in laboratory parameters. Here we evaluate hematology and chemistry laboratory safety data for dupilumab-treated children aged 6 months to 5 years with moderate-to-severe atopic dermatitis. Patients aged 6 months to 5 years with inadequately controlled moderate-to-severe AD were enrolled in LIBERTY AD PRESCHOOL (NCT03346434 part B), a randomized, double-blind placebo-controlled phase 3 study. 162 patients were randomized to either dupilumab 200/300 mg every 4 weeks (q4w; N=83; baseline weight ≥5 <15 kg: 200 mg; ≥15 to <30 kg: 300 mg) or placebo (N=79) for 16 weeks. From Day –14, all patients initiated standardized treatment with low-potency topical corticosteroids. Laboratory data was collected at baseline, weeks 4 and 16. At baseline, mean (SD) counts of hematology parameters were similar in both treatment groups: haemoglobin (dupilumab: 129.4 gL−1 [12]; placebo: 127.2 gL−1 [11.4]), lymphocyte (dupilumab: 4.6×109 L−1 [1.8]; placebo: 4.5×109 L−1 [1.7]), basophil (dupilumab: 0.07×109 L−1 [0.03]; placebo: 0.07×109 L−1 [0.04]), platelet (dupilumab: 397.7×109 L−1 [103.2]; placebo: 385.6 × 109 L−1 [112.9]) and eosinophils (dupilumab: 1.1×109 L−1 [0.7]; placebo: 1.1×109 L−1 [0.7]). Mean (SD) haemoglobin count in the dupilumab (128.4×gL−1 [11]) and placebo groups (128.2×gL−1 [11.2]), lymphocyte count in the dupilumab (4.20×109 L−1 [2.06]) and placebo groups (4.29×109 L−1 [1.52]) and basophil count in the dupilumab (0.07×109 L−1 [0.04]) and placebo groups (0.06×109 L−1 [0.03]) remained with the normal reference range for this population at week 16. The mean change (SD) in platelet count at week 16 was −16.3×109 L−1 (78.5) in the dupilumab group and +17.4×109 L−1 (106.6) in the placebo group. In the dupilumab treatment group, the mean eosinophil count increased at week 4 (mean change from baseline [SD]; +0.48×109 L−1 [1.8]) and trended downward by week 16 (+0.31×109 L−1 [1.4]) while minimal changes were noted in the placebo group at week 4 (0.1×109 L−1 [0.7]) and week 16 (−0.2×109 L−1 [0.7]). The values for creatine kinase, alkaline phosphatase, lactate dehydrogenase, blood urea nitrogen, albumin and protein at week 16 remained within the normal reference range in all treatment groups. Two patients in the dupilumab 200/300 mg q4w arm of this study reported treatment-emergent adverse events of severe and moderate eosinophilia. Neither event was associated with clinical symptoms nor led to the discontinuation of the study treatment. No clinically meaningful changes in hematology and chemistry parameters in children aged 6 months to 5 years with moderate-to-severe AD were seen with 16 weeks of dupilumab treatment. These data demonstrate that, as with adults, adolescents and older children, routine laboratory monitoring is unnecessary in this younger population. Dupilumab was generally well tolerated with an acceptable safety profile. [ABSTRACT FROM AUTHOR]

Atopic dermatitis (AD) is a common, chronic inflammatory skin disease often associated with a significant long-term disease burden. AD can profoundly impact a patient’s physical and mental health. Current AD management recommendations do not capture patient perspectives on their treatment needs, expectations and drivers of decision-making. Qualitative patient research is needed to support the creation of patient-centric recommendations for AD assessment and management. To study a large, international, ethnically diverse population of patients with AD that will enable the creation of patient-centric recommendations for AD management. Adult patients (≥18 years old) receiving treatment for AD were recruited from patient market research databases, clinician referrals, and local advertising. All patients were screened via a questionnaire to ensure a balanced and diverse range of ages, gender, educational levels, geographic locations, and AD severities, and to confirm that they were currently receiving treatment for AD. Patients participated in a 45-minute, 1 :1 telephone interview con - ducted in their native language by the research team. These interviews explored the impact of AD on patients’ lives, patients’ most troublesome symptoms, how patients make treatment decisions and patients’ treatment expectations. Patients were also questioned on their current knowledge of AD scoring systems and what they thought was most important to include in AD scoring systems. A large ethnically diverse global patient population (N =88; 15 countries) was included in the study. AD was reported to have a substantial, broad impact on patients’ lives, with patients being affected by AD at all times of the day and night. Itch, skin redness, dry/flaky skin and sleep disturbance were the most frequently reported signs and symptoms, with over 75% of patients experiencing them every 1–3 days. The itch was cited by 37% of patients as being the primary reason for changing AD treatments. In addition, the research revealed that mental health issues such as anxiety and depression are common in patients suffering from AD, and these features have the greatest negative impact on patients’ daily lives. Patients reported that AD impairs their quality of life, with many perceiving that clinicians underestimate this burden; this was reported more often for non-specialists compared with dermatologists. Patients also felt they were often not given enough time to express themselves in medical appointments and reported an inability to optimally communicate with their clinicians. Patients had little awareness of AD severity scoring systems, with almost no survey respondents reporting their use during previous healthcare encounters. When questioned about their preferences for different AD scoring systems, patients favoured using a combination of patient-reported outcomes to reflect disease burden and clinician-reported outcomes to ensure consistency across different physicians and patient populations. These preferences indicate that an optimal scoring system would consider a diverse range of symptoms, and the variable nature of AD, and be accessible regardless of education level. No single AD scoring system was preferred by all patients. Patients indicated that they would like AD scoring systems to be incorporated into clinical practice, to help them communicate their AD burden to clinicians, and to provide a clear framework for monitoring treatment response. This global patient study generated insights into the burden of AD on patients’ lives, their expectations of treatment, and their views on AD scoring methods. Results provided an evidence base for the development of patient-centric recommendations for AD management. [ABSTRACT FROM AUTHOR]

Limited treatment options are available for adolescents with moderate-to-severe atopic dermatitis (AD). Tralokinumab is a high-affinity, fully human monoclonal antibody that specifically neutralizes interleukin-13, a key driver of inflammation in AD. In the phase III ECZTRA 6 trial (NCT03526861), tralokinumab 150 or 300 mg monotherapy every 2 weeks (Q2W) was effective and well tolerated in paediatric patients aged 12–17 years, and tralokinumab 300 mg was recently approved in Europe for the treatment of adolescents with moderate-to-severe AD. To report the efficacy and safety of tralokinumab 300 mg in adolescents with AD over the entire 52-week ECZTRA 6 study period. Patients were randomized to tralokinumab 300 mg Q2W (n=97) or placebo (n=94) for 16 weeks. At week 16, patients were initiated on tralokinumab and achieved the primary endpoints (Investigator’s Global Assessment [IGA] 0/1 and/or Eczema Area and Severity Index [EASI]-75), without the use of rescue treatment (topical/systemic AD therapy), were re-randomized to tralokinumab 300 mg Q2W/Q4W monotherapy for 36 additional weeks. During this blinded maintenance period, patients exhibiting a pre-defined relapse relative to their week 16 response were transferred to the open-label arm and treatment with tralokinumab 300 mg Q2W plus optional topical calcineurin inhibitors (TCIs) or topical corticosteroids (TCSs). Patients not achieving the primary endpoints were transferred to the open-label arm at week 16. A pre-specified treatment policy approach for the analyses was adopted using observed data, regardless of rescue medication and treatment discontinuation, to better reflect real-world treatment scenarios. Missing data were imputed using multiple imputations. Treatment differences for the binary endpoints were analysed using the Cochran-Mantel-Haenszel method stratified by region, and baseline IGA. Continuous endpoints were analysed using analysis of covariance accounting for the treatment, region, baseline IGA and baseline outcome value. Post-hoc analyses were conducted by pooling week 16–52 data for all patients initially randomized to tralokinumab 300 mg Q2W, irrespective of the response achieved at week 16, the dosing regimen received beyond week 16, or whether discontinuing treatment before week 16. At week 16, greater proportions of tralokinumab-treated patients (300 mg Q2W vs. placebo) achieved EASI-75 (38.4% vs. 23.5%; difference 15.4% [standard error, SE 6.53%]; P=0.0186) and EASI-90 (23.9% vs. 10.4%, difference 13.6% [SE 5.55%]; P=0.0142). Pooling all patients initially randomized to tralokinumab 300 mg Q2W and subsequently continuing on Q2W/Q4W monotherapy or Q2W plus optional TCI/TCS, response rates increased to 68.8% (EASI-75) and 42.8% (EASI-90) at week 52. Similarly, mean [SE] EASI and SCORing AD (SCORAD) improved with tralokinumab vs. placebo (EASI: 59.62% [4.36%] vs. 37.90% [5.16%]; P=0.0006 and SCORAD: 43.72% [3.13%] vs. 24.91% [3.31%]; P<0.0001) at week 16, with further improvement to 77.95% [2.96%] and 60.77% [2.81%] at week 52, respectively. Cumulative proportions of patients using concomitant TCI/TCS as rescue therapy during the first 16 weeks were lower with tralokinumab (29.9%) vs. placebo (54.3%). Over 52 weeks, the cumulative proportion of tralokinumab-treated patients using TCI/TCS increased to 47.4%, as TCI/TCS was permitted as optional concomitant medication in the open-label arm. Through week 16, proportions of patients with ≥1 adverse event (AE) were (tralokinumab 300 mg vs. placebo) 64.9 vs. 61.7%; ≥1 serious AE, 1.0 vs. 5.3%; AEs leading to discontinuation, 0% vs. 0%. The number of patients with conjunctivitis (incl. bacterial and allergic) was low (3.1% vs. 2.1%). The safety profile of tralokinumab 300 mg through week 52 was consistent with that at week 16. At week 16, tralokinumab 300 mg improved the extent and severity of AD compared with a placebo in adolescent patients with moderate-to-severe AD. Response rates progressively improved with continued tralokinumab plus optional TCS/TCI. Tralokinumab was well tolerated with a reassuring long-term safety profile over 52 weeks. [ABSTRACT FROM AUTHOR]