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Massimo Travaglini,1 Julia-Tatjana Maul,2,3 Christian Kors,4 Shirin Zaheri,5 Jens Gerwien,6 Michaela Müller,6 Alan Brnabic,6 Silvia Sabatino,6 Christopher Schuster,6,7 Tsen-Fang Tsai8 1Centre for the Treatment of Psoriasis, Di Summa-Perrino Hospital, Brindisi, Italy; 2Department of Dermatology and Venereology, University Hospital of Zurich, Zurich, Switzerland; 3Faculty of Medicine, University of Zurich, Zurich, Switzerland; 4Private Practice Dermatology, Berlin, Germany; 5Department of Dermatology, The Harley Street Clinic, HCA Healthcare UK, London, UK; 6Eli Lilly and Company, Indianapolis, IN, USA; 7Department of Dermatology, Medical University of Vienna, Vienna, Austria; 8Department of Dermatology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei City, TaiwanCorrespondence: Tsen-Fang Tsai, Department of Dermatology, National Taiwan University Hospital and National Taiwan University College of Medicine, 7, Chung-Shan South Road, Taipei City, 100225, Taiwan, Tel +886 223123456#65734, Email tftsai@yahoo.comPurpose: Since skin is highly accessible, clinical photography is a useful tool to visually substantiate the real-world effectiveness outcomes of biologic-treated adults with moderate-to-severe psoriasis (PsO). We report the effectiveness and patient-reported outcomes at Week 12 between anti-interleukin (IL)-17A biologics and other biologics as well as ixekizumab and guselkumab in patients with available clinical photography at baseline and Week 12.Patients and Methods: The Psoriasis Study of Health Outcomes (PSoHO) is an international, non-interventional, cohort study investigating the effectiveness of biologics in adults with moderate-to-severe psoriasis at Week 12. Outcomes included the proportion of patients who achieved 90% improvement in Psoriasis Area and Severity Index (PASI90) and/or static Physician Global Assessment (sPGA) 0/1 (primary endpoint), PASI100, PASI90, Dermatology Life Quality Index (DLQI), and Itch Numeric Rating Scale (NRS) (secondary endpoints) at Week 12. Data are reported descriptively.Results: This analysis included 59 biologic-treated (23 anti-IL-17A; 36 other biologics) patients with available clinical photographs from the overall PSoHO study (n=1981). At baseline, the mean (standard deviation [SD]) age was 45.7 (11.1) years, 71.2% were male, 52.5% were bio-experienced and the median (interquartile range) duration of disease was 10.5 (12.4) years. Mean (SD) PASI was 16.9 (9.3) and sPGA was 3.5 (0.8). At Week 12, 65.2%/47.2% of the anti-IL-17A/other biologics cohort achieved the primary outcome. Response rates for PASI90/100 were numerically higher with anti-IL-17A than with other biologics. Patients receiving anti-IL-17A had numerically better outcomes for DLQI 0/1 and Itch NRS than those receiving other biologics at Week 12. Clinical photographs confirmed skin improvements in ixekizumab- and guselkumab-treated patients.Conclusion: This subgroup analysis showed that anti-IL-17A biologics are effective at rapidly improving signs and symptoms of PsO and improving quality of life. Additionally, serial photography provided visual evidence of biologic treatment response over time.Keywords: psoriasis, ixekizumab, guselkumab, real-world, clinical photography

The function of MHC class-I molecules is to sample peptides from the intracellular environment and present them to CD8+ cytotoxic T lymphocytes. To understand the molecular details of the assembly (and disassembly) of peptide-β2m-class-I complexes a biochemical peptide-class-I binding assay has been generated recently and this paper reports on a similar assay for the interaction between β2m and class I. As a model system human β2m binding to mouse class I was used. The assay is strictly biochemical using purified reagents which interact in solution and complex formation is determined by size separation. It is specific and highly sensitive. The observed affinity of the interaction, KD, is close to 0.4 nM. The rate of association at 37°C is very fast (the ka is around 5 x 104/M/s) whereas the dissociation is slow (the kd is around 8 x 10-6/s); the ratio of dissociation to association yields a calculated KD close to the observed value. At 37°C almost all of the purified class I participates in binding of the exogenously offered β2m showing that a considerable exchange of the endogenous β2m occurs. Finally, it was demonstrated that exogenous β2m enhances binding to MHC class-I of short perfectly-matching peptides as well as longer peptides. [ABSTRACT FROM AUTHOR]

The aim of this study was to test whether the availability of internal imagery elicited by words is related to ratings of word imageability. Participants are presented with target words and, after a delay allowing for processing of the word, answer questions regarding the size or weight of the word referents. Target words differ with respect to imageability. Results show faster responses to questions for high imageability words than for low imageability words. The type of question (size/weight) modulates reaction times suggesting a dominance of the visual domain over the physical-experience domain in concept representation. Results hold across two different languages (Czech/German). These findings provide further insights into the representations underlying word meaning and the role of word imageability in language acquisition and processing., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Introduction: Baricitinib, an orally available small-molecule inhibitor of Janus kinase (JAK)1 and JAK2, is indicated to treat active moderate-to-severe rheumatoid arthritis (RA)., Objective: This systematic review described the real-world clinical characteristics of baricitinib-treated patients with RA, prescription patterns, effectiveness, drug persistence, patient-reported outcomes (PROs; physical function, pain, health-related quality of life [HRQoL]), patient global assessment (PGA), and safety of baricitinib., Methods: A PRISMA systematic review of real-world studies was conducted to identify relevant literature published between January 2016 and September 2022 using MEDLINE®, EMBASE®, and evidence-based medicine review databases. Websites or online repositories of the American College of Rheumatology and the European Alliance of Associations for Rheumatology were searched manually to include relevant abstracts from conferences held between January 2016 and November 2022., Results: A total of 11,472 records were identified by searching online databases. Seventy studies were included in the study, of which 40 were abstracts. Most patients were older (51-71 years), female, and with mean RA duration of 4-19 years. Baricitinib was mostly used after the failure of one or more bDMARDs, and 4 mg dosing was prevalent in patients with RA (range 22-100%). Clinical effectiveness of baricitinib was reported in real-world settings regardless of prior biologic/targeted synthetic disease-modifying antirheumatic drug (DMARD) use and concomitant conventional synthetic DMARD use. Achievement of Clinical Disease Activity Index (CDAI) remission was reported in 8.7-60% of patients at week 12 and CDAI low disease activity (LDA) in 20.2-81.6% at week 24. The proportion of patients attaining Simple Disease Activity Index (SDAI) remission was reported in 12% at week 4 to 45.4% at 24 weeks. Drug persistence was high, similar, or equal to anti-tumor necrosis factor drugs. No new safety signals were identified., Conclusion: Baricitinib demonstrated effectiveness in the real-world setting with a consistent safety profile observed in clinical studies. Better persistence rates for baricitinib compared to bDMARDs with improvement in PROs were reported, although baricitinib-treated patients had RA with poor prognostic characteristics., (© 2023. The Author(s).)

Introduction: RA-BE-REAL is a 3-year, multinational, prospective, observational study of adult patients with rheumatoid arthritis (RA) evaluating time to discontinuation of initial RA treatment along with patient baseline characteristics. This study's primary objective was to assess the time to discontinuation of initial baricitinib, any other targeted synthetic disease-modifying anti-rheumatic drug (tsDMARD), or any biologic disease-modifying anti-rheumatic drug (bDMARD) treatment for all causes (excluding sustained clinical response) over 24 months in a European population., Methods: Patients initiated treatment with baricitinib (cohort A) or any bDMARD or tsDMARD (cohort B) for the first time. This study's primary objective was to assess the time to discontinuation of initial baricitinib, any other targeted synthetic disease-modifying anti-rheumatic drug (tsDMARD), or any biologic disease-modifying anti-rheumatic drug (bDMARD) treatment for all causes (excluding sustained clinical response) over 24 months in a European population. Comparative effectiveness analyses, over 24 months, included time to treatment discontinuation for all causes (excluding sustained clinical response), percentage of patients achieving Clinical Disease Activity Index (CDAI) remission or low disease activity (LDA), as well as mean changes from baseline for CDAI, pain visual analogue scale, and the Health Assessment Questionnaire-Disability Index (HAQ-DI). For this European subpopulation, comparative analyses were performed using a frequentist model averaging (FMA) framework based on a data-driven machine learning causal inference approach to compare time to discontinuation, effectiveness, rates of remission or LDA, and patient-reported outcomes over 24 months comparing baricitinib with TNFi, as well as non-TNFi and tsDMARD grouped as other mechanism of action (OMA) drugs., Results: In the European sample of RA-BE-REAL, patients with RA treated with baricitinib experienced fewer discontinuations in comparison to those treated with tumour necrosis factor inhibitors or OMA. Overall, patients naïve to b/tsDMARDs achieved a higher rate of LDA and remission compared with experienced patients. A significantly greater proportion of patients treated with baricitinib achieved LDA compared with b/tsDMARDs., Conclusion: This real-world data can better inform clinicians about baricitinib effectiveness and drug survival when prescribing treatment for patients with RA across different subpopulations., (© 2023. The Author(s).)

Objectives: To examine the prevalence of sleep disturbances, quantified by the Pittsburgh Sleep Quality Index (PSQI), in patients with psoriatic arthritis (PsA), psoriasis (PsO) and healthy controls (HCs), explore associations between PSQI and clinical and patient-reported outcomes, and evaluate the effect of treatment on PSQI., Method: Patients were included from the Parker Institute's PsA patient cohort to evaluate the prevalence of sleep disturbances. Univariate and multivariate regression analyses were used to explore associations between sleep disturbance and outcome measures. Treatment effect in PsA patients was assessed with a mixed-effect model for repeated measures., Results: In total, 109 PsA patients, 20 PsO patients, and 20 HCs were included. Sleep disturbances were reported by 66.1% of PsA patients, 45.0% of PsO patients, and 15.0% of HCs. Univariate regression analyses revealed statistically significant associations (p < 0.001) between PSQI and Disease Activity Score (DAS28CRP), tender points, visual analogue scale (VAS) patient global and pain, Psoriatic Arthritis Impact of Disease fatigue, Health Assessment Questionnaire (HAQ), and painDETECT score. Multivariate regression analysis demonstrated VAS patient global, VAS pain, and tender points as being independently associated with PSQI. The mixed-effect model revealed no effect of treatment., Conclusion: More PsA patients than PsO patients and HCs reported sleep disturbances. Sleep disturbances were associated with inflammatory and non-inflammatory measures possibly explaining the limited effect of treatment. This demonstrates the need for interdisciplinary approaches to improve the management of sleep disturbance in PsA. Trial registration : ClinicalTrials.gov (NCT02572700).

Research on the interrelation between language and other components of cognition makes frequent use of verbal interference paradigms. In this, participants are engaged in a primary nonverbal task, while simultaneously repeating non-sense syllables from memory or playback to occupy their articulatory buffer, which is assumed to block internal language use. However, language production involves different subprocesses and levels of representation, and no previous study has explicitly investigated which of these are affected by an occupied articulatory buffer. Thus, the current study addresses the question whether an occupied articulatory buffer significantly interferes with conceptualization. In Experiment 1, speakers name simple objects as fast and as accurately as they can under three conditions. In an interference condition, the verbalization task runs in parallel to a secondary, syllable memorization/recall task, which was expected to induce a situation in which the articulatory buffer temporarily holds phonological information while speakers engage in conceptualization. The articulatory buffer was not occupied in two control conditions. In Experiment 2, speakers performed a similar but more complex task. They verbally responded to visual depictions of actions, again under an interference condition and two control conditions. Results obtained in both experiments suggested no interference. Taken together, the findings suggest that an occupied articulatory buffer does not significantly affect conceptualization., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Event perception and cognition is integral to our everyday experience and functional ability. A commonly reported complaint in Alzheimer's disease (AD) is the inability to follow narratives - be it textual, conversational, video, or pictures. This phenomenon has received little systematic research so far. In the current study, we developed a novel paradigm to examine macro-event recognition in individuals with AD in the early stage and its preceding stage of mild cognitive impairment (MCI) in comparison with cognitively healthy older adults, using pictures depicting events. In Experiment 1, we examined participants' ability to integrate pictorially depicted sub-events into macro-events. The pictures were presented in a scrambled order, and participants were expected to arrange them in the temporally and causally appropriate sequence, as dictated by the macro-event schema. Additionally, we investigated the effect of cueing the appropriate event schema by providing a word cue (verb). In Experiment 2, macro-event recognition was examined again using a cognitively less taxing paradigm, where pictures depicting sub-events were presented in correct order, but staggered, and recognition speed was measured. We observed significant deficits in the AD and MCI groups' performance compared with the cognitively healthy older adults, across both experiments, suggesting event perception and cognition is impaired early in the course of AD. There was no effect of cueing on the performance of any of the groups. The theoretical and clinical implications of these findings are discussed., (© 2021 The Authors. Journal of Neuropsychology published by John Wiley & Sons Ltd on behalf of The British Psychological Society.)

Events, as fundamental units in human perception and cognition, are limited by quality changes of objects over time. In the present study, we investigate the role of language in shaping event units. Given fundamental cross-linguistic differences in the concepts encoded in the verb, as in French compared to German, event unit formation was tested for motion events in a verbal (online event description, experiment 1), as well as a non-verbal task (Newtson-test, experiment 2). In German, motion and direction are described by a single assertion, i.e. one verb encoding manner (to walk …), in conjunction with adpositional phrases for path and direction (… over x across y toward z). In contrast, when information on path and direction is encoded in the verb, as typically in French, each path segment requires a separate assertion (head for x, cross y, approach z). Both experiments were based on short naturalistic video clips showing a figure moving through space along a path either without changing orientation/direction (control), or with changes in orientation/direction (critical). Analysis of the verbal task concerned the probability of producing more than one assertion to refer to the motion events presented in the clips; in the non-verbal event segmentation task, the analysis concerned the probability of marking an event boundary, as indicated by pressing a button. Results show that in French, the probability of producing more than one assertion was significantly higher in the critical condition (experiment 1) and the probability to identify an event boundary was also significantly higher (experiment 2), compared to the German participants but only in the critical condition. The findings indicate language-driven effects in event unit formation. The results are discussed in the context of theories of event cognition, thereby focusing on the role of language in the formation of cognitive structures., (Copyright © 2018 Elsevier B.V. All rights reserved.)

This review describes the IL-20 family of cytokines in rheumatoid arthritis (RA) and spondyloartrhitits (SpA) including psoriatic arthritis. The IL-20 receptor (R) cytokines IL-19, IL-20, and IL-24 are produced in both the peripheral blood and the synovial joint and are induced by Toll-like receptor ligands and autoantibody-associated immune complexes in monocytes. IL-19 seems to have anti-inflammatory functions in arthritis. In contrast, IL-20 and IL-24 increase the production of proinflammatory molecules such as monocyte chemoattractant protein 1 and are associated with bone degradation and radiographic progression. IL-22 is also associated with progression of bone erosions. This suggests that the IL-22RA1 subunit shared by IL-20, IL-22, and IL-24 is important for bone homeostasis. In line with this, the IL-22RA1 has been found on preosteoclasts in early RA. IL-26 is produced in high amounts by myofibroblasts and IL-26 stimulation of monocytes is an important inducer of Th17 cells in RA. This indicates a role for IL-26 as an important factor in the interactions between resident synovial cells and infiltrating leukocytes. Clinical trials that investigate inhibitors of IL-20 (fletikumab) and IL-22 (fezakinumab) in psoriasis and RA have been terminated. Instead, it seems that the strategy for modulating the IL-20 cytokine family should take the overlap in cellular sources and effector mechanisms into account. The redundancy encourages inhibition of more than one cytokine or one of the shared receptors. All IL-20 family members utilize the Janus kinase signaling pathway and are therefore potentially inhibited by drugs targeting these enzymes. Effects and adverse effects in ongoing clinical trials with inhibitors of IL-22 and the IL-22RA1 subunit and recombinant IL-22 fusion proteins will possibly provide important information about the IL-20 subfamily of cytokines in the future.

Interaction between the activating NKG2D receptor on lymphocytes and its ligands MICA, MICB, and ULBP1-6 modulate T and NK cell activity and may contribute to the pathogenesis of Crohn's disease (CD). NKG2D ligands are generally not expressed on the cell surface of normal, non-stressed cells, but expression of MICA and MICB in CD intestine has been reported. In this exploratory study, we further characterize the expression of NKG2D and its ligands, including the less well-described ULBP4-6, in CD, and test if NKG2D ligand interactions are involved in the migration of activated T cells into the affected mucosal compartments. Intestinal tissue from CD patients and healthy controls were analyzed by flow cytometry, mass cytometry, and immunohistochemistry for expression of NKG2D and ligands, and for cytokine release. Furthermore, NKG2D-dependent chemotaxis of activated CD8 + T cells across a monolayer of ligand-expressing human intestinal endothelial cells was examined. Activated lymphocytes down-regulated NKG2D expression upon accumulation in inflamed CD intestine. NKG2D expression on CD56 + T and γδ T cells from inflamed tissue seemed inversely correlated with CRP levels and cytokine release. B cells, monocytes, mucosal epithelium, and vascular endothelium expressed NKG2D ligands in inflamed CD intestine. The expression of NKG2D ligands was correlated with cytokine release, but was highly variable between patients. Stimulation of vascular intestinal endothelial cells in vitro induced expression of NKG2D ligands, including MICA/B and ULBP2/6. Blockade of NKG2D on CD8 + T cells inhibited the migration over ligand-expressing endothelial cells. Intestinal induction of NKG2D ligands and ligand-induced down-regulation of NKG2D in CD suggest that the NKG2D-ligand interaction may be involved in both the activation and recruitment of NKG2D + lymphocytes into the inflamed CD intestine., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Crohn's disease (CD) is a chronic illness demanding better therapeutics. The marketed biologics only benefit some patients or elicit diminishing effect over time. To complement the known methods in drug development and to obtain patient specific drug responses, we optimized and validated a known human explant method to test drug candidates and pathophysiological conditions in CD intestinal biopsies. Mucosal biopsies from 27 CD patients and 6 healthy individuals were collected to validate an explant assay test where the polarized tissue was cultured on a novel metal mesh disk, slightly immersed in medium imitating an air-liquid interphase. After culture in high oxygen for 24 hours with or without biological treatment in the medium, biopsy integrity and penetration of antibodies was measured by immunohistochemistry (IHC). Nine cytokines were quantified in the conditioned medium as a read-out for degree of inflammation in individual biopsies and used to evaluate treatment efficacy. The biopsies were well-preserved, showing few structural changes. IHC revealed tissue penetration of antibodies demonstrating ability to test therapeutic antibodies. The cytokine release to the medium showed that the assay can distinguish between inflammation states and then validate the known effect of two treatment biologics confirmed by a detection panel of five specific cytokines. Our data also suggest that the assay would be able to indicate which patients are responders to anti-TNF-α therapeutics, and which are non-responders. This study demonstrates this version of an ex vivo culture as a valid and robust assay to assess inflammation in mucosal biopsies and test of the efficacy of novel drug candidates and current treatments on individual patients-potentially for a personalized medicine approach.