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Objective: To conduct subset analyses of SPIRIT-P2 (Standard Protocol Items: Recommendations for Interventional Trials, NCT02349295) to investigate the efficacy and safety of ixekizumab versus placebo in three subgroups of patients with active psoriatic arthritis (PsA) according to the concomitant conventional synthetic disease-modifying antirheumatic drug (cDMARD) received: any background cDMARDs (including methotrexate), background methotrexate only
Methods: Patients were randomised to receive placebo, ixekizumab 80 mg every 4 weeks (IXEQ4W) or every 2 weeks (IXEQ2W). Efficacy and safety were assessed when patients were subdivided according to cDMARD use at baseline. Efficacy was evaluated versus placebo at week 24 by the American College of Rheumatology criteria (ACR20/50), achievement of minimal disease activity (MDA) state, DiseaseActivityIndex for PsA (DAPSA), 28-joint DiseaseActivityScore using C reactive protein (DAS28-CRP), HealthAssessmentQuestionnaire-Disability Index and the 36-item Short-Form health survey physical functioning domain.
Results: Regardless of background cDMARD status, ACR20, ACR50 and MDA response rates were significantly higher than placebo with IXEQ4W or IXEQ2W treatment. Similarly, significant improvements were observed relative to placebo for DAS28-CRP and DAPSA across subgroups. Physical function also significantly improved relative to placebo with IXEQ4W treatment regardless of background cDMARD status and with IXEQ2W alone. Percentages of reported treatment emergent adverse events (AEs), serious AEs (including serious infections) and discontinuations due to AEs in each subgroup were comparable to the overall SPIRIT-P2 population.
Conclusion: Ixekizumab was efficacious in patients with active PsA and previous tumour necrosis factor inhibitor (TNFi)inadequate response or TNFi intolerance treated with ixekizumab alone or when added to cDMARDswith subgroup safety profiles that were consistent with that observed in the overall SPIRIT-P2 population.
80'li ve 90'lı yıllarda çeviribilim çalışmaları yaşanan kültürel dönemeç (Cultural turn) ile yeni ve bütüncül yaklaşımlarla ele alınmaya başlanmıştır. O tarihe kadar geliştirilmiş yaklaşımlardaki yapısalcı tutum, çeviriyi anlamak ve tanımlamak açısından yetersiz kaldığı nedeniyle çeviride işlev odaklı yaklaşımlara ağırlıklı olarak yer verilmeye başlanmıştır. Reiβ / Vermeer’in (1984) "Skopos Kuramı" yaklaşımı, dil ve kültürbilimin bir parçası olarak kabul etmektedirler. Bu kuram çerçevesinde çeviri örnekleri irdelenecek ve işlev odaklı çeviri yaklaşımının kültürel öğelerin çevirisi için ne gibi açılımlar sağladığı incelenecektir. Bu bağlamda işlev odaklı çeviri sürecinin birbirinden farklı dilsel ve kültürel edince sahip olan çevirmen adaylarının çeviri yaklaşımlarına nasıl yansıdığı gözlemlenecektir. Bu amaçla farklı dilsel ve kültürel edince sahip çevirmen adayların çeviri sürecinde hangi çeviri yaklaşımını benimsedikleri ve bu çevimen adaylarının işlev odaklı çeviriye ne ölçüde yaklaşabildikleri üzerinde durulacaktır. Ayrıca bu süreç içerisinde bu iki farklı grubun uyguladığı çeviri stratejilerinde fark ve benzerliklerin niteliği incelenecektir. Bu bağlamda çevirmen adaylarının çeviri örnekleri incelenmiş, işlev odaklı çeviriye ne ölçüde yaklaşıldığı ortaya konmaya çalışılmıştır. Elde edilen sonuçlar birbirinden farklı dilsel ve kültürel edince sahip iki grubun farklı çevirmen tutumlarını beraberinde getirdiğini ve işlev odaklı çeviride de farklı sonuçlara götürdüğünü ortaya koymuştur. Bu inceleme işlev odaklı çevirinin süreçleri hakkında yeni açılımlara varmayı amaçlamaktadır.
Cardiovascular disease remains a leading cause of morbidity and mortality globally. Changing natural history of the disease due to improved care of acute conditions and ageing population necessitates new strategies to tackle conditions which have more chronic and indolent course. These include an increased deployment of safe screening methods, life-long surveillance, and monitoring of both disease activity and tailored-treatment, by way of increasingly personalized medical care. Cardiovascular magnetic resonance (CMR) is a non-invasive, ionising radiation-free method, which can support a significant number of clinically relevant measurements and offers new opportunities to advance the state of art of diagnosis, prognosis and treatment. The objective of the SCMR Clinical Trial Taskforce was to summarizes the evidence to emphasize where currently CMR-guided clinical care can indeed translate into meaningful use and efficient deployment of resources results in meaningful and efficient use. The objective of the present initiative was to provide an appraisal of evidence on analytical validation, including the accuracy and precision, and clinical qualification of parameters in disease context, clarifying the strengths and weaknesses of the state of art, as well as the gaps in the current evidence This paper is complementary to the existing position papers on standardized acquisition and post-processing ensuring robustness and transferability for widespread use. Themed imaging-endpoint guidance on trial design to support drug-discovery or change in clinical practice (part II), will be presented in a follow-up paper in due course. As CMR continues to undergo rapid development, regular updates of the present recommendations are foreseen.
Introduction Current: evidence suggests that the loss of mechanoreceptors after anterior cruciate ligament (ACL) tears might be compensated by increased cortical motor planning. This occupation of cerebral resources may limit the potential to quickly adapt movements to unforeseen external stimuli in the athletic environment. To date, studies investigating such neural alterations during movement focused on simple, anticipated tasks with low ecological validity. This trial, therefore, aims to investigate the cortical and biomechanical processes associated with more sport-related and injury-related movements in ACL-reconstructed individuals.
Methods and analysis: ACL-reconstructed participants and uninjured controls will perform repetitive countermovement jumps with single leg landings. Two different conditions are to be completed: anticipated (n=35) versus unanticipated (n=35) successful landings. Under the anticipated condition, participants receive the visual information depicting the requested landing leg prior to the jump. In the unanticipated condition, this information will be provided only about 400 msec prior to landing. Neural correlates of motor planning will be measured using electroencephalography. In detail, movement-related cortical potentials, frequency spectral power and functional connectivity will be assessed. Biomechanical landing quality will be captured via a capacitive force plate. Calculated parameters encompass time to stabilisation, vertical peak ground reaction force, and centre of pressure path length. Potential systematic differences between ACL-reconstructed individuals and controls will be identified in dependence of jumping condition (anticipated/ unanticipated, injured/uninjured leg and controls) by using interference statistics. Potential associations between the cortical and biomechanical measures will be calculated by means of correlation analysis. In case of statistical significance (α<0.05.) further confounders (cofactors) will be considered.
Ethics and dissemination: The independent Ethics Committee of the University of Frankfurt (Faculty of Psychology and Sports Sciences) approved the study. Publications in peer-reviewed journals are planned. The findings will be presented at scientific conferences.
Trial status: At the time of submission of this manuscript, recruitment is ongoing.
Trial registration number: NCT03336060; Pre-results.
Background: Conversion from calcineurin inhibitor (CNI) therapy to a mammalian target of rapamycin (mTOR) inhibitor following kidney transplantation may help to preserve graft function. Data are sparse, however, concerning the impact of conversion on posttransplant diabetes mellitus (PTDM) or the progression of pre-existing diabetes.
Methods: PTDM and other diabetes-related parameters were assessed post hoc in two large open-label multicenter trials. Kidney transplant recipients were randomized (i) at month 4.5 to switch to everolimus or remain on a standard cyclosporine (CsA)-based regimen (ZEUS, n = 300), or (ii) at month 3 to switch to everolimus, remain on standard CNI therapy or convert to everolimus with reduced-exposure CsA (HERAKLES, n = 497).
Results: There were no significant differences in the incidence of PTDM between treatment groups (log rank p = 0.97 [ZEUS], p = 0.90 [HERAKLES]). The mean change in random blood glucose from randomization to month 12 was also similar between treatment groups in both trials for patients with or without PTDM, and with or without pre-existing diabetes. The change in eGFR from randomization to month 12 showed a benefit for everolimus versus comparator groups in all subpopulations, but only reached significance in larger subgroups (no PTDM or no pre-existing diabetes).
Conclusions: Within the restrictions of this post hoc analysis, including non-standardized diagnostic criteria and limited glycemia laboratory parameters, these data do not indicate any difference in the incidence or severity of PTDM with early conversion from a CsA-based regimen to everolimus, or in the progression of pre-existing diabetes.
Trial registration: clinicaltrials.gov, NCT00154310 (registered September 2005) and NCT00514514 (registered August 2007); EudraCT (2006-007021-32 and 2004-004346-40).
Gout is the most common arthritic disease in human but was long neglected and therapeutic options are not satisfying. However, with the recent approval of the urate transporter inhibitor lesinurad, gout treatment has experienced a major innovation. Here we show that lesinurad possesses considerable modulatory potency on peroxisome proliferator-activated receptor γ (PPARγ). Since gout has a strong association with metabolic diseases such as type 2 diabetes, this side-activity appears as very valuable contributing factor to the clinical efficacy profile of lesinurad. Importantly, despite robustly activating PPARγ in vitro, lesinurad lacked adipogenic activity, which seems due to differential coactivator recruitment and is characterized as selective PPARγ modulator (sPPARγM).
Kidney injury is a common complication of severe disease. Here, we report that injuries of the zebrafish embryonal kidney are rapidly repaired by a migratory response in 2-, but not in 1-day-old embryos. Gene expression profiles between these two developmental stages identify cxcl12a and myca as candidates involved in the repair process. Zebrafish embryos with cxcl12a, cxcr4b, or myca deficiency display repair abnormalities, confirming their role in response to injury. In mice with a kidney-specific knockout, Cxcl12 and Myc gene deletions suppress mitochondrial metabolism and glycolysis, and delay the recovery after ischemia/reperfusion injury. Probing these observations in zebrafish reveal that inhibition of glycolysis slows fast migrating cells and delays the repair after injury, but does not affect the slow cell movements during kidney development. Our findings demonstrate that Cxcl12 and Myc facilitate glycolysis to promote fast migratory responses during development and repair, and potentially also during tumor invasion and metastasis.
This study was designed to investigate whether epigenetic modulation by histone deacetylase (HDAC) inhibition might circumvent resistance towards the mechanistic target of rapamycin (mTOR) inhibitor temsirolimus in a prostate cancer cell model. Parental (par) and temsirolimus-resistant (res) PC3 prostate cancer cells were exposed to the HDAC inhibitor valproic acid (VPA), and tumor cell adhesion, chemotaxis, migration, and invasion were evaluated. Temsirolimus resistance was characterized by reduced binding of PC3res cells to endothelium, immobilized collagen, and fibronectin, but increased adhesion to laminin, as compared to the parental cells. Chemotaxis, migration, and invasion of PC3res cells were enhanced following temsirolimus re-treatment. Integrin α and β receptors were significantly altered in PC3res compared to PC3par cells. VPA significantly counteracted temsirolimus resistance by down-regulating tumor cell–matrix interaction, chemotaxis, and migration. Evaluation of integrin expression in the presence of VPA revealed a significant down-regulation of integrin α5 in PC3res cells. Blocking studies demonstrated a close association between α5 expression on PC3res and chemotaxis. In this in vitro model, temsirolimus resistance drove prostate cancer cells to become highly motile, while HDAC inhibition reversed the metastatic activity. The VPA-induced inhibition of metastatic activity was accompanied by a lowered integrin α5 surface level on the tumor cells.
Der vorliegende Beitrag setzt sich Zweifaches zum Ziel: erstens, Karl Dedecius' Weg zum renommierten Übersetzer der polnischen Lyrik in Deutschland sowie sein Konzept der Übersetzungskunst zu skizzieren, und daran anschließend – an zwei Gedichten von Wisława Szymborska in der Übersetzung von Dedecius ('Das erste Foto' und 'Katze in der leeren Wohnung') – aufzuzeigen, wie selbst eine große Meisterschaft an bestimmte Grenzen stößt, die dem Übertragen der Lyrik in eine andere Sprache innewohnen.
Wie keine andere kulturelle Handlung spiegelt das Tätowieren eine intentionale Ästhetisierung des menschlichen Körpers, zwischen individueller (und damit hoch-persönlicher) Schönheitsvorstellung auf der einen und öffentlicher (Selbst-)Inszenierung auf der anderen Seite schwankend. Die Haut wird dabei – quasi lebenslang beschrieben – zum Medium der Erinnerung. Zwar wurde bereits in der Antike 'tätowiert', der heutige Begriff sowie die 'Wiederentdeckung' dieser Praxis geht allerdings auf die Forschungs- und Entdeckungsreisen des 18. Jahrhunderts zurück, in denen Europäer mit fremden Kulturen in Kontakt kamen, die solche Verfahren mit einem ästhetischen oder rituellen Hintergrund praktizierten. So übernahm James Cook in seinen Aufzeichnungen den samoanischen Begriff "tatau", etymologisch die Grundlage für "to tattoo" und das deutsche "tätowieren". Inzwischen gilt die Modifikation des eigenen Körpers durch eine Tätowierung längst nicht mehr als 'verrucht' und stellt ebenso auch keine Ausnahmeerscheinung mehr dar, was sich vor allem an der explosionsartig gestiegenen Zahl von Tattoo-Studios in der Bundesrepublik ablesen lässt – und so trägt in Deutschland heute (konservativ geschätzt) etwa zehn Prozent der Gesamtbevölkerung und 23 Prozent der 16- bis 29-Jährigen mindestens ein Tattoo auf der Haut. Aber längst nicht jede Tätowierung ist auch der Ausdruck des eigenen Schönheitsempfindens oder eine vom Träger intentional auf dem Körper eingeschriebene Botschaft. Denn bereits in der griechischen Antike wurde das Verfahren auch dazu benutzt, Sklaven zu markieren, Besitzverhältnisse und damit ihre Unfreiheit auf der Haut einzuritzen; diese entpersonalisierende Markierung setzt sich mit der Häftlingstätowierung in Gefängnissen und schließlich den nationalsozialistischen Konzentrationslagern fort, die vor allem in literarischen Texten des Shoah-Diskures aufgegriffen und verhandelt wird.