Predictors of abatacept retention over 2 years in patients with rheumatoid arthritis: results from the real-world ACTION study.

Objectives Evaluate abatacept retention over 2 years in the AbataCepT In rOutiNe clinical practice (ACTION) study

The K+ Channel Opener 1-EBIO Potentiates Residual Function of Mutant CFTR in Rectal Biopsies from Cystic Fibrosis Patients

BACKGROUND: The identification of strategies to improve mutant CFTR function remains a key priority in the development of new treatments for cystic fibrosis (CF). Previous studies demonstrated that the K⁺ channel opener 1-ethyl-2-benzimidazolone (1-EBIO) potentiates CFTR-mediated Cl⁻ secretion in cultured cells and mouse colon. However, the effects of 1-EBIO on wild-type and mutant CFTR function in native human colonic tissues remain unknown. METHODS: We studied the effects of 1-EBIO on CFTR-mediated Cl⁻ secretion in rectal biopsies from 47 CF patients carrying a wide spectrum of CFTR mutations and 57 age-matched controls. Rectal tissues were mounted in perfused micro-Ussing chambers and the effects of 1-EBIO were compared in control tissues, CF tissues expressing residual CFTR function and CF tissues with no detectable Cl⁻ secretion. RESULTS: Studies in control tissues demonstrate that 1-EBIO activated CFTR-mediated Cl⁻ secretion in the absence of cAMP-mediated stimulation and potentiated cAMP-induced Cl⁻ secretion by 39.2±6.7% (P<0.001) via activation of basolateral Ca²⁺-activated and clotrimazole-sensitive KCNN4 K⁺ channels. In CF specimens, 1-EBIO potentiated cAMP-induced Cl⁻ secretion in tissues with residual CFTR function by 44.4±11.5% (P<0.001), but had no effect on tissues lacking CFTR-mediated Cl⁻ conductance. CONCLUSIONS: We conclude that 1-EBIO potentiates Cl⁻secretion in native CF tissues expressing CFTR mutants with residual Cl⁻ channel function by activation of basolateral KCNN4 K⁺ channels that increase the driving force for luminal Cl⁻ exit. This mechanism may augment effects of CFTR correctors and potentiators that increase the number and/or activity of mutant CFTR channels at the cell surface and suggests KCNN4 as a therapeutic target for CF

Standardisiertes Mobilitätsassessment AMPPRO auf Deutsch

Um Einbußen von Lebensqualität und Mobilität nach Beinamputationen zu reduzieren, müssen die Therapie und die Prothesenversorgung kontinuierlich optimiert werden. Hierzu werden aussagekräftige, praktikable Assessments benötigt, die sowohl für die Bedürfnisse der Beinamputierten, wie auch Veränderungen im Therapieverlauf sensitiv sind. In einer Expertendiskussion innerhalb des SPA-Seminars „Befunderhebung in der Beinprothetik“ 2015 wurde das Potential des englischen Mobilitätserhebungsbogens Amputee Mobility Predictor (AmP) von Robert Gailey, Univ. Miami, positiv eingeschätzt. Der AMP lag bislang nicht auf Deutsch vor und wurde für eine erste Validierung zwei unabhängigen Studentengruppen von je vier bzw. fünf Studenten ins Deutsche übersetzt. Im Anschluss wurden die Ergebnisse der Gruppen in Zusammenarbeit zu einem gemeinsamen Entwurf des Fragenbogens zusammengefügt. Dieser wurde dann von verschiedenen Experten überprüft und zur Durchführung freigegeben. Das Ziel der Validierungsstudie welche mit Hilfe von Studenten der Universität Stuttgart am Fraunhofer IPA durchgeführt wurde, war eine Bestandsaufnahme zur Eignung des AMP-Fragebogens zur Beurteilung des Mobilitätsgrades von beinamputierten Probanden in Bezug auf dessen Reliabilität und Validität. Die Ergebnisse der Validierungsstudie können im Anschluss zur Verbesserung des Fragebogens und zur Entwicklung eines standardisierten, deutschen Fragebogens zur Mobilitätsbeurteilung herangezogen werden. Untersuchung mit zwei Anleitern und 24 Studenten, die sich auf 2 abgegrenzten Flächen aufgeteilt waren. Insgesamt 6 beinamputierte Patienten führten den AMP jeweils 2 mal auf beiden Untersuchungsflächen durch, um von 24 Studenten die Inter- und Intra-Testerreliabilität zu evaluieren. Studenten und Anleiter hatten eine Schulung zur Anwendung des AMP-Bogen. Die Intrarater- und Interraterrelabilität wurde untersucht und zeigt, dass der Fragebogen grundsätzlich reliabel und auch praktikabel ist, aber durch exakte Aussagen des Durchführers statt Funktionsbeschreibungen wie in der jetzigen Formulierung profitieren würde. Generell kann die Korrelation mit der Mobilitätsklasse gezeigt werden. Eine größere Probandenzahl ist dazu jedoch im Re-Test nötig. Eine vom engl. Fragebogen abweichende Präzisierung der Durchführung wird empfohlen was aus dieser Untersuchung genau nachvollziehbar ist. Verbesserungspotentiale des Fragebogens können eindeutig abgeleitet werden

Maintien thérapeutique à deux ans de l’abatacept en pratique courante. Résultats de la cohorte française de l’étude ACTION

International audienceObjectifsLa cohorte des patients français inclus dans l’étude ACTION (2010–2013) a été analysée. Cette étude en vie réelle, prospective, portait sur des patients atteints de polyarthrite rhumatoïde modérée à sévère, ayant initié un traitement par abatacept intraveineux.MéthodesLe maintien thérapeutique de l’abatacept à 2 ans a été analysé chez 455 patients selon : la ligne de traitement, l’IMC et le statut sérologique du facteur rhumatoïde (FR) et des anticorps antipeptides citrullinés (ACPA).RésultatsÀ 2 ans, le taux global de maintien thérapeutique (IC 95 %) était de 44 % et plus élevé chez les patients naïfs de traitement biologique comparativement aux patients en échec à au moins un agent biologique, mais non significatif (48,1 % vs 41,8 %). Ce taux a été évalué en fonction de l’IMC chez 444 patients, il est de 45,5 % sans surpoids, 48,9 % avec surpoids, 36,6 % avec obésité ; sans différence significative entre sous-groupes. Ce taux a été évalué chez 390 patients en fonction du statut FR et ACPA, il est de 45,7 % pour les FR+ et ACPA+, 43,8 % pour les FR+ ou ACPA+ et de 39,1 % pour les FR− et ACPA− ; sans différence significative entre sous-groupes.ConclusionLes données de la cohorte française d’ACTION ont confirmé l’intérêt de l’abatacept, avec un maintien thérapeutique à 2 ans de 44 %. Dans cette analyse, le maintien thérapeutique n’a pas été influencé par la ligne de traitement, l’IMC et le statut sérologique

Two-year abatacept retention rate in clinical practice in the French ACTION cohort

International audienceObjectives: Abatacept retention rates were evaluated in the French cohort in the prospective ACTION study (2010-2013), which included patients with moderate-to-severe rheumatoid arthritis managed in everyday clinical practice and started on intravenous abatacept therapy.Methods: Two-year abatacept retention rates were evaluated in 455 patients classified according to treatment line, body mass index (BMI), and status for rheumatoid factor (RF) and anti-citrullinated peptide antibody (ACPA).Results: After 2 years, the overall abatacept retention rate was 44%. The retention rate was non-significantly higher in the patients with vs. without a history of unresponsiveness to at least one biologic (48.1% vs. 41.8%, respectively). No significant retention rate differences were found across BMI categories (444 patients; <25, 45.5%; ≥25 to <30, 48.9%; and ≥30, 36.6%). Neither were any significant differences demonstrated according to RF and ACPA status (RF+ and ACPA+, 45.7%; RF+ or ACPA+, 43.8%; and FR- and ACPA-, 39.1%).Conclusion: The 44% 2-year retention rate in the French ACTION cohort supports the usefulness of abatacept therapy. In this study, retention was not associated with treatment line, BMI, or antibody status

The influence of hip muscle strength on gait in individuals with a unilateral transfemoral amputation.

IntroductionA unilateral transfemoral amputation (TFA) has a major impact on function. A leg-length discrepancy is the primary structural change, accompanied by the loss of lower-limb muscle volume and function. Prostheses can help individuals with a TFA to regain function, but such individuals still do not reach the functional level of unimpaired peers and exhibit gait deviations. This study gives insight into the causality between residual limb strength and gait deviations in individuals with a TFA.MethodsA convenient sample of 13 male individuals with a TFA (38.0 ± 12.6y; 179.7cm ± 6.5cm; 82.9kg ± 12.4kg) was recruited for this study. One participant with TFA was excluded, as he differed from the rest of the cohort, in residual limb length and the use of walking aids. A cohort of 18 unimpaired subjects served as a reference group (REF; nine females; 44y ± 13y; 174cm ± 9cm; 71kg ± 12kg). All participants underwent a conventional clinical gait analysis using a marker based 3D motion capture system and force platforms. Kinematics and kinetics were determined utilizing standard modelling methods. All subjects underwent a strength test, using a custom-made device to determine isometric moments of the hip joint in abduction, adduction, extension, and flexion. Peak values for maximum isometric moments for each movement direction and selected kinematic and kinetic values were derived from the results. Differences between subjects with TFA and unimpaired were compared using a Mann-Whitney U Test and associations between groups by Spearman's rank correlation.ResultsThe participants with a TFA showed a significantly lower maximum isometric moment for hip abduction (0.85 vs. 1.41 Nm/kg p ConclusionWe showed that there are strength deficits in individuals with TFA and, that there are moderate correlations between gait deviations, i.e. lateral trunk lean during involved side stance and isometric hip abductor moment. The relation between maximum moments during gait and the corresponding maximum isometric moment may therefore be helpful to detect strength related compensation mechanisms. However, the moderate, non-significant correlation between lateral trunk lean and isometric hip abductor moment was the only one which corresponded directly to a gait deviation. Thus results must be interpreted with care. This study suggests that gait deviations in individuals with TFA are multifactorial and cannot be exclusively explained by their strength deficits. Future studies should explore the relationship between strength with kinematics and kinetics during gait in this population

A comparison between different prediction models for invasive breast cancer occurrence in the French E3N cohort

Breast cancer remains a global health concern with a lack of high discriminating prediction models. The k-nearest-neighbor algorithm (kNN) estimates individual risks using an intuitive tool. This study compares the performances of this approach with the Cox and the Gail models for the 5-year breast cancer risk prediction. The study included 64,995 women from the French E3N prospective cohort. The sample was divided into a learning (N = 51,821) series to learn the models using fivefold cross-validation and a validation (N = 13,174) series to evaluate them. The area under the receiver operating characteristic curve (AUC) and the expected over observed number of cases (E/O) ratio were estimated. In the two series, 393 and 78 premenopausal and 537 and 98 postmenopausal breast cancers were diagnosed. The discrimination values of the best combinations of predictors obtained from cross-validation ranged from 0.59 to 0.60. In the validation series, the AUC values in premenopausal and postmenopausal women were 0.583 [0.520; 0.646] and 0.621 [0.563; 0.679] using the kNN and 0.565 [0.500; 0.631] and 0.617 [0.561; 0.673] using the Cox model. The E/O ratios were 1.26 and 1.28 in premenopausal women and 1.44 and 1.40 in postmenopausal women. The applied Gail model provided AUC values of 0.614 [0.554; 0.675] and 0.549 [0.495; 0.604] and E/O ratios of 0.78 and 1.12. This study shows that the prediction performances differed according to menopausal status when using parametric statistical tools. The k-nearest-neighbor approach performed well, and discrimination was improved in postmenopausal women compared with the Gail model