A placebo-controlled trial to investigate the safety and efficacy of Penicillin G/Hydrocortisone in patients with ALS (PHALS trial)

Objective: A recent case-series described patients with ALS to improve and/or stabilize after treatment with intravenous high-dose Penicillin G/Hydrocortisone (PenGH). In this study, we determine the safety and efficacy of intravenous PenGH versus placebo in combination with riluzole in patients with ALS.Methods: Patients diagnosed with ALS according to the El Escorial criteria were randomized double-blind to four quarterly cycles of 21 d of intravenous PenGH or placebo in a 5:3 ratio. The primary outcome was change from baseline to week 48 in Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R). Secondary outcomes were lung function, muscle strength, plasma creatinine, clinical stage, gastrostomy placement, quality of life and occurrence of adverse of events.Results: In total, 16 patients were randomized (10 PenGH and 6 placebo), of which 6 (40%) completed the study. Patients treated with PenGH progressed with 2.2 (95% CI 1.1-3.3) ALSFRS-R points per month and PenGH treatment did not halt disease progression (p = 0.002). No significant differences were found between PenGH or placebo (mean difference 0.5, 95% CI -1.01 to ∞, p = 0.28). Although PenGH was well-tolerated, 6 patients (38%, 3 in each arm) had thrombotic complications due to the intravenous administration method.Conclusions: Treatment with PenGH does not halt disease or reverse progression in patients with ALS and showed no statistical difference with those who received placebo. Prolonged intravenous administration therapies may inflate thrombosis risk

Development of a Rasch-Built Amyotrophic Lateral Sclerosis Impairment Multidomain Scale to Measure Disease Progression in ALS

BACKGROUND AND OBJECTIVES: Current scales used in amyotrophic lateral sclerosis (ALS) attempt to summarize different functional domains or "dimensions" into 1 overall score, which may not accurately characterize the individual patient's disease severity or prognosis. The use of composite score risks declaring treatments ineffective if not all dimensions of ALS disease progression are affected equally. We aimed to develop the ALS Impairment Multidomain Scale (AIMS) to comprehensively characterize disease progression and increase the likelihood of identifying effective treatments. METHODS: The Revised ALS Functional Rating Scale (ALSFRS-R) and a preliminary questionnaire, based on literature review and patient input, were completed online by patients from the Netherlands ALS registry at bimonthly intervals over a period of 12 months. A 2-week test-retest, factor analysis, Rasch analysis, and a signal-to-noise optimization strategy were performed to create a multidomain scale. Reliability, longitudinal decline, and associations with survival were evaluated. The sample size required to detect a 35% reduction in progression rate over 6 or 12 months was assessed for a clinical trial that defines the ALSFRS-R or AIMS subscales as a primary endpoint family. RESULTS: The preliminary questionnaire, consisting of 110 questions, was completed by 367 patients. Three unidimensional subscales were identified, and a multidomain scale was constructed with 7 bulbar, 11 motor, and 5 respiratory questions. Subscales fulfilled Rasch model requirements, with excellent test-retest reliability of 0.91-0.94 and a strong relationship with survival ( p < 0.001). Compared with the ALSFRS-R, signal-to-noise ratios were higher as patients declined more uniformly per subscale. Consequently, the estimated sample size reductions achieved with the AIMS compared with those achieved with the ALSFRS-R were 16.3% and 25.9% for 6-month and 12-month clinical trials, respectively. DISCUSSION: We developed the AIMS, consisting of unidimensional bulbar, motor, and respiratory subscales, which may characterize disease severity better than a total score. AIMS subscales have high test-retest reliability, are optimized to measure disease progression, and are strongly related to survival time. The AIMS can be easily administered and may increase the likelihood of identifying effective treatments in ALS clinical trials

Das Schon-jetzt und Noch-nicht der Moderne. Ironisches Komplizentum zwischen Autor und Leser bei Otto Julius Bierbaum

Dank seinem Engagement als Schriftsteller, Übersetzer, Feuilletonist, Herausgeber, Gründer und Mitarbeiter von Zeitschriften sowie Mitwirkender bei der ersten deutschen Kleinkunstbühne verdient es Bierbaum, als eine zentrale Figur der Moderne und als eine typische Erscheinung der Übergangszeit zwischen dem 19. und dem 20. Jahrhundert betrachtet zu werden. An seinem Schreiben können sowohl literarische Experimentierlust als auch das Festhalten an traditionellen Erzählmustern beobachtet werden, die auf die für die damalige Übergangsepoche kennzeichnenden ästhetischen Schwankungen hinweisen. In dieser Hinsicht kann seinem Werk ein exemplarischer Charakter zugeschrieben werden, und seine Untersuchung gewährt Einblicke in die Veränderungen, durch die viele Autoren der Jahrhundertwende das Verhältnis zwischen Autor und Empfänger zu revolutionieren trachteten. Es ging um Versuche, die ansatzweise eine Richtung einschlugen, die ihre volle Entfaltung erst später in den Avantgarden fand. Anhand von Bierbaums Werk soll es im Folgenden darum gehen, die Keime dieser Richtung in ihrem historischen und epistemologischen Zusammenhang hervorzuheben und die Aufmerksamkeit auf die Rolle zu lenken, die die Adressatenfunktion dabei spielt. Das Thema wird aus kulturpoetischer und sprachwissenschaftlicher Perspektive behandelt. Abschnitte 2 und 3 bieten eine kultur- und literaturwissenschaftliche Überlegung über Bierbaums Erzählwerk im Kontext der Moderne und der angestrebten Überwindung der Trennung zwischen Literatur und Leben. Abschnitt 4 präsentiert die linguistische Analyse des exemplarisch gewählten "Ein Brief an eine Dame anstatt einer Vorrede". Diese Untersuchung hebt hervor, wie die Erzählinstanz und ihr Bezug auf den Leser versprachlicht werden, und zeigt die Verschränkung von fiktiver und realer Adressatenfunktion in Bierbaums Vorrede. Ein kurzer Vergleich mit anderen, radikaleren Autoren der damaligen Zeit schließt den Aufsatz ab (Abschnitt 5)

Critical assessment of automated flow cytometry analysis techniques

Traditional methods for flow cytometry (FCM) data processing rely on subjective manual gating. Recently, several groups have developed computational methods for identifying cell populations in multidimensional FCM data. The Flow Cytometry: Critical Assessment of Population Identification Methods (FlowCAP) challenges were established to compare the performance of these methods on two tasks: (i) mammalian cell population identification, to determine whether automated algorithms can reproduce expert manual gating and (ii) sample classification, to determine whether analysis pipelines can identify characteristics that correlate with external variables (such as clinical outcome). This analysis presents the results of the first FlowCAP challenges. Several methods performed well as compared to manual gating or external variables using statistical performance measures, which suggests that automated methods have reached a sufficient level of maturity and accuracy for reliable use in FCM data analysis