Exploring efficacy and safety of oral Pirfenidone for progressive, non-IPF lung fibrosis (RELIEF) - a randomized, double-blind, placebo-controlled, parallel group, multi-center, phase II trial

Background: Pirfenidone is currently approved in the EU for the treatment of mild to moderate idiopathic pulmonary fibrosis (IPF) and offers a beneficial risk-benefit profile. However, there are several other, progressive fibrotic lung diseases, in which conventional anti-inflammatory therapy is not sufficiently effective and antifibrotic therapies may offer a novel treatment option. Methods/Design: We designed a study protocol for inclusion of patients with progressive fibrotic lung disease despite conventional anti-inflammatory therapy (EudraCT 2014–000861-32). The study population comprises patients with collagen-vascular disease-associated lung fibrosis (CVD-LF), fibrotic non-specific interstitial pneumonia (fNSIP), chronic hypersensitivity pneumonitis (cHP), and asbestos-related lung fibrosis (ALF). Disease progression needs to be proven by slope calculation of at least three Forced Vital Capacity (FVC) values obtained within 6–24 months prior to inclusion, documenting an annualized decline in percent predicted FVC of 5% (absolute) or more despite appropriate conventional therapy. Absolute change in percent predicted FVC from baseline - analyzed using a rank analysis of covariance (ANCOVA) model - will serve as efficacy-related primary study endpoint. Discussion: There is an urgent unmet clinical need for effective therapies for patients with a progressive fibrotic lung disease other than IPF. The current study protocol is unique with respect to selecting patients with different disease entities of lung fibrosis which have, however, essential pathophysiological characteristics in common. Moreover, by selecting patients with evidence of disease progression despite conventional therapy, the protocol ensures that a cohort of interstitial lung disease (ILD) patients with a high unmet medical need is targeted and it may allow a sufficiently high event rate for evaluation of treatment responses. Trial registration: DRKS00009822 (registration date: January 13th 2016)

Micro- and nanostructures reflect the degree of diagenetic alteration in modern and fossil brachiopod shell calcite: A multi-analytical screening approach (CL, FE-SEM, AFM, EBSD)

Fossil carbonate skeletons of marine organisms are archives for understanding the development and evolution of palaeo-environments. However, the correct assessment of past environment dynamics is only possible when pristine skeletons and their biogenic characteristics are unequivocally distinguishable from diagenetically-alteredskeletal elements and non-biogenic features. In this study, we extend our work on diagenesis of biogenic aragonite (Casella et al. 2017) to the investigation of biogenic low-Mg calcite using brachiopod shells. We examined and compared microstructural characteristics inducedby laboratory-based alteration to structural features derived from diagenetic alteration in natural environments. We used four screening methods: cathodoluminescence (CL), cryogenic and conventional field emission-scanning electronmicroscopy (FE-SEM), atomic force microscopy (AFM) and electron backscatter diffraction (EBSD).We base our assessments of diagenetic alteration and overprint on measurements of, a) images of optical overprint signals, b) changes in calcite crystal orientation patterns, and c) crystal co-orientation statistics. According to the screening process, altered and overprinted samples define two groups. In Group 1 the entire shell is diagenetically overprinted, whereas in Group 2 the shell contains pristine as well as overprinted parts. In the case of Group 2 shells, alteration occurred either along the periphery of the shell including the primary layer or at the interior-facing surface of the fibrous/columnar layer. In addition, we observed an important mode of the overprinting process, namely the migration of diagenetic fluids through the endopunctae corroborated by mineral formation and overprinting in their immediate vicinity, while leaving shell parts between endopunctae in pristine condition. Luminescence (CL) and microstructural imaging (FE-SEM) screening give first-order observations of the degree of overprint as they cover macro-to micron scale alteration features. For a comprehensive assessment of diagenetic overprint these screening methods should be complemented by screening techniques such as EBSD and AFM. They visualise diagenetic changes at submicron and nanoscale levels depicting the replacement of pristine nanocomposite mesocrystal biocarbonate (NMB) by inorganic rhombohedral calcite (IRC). The integration of screening methods allows for the unequivocal identification of highly-detailed alteration features as well as an assessment of the degree of diagenetic alteration

Neurodevelopmental outcome related to cerebral risk factors in children after neonatal arterial switch operation.

BACKGROUND: Neurodevelopmental outcome after neonatal arterial switch operation for complete transposition of the great arteries is an important topic needing prospective assessment. METHODS: A group of 33 unselected children (3.0 to 4.6 years) operated on as neonates with combined deep hypothermic circulatory arrest and low flow cardiopulmonary bypass and a control group of 32 age-matched healthy children (3.0 to 4.8 years) underwent evaluation of socioeconomic and clinical neurological status and a standardized test comprising all areas of child development. Results of patients were related to those of the control group, to population norms, and to preoperative, perioperative, and postoperative cerebral risk factors. RESULTS: Clinical neurological status was normal in 26 patients (78.8%) and reduced in 7 (21.2%). Complete developmental score and the subscores for motor function, visual perception, learning and memory, cognitive function, language, and socioemotional functions were not different compared to population norms. Compared to the patients, the children of the control group scored higher on tests of complete development, cognition, and language, but also on socioeconomic status. Complete developmental score and the scores for motor, cognitive, and language functions were weakly inversely related to the duration of circulatory arrest, but not to the duration of bypass. Cerebral risk factors such as serum levels of the neuron-specific enolase, perinatal acidosis, perinatal asphyxia, peri- and postoperative cardiocirculatory insufficiency, or clinical seizures were not correlated to the test results. CONCLUSIONS: Neonatal arterial switch operation with combined circulatory arrest and low flow bypass is associated with neurological impairment, but not with reduced development as assessed by formal testing of motor, cognitive, language, and behavioral functions. Perioperative serum level of the neuron-specific enolase is not a valid marker for later developmental impairment

Monitoring the chemistry of self-healing by vibrational spectroscopy – current state and perspectives

Self-healing materials are designed to heal damage caused by, for example, mechanical stress or aging such that the original functionality of the material is at least partially restored. Thus, self-healing materials hold great promise for prolonging the lifetime of machines, particularly those in remote locations, as well as in increasing the reliability and safety associated with functional materials in, for example, aeronautics applications. Recent material science applications of self-healing have led to an increased interest in the field and, consequently, the spectroscopic characterization of a wide range of self-healing materials with respect to their mechanical properties such as stress and strain resistance and elasticity was in the focus. However, the characterization of the chemical mechanisms underlying various self-healing processes locally within the damaged region of materials still presents a major challenge. This requires experimental techniques that work non-destructively in situ and are capable of revealing the chemical composition of a sample with sufficient spatial and temporal resolution without disturbing the healing process. Along these lines, vibrational spectroscopy and, in particular Raman spectroscopy, holds great promise, largely due to the high spatial resolution in the order of several hundreds of nanometers that can be obtained. This article aims to summarize the state of the art and prospective of Raman spectroscopy to contribute significant insights to the research on self-healing materials - in particular focusing on polymer and biopolymer materials