Multiphase modelling of tumour growth and extracellular matrix interaction: mathematical tools and applications

Resorting to a multiphase modelling framework, tumours are described here as a mixture of tumour and host cells within a porous structure constituted by a remodelling extracellular matrix (ECM), which is wet by a physiological extracellular fluid. The model presented in this article focuses mainly on the description of mechanical interactions of the growing tumour with the host tissue, their influence on tumour growth, and the attachment/detachment mechanisms between cells and ECM. Starting from some recent experimental evidences, we propose to describe the interaction forces involving the extracellular matrix via some concepts coming from viscoplasticity. We then apply the model to the description of the growth of tumour cords and the formation of fibrosis

The BMP Antagonist Follistatin-Like 1 Is Required for Skeletal and Lung Organogenesis

Follistatin-like 1 (Fstl1) is a secreted protein of the BMP inhibitor class. During development, expression of Fstl1 is already found in cleavage stage embryos and becomes gradually restricted to mesenchymal elements of most organs during subsequent development. Knock down experiments in chicken and zebrafish demonstrated a role as a BMP antagonist in early development. To investigate the role of Fstl1 during mouse development, a conditional Fstl1 KO allele as well as a Fstl1-GFP reporter mouse were created. KO mice die at birth from respiratory distress and show multiple defects in lung development. Also, skeletal development is affected. Endochondral bone development, limb patterning as well as patterning of the axial skeleton are perturbed in the absence of Fstl1. Taken together, these observations show that Fstl1 is a crucial regulator in BMP signalling during mouse development

Search for Ultra-high-energy Photons from Gravitational Wave Sources with the Pierre Auger Observatory

A search for time-directional coincidences of ultra-high-energy (UHE) photons above 10 EeV with gravitational wave (GW) events from the LIGO/Virgo runs O1 to O3 is conducted with the Pierre Auger Observatory. Due to the distinctive properties of photon interactions and to the background expected from hadronic showers, a subset of the most interesting GW events is selected based on their localization quality and distance. Time periods of 1000 s around and 1 day after the GW events are analyzed. No coincidences are observed. Upper limits on the UHE photon fluence from a GW event are derived that are typically at & SIM;7 MeV cm(-2) (time period 1000 s) and & SIM;35 MeV cm(-2) (time period 1 day). Due to the proximity of the binary neutron star merger GW170817, the energy of the source transferred into UHE photons above 40 EeV is constrained to be less than 20% of its total GW energy. These are the first limits on UHE photons from GW sources

Searches for Ultra-High-Energy Photons at the Pierre Auger Observatory

The Pierre Auger Observatory, which is the largest air-shower experiment in the world, offers unprecedented exposure to neutral particles at the highest energies. Since the start of data collection more than 18 years ago, various searches for ultra-high-energy (UHE, E greater than or similar to 10^(17) eV) photons have been performed, either for a diffuse flux of UHE photons, for point sources of UHE photons or for UHE photons associated with transient events such as gravitational wave events. In the present paper, we summarize these searches and review the current results obtained using the wealth of data collected by the Pierre Auger Observatory

Arrival Directions of Cosmic Rays above 32 EeV from Phase One of the Pierre Auger Observatory

A promising energy range to look for angular correlations between cosmic rays of extragalactic origin and their sources is at the highest energies, above a few tens of EeV (1 EeV equivalent to 10^(18) eV). Despite the flux of these particles being extremely low, the area of similar to 3000 km^(2) covered at the Pierre Auger Observatory, and the 17 yr data-taking period of the Phase 1 of its operations, have enabled us to measure the arrival directions of more than 2600 ultra-high-energy cosmic rays above 32 EeV. We publish this data set, the largest available at such energies from an integrated exposure of 122,000 km^(2) sr yr, and search it for anisotropies over the 3.4 pi steradians covered with the Observatory. Evidence for a deviation in excess of isotropy at intermediate angular scales, with similar to 15 degrees Gaussian spread or similar to 25 degrees top-hat radius, is obtained at the 4 sigma significance level for cosmic-ray energies above similar to 40 EeV

Promotion of physical activity interventions for community dwelling older adults: A systematic review of reviews

Objectives While there is strong evidence that regular participation in physical activity (PA) brings numerous health benefits to older adults, and interventions to effectively promote PA are being developed and tested, the characteristics and components of the most effective interventions remain unclear. This systematically conducted review of systematic reviews evaluated the effects and characteristics of PA promotion interventions aimed at community dwelling people over 50 years old. Methods Major databases were searched for reviews from January 1990 to May 2015. TIDieR guidelines aided data extraction and the ROBIS tool was used to assess the risk of bias. Primary outcomes were objective and self-reported levels of PA. Indicators of psychological wellbeing and participation rates were secondary outcomes. Results Of 1284 records identified, 19 reviews met inclusion criteria and eight included meta-analyses. Interventions typically incorporated behaviour change techniques (BCTs) and were delivered as face-to-face, remote, group, individual or as combined interventions. Despite their heterogeneity, interventions often resulted in sustained improvements in PA over the study period, typically at 12 months, and led to improvements in general wellbeing. However, ways to ensure effective maintenance beyond one year are unclear. Certain intervention components were more clearly associated with positive effects (e.g. tailoring promotion strategy with combination of cognitive and behavioural elements, low to moderate intensity activity recommended). We found no evidence that certain other intervention characteristics were superior in achieving positive outcomes (e.g. mode of delivery, setting, professional background of the intervention provider, type of PA recommended). Conclusion The evidence suggests that interventions to promote PA among older adults are generally effective but there is uncertainty around the most beneficial intervention components. There are indications that purely cognitive strategies and BCTs might be less suitable for older adults than motivators more meaningful to them, including social and environmental support, and enjoyment coming from being physically active. A whole system-oriented approach is required that is tailored to meet the needs of older adults and aligned with social, individual and environmental factors

Spontaneous Breathing in Early Acute Respiratory Distress Syndrome: Insights From the Large Observational Study to UNderstand the Global Impact of Severe Acute Respiratory FailurE Study

OBJECTIVES: To describe the characteristics and outcomes of patients with acute respiratory distress syndrome with or without spontaneous breathing and to investigate whether the effects of spontaneous breathing on outcome depend on acute respiratory distress syndrome severity. DESIGN: Planned secondary analysis of a prospective, observational, multicentre cohort study. SETTING: International sample of 459 ICUs from 50 countries. PATIENTS: Patients with acute respiratory distress syndrome and at least 2 days of invasive mechanical ventilation and available data for the mode of mechanical ventilation and respiratory rate for the 2 first days. INTERVENTIONS: Analysis of patients with and without spontaneous breathing, defined by the mode of mechanical ventilation and by actual respiratory rate compared with set respiratory rate during the first 48 hours of mechanical ventilation. MEASUREMENTS AND MAIN RESULTS: Spontaneous breathing was present in 67% of patients with mild acute respiratory distress syndrome, 58% of patients with moderate acute respiratory distress syndrome, and 46% of patients with severe acute respiratory distress syndrome. Patients with spontaneous breathing were older and had lower acute respiratory distress syndrome severity, Sequential Organ Failure Assessment scores, ICU and hospital mortality, and were less likely to be diagnosed with acute respiratory distress syndrome by clinicians. In adjusted analysis, spontaneous breathing during the first 2 days was not associated with an effect on ICU or hospital mortality (33% vs 37%; odds ratio, 1.18 [0.92-1.51]; p = 0.19 and 37% vs 41%; odds ratio, 1.18 [0.93-1.50]; p = 0.196, respectively ). Spontaneous breathing was associated with increased ventilator-free days (13 [0-22] vs 8 [0-20]; p = 0.014) and shorter duration of ICU stay (11 [6-20] vs 12 [7-22]; p = 0.04). CONCLUSIONS: Spontaneous breathing is common in patients with acute respiratory distress syndrome during the first 48 hours of mechanical ventilation. Spontaneous breathing is not associated with worse outcomes and may hasten liberation from the ventilator and from ICU. Although these results support the use of spontaneous breathing in patients with acute respiratory distress syndrome independent of acute respiratory distress syndrome severity, the use of controlled ventilation indicates a bias toward use in patients with higher disease severity. In addition, because the lack of reliable data on inspiratory effort in our study, prospective studies incorporating the magnitude of inspiratory effort and adjusting for all potential severity confounders are required

Identifying associations between diabetes and acute respiratory distress syndrome in patients with acute hypoxemic respiratory failure: an analysis of the LUNG SAFE database

Background: Diabetes mellitus is a common co-existing disease in the critically ill. Diabetes mellitus may reduce the risk of acute respiratory distress syndrome (ARDS), but data from previous studies are conflicting. The objective of this study was to evaluate associations between pre-existing diabetes mellitus and ARDS in critically ill patients with acute hypoxemic respiratory failure (AHRF). Methods: An ancillary analysis of a global, multi-centre prospective observational study (LUNG SAFE) was undertaken. LUNG SAFE evaluated all patients admitted to an intensive care unit (ICU) over a 4-week period, that required mechanical ventilation and met AHRF criteria. Patients who had their AHRF fully explained by cardiac failure were excluded. Important clinical characteristics were included in a stepwise selection approach (forward and backward selection combined with a significance level of 0.05) to identify a set of independent variables associated with having ARDS at any time, developing ARDS (defined as ARDS occurring after day 2 from meeting AHRF criteria) and with hospital mortality. Furthermore, propensity score analysis was undertaken to account for the differences in baseline characteristics between patients with and without diabetes mellitus, and the association between diabetes mellitus and outcomes of interest was assessed on matched samples. Results: Of the 4107 patients with AHRF included in this study, 3022 (73.6%) patients fulfilled ARDS criteria at admission or developed ARDS during their ICU stay. Diabetes mellitus was a pre-existing co-morbidity in 913 patients (22.2% of patients with AHRF). In multivariable analysis, there was no association between diabetes mellitus and having ARDS (OR 0.93 (0.78-1.11); p = 0.39), developing ARDS late (OR 0.79 (0.54-1.15); p = 0.22), or hospital mortality in patients with ARDS (1.15 (0.93-1.42); p = 0.19). In a matched sample of patients, there was no association between diabetes mellitus and outcomes of interest. Conclusions: In a large, global observational study of patients with AHRF, no association was found between diabetes mellitus and having ARDS, developing ARDS, or outcomes from ARDS. Trial registration: NCT02010073. Registered on 12 December 2013

Epidemiology and patterns of tracheostomy practice in patients with acute respiratory distress syndrome in ICUs across 50 countries

Background: To better understand the epidemiology and patterns of tracheostomy practice for patients with acute respiratory distress syndrome (ARDS), we investigated the current usage of tracheostomy in patients with ARDS recruited into the Large Observational Study to Understand the Global Impact of Severe Acute Respiratory Failure (LUNG-SAFE) study. Methods: This is a secondary analysis of LUNG-SAFE, an international, multicenter, prospective cohort study of patients receiving invasive or noninvasive ventilation in 50 countries spanning 5 continents. The study was carried out over 4 weeks consecutively in the winter of 2014, and 459 ICUs participated. We evaluated the clinical characteristics, management and outcomes of patients that received tracheostomy, in the cohort of patients that developed ARDS on day 1-2 of acute hypoxemic respiratory failure, and in a subsequent propensity-matched cohort. Results: Of the 2377 patients with ARDS that fulfilled the inclusion criteria, 309 (13.0%) underwent tracheostomy during their ICU stay. Patients from high-income European countries (n = 198/1263) more frequently underwent tracheostomy compared to patients from non-European high-income countries (n = 63/649) or patients from middle-income countries (n = 48/465). Only 86/309 (27.8%) underwent tracheostomy on or before day 7, while the median timing of tracheostomy was 14 (Q1-Q3, 7-21) days after onset of ARDS. In the subsample matched by propensity score, ICU and hospital stay were longer in patients with tracheostomy. While patients with tracheostomy had the highest survival probability, there was no difference in 60-day or 90-day mortality in either the patient subgroup that survived for at least 5 days in ICU, or in the propensity-matched subsample. Conclusions: Most patients that receive tracheostomy do so after the first week of critical illness. Tracheostomy may prolong patient survival but does not reduce 60-day or 90-day mortality. Trial registration: ClinicalTrials.gov, NCT02010073. Registered on 12 December 2013