Application of average volume assured pressure support (AVAPS) and ultrasound assessment in COVID-19 infection: real-life observation.

BACKGROUND: ARDS in COVID-19 patients admitted to Emergency Departments (ED) is characterized by reduced diaphragm motility and increased work of breathing (WOB) by accessory respiratory muscles. Reduced perfusion of compliant lungs as consequence of vascular abnormalities has been highlighted as possible explanation of typical hypoxemia. Non-invasive mechanical ventilation (NIMV) has been proposed to treat ARDS. AVAPS is a hybrid modality of NIMV combining features of pressure and volume ventilation. METHODS: we enrolled 38 patients with COVID-19 ARDS to whom we applied NIMV with AVAPS modality. We assessed Tidal Volume (TV), diaphragm excursion (DE) and PaO2/FiO2 before starting NIMV and after three (T3) and six hours (T6) of ventilation. RESULTS: Admissions to ICU were avoided in 68% of our patients. TV (627±147.6 vs. 747.1±226 mL, P<0.00005) and DE (21.8±5.4 vs. 17.9±6.1 mm, P<0.00005) already improved after three hours of AVAPS. TV (521.5±120 mL, P<0.00005), DE (25.8±6.9 mm, P<0.00005) and PaO2/FiO2 (197.3±75.3 vs. 158±67.7, P<0.005) significantly improved in our cohort of patients after six hours. CONCLUSIONS: NIMV with AVAPS modality can be confidently used in the clinical management of COVID-19 patients with ARDS, since AVAPS has positive effects on ventilation-perfusion matching and WOB. We recommend low PEEP value and ultrasound assessment of diaphragm motility and lung characteristics, although further studies are needed to individuate clinical features of NIMV best-responder patients

FALCON Handbook : Understanding what influences modal choice

Freight transport with all modes plays a crucial role for the functioning of economies while simultaneously being responsible for negative external effects such as congestion, noise and various forms of pollution. The transport system consists of the firms that provide logistics and transport services, their personnel, the different vehicles and energies used and the transport- and ITS-infrastructure. The challenge is to achieve a sustainable transport system that can cope with increasing freight transport volumes. Total freight transport activity (in tonne-km) is projected to increase by about 58% (1.2% annually) between 2010 and 2050 (European Commission, 2016). Another challenge is to contribute to the goals of the European Union regarding energy efficiency, green-house gas emissions and air pollution/clean air1, as well as fulfilling the 30% improvement of end-to-end logistics performance by 2030 set out by the European Technology Platform Alice (ETP-Alice 2017)2. A key input for striving towards such a system is policy-makers’ and transport authorities’ solid understanding of the freight transport sector in general, and the influences on the choice of transport solutions and modes in particular. In the light of this, the objective of this handbook is to provide a detailed review of the factors influencing modal choice, describe developments in the transport sector and the data and tools needed to analyse the impacts of trends and policy measures. The handbook is aimed towards authorities responsible for transport and infrastructure in Europe. Focus is on national road administrations (NRAs), which are organized in different ways in different countries

Integrated lung ultrasound score for early clinical decision-making in patients with COVID-19: results and implications

Background and objectives: Lung Ultrasound Score (LUS) identifies and monitors pneumonia by assigning increasing scores. However, it does not include parameters, such as inferior vena cava (IVC) diameter and index of collapse, diaphragmatic excursions and search for pleural and pericardial effusions. Therefore, we propose a new improved scoring system, termed "integrated" lung ultrasound score (i-LUS) which incorporates previously mentioned parameters that can help in prediction of disease severity and survival, choice of oxygenation mode/ventilation and assignment to subsequent areas of care in patients with COVID-19 pneumonia.Methods: Upon admission at the sub-intensive section of the emergency medical department (SEMD), 143 consecutively examined COVID-19 patients underwent i-LUS together with all other routine analysis. A database for anamnestic information, laboratory data, gas analysis and i-LUS parameters was created and analyzed.Results: Of 143 enrolled patients, 59.4% were male (mean age 71 years) and 40.6% female. (mean age 79 years: p= 0.005). Patients that survived at 1 month had i-LUS score of 16, which was lower than that of non-survivors (median 20; p= 0.005). Survivors had a higher PaO2/FiO2 (median 321.5) compared to non-survivors (median 229, p < 0.001). There was a correlation between i-LUS and PaO2/FiO2 ratio (rho:-0.4452; p < 0.001), PaO2/FiO2 and survival status (rho:-0.3452; p <0.001), as well as i-LUS score and disease outcome (rho:0.24; p= 0.005). In non-survivors, the serum values of different significant COVID indicators were severely expressed. The i-LUS score was higher (median 20) in patients who required non-invasive ventilation (NIV) than in those treated only by oxygen therapy (median 15.42; p= 0.003). The odds ratio for death outcome was 1.08 (confidence interval 1.02-1.15) for each point increased. At 1-month follow-up, 65 patients (45.5%) died and 78 (54.5%) survived. Patients admitted to the high critical ward had higher i-LUS score than those admitted to the low critical one (p < 0.003).Conclusions: i-LUS could be used as a helpful clinical tool for early decision-making in patients with COVID-19 pneumonia

The TRAPP complex mediates secretion arrest induced by stress granule assembly

The TRAnsport Protein Particle (TRAPP) complex controls multiple membrane trafficking steps and is strategically positioned to mediate cell adaptation to diverse environmental conditions, including acute stress. We have identified the TRAPP complex as a component of a branch of the integrated stress response that impinges on the early secretory pathway. The TRAPP complex associates with and drives the recruitment of the COPII coat to stress granules (SGs) leading to vesiculation of the Golgi complex and arrest of ER export. The relocation of the TRAPP complex and COPII to SGs only occurs in cycling cells and is CDK1/2-dependent, being driven by the interaction of TRAPP with hnRNPK, a CDK substrate that associates with SGs when phosphorylated. In addition, CDK1/2 inhibition impairs TRAPP complex/COPII relocation to SGs while stabilizing them at ER exit sites. Importantly, the TRAPP complex controls the maturation of SGs. SGs that assemble in TRAPP-depleted cells are smaller and are no longer able to recruit RACK1 and Raptor, two TRAPP-interactive signaling proteins, sensitizing cells to stress-induced apoptosis

Design and synthesis of multifunctional microtubule targeting agents endowed with dual pro-apoptotic and anti-autophagic efficacy

Autophagy is a lysosome dependent cell survival mechanism and is central to the maintenance of organismal homeostasis in both physiological and pathological situations. Targeting autophagy in cancer therapy attracted considerable attention in the past as stress-induced autophagy has been demonstrated to contribute to both drug resistance and malignant progression and recently interest in this area has re- emerged. Unlocking the therapeutic potential of autophagy modulation could be a valuable strategy for designing innovative tools for cancer treatment. Microtubule-targeting agents (MTAs) are some of the most successful anti-cancer drugs used in the clinic to date. Scaling up our efforts to develop new anti- cancer agents, we rationally designed multifunctional agents 5a-l with improved potency and safety that combine tubulin depolymerising efficacy with autophagic flux inhibitory activity. Through a combination of computational, biological, biochemical, pharmacokinetic-safety, metabolic studies and SAR analyses we identified the hits 5i,k. These MTAs were characterised as potent pro-apoptotic agents and also demonstrated autophagy inhibition efficacy. To measure their efficacy at inhibiting autophagy, we investigated their effects on basal and starvation-mediated autophagic flux by quantifying the expression of LC3II/LC3I and p62 proteins in oral squamous cell carcinoma and human leukaemia through western blotting and by immunofluorescence study of LC3 and LAMP1 in a cervical carcinoma cell line. Analogues 5i and 5k, endowed with pro-apoptotic activity on a range of hematological cancer cells (including ex-vivo chronic lymphocytic leukaemia (CLL) cells) and several solid tumor cell lines, also behaved as late- stage autophagy inhibitors by impairing autophagosome-lysosome fusion