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A Novel LC-MS/MS Method for the Measurement of Elexacaftor, Tezacaftor and Ivacaftor in Plasma, Dried Plasma Spot (DPS) and Whole Blood in Volumetric Absorptive Microsampling (VAMS) Devices
No full textBackground: The combination of ivacaftor, tezacaftor and elexacaftor (ETI) is approved for patients with cystic fibrosis (CF) aged two years and older and at least one F508del mutation in the CFTR gene. Variability in ETI treatment response has been repeatedly reported, and its reasons are unclear and understudied. Objectives: We present a novel liquid chromatography–tandem mass spectrometry (LC–MS/MS) method for the rapid and simultaneous quantification of ETI in plasma, dried plasma spots (DPS), and whole blood volumetric absorptive microsampling (VAMS). Methods: The method utilizes a rapid extraction protocol with 200 μL methanol after the addition of deuterated internal standards. Chromatographic separation was achieved using a reversed-phase Hypersil Gold aQ column (Thermo Fisher Scientific). The method was validated according to ICH (International Council on Harmonisation) guidelines M10 for bioanalytical method validation, demonstrating linearity in the concentration range 0.020–12.000 μg/mL. It was also proved accurate and reproducible with no matrix effect. This method was applied to anonymized samples from patients undergoing ETI treatment: eight plasma and DPS and five VAMS samples were analyzed. Results: ETI concentrations measured in plasma and DPS were interchangeable, whereas ETI concentrations in VAMS were lower than in plasma, as expected for molecules with high plasma protein binding (99%). A correction factor based on the hematocrit value was used to calculate the equivalent plasma concentration from VAMS concentrations. Conclusions: This method is suitable for pharmacokinetic (PK) studies and could facilitate the centralization of samples to specialized laboratories, supporting multicenter studies
Consensus Statements on Airway Clearance Interventions in Intubated Critically Ill Patients—Protocol for a Delphi Study
No full textEffects of Positive Expiratory Pressure on Gas Exchange, Atelectasis, Hemodynamics, and Dyspnea in Spontaneously Breathing Critically Ill Subjects
No full textBackground: EzPAP Positive Airway Pressure System (EzPAP) is a noninvasive positive expiratory pressure (PEP) device designed to promote lung expansion. The aim of this study was to evaluate the effects of PEP on gas exchange. Secondary objectives included assessing the early effects of PEP on radiological atelectasis score (RAS), hemodynamics, and dyspnea. These outcomes were compared between spontaneously breathing subjects with and without tracheostomy. Methods: This observational single-center study was conducted at a university hospital. Inclusion criteria were spontaneously breathing adult subjects with RAS >= 2 and a worsened PaO2/FIO2. Exclusion criteria included life-threatening conditions, intracranial hypertension, hemodynamic instability, and pneumothorax. Gas-exchange, hemodynamic parameters, and dyspnea measured with the Respiratory Distress Observation Scale (RDOS) were assessed at 3 time points: T0 (before PEP), T1 (immediately after PEP), and T2 (2 h after PEP). RAS was assessed at T0 and 1-week post treatment (T3). Results: Of 213 patients assessed for eligibility, 186 were excluded for various reasons, leaving 27 subjects (19 without and 8 with tracheostomy) enrolled in the study. The median [interquartile range] age was 65 [58-74] y, with 66.7% being male. In the overall sample and in subjects without tracheostomy, PaO2/FIO2 did not differ significantly between T1 and T0 (P = .52 and P = .54, respectively) or between T2 and T0 (P = .47 and P = .85, respectively). In subjects with tracheostomy, PaO2/FIO2was higher at T1 compared to T0 (P = .039) but not between T2 and T0 (P = .58). Arterial PaO2 and hemodynamic parameters remained unchanged in the overall cohort. The RAS improved within 1 week of treatment in the overall cohort (T3 vs T0, P < .001) and in subjects without tracheostomy (T3 vs T0, P = .001). However, PEP therapy did not improve RDOS. Conclusions: In critically ill, spontaneously breathing subjects, PEP therapy significantly improved RAS without affecting hemodynamic stability or respiratory symptoms
A GIS-Based Safe System Approach for Risk Assessment in the Transportation of Dangerous Goods: A Case Study in Italian Regions
No full textThe Dangerous Goods Transportation (DGT) presents significant challenges, requiring a strong and systematic risk assessment framework to ensure the safety and efficiency of the supply chain. This study addresses a critical gap by integrating a deterministic and holistic approach to risk assessment and management. Utilizing Geographic Information Systems (GIS), meteorological data, and material-specific information, the research develops a data-driven approach to identify analyze, evaluate, and mitigate risks associated with DGT. The main objectives include monitoring dangerous goods flows to identify critical risk areas, optimizing emergency response using a shared model, and providing targeted training for stakeholders involved in DGT. The study leverages Information and Communication Technologies (ICT) to systematically collect, interpret, and evaluate data, producing detailed risk scenario maps. These maps are instrumental in identifying vulnerable areas, predicting potential accidents, and assessing the effectiveness of risk management strategies. This work introduces an innovative GIS-based risk assessment model that combines static and dynamic data to address various aspects of DGT, including hazard identification, accident prevention, and real-time decision support. The results contribute to enhancing safety protocols and provide actionable insights for policymakers and practitioners aiming to improve the resilience of technological systems for road transport networks handling dangerous goods
Modification of monocyte compartments following exposure to bacterial lysates
No full textABSTRACT
Polyvalent mechanical bacterial lysate (PMBL) has been reported to effectively prevent and treat recurrent respiratory infections, including those of viral aetiology. It confers protection and improves immune response by modulating cellular and humoral responses. Although its immunogenic capabilities have been studied in different cell types, its fine molecular mechanisms of action remain poorly elucidated.
In this study, we investigated the potential immunomodulatory effects of bacterial lysates in regulating the immune responses of human monocytes (Mo).
In a well-established in vitro model of human monocytes, we found that PMBL treatment skews the conventional Mo subsets distribution, inducing a switch to a Non-classical (NC) population. We observed a sizable fraction of the Mo pool expressing high levels of surface marker CD16 with a lower level of CD14; remarkably, this subset also significantly expanded in peripheral blood after sublingual administration in individuals undergoing PMBL treatment. Expression of SLAN and CX3CR1 in the absence of CCR2, high level of HLA-DR, and preponderant expression of FcγIIIR, was the dominant pattern among the increased CD16++ cells confirming the NC-like features of this subpopulation. The transition from classical to NC subsets was observed also by culturing highly purified classical Mo with lysate, suggesting a direct involvement of PMBL in driving the conversion between the two monocyte subsets, rather than a decrease/increase of one of the two subsets PMBL could also modulate Mo immune functions leading to increased cytokine production when subsequently challenged with microbial or viral stimuli, indicating a trained immunity rewiring. Analysing their functional traits, we observed that PMBL-treated Mo displayed a boost in TNF-α, IL-6, and IL-1β response upon restimulation with LPS or R848, highlighting the role of PMBL in modulating genes of the pro-inflammatory signalling pathway, one of the main hallmarks described for the phenomenon of trained immunity. PMBL also interferes with the phosphorylation of p38-MAPK and ERK 1/2, critical intracellular signal transduction pathways involved in the inflammatory response. Additionally, PMBL training in combination with CD16 triggering resulted in a synergic effect for their effector functions. On the other hand, PMBL-treated Mo secreted a large amount of IL-10, capable of calming down and limiting hyper-responsiveness during their activation via CD16.
Collectively, our results demonstrated that PMBL modulates Mo immune responses by prompting a phenotypic and functional switch toward an NC-Mo subset interfering with the intracellular signalling cascade that regulates monocyte-mediated inflammation, acquiring antibody-dependent cellular cytotoxicity (ADCC) via CD16, and endowed with increased response to the second challenge inducing trained immunity.
These results indicate that PMBL could exert their protective role also through this mechanism of action. Expression of CD16 and induction of a trained immunity in Mo should enhance both innate and antigen-specific adaptive immune responses, also conferring a broader protection against different pathogens and counteracting a much wider array of diseases
Rapid eye movement sleep and epilepsy: exploring interactions and therapeutic prospects
No full textWhile research interest in the relationship between sleep and epilepsy is growing, it primarily centres on the effects of non-rapid eye movement (NREM) sleep in favouring seizures. Nonetheless, a noteworthy aspect is the observation that, in the lives of patients with epilepsy, REM sleep represents the moment with the least epileptic activity and the lowest probability of having a seizure. Studies demonstrate a suppressive effect of phasic REM sleep on interictal epileptiform discharges, potentially offering insights into epilepsy localisation and management. Furthermore, epilepsy impacts REM sleep, with successful treatment correlating with improved REM sleep quality. Novel therapeutic strategies aim to harness REM's anti-epileptic effects, including pharmacological approaches targeting orexinergic systems and neuromodulation techniques promoting cortical desynchronisation. These findings underscore the intricate relationship between REM sleep and epilepsy, highlighting avenues for further research and therapeutic innovation in epilepsy management
Comparison of Virtual Inertia Support in GFM Inverter-Based Resources with Different DC Sources
No full textThe modern electric power system is currently undergoing significant changes in its generation structure, substituting synchronous machines with Inverter-Based Resources (IBRs). This shift reduces the availability of rotating masses, challenging the stability of the power system due to the resulting decrease in grid inertia. Virtual Synchronous Generator (VSG) based Grid-forming (GFM) addresses these stability concerns. However, to the best of the authors' knowledge, a comprehensive analysis of virtual inertia provision for modeling the DC side with different sources has not yet been provided. This paper presents a review of DC side modeling considering three sources: an ideal DC source model, a battery model, and finally a wind turbine model. Case studies have been implemented within the MATLAB/Simulink environment which are illustrated and evaluated in terms of the Rate of Change of Frequency (RoCoF) and the frequency nadir. Finally, the IBRs modeled with these three different DC sources are compared with a Synchronous Generator (SG) of equivalent size and inertia values to assess the synthetic inertia against the inertia of the SG