Dysfunctional inflammation in cystic fibrosis airways: From mechanisms to novel therapeutic approaches

Cystic fibrosis (CF) is an inherited disorder caused by mutations in the gene encoding for the cystic fibrosis transmembrane conductance regulator (CFTR) protein, an ATP-gated chloride channel expressed on the apical surface of airway epithelial cells. CFTR absence/dysfunction results in defective ion transport and subsequent airway surface liquid dehydration that severely compromise the airway microenvironment. Noxious agents and pathogens are entrapped inside the abnormally thick mucus layer and establish a highly inflammatory environment, ultimately leading to lung damage. Since chronic airway inflammation plays a crucial role in CF pathophysiology, several studies have investigated the mechanisms responsible for the altered inflammatory/immune response that, in turn, exacerbates the epithelial dysfunction and infection susceptibility in CF patients. In this review, we address the evidence for a critical role of dysfunctional inflammation in lung damage in CF and discuss current therapeutic approaches targeting this condition, as well as potential new treatments that have been developed recently. Traditional therapeutic strategies have shown several limitations and limited clinical benefits. Therefore, many efforts have been made to develop alternative treatments and novel therapeutic approaches, and recent findings have identified new molecules as potential anti-inflammatory agents that may exert beneficial effects in CF patients. Furthermore, the potential anti-inflammatory properties of CFTR modulators, a class of drugs that directly target the molecular defect of CF, also will be critically reviewed. Finally, we also will discuss the possible impact of SARS-CoV-2 infection on CF patients, with a major focus on the consequences that the viral infection could have on the persistent inflammation in these patients

Hybrid active focusing with adaptive dispersion for higher defect sensitivity in guided wave inspection of cylindrical structures

This is an Accepted Manuscript of an article published by Taylor & Francis in Nondestructive Testing and Evaluation on 23/11/2015, available online: https://www.tandfonline.com/doi/full/10.1080/10589759.2015.1093628.Ultrasonic guided wave inspection is widely used for scanning prismatic structures such as pipes for metal loss. Recent research has investigated focusing the sound energy into predetermined regions of a pipe in order to enhance the defect sensitivity. This paper presents an active focusing technique which is based on a combination of numerical simulation and time reversal concept. The proposed technique is empirically validated using a 3D laser vibrometry measurement of the focal spot. The defect sensitivity of the proposed technique is compared with conventional active focusing, time reversal focusing and synthetic focusing through an empirically validated finite element parametric study. Based on the results, the proposed technique achieves approximately 10 dB improvement of signal-to-coherent-noise ratio compared to the conventional active focusing and time reversal focusing. It is also demonstrated that the proposed technique to have an amplitude gain of around 5 dB over synthetic focusing for defects <0.5λs. The proposed technique is shown to have the potential to improve the reliably detectable flaw size in guided wave inspection from 9% to less than 1% cross-sectional area loss.TWI Ltd and the Center for Electronic System Research (CESR) of Brunel University

Hybrid active focusing with adaptive dispersion for higher defect sensitivity in guided wave inspection of cylindrical structures

This is an Accepted Manuscript of an article published by Taylor & Francis in Nondestructive Testing and Evaluation on 23/11/2015, available online: https://www.tandfonline.com/doi/full/10.1080/10589759.2015.1093628.Ultrasonic guided wave inspection is widely used for scanning prismatic structures such as pipes for metal loss. Recent research has investigated focusing the sound energy into predetermined regions of a pipe in order to enhance the defect sensitivity. This paper presents an active focusing technique which is based on a combination of numerical simulation and time reversal concept. The proposed technique is empirically validated using a 3D laser vibrometry measurement of the focal spot. The defect sensitivity of the proposed technique is compared with conventional active focusing, time reversal focusing and synthetic focusing through an empirically validated finite element parametric study. Based on the results, the proposed technique achieves approximately 10 dB improvement of signal-to-coherent-noise ratio compared to the conventional active focusing and time reversal focusing. It is also demonstrated that the proposed technique to have an amplitude gain of around 5 dB over synthetic focusing for defects <0.5λs. The proposed technique is shown to have the potential to improve the reliably detectable flaw size in guided wave inspection from 9% to less than 1% cross-sectional area loss.TWI Ltd and the Center for Electronic System Research (CESR) of Brunel University

Validation of Floating Node Method Using Three-Point Bend Doubler Under Quasi-Static Loading

The NASA Advanced Composite Project (ACP), an industry/government/university partnership, has embarked upon the task of developing technology that can aid in reducing the time line for structural certification of aircraft composite parts using a combination of technologies, one of which is high fidelity damage progression computational methods. Phase II of this project included a task for validating an approach based on the Floating Node Method combined with Directional Cohesive Elements (FNM-DCZE). This paper discusses predicted damage onset and growth in a three-point bend doubler specimen compared to experimental results. Sensitivity of the simulations to mesh refinement as well as key material properties and thermal effects are studied and reported. Overall, qualitative results suggest the main aspects of the damage progression have been captured, with the simulated damage morphology and sequence of events resembling closely what was observed experimentally. Quantitatively, the first load-peak is predicted. However, the re-loading observed in the experiments, after the first load peak, is not captured numerically, suggesting further investigation may be worth pursuing

Statistical properties of earthquakes clustering

International audienceOften in nature the temporal distribution of inhomogeneous stochastic point processes can be modeled as a realization of renewal Poisson processes with a variable rate. Here we investigate one of the classical examples, namely, the temporal distribution of earthquakes. We show that this process strongly departs from a Poisson statistics for both catalogue and sequence data sets. This indicate the presence of correlations in the system probably related to the stressing perturbation characterizing the seismicity in the area under analysis. As shown by this analysis, the catalogues, at variance with sequences, show common statistical properties

The quadrupole collective model from a Cartan-Weyl perspective

The matrix elements of the quadrupole variables and canonic conjugate momenta, emerging from collective nuclear models are calculated within a $SU(1,1)\times O(5)$ basis. Using a harmonic oscillator implementation of the SU(1,1) degree of freedom, it can be shown that the matrix elements of the quadrupole phonon creation and annihilation operators can be calculated in a pure algebraic way, making use of an intermediate state method.Comment: Special issue of journal of physics for the QTS5 conferenc

Omission of postoperative radiation after breast conserving surgery: A progressive paradigm shift towards precision medicine

Radiation therapy is a standard therapeutic option in the post-operative setting for early breast cancer patients after breast conserving surgery, providing a substantial benefit in reducing the risk of local relapse with a consequent survival gain. Nevertheless, the reduction in the burden related to treatment is becoming crucial in modern oncology for both local and systemic therapies and investigational efforts are being put forward by radiations oncologists to identify a subset of women at very low risk to be potentially omitted from post-operative irradiation after breast conservation. Clinical factors, classical pathological parameters and new predictive scores derived from gene expression and next generation sequencing techniques are being integrated in the quest toward a reliable low-risk profile for breast cancer patients. We herein provide a comprehensive overview on the topic

Multivariable analysis to determine risk factors associated with early pregnancy loss in thoroughbred broodmares

Early pregnancy loss (EPL) between days 15–65 after breeding has been shown to occur in 7.9% of equine pregnancies with substantial economical, welfare and safety implications. Whilst maternal age has been recognised as an important risk factor in relation to the incidence of EPL, few other risk factors have been conclusively identified. Further, multivariable data analysis of risk factors for EPL is sparse. A prospective cohort investigation of thoroughbred broodmares in the United Kingdom was conducted over the 2013 and 2014 breeding seasons. Information relating to 28 factors including mare, stallion, pregnancy and therapeutic interventions was collected using questionnaires and entered into a custom-designed Microsoft Access database. Mixed effects logistic regression was used to determine risk factors for EPL, including ‘mare’ as a random effect to account for repeat pregnancies in the same mare. Stallion, stud and veterinarian were also evaluated as random effects. Variables with a p-value of <0.25 in univariable analysis were taken forward for consideration in the multivariable model which was built using a forward stepwise approach. Data were collected on 2245 pregnancies in 1753 mares. Increasing mare age (OR = 1.11, 95% confidence interval (CI) = 1.04, 1.18, p = 0.001), having had one previous foal (OR = 3.52, 95% CI = 1.56, 7.95, p = 0.002) and presence of uterine cysts (OR = 1.76, 95% CI = 1.07, 2.91, p = 0.03) were all associated with increased odds of EPL following multivariable analysis. Increasing day 15/16 scan vesicle size (OR = 0.24, 95% CI = 0.16, 0.38, p < 0.001) and the use of ovulatory induction agents (OR = 0.31, 95% CI = 0.17, 0.55, p < 0.001) were negatively associated with EPL. Stallion, stud and veterinarian were not significantly associated with EPL. Analysis of a subpopulation of 344 multiple (twin and triplet) pregnancies found that the use of flunixin meglumine at the time of manual reduction of a multiple pregnancy resulted in reduced odds of EPL (OR = 0.34, 95% CI = 0.14, 0.84, p = 0.02). Results from this study can be used by stud farm personnel when assessing their broodmare population and by clinicians when deciding upon therapeutic strategies. Additional work can be focused around these risk factors to further our understanding of the pathophysiology of EPL