Design and rationale of a multi-center, pragmatic, open-label randomized trial of antimicrobial therapy - the study of clinical efficacy of antimicrobial therapy strategy using pragmatic design in Idiopathic Pulmonary Fibrosis (CleanUP-IPF) clinical trial

Compelling data have linked disease progression in patients with idiopathic pulmonary fibrosis (IPF) with lung dysbiosis and the resulting dysregulated local and systemic immune response. Moreover, prior therapeutic trials have suggested improved outcomes in these patients treated with either sulfamethoxazole/ trimethoprim or doxycycline. These trials have been limited by methodological concerns. This trial addresses the primary hypothesis that long-term treatment with antimicrobial therapy increases the time-to-event endpoint of respiratory hospitalization or all-cause mortality compared to usual care treatment in patients with IPF. We invoke numerous innovative features to achieve this goal, including: 1) utilizing a pragmatic randomized trial design; 2) collecting targeted biological samples to allow future exploration of 'personalized' therapy; and 3) developing a strong partnership between the NHLBI, a broad range of investigators, industry, and philanthropic organizations. The trial will randomize approximately 500 individuals in a 1:1 ratio to either antimicrobial therapy or usual care. The site principal investigator will declare their preferred initial antimicrobial treatment strategy (trimethoprim 160 mg/ sulfamethoxazole 800 mg twice a day plus folic acid 5 mg daily or doxycycline 100 mg once daily if body weight is < 50 kg or 100 mg twice daily if ≥50 kg) for the participant prior to randomization. Participants randomized to antimicrobial therapy will receive a voucher to help cover the additional prescription drug costs. Additionally, those participants will have 4-5 scheduled blood draws over the initial 24 months of therapy for safety monitoring. Blood sampling for DNA sequencing and genome wide transcriptomics will be collected before therapy. Blood sampling for transcriptomics and oral and fecal swabs for determination of the microbiome communities will be collected before and after study completion. As a pragmatic study, participants in both treatment arms will have limited in-person visits with the enrolling clinical center. Visits are limited to assessments of lung function and other clinical parameters at time points prior to randomization and at months 12, 24, and 36. All participants will be followed until the study completion for the assessment of clinical endpoints related to hospitalization and mortality events. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT02759120

Multimodality of rich clusters from the SDSS DR8 within the supercluster-void network

We study the relations between the multimodality of galaxy clusters drawn from the SDSS DR8 and the environment where they reside. As cluster environment we consider the global luminosity density field, supercluster membership, and supercluster morphology. We use 3D normal mixture modelling, the Dressler-Shectman test, and the peculiar velocity of cluster main galaxies as signatures of multimodality of clusters. We calculate the luminosity density field to study the environmental densities around clusters, and to find superclusters where clusters reside. We determine the morphology of superclusters with the Minkowski functionals and compare the properties of clusters in superclusters of different morphology. We apply principal component analysis to study the relations between the multimodality parametres of clusters and their environment simultaneously. We find that multimodal clusters reside in higher density environment than unimodal clusters. Clusters in superclusters have higher probability to have substructure than isolated clusters. The superclusters can be divided into two main morphological types, spiders and filaments. Clusters in superclusters of spider morphology have higher probabilities to have substructure and larger peculiar velocities of their main galaxies than clusters in superclusters of filament morphology. The most luminous clusters are located in the high-density cores of rich superclusters. Five of seven most luminous clusters, and five of seven most multimodal clusters reside in spider-type superclusters; four of seven most unimodal clusters reside in filament-type superclusters. Our study shows the importance of the role of superclusters as high density environment which affects the properties of galaxy systems in them.Comment: 16 pages, 12 figures, 2 online tables, accepted for publication in Astronomy and Astrophysic

A Critical Approach To Engineering Mathematics Activities For Sustainable Development

Engineering projects are frequently experienced through the complexity of knowledge co-production between experts and local communities. This involves an ability to work critically and creatively within unfamiliar epistemologies, drawing from quantitative, social and scientific methods to realise high-impact solutions. In this work-in-progress paper, we put forward a prototype for a case-control study aiming to evaluate student buy-in and learning outcomes for a cross-cultural implementation of critical mathematics approaches contextualised by sustainability challenges. We outline and discuss aspects of mathematical modelling activities that can scaffold an environment where human subjectivity amplifies the quality and relevance of quantitative arguments. As proof-of-concept, we analyse exemplary work of first-year engineering students as they design, implement, and evaluate a model of population dynamics towards proposing solutions for the endangerment of a wild species. We then identify critical learning outcomes springing from the social and subjective context that envelops the processes of mathematical modelling, analysis and communication in the real world. Our initial results show that interdisciplinary sustainability-driven mathematics activities have the potential to empower students to adopt a conscious approach to societal and environmental challenges

Energy Contents of Some Well-Known Solutions in Teleparallel Gravity

In the context of teleparallel equivalent to General Relativity, we study energy and its relevant quantities for some well-known black hole solutions. For this purpose, we use the Hamiltonian approach which gives reasonable and interesting results. We find that our results of energy exactly coincide with several prescriptions in General Relativity. This supports the claim that different energy-momentum prescriptions can give identical results for a given spacetime. We also evaluate energy-momentum flux of these solutions.Comment: 16 pages, accepted for publication in Astrophys. Space Sc

Multimodality in galaxy clusters from SDSS DR8: substructure and velocity distribution

We search for the presence of substructure, a non-Gaussian, asymmetrical velocity distribution of galaxies, and large peculiar velocities of the main galaxies in galaxy clusters with at least 50 member galaxies, drawn from the SDSS DR8. We employ a number of 3D, 2D, and 1D tests to analyse the distribution of galaxies in clusters: 3D normal mixture modelling, the Dressler-Shectman test, the Anderson-Darling and Shapiro-Wilk tests and others. We find the peculiar velocities of the main galaxies, and use principal component analysis to characterise our results. More than 80% of the clusters in our sample have substructure according to 3D normal mixture modelling, the Dressler-Shectman (DS) test shows substructure in about 70% of the clusters. The median value of the peculiar velocities of the main galaxies in clusters is 206 km/s (41% of the rms velocity). The velocities of galaxies in more than 20% of the clusters show significant non-Gaussianity. While multidimensional normal mixture modelling is more sensitive than the DS test in resolving substructure in the sky distribution of cluster galaxies, the DS test determines better substructure expressed as tails in the velocity distribution of galaxies. Richer, larger, and more luminous clusters have larger amount of substructure and larger (compared to the rms velocity) peculiar velocities of the main galaxies. Principal component analysis of both the substructure indicators and the physical parameters of clusters shows that galaxy clusters are complicated objects, the properties of which cannot be explained with a small number of parameters or delimited by one single test. The presence of substructure, the non-Gaussian velocity distributions, as well as the large peculiar velocities of the main galaxies, shows that most of the clusters in our sample are dynamically young.Comment: 15 pages, 11 figures, 2 online tables, accepted for publication in Astronomy and Astrophysic

Modelling the Physics of Bubble Nucleation in Histotripsy

This work aims to establish a theoretical framework for the modeling of bubble nucleation in histotripsy. A phenomenological version of the classical nucleation theory was parametrized with histotripsy experimental data, fitting a temperature-dependent activity factor that harmonizes theoretical predictions and experimental data for bubble nucleation at both high and low temperatures. Simulations of histotripsy pressure and temperature fields are then used in order to understand spatial and temporal properties of bubble nucleation at varying sonication conditions. This modeling framework offers a thermodynamic understanding on the role of the ultrasound frequency, waveforms, peak focal pressures, and duty cycle on patterns of ultrasound-induced bubble nucleation. It was found that at temperatures lower than 50 °C, nucleation rates are more appreciable at very large negative pressures such as -30 MPa. For focal peak-negative pressures of -15 MPa, characteristic of boiling histotripsy, nucleation rates grow by 20 orders of magnitude in the temperature interval 60 °C-100 °C

Mechanisms of nuclei growth in ultrasound bubble nucleation

This paper interrogates the intersections between bubble dynamics and classical nucleation theory (CNT) towards constructing a model that describes intermediary nucleation events between the extrema of cavitation and boiling. We employ Zeldovich's hydrodynamic approach to obtain a description of bubble nuclei that grow simultaneously via hydrodynamic excitation by the acoustic field and vapour transport. By quantifying the relative dominance of both mechanisms, it is then possible to discern the extent to which viscosity, inertia, surface tension and vapour transport shape the growth of bubble nuclei through non-dimensional numbers that naturally arise within the theory. The first non-dimensional number Φ12/Φ2 is analogous to the Laplace number, representing the balance between surface tension and inertial constraints to viscous effects. The second non-dimensional number δ represents how enthalpy transport into the bubble can reduce nucleation rates by cooling the surrounding liquid. This formulation adds to the current understanding of ultrasound bubble nucleation by accounting for bubble dynamics during nucleation, quantifying the physical distinctions between “boiling” and “cavitation” bubbles through non-dimensional parameters, and outlining the characteristic timescales of nucleation according to the growth mechanism of bubbles throughout the histotripsy temperature range. We observed in our simulations that viscous effects control the process of ultrasound nucleation in water-like media throughout the 0–120 °C temperature range, although this dominance decreases with increasing temperatures. Enthalpy transport was found to reduce nucleation rates for increasing temperatures. This effect becomes significant at temperatures above 30 °C and favours the creation of fewer nuclei that are larger in size. Conversely, negligible enthalpy transport at lower temperatures can enable the nucleation of dense clusters of small nuclei, such as cavitation clouds. We find that nuclei growth as modelled by the Rayleigh-Plesset equation occurs over shorter timescales than as modelled by vapour-dominated growth. This suggests that the first stage of bubble nuclei growth is hydrodynamic, and vapour transport effects can only be observed over longer timescales. Finally, we propose that this framework can be used for comparison between different experiments in bubble nucleation, towards standardisation and dosimetry of protocols

The interaction of shockwaves with a vapour bubble in boiling histotripsy: The shock scattering effect

Boiling histotripsy is a High Intensity Focused Ultrasound (HIFU) technique which uses a number of short pulses with high acoustic pressures at the HIFU focus to induce mechanical tissue fractionation. In boiling histotripsy, two different types of acoustic cavitation contribute towards mechanical tissue destruction: a boiling vapour bubble and cavitation clouds. An understanding of the mechanisms underpinning these phenomena and their dynamics is therefore paramount to predicting and controlling the overall size of a lesion produced for a given boiling histotripsy exposure condition. A number of studies have shown the effects of shockwave heating in generating a boiling bubble at the HIFU focus and have studied its dynamics under boiling histotripsy insonation. However, not much is known about the subsequent production of cavitation clouds that form between the HIFU transducer and the boiling bubble. The main objective of the present study is to examine what causes this bubble cluster formation after the generation of a boiling vapour bubble. A numerical simulation of 2D nonlinear wave propagation with the presence of a bubble at the focus of a HIFU field was performed using the k-Wave MATLAB toolbox for time domain ultrasound simulations, which numerically solves the generalised Westervelt equation. The numerical results clearly demonstrate the appearance of the constructive interference of a backscattered shockwave by a bubble with incoming incident shockwaves. This interaction (i.e., the reflected and inverted peak positive phase from the bubble with the incoming incident rarefactional phase) can eventually induce a greater peak negative pressure field compared to that without the bubble at the HIFU focus. In addition, the backscattered peak negative pressure magnitude gradually increased from 17.4 MPa to 31.6 MPa when increasing the bubble size from 0.2 mm to 1.5 mm. The latter value is above the intrinsic cavitation threshold of –28 MPa in soft tissue. Our results suggest that the formation of a cavitation cloud in boiling histotripsy is a threshold effect which primarily depends (a) the size and location of a boiling bubble, and (b) the sum of the incident field and that scattered by a bubble

Airway response to respiratory syncytial virus has incidental antibacterial effects

RSV infection is typically associated with secondary bacterial infection. We hypothesise that the local airway immune response to RSV has incidental antibacterial effects. Using coordinated proteomics and metagenomics analysis we simultaneously analysed the microbiota and proteomes of the upper airway and determined direct antibacterial activity in airway secretions of RSV-infected children. Here, we report that the airway abundance of Streptococcus was higher in samples collected at the time of RSV infection compared with samples collected one month later. RSV infection is associated with neutrophil influx into the airway and degranulation and is marked by overexpression of proteins with known antibacterial activity including BPI, EPX, MPO and AZU1. Airway secretions of children infected with RSV, have significantly greater antibacterial activity compared to RSV-negative controls. This RSV-associated, neutrophil-mediated antibacterial response in the airway appears to act as a regulatory mechanism that modulates bacterial growth in the airways of RSV-infected children

The effects of the size of a boiling bubble on lesion production in boiling histotripsy

Boiling histotripsy employs a number of millisecond-long High Intensity Focused Ultrasound (HIFU) pulses with high acoustic peak pressures at the HIFU focus to mechanically fractionate soft tissue. Studies have shown the mechanisms underpinning this tissue fractionation process; however, the question of how HIFU exposure conditions affect lesion formation still remains unclear. In the present work, a high-speed camera and a passive cavitation detection (PCD) system were used to investigate the dynamics of bubbles induced and the corresponding mechanical damage generated in optically transparent tissue-mimicking phantoms with two different boiling histotripsy exposure conditions (1. P + = 85.4 MPa, P - = - 15.6 MPa; 2. P + = 71.5 MPa, P - = - 13.4 MPa at focus). Our results clearly showed that there is a positive relationship between the size of a boiling bubble and the lesion dimension. At P + = 85.4 MPa and P - = - 15.6 MPa, a relatively larger boiling bubble was, for instance, produced at the focus in the gel phantom followed by the presence of a wider cavitation cluster progressing toward the HIFU transducer, resulting in the formation of a larger lesion compared to that with P + = 71.5 MPa and P - = - 13.4 MPa