The Australasian COVID-19 Trial (ASCOT) to assess clinical outcomes in hospitalised patients with SARS-CoV-2 infection (COVID-19) treated with lopinavir/ritonavir and/or hydroxychloroquine compared to standard of care: A structured summary of a study protocol for a randomised controlled trial

Objectives: To determine if lopinavir/ritonavir +/- hydroxychloroquine will reduce the proportion of participants who survive without requiring ventilatory support, 15 days after enrolment, in adult participants with non-critically ill SARS-CoV-2 infection. Trial design: ASCOT is an investigator-initiated, multi-centre, open-label, randomised controlled trial. Participants will have been hospitalised with confirmed COVID-19, and will be randomised 1:1:1:1 to receive lopinavir /ritonavir, hydroxychloroquine, both or neither drug in addition to standard of care management. Participants: Participants will be recruited from >80 hospitals across Australia and New Zealand, representing metropolitan and regional centres in both public and private sectors. Admitted patients will be eligible if aged ≥ 18 years, have confirmed SARS-CoV-2 by nucleic acid testing in the past 12 days and are expected to remain an inpatient for at least 48 hours from the time of randomisation. Potentially eligible participants will be excluded if admitted to intensive care or requiring high level respiratory support, are currently receiving study drugs or their use is contraindicated due to allergy, drug interaction or comorbidities (including baseline QTc prolongation of 470ms for women or 480ms for men), or death is anticipated imminently

Epithelial IL-6 trans-signaling defines a new asthma phenotype with increased airway inflammation

Background: Although several studies link high levels of IL-6 and soluble IL-6 receptor (sIL-6R) to asthma severity and decreased lung function, the role of IL-6 trans-signaling (IL-6TS) in asthmatic patients is unclear. Objective: We sought to explore the association between epithelial IL-6TS pathway activation and molecular and clinical phenotypes in asthmatic patients. Methods: An IL-6TS gene signature obtained from air-liquid interface cultures of human bronchial epithelial cells stimulated with IL-6 and sIL-6R was used to stratify lung epithelial transcriptomic data (Unbiased Biomarkers in Prediction of Respiratory Disease Outcomes [U-BIOPRED] cohorts) by means of hierarchical clustering. IL-6TS-specific protein markers were used to stratify sputum biomarker data (Wessex cohort). Molecular phenotyping was based on transcriptional profiling of epithelial brushings, pathway analysis, and immunohistochemical analysis of bronchial biopsy specimens. Results: Activation of IL-6TS in air-liquid interface cultures reduced epithelial integrity and induced a specific gene signature enriched in genes associated with airway remodeling. The IL-6TS signature identified a subset of patients with IL-6TS-high asthma with increased epithelial expression of IL-6TS-inducible genes in the absence of systemic inflammation. The IL-6TS-high subset had an overrepresentation of frequent exacerbators, blood eosinophilia, and submucosal infiltration of T cells and macrophages. In bronchial brushings Toll-like receptor pathway genes were upregulated, whereas expression of cell junction genes was reduced. Sputum sIL-6R and IL-6 levels correlated with sputum markers of remodeling and innate immune activation, in particular YKL-40, matrix metalloproteinase 3, macrophage inflammatory protein 1 beta, IL-8, and IL-1 beta. Conclusions: Local lung epithelial IL-6TS activation in the absence of type 2 airway inflammation defines a novel subset of asthmatic patients and might drive airway inflammation and epithelial dysfunction in these patients.Peer reviewe

The genetic architecture of the human cerebral cortex

INTRODUCTION The cerebral cortex underlies our complex cognitive capabilities. Variations in human cortical surface area and thickness are associated with neurological, psychological, and behavioral traits and can be measured in vivo by magnetic resonance imaging (MRI). Studies in model organisms have identified genes that influence cortical structure, but little is known about common genetic variants that affect human cortical structure. RATIONALE To identify genetic variants associated with human cortical structure at both global and regional levels, we conducted a genome-wide association meta-analysis of brain MRI data from 51,665 individuals across 60 cohorts. We analyzed the surface area and average thickness of the whole cortex and 34 cortical regions with known functional specializations. RESULTS We identified 306 nominally genome-wide significant loci (P < 5 × 10−8) associated with cortical structure in a discovery sample of 33,992 participants of European ancestry. Of the 299 loci for which replication data were available, 241 loci influencing surface area and 14 influencing thickness remained significant after replication, with 199 loci passing multiple testing correction (P < 8.3 × 10−10; 187 influencing surface area and 12 influencing thickness). Common genetic variants explained 34% (SE = 3%) of the variation in total surface area and 26% (SE = 2%) in average thickness; surface area and thickness showed a negative genetic correlation (rG = −0.32, SE = 0.05, P = 6.5 × 10−12), which suggests that genetic influences have opposing effects on surface area and thickness. Bioinformatic analyses showed that total surface area is influenced by genetic variants that alter gene regulatory activity in neural progenitor cells during fetal development. By contrast, average thickness is influenced by active regulatory elements in adult brain samples, which may reflect processes that occur after mid-fetal development, such as myelination, branching, or pruning. When considered together, these results support the radial unit hypothesis that different developmental mechanisms promote surface area expansion and increases in thickness. To identify specific genetic influences on individual cortical regions, we controlled for global measures (total surface area or average thickness) in the regional analyses. After multiple testing correction, we identified 175 loci that influence regional surface area and 10 that influence regional thickness. Loci that affect regional surface area cluster near genes involved in the Wnt signaling pathway, which is known to influence areal identity. We observed significant positive genetic correlations and evidence of bidirectional causation of total surface area with both general cognitive functioning and educational attainment. We found additional positive genetic correlations between total surface area and Parkinson’s disease but did not find evidence of causation. Negative genetic correlations were evident between total surface area and insomnia, attention deficit hyperactivity disorder, depressive symptoms, major depressive disorder, and neuroticism. CONCLUSION This large-scale collaborative work enhances our understanding of the genetic architecture of the human cerebral cortex and its regional patterning. The highly polygenic architecture of the cortex suggests that distinct genes are involved in the development of specific cortical areas. Moreover, we find evidence that brain structure is a key phenotype along the causal pathway that leads from genetic variation to differences in general cognitive function

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Nonstationary vortices in a water glass

¿Quién no ha experimentado la formación de un vórtice o de un remolino en un vaso cuando disuelve el cacao en la leche y le da vueltas con una cuchara? En este artículo, se analizan los aspectos mecánicos de los vórtices no estacionarios formados cuando se agita agua con una cuchara alrededor de un eje central en un vaso de precipitados cilíndrico. Se mostrará que el vórtice no estacionario formado después de agitar el agua con la cuchara es de tipo forzado y se comparará la dinámica del fluido de este vórtice no estacionario con los conocidos vórtices libres estacionarios y forzados y con el de la dinámica del vórtice aislado libre (también conocido como el vórtice de Oseen-Lamb). Mostraremos que la observación de la generación y del decaimiento del vórtice no estacionario en el recipiente cilíndrico del agua en rotación es un simple experimento que puede constituir una experiencia muy fructífera para el entendimiento de los aspectos cinemáticos, dinámicos, y estáticos de la rotación axisimétrica, radial, o torsional de un fluido homogéneo e incompresible.Who has not experienced the formation of a vortex or a whirlpool in a glass of milk when trying to dissolve cocoa in it by stirring the liquid with a spoon? In this paper, we analyse the mechanical aspects of the unsteady vortex formed in swirling water that was stirred with a spoon around a central axis in a cylindrical glass. We show that the formed unsteady vortex is of forced type and we compare the fluid dynamics of this unsteady vortex to that of the well-known steady free and forced vortices and with the dynamics of the unsteady free isolated vortex (also known as Oseen-Lamb’s vortex). We show that the observation of the generation and decay of the unsteady vortex in a cylindrical glass of rotating water is a simple experiment that may constitute a very fruitful experience for understanding the kinematics, dynamics, and static aspects of the axisymmetric, rotational, or torsional flow of an homogeneous and incompressible fluid.F.J.M. y J.A.M. agradecen al Instituto de Ciencias de la Educación de la Universitat Politècnica de València por su ayuda a los Equipos Innovación y Calidad Educativa e-MACAFI y MoMa. A.B. agradece el apoyo del Vicerrectorado de Tecnologías de la Información de la Universidad de Alicante a través del proyecto GITE-09006-UA. E.A, A.N. y J.M.V. agradecen a Cajasol-La Caixa la financiación parcial de este trabajo

Validation and pilot application of [ 18F]FDG-PET in evaluation of a metabolic therapy for Alzheimer's disease

Here we describe methods for application of quantitative fluorodeoxyglucose positron emission tomography ([ 18F]FDG-PET) measures of brain glucose metabolism in multi-centre clinical trials for Alzheimer's disease. We validated methods and demonstrated their use in the context of a treatment trial with the PPARγ agonist Rosiglitazone XR versus placebo in mild to moderate AD patients. Novel quantitative indices related to the combined forward rate constant for [ 18F]FDG uptake $({K}-{i}^{index})$ and to the rate of cerebral glucose utilization $(CM{R}-{glu}^{index})$ were applied. Active treatment was associated with a sustained but not statistically significant trend from the first month for higher mean values in both. However, neither these nor another analytical approach recently validated using data from the Alzheimer's Disease Neuroimaging Initiative suggested that active treatment decreased the progression of decline in brain glucose metabolism. Rates of brain atrophy were similar between active and placebo groups and measures of cognition also did not demonstrate clear group differences. Our study demonstrates the feasibility of using [ 18F]FDG-PET as part of a multi-centre therapeutics trial and describes new measures that can be employed. It suggests that Rosiglitazone is associated with an early increase in whole brain glucose utilisation, but not with any biological or clinical evidence for slowing progression over the period of study in the selected patient group

A Multi-Center Randomized Proof-of-Concept Clinical Trial Applying [18F]FDG-PET for Evaluation of Metabolic Therapy with Rosiglitazone XR in Mild to Moderate Alzheimer's Disease

Here we report the first multi-center clinical trial in Alzheimer's disease (AD) using fluorodeoxyglucose positron emission tomography ([18F]FDG-PET) measures of brain glucose metabolism as the primary outcome. We contrasted effects of 12 months treatment with the PPARγ agonist Rosiglitazone XR versus placebo in 80 mild to moderate AD patients. Secondary objectives included testing for reduction in the progression of brain atrophy and improvement in cognition. Active treatment was associated with a sustained but not statistically significant trend from the first month for higher mean values in Kiindex and CMRgluindex, novel quantitative indices related to the combined forward rate constant for [18F]FDG uptake and to the rate of cerebral glucose utilization, respectively. However, neither these nor another analytical approach recently validated using data from the Alzheimer's Disease Neuroimaging Initiative indicated that active treatment decreased the progression of decline in brain glucose metabolism. Rates of brain atrophy were similar between active and placebo groups and measures of cognition also did not suggest clear group differences. Our study demonstrates the feasibility of using [18F]FDG-PET as part of a multi-center therapeutics trial. It suggests that Rosiglitazone is associated with an early increase in whole brain glucose metabolism, but not with any biological or clinical evidence for slowing progression over a 1 year follow up in the symptomatic stages of AD