The inability of neutrophils to eradicate Pseudomonas aeruginosa within the cystic fibrosis (CF) airway eventually results in chronic infection by the bacteria in nearly 80 percent of patients. ...Phagocytic killing of P. aeruginosa by CF neutrophils is impaired due to decreased cystic fibrosis transmembrane conductance regulator (CFTR) function and virulence factors acquired by the bacteria. Recently, neutrophil extracellular traps (NETs), extracellular structures composed of neutrophil chromatin complexed with granule contents, were identified as an alternative mechanism of pathogen killing. The hypothesis that NET-mediated killing of P. aeruginosa is impaired in the context of the CF airway was tested. P. aeruginosa induced NET formation by neutrophils from healthy donors in a bacterial density dependent fashion. When maintained in suspension through continuous rotation, P. aeruginosa became physically associated with NETs. Under these conditions, NETs were the predominant mechanism of killing, across a wide range of bacterial densities. Peripheral blood neutrophils isolated from CF patients demonstrated no impairment in NET formation or function against P. aeruginosa. However, isogenic clinical isolates of P. aeruginosa obtained from CF patients early and later in the course of infection demonstrated an acquired capacity to withstand NET-mediated killing in 8 of 9 isolates tested. This resistance correlated with development of the mucoid phenotype, but was not a direct result of the excess alginate production that is characteristic of mucoidy. Together, these results demonstrate that neutrophils can kill P. aeruginosa via NETs, and in vitro this response is most effective under non-stationary conditions with a low ratio of bacteria to neutrophils. NET-mediated killing is independent of CFTR function or bacterial opsonization. Failure of this response in the context of the CF airway may occur, in part, due to an acquired resistance against NET-mediated killing by CF strains of P. aeruginosa.
There is increasing evidence that autonomic dysfunction is an important factor in the progression of glaucoma. Mechanism of the association between autonomic dysfunction and progression of glaucoma ...is poorly understood. Since blood circulation is basically regulated by the autonomic nervous system, autonomic dysfunction may contribute to unstable or fluctuating blood pressure. Therefore, It is hypothesized that autonomic dysfunction may contribute to impaired ocular blood flow and lead to glaucoma progression. However, no clinical study yet has evaluated the relationship between ocular blood flow and autonomic nervous function. We enrolled 152 open angle glaucoma patient. Ocular blood flow was assessed by measuring vessel density (VD) using optical coherence tomography angiography, and autonomic nervous function was evaluated with heart-rate variability (HRV) parameters. The low frequency/high frequency (LF/HF) ratio, which is one of the HRV parameters, quantified the degree of sympathovagal balance. This indicator could represent autonomic dysfunction. Higher LF/HF ratio was associated with reduction of the deep parapapillary VD (R = - 0.243, P = 0.003). Linear regression analysis showed a significant negative association between parapapillary choroidal VD and LF/HF ratio (β = - 0.249; 95% confidential interval = - 1.193 to - 0.249; P = 0.002) in multivariate analysis. We demonstarted the association between impaired ocular blood flow (parapapillary choroidal vessel density) and autonomic dysfunction (LF/HF ratio). This study could help understand the role of the autonomic dysfunction in pathophysiology of glaucoma progression.
Mitochondrial disease prevalence has been estimated at 1 in 4000 in the United States, and 1 in 5000 worldwide. Prevalence in Canada has not been established, though multi-linked health ...administrative data resources present a unique opportunity to establish robust population-based estimates in a single-payer health system. This study used administrative data for the Ontario, Canada population between April 1988 and March 2019 to measure mitochondrial disease prevalence and describe patient characteristics and health care costs.
3069 unique individuals were hospitalized with mitochondrial disease in Ontario and eligible for the study cohort, representing a period prevalence of 2.51 per 10,000 or 1 in 3989. First hospitalization was most common between ages 0-9 or 50-69. The mitochondrial disease population experiences a high need for health care and incurred high costs (mean = CAD$24,023 in 12 months before first hospitalization) within the single-payer Ontario health care system.
This study provides needed insight into mitochondrial disease in Canada, and demonstrates the high health burden on patients. The methodology used can be adapted across jurisdictions with similar routine collection of health data, such as in other Canadian provinces. Future work should seek to validate this approach via record linkage of existing disease cohorts in Ontario, and identify specific comorbidities with mitochondrial disease that may contribute to high health resource utilization.
The spatial presentation of mechanical information is a key parameter for cell behavior. We have developed a method of polymerization control in which the differential diffusion distance of unreacted ...cross-linker and monomer into a prepolymerized hydrogel sink results in a tunable stiffness gradient at the cell–matrix interface. This simple, low-cost, robust method was used to produce polyacrylamide hydrogels with stiffness gradients of 0.5, 1.7, 2.9, 4.5, 6.8, and 8.2 kPa/mm, spanning the in vivo physiological and pathological mechanical landscape. Importantly, three of these gradients were found to be nondurotactic for human adipose-derived stem cells (hASCs), allowing the presentation of a continuous range of stiffnesses in a single well without the confounding effect of differential cell migration. Using these nondurotactic gradient gels, stiffness-dependent hASC morphology, migration, and differentiation were studied. Finally, the mechanosensitive proteins YAP, Lamin A/C, Lamin B, MRTF-A, and MRTF-B were analyzed on these gradients, providing higher-resolution data on stiffness-dependent expression and localization.
Since the last Pluto volatile transport models were published in 1996, we have (1) new stellar occultation data from 2002 and 2006-2012 that show roughly twice the pressure as the first definitive ...occultation from 1988, (2) new information about the surface properties of Pluto, (3) a spacecraft due to arrive at Pluto in 2015, and (4) a new volatile transport model that is rapid enough to allow a large parameter-space search. Such a parameter-space search coarsely constrained by occultation results reveals three broad solutions: a high-thermal inertia, large volatile inventory solution with permanent northern volatiles (PNVs; using the rotational north pole convention); a lower thermal-inertia, smaller volatile inventory solution with exchanges of volatiles between hemispheres and a pressure plateau beyond 2015 (exchange with pressure plateau, EPP); and solutions with still smaller volatile inventories, with exchanges of volatiles between hemispheres and an early collapse of the atmosphere prior to 2015 (exchange with early collapse, EEC). PNV and EPP are favored by stellar occultation data, but EEC cannot yet be definitively ruled out without more atmospheric modeling or additional occultation observations and analysis.
Scale development and validation are critical to much of the work in the health, social, and behavioral sciences. However, the constellation of techniques required for scale development and ...evaluation can be onerous, jargon-filled, unfamiliar, and resource-intensive. Further, it is often not a part of graduate training. Therefore, our goal was to concisely review the process of scale development in as straightforward a manner as possible, both to facilitate the development of new, valid, and reliable scales, and to help improve existing ones. To do this, we have created a primer for best practices for scale development in measuring complex phenomena. This is not a systematic review, but rather the amalgamation of technical literature and lessons learned from our experiences spent creating or adapting a number of scales over the past several decades. We identified three phases that span nine steps. In the first phase, items are generated and the validity of their content is assessed. In the second phase, the scale is constructed. Steps in scale construction include pre-testing the questions, administering the survey, reducing the number of items, and understanding how many factors the scale captures. In the third phase, scale evaluation, the number of dimensions is tested, reliability is tested, and validity is assessed. We have also added examples of best practices to each step. In sum, this primer will equip both scientists and practitioners to understand the ontology and methodology of scale development and validation, thereby facilitating the advancement of our understanding of a range of health, social, and behavioral outcomes.
Radiomics features extracted from oncological PET images are currently under intense scrutiny within the context of risk stratification for a variety of cancers. However, the lack of robustness ...assessment poses problems for their application across institutions and for broader patient populations. The objective of the current study was to examine the extent to which radiomics parameters from oncological PET vary in response to manual contouring variability in lung cancer. Imaging data employed in the study consisted of 26 PET scans with lesions in the lung being created through the use of an anthropomorphic phantom in conjunction with Monte Carlo simulations. From each of the simulated lesions, 25 radiomics features related to the gray-level co-occurrence matrices (GLCOM), gray-level size zone matrices (GLSZM), and gray-level neighborhood difference matrices (GLNDM) were extracted from ground truth contour and from manual contours provided by 10 raters in regard to four intensity discretization schemes with number of gray levels of 32, 64, 128, and 256, respectively. The impact of interrater variability in tumor delineation upon the agreement between raters on radiomics features was examined via interclass correlation and leave-p-out assessment. Only weak and moderate correlations were found between segmentation accuracy as measured by the Dice coefficient and percent feature error from ground truth for the vast majority of the features being examined. GLNDM-based texture parameters emerged as the top performing category of radiomcs features in terms of robustness against contouring variability for discretization schemes engaging number of gray levels of 32, 64, and 128 while GLCOM-based parameters stood out for discretization scheme engaging 256 gray levels. How and to what extent interrater reliability of radiomics features vary in response to the number of raters were largely feature-dependent. It was concluded that impact of contouring variability on PET-based radiomics features is present to varying degrees and could be experienced as a barrier to convey PET-based radiomics research to clinical relevance.
The coronavirus disease 2019 (COVID-19) pandemic resulted in physical isolation measures in many parts of the world. In Australia, nationwide restrictions included staying at home, unless seeking ...medical care, providing care, purchasing food, undertaking exercise, or attending work in an essential service. All undergraduate university classes transitioned to online, mostly home-based learning. We, therefore, examined the effect of isolation measures during the early phase of the COVID-19 pandemic in Australia (March/April) on diet (24-h recall) and physical activity (Active Australia Survey) patterns in third-year biomedical students. Findings were compared with students enrolled in the same course in the previous two years. In females, but not males, energy intake was ~20% greater during the pandemic, and snacking frequency and energy density of consumed snacks also increased compared with 2018 and 2019. Physical activity was impacted for both sexes during the pandemic with ~30% fewer students achieving "sufficient" levels of activity, defined by at least 150 min over at least five sessions, compared with the previous two years. In a follow-up study six to eight weeks later (14-18% response rate), during gradual easing of nationwide restrictions albeit continued gym closures and online learning, higher energy intake in females and reduced physical activity levels in both sexes persisted. These data demonstrate the health impacts of isolation measures, with the potential to affect long-term diet and activity behaviours.
Recurrent implantation failure (RIF) is a poorly defined clinical scenario marked by failure to achieve pregnancy after multiple embryo transfers. The causes and definitions of implantation failure ...are heterogeneous, posing limitations on study design as well as the interpretation and application of findings. Recent studies suggest a novel, personalized approach to defining RIF. Here, we review the implantation physiology and definitions of the implantation rate, failure, and RIF.
Diffusion tensor imaging (DTI) studies consistently reported abnormalities in fractional anisotropy (FA) and radial diffusivity (RD), measures of the integrity of white matter (WM), in bipolar ...disorder (BD), that may reflect underlying pathophysiologic processes. There is, however, a pressing need to identify peripheral measures that are related to these WM measures, to help identify easily obtainable peripheral biomarkers of BD. Given the high lipid content of axonal membranes and myelin sheaths, and that elevated serum levels of lipid peroxidation are reported in BD, these serum measures may be promising peripheral biomarkers of underlying WM abnormalities in BD. We used DTI and probabilistic tractography to compare FA and RD in ten prefrontal-centered WM tracts, 8 of which are consistently shown to have abnormal FA (and/or RD) in BD, and also examined serum lipid peroxidation (lipid hydroperoxides, LPH and 4-hydroxy-2-nonenal, 4-HNE), in 24 currently euthymic BD adults (BDE) and 19 age- and gender-matched healthy adults (CONT). There was a significant effect of group upon FA in these a priori WM tracts (BDE<CONT: F1,41=6.8; P=0.013) and RD (BDE>CONT: F1,41=10.3; P=0.003), and a significant between-group difference in LPH (BDE>CONT: t40=2.4; P=0.022), but not in 4-HNE. Multivariate multiple regression analyses revealed that LPH variance explained, respectively, 59 and 51% of the variance of FA and RD across all study participants. This is the first study to examine relationships between measures of WM integrity and peripheral measures of lipid peroxidation. Our findings suggest that serum LPH may be useful in the development of a clinically relevant, yet easily obtainable and inexpensive, peripheral biomarkers of BD.
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