Presence of procoagulant peripheral blood mononuclear cells in severe COVID-19 patients relate to ventilation perfusion mismatch and precede pulmonary embolism.

PURPOSE: Pulmonary emboli (PE) contribute substantially to coronavirus disease 2019 (COVID-19) related mortality and morbidity. Immune cell-mediated hyperinflammation drives the procoagulant state in COVID-19 patients, resulting in immunothrombosis. To study the role of peripheral blood mononuclear cells (PBMC) in the procoagulant state of COVID-19 patients, we performed a functional bioassay and related outcomes to the occurrence of PE. Secondary aims were to relate this functional assay to plasma D-dimer levels, ventilation perfusion mismatch and TF expression on monocyte subsets. METHODS: PBMC from an ICU biobank were obtained from 20 patients with a computed tomography angiograph (CTA) proven PE and compared to 15 COVID-19 controls without a proven PE. Functional procoagulant properties of PBMC were measured using a modified fibrin generation time (MC-FGT) assay. Tissue factor (TF) expression on monocyte subsets were measured by flow cytometry. Additional clinical data were obtained from patient records including end-tidal to arterial carbon dioxide gradient. RESULTS: MC-FGT levels were highest in the samples taken closest to the PE detection, similar to the end-tidal to arterial carbon dioxide gradient (ETCO2 - PaCO2), a measurement to quantify ventilation-perfusion mismatch. In patients without proven PE, peak MC-FGT relates to an increase in end-tidal to arterial carbon dioxide gradient. We identified non-classical, CD16 positive monocytes as the subset with increased TF expression. CONCLUSION: We show that the procoagulant state of PBMC could aid in early detection of PE in COVID-19 ICU patients. Combined with end-tidal to ETCO2 - PaCO2 gradient, these tests could improve early detection of PE on the ICU.

An ancient, Antarctic-specific species complex: large divergences between multiple Antarctic lineages of the tardigrade genus Mesobiotus.

Antarctica has been isolated and progressively glaciated for over 30 million years, with only approximately 0.3 % of its area currently ice-free and capable of supporting terrestrial ecosystems. As a result, invertebrate populations have become isolated and fragmented, in some cases leading to speciation. Terrestrial invertebrate species currently found in Antarctica often show multi-million year, and even Gondwanan, heritage, with little evidence of recent colonisation. Mesobiotus is a globally distributed tardigrade genus. It has commonly been divided into two "groups", referred to as harmsworthi and furciger, with both groups currently considered cosmopolitan, with global reports including from both the Arctic and the Antarctic. However, some authors considered that Meb. furciger, as originally described, may represent an Antarctic-specific lineage. Using collections of tardigrades from across the Antarctic continent and publicly available sequences obtained from online databases, we use mitochondrial and nuclear ribosomal sequence data to clarify the relationships of Antarctic Mesobiotus species. Our analyses show that all Antarctic members belong to a single lineage, evolving separately from non-Antarctic representatives. Within this Antarctic lineage there are further deep divisions among geographic regions of the continent, consistent with the presence of a species complex. Based on our data confirming the deep divisions between this Antarctic lineage, which includes representatives of both groups, we recommend that the use of furciger and harmsworthi group terminology is now abandoned, as it leads to systematic and biogeographical confusion.

Animal and translational models of SARS-CoV-2 infection and COVID-19.

COVID-19 is causing a major once-in-a-century global pandemic. The scientific and clinical community is in a race to define and develop effective preventions and treatments. The major features of disease are described but clinical trials have been hampered by competing interests, small scale, lack of defined patient cohorts and defined readouts. What is needed now is head-to-head comparison of existing drugs, testing of safety including in the background of predisposing chronic diseases, and the development of new and targeted preventions and treatments. This is most efficiently achieved using representative animal models of primary infection including in the background of chronic disease with validation of findings in primary human cells and tissues. We explore and discuss the diverse animal, cell and tissue models that are being used and developed and collectively recapitulate many critical aspects of disease manifestation in humans to develop and test new preventions and treatments.

Cyclosporiasis Epidemiologically Linked to Consumption of Green Onions: Houston Metropolitan Area, August 2017.

ABSTRACT: During July 2017, Texas public health officials noted an increase in the number of reported cyclosporiasis cases. They detected a cluster in the Houston metropolitan area that involved four locations of a Mediterranean restaurant chain, restaurant A. A case-control study was conducted among patrons of restaurant A to identify a common food vehicle among items containing fresh produce. In matched case-control ingredient-level analyses that included both probable and confirmed cases, consumption of green onions, red onions, tomatoes, and cabbage was significantly associated with illness. A substantial percentage of case patients reported consumption of green onions, and only green onions remained statistically significantly associated with illness, whether probable and confirmed cases were included in analyses (matched odds ratio: 11.3; 95% confidence interval: 2.5 to 104.7), or only confirmed cases were included in analyses (matched odds ratio: 17.6; 95% confidence interval: 2.5 to 775.7). These results provide evidence that green onions were the likely vehicle of infection. It was not possible to trace the green onions to their source due to the need to redirect public health resources to Hurricane Harvey response efforts in Texas.

Periodic solutions and chaos in the Barkley pipe model on a finite domain.

Barkley's bipartite pipe model is a continuous two-state reaction-diffusion system that models the transition to turbulence in pipes, and reproduces many qualitative features of puffs and slugs, localized turbulent structures seen during the transition. Extensions to the continuous model, including the incorporation of time delays and constraining the system to finite open domains-a trigger for convective instability-reveal additional solutions to the system, including periodic solutions and chaos unseen in the original 1+1-dimensional system. It is found that the nature of solutions depends strongly on the size of the domain under study as well as choice of boundary conditions: on a finite domain for a particular window of parameter space, period doubling and chaos are observed.

Longitudinal vocabulary development in Australian urban Aboriginal children: Protective and risk factors.

BACKGROUND: Vocabulary is a key component of language that can impact on children's future literacy and communication. The gap between Australian Aboriginal and non-Aboriginal children's reading and academic outcomes is well reported and similar to Indigenous/non-Indigenous gaps in other nations. Determining factors that influence vocabulary acquisition over time and may be responsive to treatment is important for improving Aboriginal children's communication and academic outcomes. AIM: To determine what factors influence Australian urban Aboriginal children's receptive vocabulary acquisition and whether any of these are risks or protective for vocabulary development. METHOD: One hundred thirteen Aboriginal children in South Western Sydney from the longitudinal birth cohort Gudaga study were assessed on The Peabody Picture Vocabulary Test multiple times: 3 years, just prior to school entry, at the end of the first and second years of formal schooling. Multilevel models were used to determine the effects of 13 fixed and manipulable maternal, child, and family variables drawn from previous research. RESULTS: Higher maternal education was found to be protective at 3 years and over time. The number of children in urban Australian Aboriginal households made an impact on vocabulary development and this varied over time. From 3 to 6 years, those with early poor non-verbal cognitive skills had vocabulary skills that remained below those with stronger non-verbal skills at 3 years. Girls exhibit an earlier advantage in vocabulary acquisition, but this difference is not sustained after 4 years of age. CONCLUSIONS: The risk and protective factors for vocabulary development in Australian Aboriginal children are similar to those identified in other studies with some variation related to the number of children in the home. In this limited set of predictors, maternal education, gender, non-verbal cognitive skills, and the number of children in households were all shown to impact on the acquisition of vocabulary to 3 years and or the developmental trajectory over time.

A spatially-averaged mathematical model of kidney branching morphogenesis.

Kidney development is initiated by the outgrowth of an epithelial ureteric bud into a population of mesenchymal cells. Reciprocal morphogenetic responses between these two populations generate a highly branched epithelial ureteric tree with the mesenchyme differentiating into nephrons, the functional units of the kidney. While we understand some of the mechanisms involved, current knowledge fails to explain the variability of organ sizes and nephron endowment in mice and humans. Here we present a spatially-averaged mathematical model of kidney morphogenesis in which the growth of the two key populations is described by a system of time-dependant ordinary differential equations. We assume that branching is symmetric and is invoked when the number of epithelial cells per tip reaches a threshold value. This process continues until the number of mesenchymal cells falls below a critical value that triggers cessation of branching. The mathematical model and its predictions are validated against experimentally quantified C57Bl6 mouse embryonic kidneys. Numerical simulations are performed to determine how the final number of branches changes as key system parameters are varied (such as the growth rate of tip cells, mesenchyme cells, or component cell population exit rate). Our results predict that the developing kidney responds differently to loss of cap and tip cells. They also indicate that the final number of kidney branches is less sensitive to changes in the growth rate of the ureteric tip cells than to changes in the growth rate of the mesenchymal cells. By inference, increasing the growth rate of mesenchymal cells should maximise branch number. Our model also provides a framework for predicting the branching outcome when ureteric tip or mesenchyme cells change behaviour in response to different genetic or environmental developmental stresses.

Evaluation of DXA vs. MRI for body composition measures in 1-month olds.

BACKGROUND: Detailed measures of infant body composition are needed for understanding the impact of genes and environment on growth early in life. OBJECTIVE: The purpose of this study was to compare the accuracy and bias of body composition in infants. METHODS: Dual energy X-ray absorptiometry (DXA) and magnetic resonance imaging (MRI) were used to determine body composition and the trunk depot. The depots measured were total fat mass (FM), total fat-free mass (FFM) and trunk FM and FFM using DXA and MRI in 14 infants. RESULTS: None of the regression lines between DXA and MRI significantly deviate from the line of identity for any of the depots studied. However, Bland-Altman analyses revealed bias for trunk FM and trunk FFM. CONCLUSION: Our data showed DXA to be accurate (regression not significantly deviating from the line of identity), with high agreement (indicated by high R(2) ) and without bias (non-significant Bland-Altman) when estimating total FM and FFM. This could not be said for trunk estimates.

Tracheostomy in the critically ill: the myth of dead space.

Benefits and advantages of tracheostomy have been vigorously debated. There is a lack of consensus as to whether perceived clinical improvement is attributable to fundamental changes in respiratory dynamics. We compare the effect of tracheostomy versus endotracheal tube on dead space, airway resistance and other lung parameters in critically ill ventilated patients. Data collected included patients who were admitted to surgical, burn and neurosurgical intensive care units at the University of North Carolina. Twenty-four intubated patients were included in our analysis with various aetiologies of respiratory failure. Tracheostomy was deemed necessary either for severe neurological devastation or failure to wean from the ventilator. The diameter of the endotracheal tubes ranged from 6-8 mm and the tracheostomy tube diameters were from 6.4-8.9 mm. Internal diameters between endotracheal tube and tracheostomy tubes, ventilator settings and sedation were kept consistent throughout the study. Respiratory parameters were measured using the Respironics' non-invasive cardiac output 2 device (Phillips, Andover, MA) immediately prior to tracheostomy and repeated within 24 hours of tracheostomy. Only two (8%) of the patients had slight improvement (>6% decrease in dead space). The average dead space of endotracheal versus tracheostomy tubes was 41±12.6% and 40±14.6%, respectively (P=0.75). The remaining 22 patients (92%) had no significant change in dead space, compliance or other respiratory parameters. This study shows that there is no significant difference in respiratory mechanics and dead space with a tracheostomy versus endotracheal tube.

Incidence of extramedullary disease in patients with multiple myeloma in the era of novel therapy, and the activity of pomalidomide on extramedullary myeloma.

We studied 174 consecutive patients with relapsed refractory multiple myeloma (MM) enrolled on a phase II clinical trial of pomalidomide plus low-dose dexamethasone at Mayo Clinic. Extramedullary disease (EMD) was present at the time of trial entry in 7.5% (13 of 174 patients). The rate of EMD in the first 3 years following diagnosis of MM was 3%. The response of EMD to pomalidomide plus low-dose dexamethasone included two complete and two partial responses among the 13 patients (response rate, 31%). Overall survival measured from trial entry was significantly shorter for patients with treatment-emergent EMD compared with those who did not have EMD, (median 16 months versus not reached, P=0.002).

Pomalidomide (CC4047) plus low dose dexamethasone (Pom/dex) is active and well tolerated in lenalidomide refractory multiple myeloma (MM).

Patients with multiple myeloma progressing on current therapies have limited treatment options. Pomalidomide (CC4047), an immunomodulatory drug, has significant activity in relapsed myeloma and previous studies suggest activity in lenalidomide refractory disease. To better define its efficacy in this group, we treated a cohort of lenalidomide refractory patients. Pomalidomide was given orally (2 mg) daily, continuously in 28-day cycles along with dexamethasone (40 mg) given weekly. Responses were assessed by the International Myeloma Working Group Criteria. Thirty-four patients were enrolled. The best response was very good partial response in 3 (9%), partial response (PR) in 8 (23%), best responses (MR) in 5 (15%), stable disease in 12 (35%) and progressive disease in 6 (18%), for an overall response rate of 47%. Of the 14 patients that were considered high risk, 8 (57%) had responses including 4 PR and 4 MR. The median time to response was 2 months and response duration was 9.1 months, respectively. The median overall survival was 13.9 months. Toxicity was primarily hematologic, with grade 3 or 4 toxicity seen in 18 patients (53%) consisting of anemia (12%), thrombocytopenia (9%) and neutropenia (26%). The combination of pomalidomide and dexamethasone (Pom/dex) is highly active and well tolerated in patients with lenalidomide-refractory myeloma.

Microstructural and compositional analysis of strontium-doped lead zirconate titanate thin films on gold-coated silicon substrates.

This article discusses the results of transmission electron microscopy (TEM)-based characterization of strontium-doped lead zirconate titanate (PSZT) thin films. The thin films were deposited by radio frequency magnetron sputtering at 300 degrees C on gold-coated silicon substrates, which used a 15 nm titanium adhesion layer between the 150 nm thick gold film and (100) silicon. The TEM analysis was carried out using a combination of high-resolution imaging, energy filtered imaging, energy dispersive X-ray (EDX) analysis, and hollow cone illumination. At the interface between the PSZT films and gold, an amorphous silicon-rich layer (about 4 nm thick) was observed, with the film composition remaining uniform otherwise. The films were found to be polycrystalline with a columnar structure perpendicular to the substrate. Interdiffusion between the bottom metal layers and silicon was observed and was confirmed using secondary ion mass spectrometry. This occurs due to the temperature of deposition (300 degrees C) being close to the eutectic point of gold and silicon (363 degrees C). The diffused regions in silicon were composed primarily of gold (analyzed by EDX) and were bounded by (111) silicon planes, highlighted by the triangular diffused regions observed in the two-dimensional TEM image.

Thin film piezoelectric response characterisation using atomic force microscopy with standard contact mode imaging.

This article introduces a technique for observing and quantifying the piezoelectric response of thin films, using standard atomic force microscopes (AFMs). The technique has been developed and verified using strontium-doped lead zirconate titanate (PSZT) thin films, which are known for their high piezoelectric response. Quantification of the electro-mechanical voltage coefficient d(33) (pm/V) is made directly based on the applied peak-to-peak voltage and the corresponding peak-to-peak displacement in the obtained scan image. Under the proposed technique the AFM is configured in contact mode, where the silicon nitride tip is set to follow the film displacement at a single point. A known sinusoidal voltage is applied across the film and the displacement determined as a function of time, rather than the typical AFM measurement of displacement versus tip position. The resulting raster image contains several bands, which are directly related to the AFM scan frequency and the applied sinusoidal voltage and its frequency. Different combinations of the AFM scan frequency and the applied sinusoid frequency have been used to characterise the PSZT thin films, with estimated values of d(33) between 109 and 205 pm/V.

Influence of oxygen partial pressure on the composition and orientation of strontium-doped lead zirconate titanate thin films.

The influence of oxygen partial pressure during the deposition of piezoelectric strontium-doped lead zirconate titanate thin films is reported. The thin films have been deposited by RF magnetron sputtering in an atmosphere of high purity argon and oxygen (in the ratio of 9:1), on platinum-coated silicon substrates (heated to 650 degrees C). The influence of oxygen partial pressure is studied to understand the manner in which the stoichiometry of the thin films is modified, and to understand the influence of stoichiometry on the perovskite orientation. This article reports on the results obtained from films deposited at oxygen partial pressures of 1-5 mTorr. The thin films have been studied using a combination of X-ray photoelectron spectroscopy (XPS), glancing angle X-ray diffraction (GA-XRD), and atomic force microscopy (AFM). XPS analysis highlights the marked influence of variations in oxygen pressure during sputtering, observed by variations in oxygen concentration in the thin films, and in some cases by the undesirable decrease in lead concentration in the thin films. GA-XRD is used to study the relative variations in perovskite peak intensities, and has been used to determine the deposition conditions to attain the optimal combination of stoichiometry and orientation. AFM scans show the marked influence of the oxygen partial pressure on the film morphology.

Microstructural investigation of nickel silicide thin films and the silicide-silicon interface using transmission electron microscopy.

This article discusses the results of transmission electron microscopy (TEM)-based investigation of nickel silicide (NiSi) thin films grown on silicon. Nickel silicide is currently used as the CMOS technology standard for local interconnects and in electrical contacts. Films were characterized with a range of TEM-based techniques along with glancing angle X-ray diffraction. The nickel silicide thin films were formed by vacuum annealing thin films of nickel (50 nm) deposited on (100) silicon. The cross-sectional samples indicated a final silicide thickness of about 110 nm. This investigation studied and reports on three aspects of the thermally formed thin films: the uniformity in composition of the film using jump ratio maps; the nature of the interface using high resolution imaging; and the crystalline orientation of the thin films using selected-area electron diffraction (SAED). The analysis highlighted uniform composition in the thin films, which was also substantiated by spectroscopy techniques; an interface exhibiting the desired abrupt transition from silicide to silicon; and desired and preferential crystalline orientation corresponding to stoichiometric NiSi, supported by glancing angle X-ray diffraction results.

In situ micro-Raman analysis and X-ray diffraction of nickel silicide thin films on silicon.

This article reports on the in situ analysis of nickel silicide (NiSi) thin films formed by thermal processing of nickel thin films deposited on silicon substrates. The in situ techniques employed for this study include micro-Raman spectroscopy (microRS) and X-ray diffraction (XRD); in both cases the variations for temperatures up to 350 degrees C has been studied. Nickel silicide thin films formed by vacuum annealing of nickel on silicon were used as a reference for these measurements. In situ analysis was carried out on nickel thin films on silicon, while the samples were heated from room temperature to 350 degrees C. Data was gathered at regular temperature intervals and other specific points of interest (such as 250 degrees C, where the reaction between nickel and silicon to form Ni(2)Si is expected). The transformations from the metallic state, through the intermediate reaction states, until the desired metal-silicon reaction product is attained, are discussed. The evolution of nickel silicide from the nickel film can be observed from both the microRS and XRD in situ studies. Variations in the evolution of silicide from metal for different silicon substrates are discussed, and these include (100) n-type, (100) p-type, and (110) p-type silicon substrates.

Development of a microbial population within a hot-drinks vending machine and the microbial load of vended hot chocolate drink.

In order to understand the development of the microbial population within a hot-drinks vending machine a new machine was placed in a staff area of a university campus vending only hot chocolate. The machine was cleaned weekly using a detergent based protocol. Samples from the mixing bowl, dispense area, and drink were taken over a 19-wk period and enumerated using plate count agar. Bacillus cereus was identified using biochemical methods. Vended drinks were sampled at 0, 3, 6, and 9 min after vending; the hot chocolate powder was also sampled. Over the 1st 8 wk, a significant increase in the microbial load of the machine components was observed. By the end of the study, levels within the vended drink had also increased significantly. Inactivation of the automatic flush over a subsequent 5-wk period led to a statistically but not operationally significant increase in the microbial load of the dispense area and vended drink. The simple weekly clean had a significant impact on the microbial load of the machine components and the vended drink. This study demonstrated that a weekly, detergent-based cleaning protocol was sufficient to maintain the microbial population of the mixing bowl and dispense point in a quasi-steady state below 3.5 log CFU/cm2 ensuring that the microbial load of the vended drinks was maintained below 3.4 log CFU/mL. The microbial load of the drinks showed no significant changes over 9 min after vending, suggesting only spores are present in the final product.

1% hydrocortisone ointment is an effective treatment of pruritus ani: a pilot randomized controlled crossover trial.

BACKGROUND: Pruritus ani (PA) is a common condition which is difficult to treat in the absence of obvious predisposing factors. There is paucity of evidence-based guidelines on the treatment of this condition. We examined whether 1% hydrocortisone ointment is an effective treatment for PA. MATERIALS AND METHODS: A pilot randomized, double-blind, placebo-controlled, crossover trial was carried out. Eleven patients consented to take part in the trial and ten completed the study. After a 2-week run-in period, patients with primary PA were randomly allocated to receive 1% hydrocortisone ointment or placebo for 2 weeks followed by the opposite treatment for a further 2-week period. There was a washout period of 2 weeks between treatments. The primary outcome measure was reduction in itch using a visual analogue score (VAS). The secondary outcome measures were improvement in quality of life measured using a validated questionnaire (Dermatology Life Quality Index, DLQI) and improvement in clinical appearance of the perianal skin using the Eczema Area and Severity Index (EASI) score. RESULTS: Treatment with 1% hydrocortisone ointment resulted in a 68% reduction in VAS compared with placebo (P=0.019), a 75% reduction in DLQI score (P=0.067), and 81% reduction in EASI score (P=0.01). CONCLUSION: A short course of mild steroid ointment is an effective treatment for PA.