Coronavirus disease 2019 (COVID-19): Focus on peripheral blood cell morphology.

Numerous studies have shown peculiar morphological anomalies in COVID-19 patients' smears. We searched all the peer-reviewed scientific publications that explicitly reference the cytomorphological alterations on peripheral blood smears of patients with COVID-19. We extracted data from sixty-five publications (case reports, patient group studies, reviews, and erythrocyte morphology studies). The results show that frequent alterations concern the morphology of lymphocytes (large lymphocytes with weakly basophilic cytoplasm, plasmacytoid lymphocytes, large granular lymphocytes). Neutrophils display abnormal nuclei and cytoplasm in a distinctive cytomorphological picture. Besides a left shift in maturation, granulations can be increased (toxic type) or decreased with areas of basophilia. Nuclei are often hyposegmented (pseudo-Pelger-Huёt anomaly). Apoptotic or pycnotic cells are not uncommon. Monocytes typically have a large cytoplasm loaded with heterogeneous and coalescing vacuoles. Platelets show large and giant shapes. The presence of erythrocyte fragments and schistocytes is especially evident in the forms of COVID-19 that are associated with thrombotic microangiopathies. Such atypia of blood cells reflects the generalized activation in severe COVID-19, which has been demonstrated with immunophenotypic, molecular, genetic, and functional methods. Neutrophils, in particular, are involved in the pathophysiology of hyperinflammation with cytokine storm, which characterizes the most unfavorable evolution.

Coordinate invariance as a fundamental constraint on the form of stimulus-specific information measures.

The value of Shannon's mutual information is commonly used to describe the total amount of information that the neural code transfers between the ensemble of stimuli and the ensemble of neural responses. In addition, it is often desirable to know which features of the stimulus or response are most informative. The literature offers several different decompositions of the mutual information into its stimulus or response-specific components, such as the specific surprise or the uncertainty reduction, but the number of mutually distinct measures is in fact infinite. We resolve this ambiguity by requiring the specific information measures to be invariant under invertible coordinate transformations of the stimulus and the response ensembles. We prove that the Kullback-Leibler divergence is then the only suitable measure of the specific information. On a more general level, we discuss the necessity and the fundamental aspects of the coordinate invariance as a selection principle. We believe that our results will encourage further research into invariant statistical methods for the analysis of neural coding.

The Jacobi diffusion process as a neuronal model.

The Jacobi process is a stochastic diffusion characterized by a linear drift and a special form of multiplicative noise which keeps the process confined between two boundaries. One example of such a process can be obtained as the diffusion limit of the Stein's model of membrane depolarization which includes both excitatory and inhibitory reversal potentials. The reversal potentials create the two boundaries between which the process is confined. Solving the first-passage-time problem for the Jacobi process, we found closed-form expressions for mean, variance, and third moment that are easy to implement numerically. The first two moments are used here to determine the role played by the parameters of the neuronal model; namely, the effect of multiplicative noise on the output of the Jacobi neuronal model with input-dependent parameters is examined in detail and compared with the properties of the generic Jacobi diffusion. It appears that the dependence of the model parameters on the rate of inhibition turns out to be of primary importance to observe a change in the slope of the response curves. This dependence also affects the variability of the output as reflected by the coefficient of variation. It often takes values larger than one, and it is not always a monotonic function in dependency on the rate of excitation.

Two-boundary first exit time of Gauss-Markov processes for stochastic modeling of acto-myosin dynamics.

We consider a stochastic differential equation in a strip, with coefficients suitably chosen to describe the acto-myosin interaction subject to time-varying forces. By simulating trajectories of the stochastic dynamics via an Euler discretization-based algorithm, we fit experimental data and determine the values of involved parameters. The steps of the myosin are represented by the exit events from the strip. Motivated by these results, we propose a specific stochastic model based on the corresponding time-inhomogeneous Gauss-Markov and diffusion process evolving between two absorbing boundaries. We specify the mean and covariance functions of the stochastic modeling process taking into account time-dependent forces including the effect of an external load. We accurately determine the probability density function (pdf) of the first exit time (FET) from the strip by solving a system of two non singular second-type Volterra integral equations via a numerical quadrature. We provide numerical estimations of the mean of FET as approximations of the dwell-time of the proteins dynamics. The percentage of backward steps is given in agreement to experimental data. Numerical and simulation results are compared and discussed.

Lifestyle and DNA base composition in polychaetes.

A comparative analysis of polychaete species, classified as motile and low-motile forms, highlighted that the former were characterized not only by a higher metabolic rate (MR), but also by a higher genomic GC content. The fluctuation of both variables was not affected by the phylogenetic relationship of the species. Thus, present results further support that a very active lifestyle affects MR and GC at the same time, showing an unexpected similarity between invertebrates and vertebrates. In teleosts, indeed, a similar pattern has been also observed in comparisons of migratory and nonmigratory species. A cause-effect link between MR and GC has not yet been proved, but the fact that the two variables are significantly linked in all the organisms so far analyzed is, most probably, of relevant biological and evolutionary meaning. The present results fit very well within the frame of the metabolic rate hypothesis proposed to explain the DNA base composition variability among organisms. On the contrary, the thermostability hypothesis was not supported. At present, no data about the recombination rate in polychaetes were available to test the biased gene conversion (BGC hypothesis).

On the genome base composition of teleosts: the effect of environment and lifestyle.

BACKGROUND: The DNA base composition is well known to be highly variable among organisms. Bio-physic studies on the effect of the GC increments on the DNA structure have shown that GC-richer DNA sequences are more bendable. The result was the keystone of the hypothesis proposing the metabolic rate as the major force driving the GC content variability, since an increased resistance to the torsion stress is mainly required during the transcription process to avoid DNA breakage. Hence, the aim of the present work is to test if both salinity and migration, suggested to affect the metabolic rate of teleostean fishes, affect the average genomic GC content as well. Moreover, since the gill surface has been reported to be a major morphological expression of metabolic rate, this parameter was also analyzed in the light of the above hypothesis. RESULTS: Teleosts living in different environments (freshwater and seawater) and with different lifestyles (migratory and non-migratory) were analyzed studying three variables: routine metabolic rate, gill area and genomic GC-content, none of them showing a phylogenetic signal among fish species. Routine metabolic rate, specific gill area and average genomic GC were higher in seawater than freshwater species. The same trend was observed comparing migratory versus non-migratory species. Crossing salinity and lifestyle, the active migratory species living in seawater show coincidentally the highest routine metabolic rate, the highest specific gill area and the highest average genomic GC content. CONCLUSIONS: The results clearly highlight that environmental factors (salinity) and lifestyle (migration) affect not only the physiology (i.e. the routine metabolic rate), and the morphology (i.e. gill area) of teleosts, but also basic genome feature (i.e. the GC content), thus opening to an interesting liaison among the three variables in the light of the metabolic rate hypothesis.

Artificial intelligence and the blood film: Performance of the MC-80 digital morphology analyzer in samples with neoplastic and reactive cell types.

INTRODUCTION: Implementing artificial intelligence-based instruments in hematology laboratories requires evidence of efficiency in classifying pathological cells. In two-Universities, we assessed the performance of the Mindray® MC-80 for hematology patients with frequent leukemic and dysplastic cells. METHODS: The Mindray MC-80® locates and pre-classifies cells in blood films. In a two-university study, four films were prepared from 591 samples, two each for the analyser MC-80 and the microscope reference method, using reagents from two different manufacturers. We used Microsoft Excel® statistics for imprecision and distributional inaccuracy and a matrix table model (H20-A2 CLSI standard) for sensitivity, specificity and predictive value for atypical cells. RESULTS: The results indicate minimal within-run imprecision (ICSH method) and good intra-method consistency even on duplicate analysis of 413 samples with a high incidence of hematological abnormalities (r = 0.942 or more, except for basophils, r = 0.841, and reactive lymphocytes, r = 0.847). Distributional inaccuracy was also very low compared to the microscope reference, with a pass rate higher than 80% for pathological cells (except 75.1% for reactive lymphocytes). The primary causes of discrepancy were bizarre shapes of dysplastic neutrophils and inconsistent nomenclature for lymphoma cells. Sensitivity for critical samples containing cells typically absent in circulating blood (immature or malignant) was 98.8% for immature granulocytes, 83.8% for all types of neoplastic cells, 93.6% for reactive lymphocytes and 97.5% for nucleated red blood cells. The negative predictive values of MC-80 were 98.8% for immature granulocytes, 88.4% for the different types of neoplastic cells, 97.8% for reactive lymphocytes, and 96.9% for nucleated red blood cells. CONCLUSION: Our study highlights the outstanding diagnostic performance of this artificial intelligence-based blood film analyzer for hematology patients with circulating abnormal cells. We appreciated the morphological harmonization of cells observed on the screen and those seen in the microscope.

The footprint of metabolism in the organization of mammalian genomes.

BACKGROUND: At present five evolutionary hypotheses have been proposed to explain the great variability of the genomic GC content among and within genomes: the mutational bias, the biased gene conversion, the DNA breakpoints distribution, the thermal stability and the metabolic rate. Several studies carried out on bacteria and teleostean fish pointed towards the critical role played by the environment on the metabolic rate in shaping the base composition of genomes. In mammals the debate is still open, and evidences have been produced in favor of each evolutionary hypothesis. Human genes were assigned to three large functional categories (as well as to the corresponding functional classes) according to the KOG database: (i) information storage and processing, (ii) cellular processes and signaling, and (iii) metabolism. The classification was extended to the organisms so far analyzed performing a reciprocal Blastp and selecting the best reciprocal hit. The base composition was calculated for each sequence of the whole CDS dataset. RESULTS: The GC3 level of the above functional categories was increasing from (i) to (iii). This specific compositional pattern was found, as footprint, in all mammalian genomes, but not in frog and lizard ones. Comparative analysis of human versus both frog and lizard functional categories showed that genes involved in the metabolic processes underwent the highest GC3 increment. Analyzing the KOG functional classes of genes, again a well defined intra-genomic pattern was found in all mammals. Not only genes of metabolic pathways, but also genes involved in chromatin structure and dynamics, transcription, signal transduction mechanisms and cytoskeleton, showed an average GC3 level higher than that of the whole genome. In the case of the human genome, the genes of the aforementioned functional categories showed a high probability to be associated with the chromosomal bands. CONCLUSIONS: In the light of different evolutionary hypotheses proposed so far, and contributing with different potential to the genome compositional heterogeneity of mammalian genomes, the one based on the metabolic rate seems to play not a minor role. Keeping in mind similar results reported in bacteria and in teleosts, the specific compositional patterns observed in mammals highlight metabolic rate as unifying factor that fits over a wide range of living organisms.

Scientific expertise and the Athlete Biological Passport: 3 years of experience.

Expert evaluation of biological data is a key component of the Athlete Biological Passport approach in the fight against doping. The evaluation consists of a longitudinal assessment of biological variables to determine the probability of the data being physiological on the basis of the athlete's on own previous values (performed by an automated software system using a Bayesian model) and a subjective evaluation of the results in view of possible causes (performed by experts). The role of the expert is therefore a key component in the process. Experts should be qualified to evaluate the data regarding possible explanations related to the influence of doping products and methods, analytical issues, and the influence of exercise or pathological conditions. The evaluation provides a scientific basis for the decision taken by a disciplinary panel. This evaluation should therefore encompass and balance all possible causes for a given blood profile and provide a likelihood for potential scenarios (pathology, normal variation, doping) that might have caused the pattern. It should comply with the standards for the evaluation of scientific evidence in forensics. On the basis of their evaluation of profiles, experts might provide assistance in planning appropriate target testing schemes.

Peculiar patterns of amino acid substitution and conservation in the fast evolving tunicate Oikopleura dioica.

We analyze the patterns and rates of amino acid evolution in tunicates with special interest on the extremely fast evolving Oikopleura dioica. We show that this species, on average, is twice as fast as the already fast evolving Ciona intestinalis. The acceleration in both species seems to be affected by similar evolutionary forces yet to different extent, since a substantial proportion of the most and less accelerated genes are orthologous between the two species. Among the possible causes that underlie the genome wide acceleration in Oikopleura, relaxation of functional constraints appears to be an important one, since all amino acids exhibit surprisingly homogenous levels of divergence. Such homogeneity, however, is not observed in Ciona. Apart from the genome wide acceleration, detailed analysis of functional groups of genes revealed that genes associated with regulatory functions (transcription regulators, chromatin remodeling proteins and metabolic regulators), have been subjected to an even more extreme process of acceleration, suggesting that adaptive evolution is the most probable cause of their unusual exacerbated rates. Another remarkable observation is that cysteine is among the less conserved amino acids, contrary to what is commonly observed in other species. The possible causes of this particular behavior are discussed.

Standardization of reticulocyte counts in the athlete biological passport: A practical update.

INTRODUCTION: The athlete biological passport monitors blood variables over time to uncover blood doping. With the phasing in of a new series of blood analyzers, the Sysmex XN series, it was necessary to examine the comparability of results with the previously employed XT/XE series. A previous comparison between XN and XT/XE series suggested a small but significant bias between the two instruments in the measurements of RET%. Here, we examined the comparability of RET% on the XN and XT/XE platform using data collected over the first year since the transition. METHODS: The comparability of results obtained from XN and XT/XE instruments was assessed using three datasets: (i) 767 blood samples measured on both instrument series in 22 WADA-accredited laboratories, (ii) 27 323 samples measured on either instrument across 31 laboratories, and (iii) 119 clinical samples and 110 anti-doping samples measured on both instruments in a single laboratory. RESULTS: Analysis of the three datasets confirms the previous observation of a bias toward higher RET% values for samples measured on Sysmex XN instruments compared with the XT/XE series. Using data across a larger number of XN instruments and a larger athlete population, the current work suggests that the bias is proportional and slightly higher than previously observed across most of the range RET% values. CONCLUSION: A model is proposed for the comparison of data across XN and XT/XE technologies whereby the instrument bias increases proportionally with RET% measured on Sysmex XN Series, but where the rate of increase is negatively related to IRF%.

Full-field hemocytometry. Forty years of progress seen through Clinical and Laboratory Hematology and the International Journal of Laboratory Hematology.

The extraordinary advances in clinical hematology, biology, and oncology in the last decades would not have been possible without discovering how to identify and count the cells circulating in the blood. For centuries, scientists have used slides, counting chambers (hemocytometers), and diluting and staining solutions for this task. Then, automated hemocytometry began. This science, now linked to the daily routine of laboratory hematology, has completed an overwhelming path over a few decades. Our laboratories today operate with versatile multiparameter systems, ranging from complex single-channel instruments to bulky continuous flow machines. In terms of clinical information obtained from a simple routine blood test, the full exploitation of their potential depends on the operators' imagination and courage. A comprehensive review of the scientific publications that have accompanied the development of hemocytometry from the 1950s to today would require entire volumes. More than seven hundred contributions that authors worldwide have published in Clinical and Laboratory Haematology until 2007 and then the International Journal of Laboratory Hematology are summarized. Such journals have represented and hopefully will continue to represent the privileged place of welcome for future scientific research in hemocytometry. Improved technologies, attention to quality, new reagents and electronics, information technology, and scientist talent ensure a more profound and deeper knowledge of cell properties: current laboratory devices measure and count even minor immature or pathological cell subpopulations. Full-field hemocytometry includes the analysis of nonhematic fluids, digital adds to the microscope, and the development of effective point-of-care devices.

2021 update of the 2012 ICSH Recommendations for identification, diagnostic value, and quantitation of schistocytes: Impact and revisions.

In 2012, the International Council for Standardization in Hematology (ICSH) published recommendations for the identification, quantitation, and diagnostic value of schistocytes. In the present review, the impact of these recommendations is evaluated. This work is based on citations in peer-reviewed papers published since 2012. The first 2012 ICSH Recommendations have also been revised to incorporate newly published data in the literature and current best laboratory practice. Recommended reference ranges have been proposed for healthy adults and full-term neonates of 1% or less schistocytes. More than 1% of morphologically identified schistocytes on the blood film are considered suspicious for thrombotic microangiopathy. For preterm infants, a normal level of 5% or less is recommended. The fragment red cell count (FRC) generated by some automated hematological analyzers provides a valuable screening tool for the presence of schistocytes. Specifically, the absence of FRCs can be used as a valuable parameter to exclude the presence of schistocytes on the blood film. The validity and usefulness of microscope schistocytes and automated FRCs, respectively, are discussed in the context of the laboratory diagnostic tests used for thrombotic microangiopathies.

The hematology laboratory's response to the COVID-19 pandemic: A scoping review.

The ongoing COVID-19 pandemic has had a profound worldwide impact on the laboratory hematology community. Nevertheless, the pace of COVID-19 hematology-related research has continued to accelerate and has established the role of laboratory hematology data for many purposes including disease prognosis and outcome. The purpose of this scoping review was to assess the current state of COVID-19 laboratory hematology research. A comprehensive search of the literature published between December 1, 2019, and July 3, 2020, was performed, and we analyzed the sources, publication dates, study types, and topics of the retrieved studies. Overall, 402 studies were included in this scoping review. Approximately half of these studies (n = 202, 50.37%) originated in China. Retrospective cohort studies comprised the largest study type (n = 176, 43.89%). Prognosis/ risk factors, epidemiology, and coagulation were the most common topics. The number of studies published per day has increased through the end of May. The studies were heavily biased in favor of papers originating in China and on retrospective clinical studies with limited use of and reporting of laboratory data. Despite the major improvements in our understanding of the role of coagulation, automated hematology, and cell morphology in COVID-19, there are gaps in the literature, including biosafety and the laboratory role in screening and prevention of COVID-19. There is a gap in the publication of papers focused on guidelines for the laboratory. Our findings suggest that, despite the large number of publications related to laboratory data and their use in COVID-19 disease, many areas remain unexplored or under-reported.

A European consensus report on blood cell identification: terminology utilized and morphological diagnosis concordance among 28 experts from 17 countries within the European LeukemiaNet network WP10, on behalf of the ELN Morphology Faculty.

This paper describes the methodology used to develop a consensual glossary for haematopoietic cells within Diagnostics-WP10 of European-LeukemiaNet EU-project. This highly interactive work was made possible through the use of the net, requiring only a single two-day meeting of actual confrontation and debate. It resulted in the production of a freely accessible tool that could be useful for training as well as harmonization of morphological reports in onco-haematology especially, without geographic limitation, not limited to European countries. Moreover, this collective work resulted in the production of a consensus statement, taking into account individual practices, collegial agreement and literature data.

COVID-19 and the clinical hematology laboratory.

The ongoing COVID-19 pandemic originated in Wuhan, Hubei Province, China, in December 2019. The etiologic agent is a novel coronavirus of presumed zoonotic origin with structural similarity to the viruses responsible for severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS). Like SARS and MERS, COVID-19 infection manifests most frequently with lower respiratory symptoms. A minority of patients progress to acute respiratory distress syndrome/ diffuse alveolar damage. In addition to its central role in the diagnosis of COVID-19 infection, the clinical laboratory provides critical information to clinicians regarding prognosis, disease course, and response to therapy. The purpose of this review is to (a) provide background context about the origins and course of the pandemic, (b) discuss the laboratory's role in the diagnosis of COVID-19 infection, (c) summarize the current state of biomarker analysis in COVID-19 infection, with an emphasis on markers derived from the hematology laboratory, (d) comment on the impact of COVID-19 on hematology laboratory safety, and (e) describe the impact the pandemic has had on organized national and international educational activities worldwide.

Characterization of anti-D monoclonal antibody reagents based on their reactivity with the weak D phenotype.

BACKGROUND: Anti-D monoclonal antibody (MoAb) reagents have improved D typing in routine tests. However, they exhibit a wide range of reactivity with the weak D phenotype depending on the characteristics of the different MoAbs used. We analyzed the reactivity of immunoglobulin (IgM) anti-D by cluster analysis to characterize MoAb that have similar reactivities with the weak D phenotype. STUDY DESIGN AND METHODS: We used 36 consecutive samples with weak D phenotype in routine testing and determined their reactivity with different IgM and IgG anti-D MoAbs. The samples were characterized as belonging to a weak D type or category using commercial molecular biology kits. RESULTS: The various anti-D MoAbs showed a wide grade of reactivity with the weak D samples. Similarities and dissimilarities in the behavior of the anti-D MoAbs with the weak D phenotype samples were detected with cluster analysis and the multidimensional scaling analysis. These analyses indicated different families of MoAbs characterized as having a high degree of homogeneity in their reactivity with the weak D phenotype. Between these MoAb families, the most effective at reacting with the weak D phenotype were RUM-1 and 175-2. CONCLUSIONS: The results show that it is possible to classify the anti-D MoAbs on the basis of their reactivity with the weak D phenotype. This provides information about different MoAbs' properties on the basis of their belonging to a given of anti-D family.

How fast is the sessile ciona?

Genomewide analyses of distances between orthologous gene pairs from the ascidian species Ciona intestinalis and Ciona savignyi were compared with those of vertebrates. Combining this data with a detailed and careful use of vertebrate fossil records, we estimated the time of divergence between the two ascidians nearly 180 My. This estimation was obtained after correcting for the different substitution rates found comparing several groups of chordates; indeed we determine here that on average Ciona species evolve 50% faster than vertebrates.