Monocyte Anisocytosis is Associated with Sepsis in Children with Suspected Infection.

Background: Early, accurate determination of disease severity in an emergency setting is paramount for improving patient outcomes and healthcare costs. Monocyte anisocytosis, quantified as monocyte distribution width (MDW), has been shown to correspond with immune dysregulation. We hypothesize that MDW is broadly associated with illness severity related to sepsis and serious infection in children.

Haematological setpoints are a stable and patient-specific deep phenotype.

The complete blood count (CBC) is an important screening tool for healthy adults and a common test at periodic exams. However, results are usually interpreted relative to one-size-fits-all reference intervals, undermining the precision medicine goal to tailor care for patients on the basis of their unique characteristics. Here we study thousands of diverse patients at an academic medical centre and show that routine CBC indices fluctuate around stable values or setpoints, and setpoints are patient-specific, with the typical healthy adult's nine CBC setpoints distinguishable as a group from those of 98% of other healthy adults, and setpoint differences persist for at least 20 years.

Genetic reversal of the globin switch concurrently modulates both fetal and sickle hemoglobin and reduces red cell sickling.

We previously reported initial clinical results of post-transcriptional gene silencing of BCL11A expression (NCT03282656) reversing the fetal to adult hemoglobin switch. A goal of this approach is to increase fetal hemoglobin (HbF) expression while coordinately reducing sickle hemoglobin (HbS) expression. The resulting combinatorial effect should prove effective in inhibiting HbS polymerization at lower physiologic oxygen values thereby mitigating disease complications.

Computer vision quantitation of erythrocyte shape abnormalities provides diagnostic, prognostic, and mechanistic insight.

Examination of red blood cell (RBC) morphology in peripheral blood smears can help diagnose hematologic diseases, even in resource-limited settings, but this analysis remains subjective and semiquantitative with low throughput. Prior attempts to develop automated tools have been hampered by their poor reproducibility and limited clinical validation. Here, we present a novel, open-source machine-learning approach (denoted as RBC-diff) to quantify abnormal RBCs in peripheral smear images and generate an RBC morphology differential.

Microfluidic study of retention and elimination of abnormal red blood cells by human spleen with implications for sickle cell disease.

The spleen clears altered red blood cells (RBCs) from circulation, contributing to the balance between RBC formation (erythropoiesis) and removal. The splenic RBC retention and elimination occur predominantly in open circulation where RBCs flow through macrophages and inter-endothelial slits (IESs). The mechanisms underlying and interconnecting these processes significantly impact clinical outcomes.

The Effects of Daily Prednisone and Tocilizumab on Hemoglobin A During the Treatment of Giant Cell Arteritis.

Objective: To study the longitudinal effects of both glucocorticoids and tocilizumab, an interleukin-6 receptor inhibitor, on hemoglobin A (HbA ) levels during glucocorticoid tapering.

Methods: We analyzed patients with complete data from the Giant Cell Arteritis Clinical Research Study (GiACTA) to investigate the impact of both glycemic and nonglycemic factors on changes in HbA levels over the 52-week trial. Giant cell arteritis (GCA) patients were randomized to receive either tocilizumab or placebo in addition to glucocorticoids.

Clonal hematopoiesis of indeterminate potential and risk of death from COVID-19.

Two Letters to address the risks of COVID-19 in populations with precursors of hematological disease. In the first article, Miller and colleagues report on whether clonal hematopoiesis of intermediate potential (CHIP) is associated with adverse outcomes with COVID-19, finding no association between CHIP and 28-day mortality while providing data indirectly linking IL-6 signaling and patient outcomes. In the second article, Ho and colleagues investigate the outcomes of patients with monoclonal gammopathy of undetermined significance (MGUS) with COVID-19, reporting that one-fourth had a severe infection and that on multivariable analysis, adverse outcomes are more likely if immunoparesis is present.

Human acute inflammatory recovery is defined by co-regulatory dynamics of white blood cell and platelet populations.

Inflammation is the physiologic reaction to cellular and tissue damage caused by trauma, ischemia, infection, and other pathologic conditions. Elevation of white blood cell count (WBC) and altered levels of other acute phase reactants are cardinal signs of inflammation, but the dynamics of these changes and their resolution are not well established. Here we studied inflammatory recovery from trauma, ischemia, and infection by tracking longitudinal dynamics of clinical laboratory measurements in hospitalized patients.

Set Norm and Equivariant Skip Connections: Putting the Deep in Deep Sets.

Permutation invariant neural networks are a promising tool for making predictions from sets. However, we show that existing permutation invariant architectures, Deep Sets and Set Transformer, can suffer from vanishing or exploding gradients when they are deep. Additionally, layer norm, the normalization of choice in Set Transformer, can hurt performance by removing information useful for prediction.

Cardiovascular Risk Assessment Using Artificial Intelligence-Enabled Event Adjudication and Hematologic Predictors.

Background: Researchers routinely evaluate novel biomarkers for incorporation into clinical risk models, weighing tradeoffs between cost, availability, and ease of deployment. For risk assessment in population health initiatives, ideal inputs would be those already available for most patients. We hypothesized that common hematologic markers (eg, hematocrit), available in an outpatient complete blood count without differential, would be useful to develop risk models for cardiovascular events.

B lymphocyte-derived acetylcholine limits steady-state and emergency hematopoiesis.

Autonomic nerves control organ function through the sympathetic and parasympathetic branches, which have opposite effects. In the bone marrow, sympathetic (adrenergic) nerves promote hematopoiesis; however, how parasympathetic (cholinergic) signals modulate hematopoiesis is unclear. Here, we show that B lymphocytes are an important source of acetylcholine, a neurotransmitter of the parasympathetic nervous system, which reduced hematopoiesis.

Feature tracking microfluidic analysis reveals differential roles of viscosity and friction in sickle cell blood.

Characterization of blood flow rheology in hematological disorders is critical for understanding disease pathophysiology. Existing methods to measure blood rheological parameters are limited in their physiological relevance, and there is a need for new tools that focus on the microcirculation and extract properties at finer resolution than overall flow resistance. Herein, we present a method that combines microfluidic systems and powerful object-tracking computational technologies with mathematical modeling to separate the red blood cell flow profile into a bulk component and a wall component.

The effect of rigid cells on blood viscosity: linking rheology and sickle cell anemia.

Sickle cell anemia (SCA) is a disease that affects red blood cells (RBCs). Healthy RBCs are highly deformable objects that under flow can penetrate blood capillaries smaller than their typical size. In SCA there is an impaired deformability of some cells, which are much stiffer and with a different shape than healthy cells, and thereby affect regular blood flow.

Ionophore-mediated swelling of erythrocytes as a therapeutic mechanism in sickle cell disease.

Sickle cell disease (SCD) is characterized by sickle hemoglobin (HbS) which polymerizes under deoxygenated conditions to form a stiff, sickled erythrocyte. The dehydration of sickle erythrocytes increases intracellular HbS concentration and the propensity of erythrocyte sickling. Prevention of this mechanism may provide a target for potential SCD therapy investigation.

White Blood Cell and Platelet Dynamics Define Human Inflammatory Recovery.

Inflammation is the physiologic reaction to cellular and tissue damage caused by pathologic processes including trauma, infection, and ischemia . Effective inflammatory responses integrate molecular and cellular functions to prevent further tissue damage, initiate repair, and restore homeostasis, while futile or dysfunctional responses allow escalating injury, delay recovery, and may hasten death . Elevation of white blood cell count (WBC) and altered levels of other acute phase reactants are cardinal signs of inflammation, but the dynamics of these changes and their resolution are not established .

MetAP2 inhibition modifies hemoglobin S to delay polymerization and improves blood flow in sickle cell disease.

Sickle cell disease (SCD) is associated with hemolysis, vascular inflammation, and organ damage. Affected patients experience chronic painful vaso-occlusive events requiring hospitalization. Hypoxia-induced polymerization of sickle hemoglobin S (HbS) contributes to sickling of red blood cells (RBCs) and disease pathophysiology.

Association of Red Blood Cell Distribution Width With Mortality Risk in Hospitalized Adults With SARS-CoV-2 Infection.

Importance: Coronavirus disease 2019 (COVID-19) is an acute respiratory illness with a high rate of hospitalization and mortality. Biomarkers are urgently needed for patient risk stratification. Red blood cell distribution width (RDW), a component of complete blood counts that reflects cellular volume variation, has been shown to be associated with elevated risk for morbidity and mortality in a wide range of diseases.

Diminished Reactive Hematopoiesis and Cardiac Inflammation in a Mouse Model of Recurrent Myocardial Infarction.

Background: Recurrent myocardial infarction (MI) is common in patients with coronary artery disease and is associated with high mortality. Long-term reprogramming of myeloid progenitors occurs in response to inflammatory stimuli and alters the organism's response to secondary inflammatory challenges.

Objectives: This study examined the effect of recurrent MI on bone marrow response and cardiac inflammation.

Non-Parametric Combined Reference Regions and Prediction of Clinical Risk.

Background: Many clinical decisions depend on estimating patient risk of clinical outcomes by interpreting test results relative to reference intervals, but standard application of reference intervals suffers from two major limitations that reduce the accuracy of clinical decisions: (1) each test result is assessed separately relative to a univariate reference interval, ignoring the rich pathophysiologic information in multivariate relationships, and (2) reference intervals are intended to reflect a population's biological characteristics and are not calibrated for outcome prediction.

Methods: We developed a combined reference region (CRR), derived CRRs for some pairs of complete blood count (CBC) indices (RBC, MCH, RDW, WBC, PLT), and assessed whether the CRR could enhance the univariate reference interval's prediction of a general clinical outcome, 5-year mortality risk (MR).

Results: The CRR significantly improved MR estimation for 21/21 patient subsets defined by current univariate reference intervals.

Longitudinal Changes in the Relationship Between Hemoglobin A1c and Glucose Tolerance Across Pregnancy and Postpartum.

Objective: To characterize the relationship between hemoglobin A1c (HbA1c) levels and glucose tolerance across pregnancy and postpartum.

Design And Participants: In a longitudinal study of pregnant women with gestational diabetes risk factors (N = 102), we performed oral glucose tolerance testing (OGTT) and HbA1c measurements at 10-15 weeks of gestation, 24-30 weeks of gestation (N = 73), and 6-24 weeks postpartum (N = 42). Complete blood counts were obtained from clinical records.

Unraveling Disease Pathophysiology with Mathematical Modeling.

Modeling has enabled fundamental advances in our understanding of the mechanisms of health and disease for centuries, since at least the time of William Harvey almost 500 years ago. Recent technological advances in molecular methods, computation, and imaging generate optimism that mathematical modeling will enable the biomedical research community to accelerate its efforts in unraveling the molecular, cellular, tissue-, and organ-level processes that maintain health, predispose to disease, and determine response to treatment. In this review, we discuss some of the roles of mathematical modeling in the study of human physiology and pathophysiology and some challenges and opportunities in general and in two specific areas: in vivo modeling of pulmonary function and in vitro modeling of blood cell populations.