Mechanics and microstructure of blood plasma clots in shear driven rupture.

Intravascular blood clots are subject to hydrodynamic shear and other forces that cause clot deformation and rupture (embolization). A portion of the ruptured clot can block blood flow in downstream vessels. The mechanical stability of blood clots is determined primarily by the 3D polymeric fibrin network that forms a gel. Previous studies have primarily focused on the rupture of blood plasma clots under tensile loading (Mode I), our current study investigates the rupture of fibrin induced by shear loading (Mode II), dominating under physiological conditions induced by blood flow. Using experimental and theoretical approaches, we show that fracture toughness, i.e. the critical energy release rate, is relatively independent of the type of loading and is therefore a fundamental property of the gel. Ultrastructural studies and finite element simulations demonstrate that cracks propagate perpendicular to the direction of maximum stretch at the crack tip. These observations indicate that locally, the mechanism of rupture is predominantly tensile. Knowledge gained from this study will aid in the development of methods for prediction/prevention of thrombotic embolization.

A continuum mechanical model of cell motion driven by a biphasic traction stress.

The aim of this paper is to place the cell locomotion problem within the general framework of classical continuum mechanics, and while doing so, to account for the deformation of the actin network in the cytoskeleton; the myosin activity on the lamellum including its effect on depolymerization at the trailing edge; model the stress-dependent driving forces and kinetic laws controlling polymerization at the leading edge, depolymerization at the trailing edge and ATP hydrolysis consistently with the dissipation inequality; and, based on the observations in Gardel et al. (Gardel et al. 2008 J. Cell Biol. 183, 999-1005 (doi:10.1083/jcb.200810060)), include a biphasic velocity-dependent traction stress acting on the actin network. While we chose certain specific models for each of these, in part to allow for an analytical solution, the generality of the framework allows one to readily introduce different constitutive laws to describe these phenomena as might be needed, for example, to study some different type of cells. As described in §5, the predictions of the model compare well with observations such as the magnitude of the very different actin retrograde speeds in the lamellum and lamellipodium including their jump at the interface, the magnitude of the cell speed, and the relative lengths of the lamellipodium and lamellum.

Cracks in tensile-contracting and tensile-dilating poroelastic materials.

Fibrous gels such as cartilage, blood clots, and carbon-nanotube-based sponges with absorbed oils suffer a reduction in volume by the expulsion of liquid under uniaxial tension, and this directly affects crack-tip fields and energy release rates. A continuum model is formulated for isotropic fibrous gels that exhibit a range of behaviors from volume increasing to volume decreasing in uniaxial tension by changing the ratio of two material parameters. The motion of liquid in the pores of such gels is modeled using poroelasticity. The direction of liquid fluxes around cracks is shown to depend on whether the gel locally increases or decreases in volume. The energy release rate for cracks is computed using a surface-independent integral and it is shown to have two contributions - one from the stresses in the solid network, and another from the flow of liquid. The contribution to the integral from liquid permeation tends to be negative when the gel exhibits volume decrease, which effectively is a crack shielding mechanism.

Mechanical fatigue testing in silico: Dynamic evolution of material properties of nanoscale biological particles.

Biological particles have evolved to possess mechanical characteristics necessary to carry out their functions. We developed a computational approach to "fatigue testing in silico", in which constant-amplitude cyclic loading is applied to a particle to explore its mechanobiology. We used this approach to describe dynamic evolution of nanomaterial properties and low-cycle fatigue in the thin spherical encapsulin shell, thick spherical Cowpea Chlorotic Mottle Virus (CCMV) capsid, and thick cylindrical microtubule (MT) fragment over 20 cycles of deformation. Changing structures and force-deformation curves enabled us to describe their damage-dependent biomechanics (strength, deformability, stiffness), thermodynamics (released and dissipated energies, enthalpy, and entropy) and material properties (toughness). Thick CCMV and MT particles experience material fatigue due to slow recovery and damage accumulation over 3-5 loading cycles; thin encapsulin shells show little fatigue due to rapid remodeling and limited damage. The results obtained challenge the existing paradigm: damage in biological particles is partially reversible owing to particle's partial recovery; fatigue crack may or may not grow with each loading cycle and may heal; and particles adapt to deformation amplitude and frequency to minimize the energy dissipated. Using crack size to quantitate damage is problematic as several cracks might form simultaneously in a particle. Dynamic evolution of strength, deformability, and stiffness, can be predicted by analyzing the cycle number (N) dependent damage, [Formula: see text] , where α is a power law and Nf is fatigue life. Fatigue testing in silico can now be used to explore damage-induced changes in the material properties of other biological particles. STATEMENT OF SIGNIFICANCE: Biological particles possess mechanical characteristics necessary to perform their functions. We developed "fatigue testing in silico" approach, which employes Langevin Dynamics simulations of constant-amplitude cyclic loading of nanoscale biological particles, to explore dynamic evolution of the mechanical, energetic, and material properties of the thin and thick spherical particles of encapsulin and Cowpea Chlorotic Mottle Virus, and the microtubule filament fragment. Our study of damage growth and fatigue development challenge the existing paradigm. Damage in biological particles is partially reversible as fatigue crack might heal with each loading cycle. Particles adapt to deformation amplitude and frequency to minimize energy dissipation. The evolution of strength, deformability, and stiffness, can be accurately predicted by analyzing the damage growth in particle structure.

Fracture toughness of fibrin gels as a function of protein volume fraction: Mechanical origins.

The mechanical stability of blood clots necessary for their functions is provided by fibrin, a fibrous gel. Rupture of clots leads to life-threatening thrombotic embolization, which is little understood. Here, we combine experiments and simulations to determine the toughness of plasma clots as a function of fibrin content and correlate toughness with fibrin network structure characterized by confocal and scanning electron microscopy. We develop fibrin constitutive laws that scale with fibrin concentration and capture the force-stretch response of cracked clot specimens using only a few material parameters. Toughness is calculated from the path-independent J* integral that includes dissipative effects due to fluid flow and uses only the constitutive model and overall stretch at crack propagation as input. We show that internal fluid motion, which is not directly measurable, contributes significantly to clot toughness, with its effect increasing as fibrin content increases, because the reduced gel porosity at higher density results in greater expense of energy in fluid motion. Increasing fibrin content (1→10mg/mL) results in a significant increase in clot toughness (3→15 N/m) in accordance with a power law relation reminiscent of cellular solids and elastomeric gels. These results provide a basis for understanding and predicting the tendency for thrombotic embolization. STATEMENT OF SIGNIFICANCE: Fibrin, a naturally occurring biomaterial, is the major determinant of the structural and mechanical integrity of blood clots. We determined that increasing the fibrin content in clots, as in some thrombi and fibrin-based anti-bleeding sealants, results in an increase in clot toughness. Toughness corresponds to the ability to resist rupturing in the presence of a defect. We couple bulk mechanical testing, microstructural measurements, and finite element modeling to capture the force-stretch response of fibrin clots and compute toughness. We show that increased fibrin content in clots reduces porosity and limits fluid motion and that fluid motion drastically alters the clot toughness. These results provide a fundamental understanding of blood clot rupture and could help in rational design of fibrin-containing biomaterials.

Acute Rhabdomyolysis in a Child with Multiple Suspicious Gene Variants.

Rhabdomyolysis is diagnosed with creatinine kinase (CK) elevation beyond 1000 U/L or ten times above the normal upper limit. Severe episodes can be fatal from electrolyte imbalance, acute renal failure, and disseminated intravascular coagulation. A 13-month-old child was admitted with a CK of 82,090 U/L in the setting of respiratory tract infection-related hyperthermia of 106.9° farenheit. His medical history was significant for prematurity, dystonia, and recurrent rhabdomyolysis. His home medications clonazepam, clonidine, and baclofen were continued upon admission. He exhibited uncontrolled dystonia despite treatment for dystonia. Therefore, sedative infusions and forced alkaline diuresis were begun to prevent heme pigment-induced renal injury. Despite these interventions, his CK peaked at 145,920 U/L, which is rarely reported in this age group. The patient also developed pulmonary edema despite diuresis and required mechanical ventilation. Sedative infusions were not enough for dystonia management, and he needed the addition of a neuromuscular blocking infusion. He finally responded to these interventions, and the CK normalized after a month. He required a month of mechanical ventilation and two and a half months of hospitalization and extensive rehabilitation. We were able to avert renal replacement therapy despite pulmonary edema and an estimated glomerular filtration rate nadir of 21 mL/min/1.73 m2 based on the bedside Schwartz formula. He made a complete recovery and was discharged home. His growth and development were satisfactory for two years after that event. His extensive diagnostic workup was negative. Unfortunately, he died from septic and cardiogenic shock with mild rhabdomyolysis two years later. Prompt recognition, early institution of appropriate therapies, identification of underlying disease, and triggering events are pivotal in rhabdomyolysis management. Evidence-based guidelines are needed in this context.

A Rare Etiology for Ascending Paralysis in an Infant.

An 11-month-old male infant with ascending paralysis had an unremarkable initial cerebrospinal fluid (CSF) analysis and imaging. Progressive neurological symptoms resulted in repeated CSF sampling, microscopy, and plasma microbial cell-free DNA next-generation sequencing analysis, that in combination with epidemiology, confirmed the diagnosis.

Biomechanical origins of inherent tension in fibrin networks.

Blood clots form at the site of vascular injury to seal the wound and prevent bleeding. Clots are in tension as they perform their biological functions and withstand hydrodynamic forces of blood flow, vessel wall fluctuations, extravascular muscle contraction and other forces. There are several mechanisms that generate tension in a blood clot, of which the most well-known is the contraction/retraction caused by activated platelets. Here we show through experiments and modeling that clot tension is generated by the polymerization of fibrin. Our mathematical model is built on the hypothesis that the shape of fibrin monomers having two-fold symmetry and off-axis binding sites is ultimately the source of inherent tension in individual fibers and the clot. As the diameter of a fiber grows during polymerization the fibrin monomers must suffer axial twisting deformation so that they remain in register to form the half-staggered arrangement characteristic of fibrin protofibrils. This deformation results in a pre-strain that causes fiber and network tension. Our results for the pre-strain in single fibrin fibers is in agreement with experiments that measured it by cutting fibers and measuring their relaxed length. We connect the mechanics of a fiber to that of the network using the 8-chain model of polymer elasticity. By combining this with a continuum model of swellable elastomers we can compute the evolution of tension in a constrained fibrin gel. The temporal evolution and tensile stresses predicted by this model are in qualitative agreement with experimental measurements of the inherent tension of fibrin clots polymerized between two fixed rheometer plates. These experiments also revealed that increasing thrombin concentration leads to increasing internal tension in the fibrin network. Our model may be extended to account for other mechanisms that generate pre-strains in individual fibers and cause tension in three-dimensional proteinaceous polymeric networks.

Humidity dependence of fracture toughness of cellulose fibrous networks.

Cellulose-based materials are increasingly finding applications in technology due to their sustainability and biodegradability. The sensitivity of cellulose fiber networks to environmental conditions such as temperature and humidity is well known. Yet, there is an incomplete understanding of the dependence of the fracture toughness of cellulose networks on environmental conditions. In the current study, we assess the effect of moisture content on the out-of-plane (i.e., z-dir.) fracture toughness of a particular cellulose network, specifically Whatman cellulose filter paper. Experimental measurements are performed at 16% RH along the desorption isotherm and 23, 37, 50, 75% RH along the adsorption isotherm using out-of-plane tensile tests and double cantilever beam (DCB) tests. Cohesive zone modeling and finite element simulations are used to extract quantitative properties that describe the crack growth behavior. Overall, the fracture toughness of filter paper decreased with increasing humidity. Additionally, a novel model is developed to capture the high peak and sudden drop in the experimental force measurement caused by the existence of an initiation region. This model is found to be in good agreement with experimental data. The relative effect of each independent cohesive parameter is explored to better understand the cohesive zone-based humidity dependence model. The methods described here may be applied to study rupture of other fiber networks with weak bonds.

Mothball Ingestion in the Setting of G6PD Deficiency Causing Severe Hemolytic Anemia, Methemoglobinemia, and Multiple Organ Failure in a Toddler.

Mothballs containing naphthalene or paradichlorobenzene are known to cause hemolysis and methemoglobinemia. They can also affect the other organs, including the kidneys, liver, lungs, and skeletal muscles. The involvement of 1 or 2 organs at a time has been commonly reported. However, more than 2 organ dysfunction in mothball intoxication is rare and usually indicates severe illness. The intoxication can have more pronounced symptoms in children with glucose-6-phosphate dehydrogenase (G6PD) deficiency. We report this case of a previously healthy 13-month-old patient who presented with severe hemolysis, lactic acidosis, methemoglobinemia, acute renal failure, hepatic dysfunction, and rhabdomyolysis. He required aggressive fluid resuscitation, blood transfusions, and mechanical ventilation. The underlying etiology of his illness was initially unclear; however, upon repeated questioning, the father recalled the patient chewing on a mothball 3-4 days before admission. Hence, mothball intoxication was considered the most plausible clinical diagnosis in this patient. He was given N-acetylcysteine, instead of methylene blue, because of hepatic dysfunction and the fact that G6PD deficiency could not be ruled out in the presence of acute hemolysis. The patient made a full recovery after 2 weeks of intensive care unit management. G6PD testing after 3 months confirmed the deficiency. These mothballs are available in Hawai'i, but this is the first report of such a severe presentation to our knowledge. The presence of methemoglobinemia, severe hemolysis, and thorough history-taking helped us determine the diagnosis of mothball intoxication and enabled definitive treatment.

Rheology of fibrous gels under compression.

A number of biological tissues and synthetic gels consist of a fibrous network infused with liquid. There have been a few experimental studies of the rheological properties of such gels under applied compressive strain. Their results suggest that a plot of rheological moduli as a function of applied compressive strain has a long plateau flanked by a steeply increasing curve for large compressive strains and a slowly decreasing curve for small strains. In this paper we explain these trends in rheological properties using a chemo-elastic model characterized by a double-well strain energy function for the underlying fibrous network. The wells correspond to rarefied and densified phases of the fibrous network at low and high strains, respectively. These phases can co-exist across a movable transition front in the gel in order to accommodate overall applied compression. We find that the rheological properties of fibrous gels share similarities with a Kelvin-Voigt visco-elastic solid. The storage modulus has its origins in the elasticity of the fibrous network, while the loss modulus is determined by the dissipation caused by liquid flow through pores. The rheological properties can depend on the number of phase transition fronts present in a compressed sample. Our analysis may explain the dependence of storage and loss moduli of fibrin gels on the loading history. We also point to the need for combining rheological measurements on gels with a microstructural analysis that could shed light on various dissipation mechanisms.

Wave manipulation using a bistable chain with reversible impurities.

We systematically study linear and nonlinear wave propagation in a chain composed of piecewise-linear bistable springs. Such bistable systems are ideal test beds for supporting nonlinear wave dynamical features including transition and (supersonic) solitary waves. We show that bistable chains can support the propagation of subsonic wave packets which in turn can be trapped by a low-energy phase to induce energy localization. The spatial distribution of these energy foci strongly affects the propagation of linear waves, typically causing scattering, but, in special cases, leading to a reflectionless mode analogous to the Ramsauer-Townsend effect. Furthermore, we show that the propagation of nonlinear waves can spontaneously generate or remove additional foci, which act as effective "impurities." This behavior serves as a new mechanism for reversibly programming the dynamic response of bistable chains.

Osteoporosis treatment rates after hip fracture 2011-2019 in Hawaii: Undertreatment of men after hip fractures.

OBJECTIVES: To investigate trends of osteoporosis treatment rates, and factors affecting osteoporosis treatment after hip fracture admission within a single health care system in Hawaii. METHODS: A retrospective chart review was conducted of patients aged 50 years or older and hospitalized for hip fractures between January 1, 2011 and December 31, 2019 at Hawaii Pacific Health, a large health care system in Hawaii. We collected data on basic demographics and osteoporosis medication prescription from electronic medical records. We evaluated trends of osteoporosis treatment rates and performed logistic regression to determine factors associated with osteoporosis treatment. RESULTS: The mean for treatment rates for osteoporosis from 2011 to 2019 was 17.2% (range 8.8%-26.0%). From 2011 to 2019 there was a small increase in treatment rates from 16.3% in 2011 to 24.1% in 2019. Men were less likely to receive osteoporosis treatment after admission for hip fracture. Patients discharged to a facility were more likely to receive osteoporosis treatment. As compared to women, men who had a hip fracture were less likely to receive dual-energy X-ray absorptiometry scan, and osteoporosis medication before hip fracture admission. CONCLUSIONS: The use of osteoporosis medication for secondary prevention after admission for hip fracture in Hawaii from 2011 to 2019 was low. However, there was a small increase in treatment rates from 2011 to 2019. Disparities in treatment of osteoporosis after hip fracture were noted in men. Significant work is needed to increase treatment rates further, and to address the disparity in osteoporosis treatment between men and women.

Junctional Tachycardia as a Diagnostic Criterion in Acute Rheumatic Fever.

Acute rheumatic fever (ARF) is an acute inflammatory process resulting in rheumatic carditis, one of the most common acquired heart diseases in youth. Among the clinical manifestations of carditis, pathologic valve regurgitation and atrioventricular block are included in the criteria for the diagnosis of ARF. Besides atrioventricular block, ARF may often present with other arrhythmias, such as junctional tachycardia (JT). However, JT is currently not recognized as a criterion for the diagnosis of ARF. Three adolescents presented in our hospital with JT, polyarthralgia, and laboratory signs of inflammation with evidence of preceding group A Streptococcus infection. None of the patients fulfilled the diagnostic criteria of ARF. On the basis of the presumed diagnosis of ARF, all 3 patients were treated with intravenous steroids. Steroid therapy was given, and JT converted to sinus rhythm within an average of 62 hours. Subsequent electrocardiograms revealed variable degree of atrioventricular block in all 3 patients, providing clinical evidence and fulfilling the diagnostic criteria of ARF. Patients were monitored for a total 2 to 8 days before discharge on standard antiinflammatory treatment. Follow-up electrocardiograms and Holter monitoring revealed resolution of the atrioventricular block and lack of JT recurrence in all patients. On the basis of these sentinel cases, we propose that JT should be included as a diagnostic criterion for the diagnosis of ARF.

Bacterial activity hinders particle sedimentation.

Sedimentation in active fluids has come into focus due to the ubiquity of swimming micro-organisms in natural and industrial processes. Here, we investigate sedimentation dynamics of passive particles in a fluid as a function of bacteria E. coli concentration. Results show that the presence of swimming bacteria significantly reduces the speed of the sedimentation front even in the dilute regime, in which the sedimentation speed is expected to be independent of particle concentration. Furthermore, bacteria increase the dispersion of the passive particles, which determines the width of the sedimentation front. For short times, particle sedimentation speed has a linear dependence on bacterial concentration. Mean square displacement data shows, however, that bacterial activity decays over long experimental (sedimentation) times. An advection-diffusion equation coupled to bacteria population dynamics seems to capture concentration profiles relatively well. A single parameter, the ratio of single particle speed to the bacteria flow speed can be used to predict front sedimentation speed.

Diarrhea in an infant due to Shigella flexneri 1 carrying multiple cephalosporinase-encoding genes.

BACKGROUND: Infections caused by multidrug-resistant shigellae resistant to broad-spectrum cephalosporins are becoming more prevalent in the Middle East. We report a case of severe diarrhea due to a multiresistant Shigella flexneri 1 strain carrying four different ß-lactamase genes. CASE PRESENTATION: A one-year-old Syrian infant presented with severe acute diarrhea, vomiting and dehydration. She did not respond to empirical treatment with amoxicillin-clavulanic acid followed by cefotaxime. Later, stool culture revealed S. flexneri 1 resistant to both these drugs. The patient was successfully treated with meropenem to which S. flexneri 1 was susceptible. The isolate was resistant to eight classes of antibiotics, and the whole genome sequence (WGS) identified four ß-lactamase genes (blaCTX-M-15, blaEC-8, blaOXA-1, and blaTEM-1) along with genes mediating resistance to seven other antibiotic classes. The WGS also identified several virulence genes including senA that encodes ShET-2 which induces watery diarrhea. Phylogenetically, the isolate was closely related to isolates from South Asia. CONCLUSIONS: This report highlights the emergence of extremely resistant Shigella that has acquired multiple resistance genes to cephalosporins rendering these drugs ineffective.

Harnessing fluctuation theorems to discover free energy and dissipation potentials from non-equilibrium data.

The Jarzynski relation, as an equality form of the second law of thermodynamics, represents an exact thermodynamic statement that is valid arbitrarily far away from equilibrium. This remarkable relation directly links the equilibrium free energy difference between two states and the probability distribution of the work done along a process that drives the system from one state to the other. Here, we leverage the Jarzynski equality and a local equilibrium assumption, to go beyond the calculation of free energy differences and also extract the dissipation potential from additional measurements of kinematic field variables (strain and velocity fields). The proposed strategy is exemplified over pulling experiments of mass-spring models obeying overdamped Langevin dynamics, which is a prototype for nanorods, fibrous macro-molecules and the Rouse model of polymers. Different interaction potentials, fluid viscosities and bath temperatures are studied, so as to intrinsically control how close or far away the system is from equilibrium. The data-inferred continuum models are then validated against processes governed by different pulling protocols, thereby demonstrating their predictive capability. The methods presented here represent a first step toward full material characterization from non-equilibrium data of macroscopic observables, which could potentially be obtained from experimental observations.