Utility of rapid atrial pacing before and after TAVR with balloon-expandable valve in predicting permanent pacemaker implantation.

BACKGROUND: High-grade or complete atrioventricular block (AVB) requiring permanent pacemaker (PPM) implantation is a known complication of transcatheter aortic valve replacement (TAVR). Wenckebach AVB induced by rapid atrial pacing (RAP) after TAVR was previously demonstrated in an observational analysis to be an independent predictor for PPM. We sought to investigate the utility of both pre- and post-TAVR RAP in predicting PPM implantation. METHODS: In a single-center, prospective study, 421 patients underwent TAVR with balloon-expandable valves (BEV) between April 2020 and August 2021. Intraprocedural RAP was performed in patients without a pre-existing pacemaker, atrial fibrillation/flutter, or intraprocedural complete AVB to assess for RAP-induced Wenckebach AVB. The primary outcome was PPM within 30 days after TAVR. RESULTS: RAP was performed in 253 patients, of whom 91.3% underwent post-TAVR RAP and 61.2% underwent pre-TAVR RAP. The overall PPM implantation rate at 30 days was 9.9%. Although there was a numerically higher rate of PPM at 30 days in patients with RAP-induced Wenckebach AVB, it did not reach statistical significance (13.3% vs. 8.4%, p = 0.23). In a multivariable analysis, RAP-induced Wenckebach was not an independent predictor for PPM implantation at 30 days after TAVR. PPM rates at 30 days were comparable in patients with or without pre-TAVR pacing-induced Wenckebach AVB (11.8% vs. 8.2%, p = 0.51) and post-TAVR pacing-induced Wenckebach AVB (10.2% vs. 5.8%, p = 0.25). CONCLUSION: In patients who underwent TAVR with BEV, there were no statistically significant differences in PPM implantation rates at 30 days regardless of the presence or absence of RAP-induced Wenckebach AVB. Due to conflicting results between the present study and the prior observational analysis, future studies with larger sample sizes are warranted to determine the role of RAP during TAVR as a risk-stratification tool for significant AVB requiring PPM after TAVR.

An Unusual Case of ST-Elevation Myocardial Infarction (STEMI) Mimicker: Pneumopericardium Secondary to Gastro-Pericardial Fistula.

Pneumopericardium is defined as the collection of air inside the pericardium. Gastro-pericardial fistula is one of its rarest etiologies. We are presenting a case of pneumopericardium due to gastro-pericardial fistula secondary to gastric cancer presented with an inferior ST-elevation myocardial infarction (STEMI)-like picture. Our case is a 57-year-old male with a past medical history of metastatic gastric cancer status post chemotherapy and radiotherapy who presented to the emergency with acute onset severe burning chest pain with radiation to his back. He was diaphoretic, saturating 96% on room air, and hypotensive with a blood pressure of 80/50 mmHg, and his EKG showed sinus rhythm with a heart rate of 60 BPM and ST elevation in inferior leads meeting STEMI criteria. The patient was transferred for an emergency coronary angiogram with possible percutaneous intervention. Surprisingly, no significant lesions in his epicardial vessels would corroborate his clinical presentation and EKG changes. The decision was to obtain CT angiography to exclude aortic dissection and pulmonary embolism. His CT chest revealed a large pneumopericardium with a gastric-pericardial fistula. A nasogastric tube was placed with suctioning of gastric contents. Given his tamponade physiology, it was decided to do emergent pericardiocentesis draining only 20 cc of gastric contents and a significant amount of air. After the procedure, the patient was transferred to the ICU with stable hemodynamics. The case was discussed with surgery, but given his inoperable cancer, a palliative team was involved. Acknowledging his very poor prognosis, the patient requested discharge to home with home hospice. As reported in the literature, pneumopericardium is rare, and gastro-pericardial fistula associated with gastric cancer is even rarer. Clinical presentation is variable and can be confusing. Providers should be aware of how a patient with gastric cancer can be complicated with pneumopericardium, and they should have a lower threshold of suspicion in patients having risk factors. CT scan is the most sensitive tool for diagnosis.

Exact solutions and bounds for network SIR and SEIR models using a rooted-tree approximation.

In this paper, we develop a new node-based approximate model to describe contagion dynamics on networks. We prove that our approximate model is exact for Markovian SIR (susceptible-infectious-recovered) and SEIR (susceptible-exposed-infectious-recovered) dynamics on tree graphs with a single source of infection, and that the model otherwise gives upper bounds on the probabilities of each node being susceptible. Our analysis of SEIR contagion dynamics is general to SEIR models with arbitrarily many classes of exposed/latent state. In all cases of a tree graph with a single source of infection, our approach yields a system of linear differential equations that exactly describes the evolution of node-state probabilities; we use this to state explicit closed-form solutions for an SIR model on a tree. For more general networks, our approach yields a cooperative system of differential equations that can be used to bound the true solution.

Cost-effectiveness analysis of the nonavalent human papillomavirus vaccine for the prevention of cervical cancer in Singapore.

BACKGROUND: The nonavalent human papillomavirus (HPV) vaccine has been shown to extend protection against oncogenic HPV types 31/33/45/52/58 (HPV-OV) not covered by the bivalent and quadrivalent HPV vaccines. Besides its clinical benefit, evidence on the economic value of the nonavalent vaccine is required to inform local vaccination strategies and funding decisions. This study evaluated the cost-effectiveness of replacing the bivalent vaccine with the nonavalent vaccine in the national school-based HPV vaccination programme in Singapore. METHODS: An existing age-structured dynamic transmission model coupled with stochastic individual-based simulations was adapted to project the health and economic impact of vaccinating 13-year-old girls with two doses of the nonavalent or bivalent HPV vaccines in Singapore. Direct costs (in Singapore dollars, S$) were obtained from public healthcare institutions in Singapore, while health state utilities were sourced from the literature. Incremental cost-effectiveness ratios (ICERs) were estimated over a lifetime horizon, from a healthcare system perspective. Probabilistic sensitivity analysis was performed to obtain the ICERs and corresponding variations across variable uncertainty. Particularly, this study tested the scenarios of lifelong and 20-year vaccine-induced protection, assumed 96.0% and 22.3% cross-protection against HPV-OV by nonavalent and bivalent vaccines respectively, and fixed vaccine prices per dose at S$188 for nonavalent and S$61.50 for bivalent vaccines. RESULTS: Compared with the bivalent vaccine, the use of the nonavalent vaccine was associated with an ICER of S$61,629 per quality-adjusted life year gained in the base case. The result was robust across a range of plausible input values, and to assumptions regarding the duration of vaccine protection. CONCLUSION: Given the high ICER, the nonavalent vaccine is unlikely to represent a cost-effective option compared with the bivalent vaccine for school-based HPV vaccination of 13-year old female students in Singapore. Substantial price reductions would be required to justify its inclusion in the school-based programme in the future.

Role of modularity in self-organization dynamics in biological networks.

Interconnected ensembles of biological entities are perhaps some of the most complex systems that modern science has encountered so far. In particular, scientists have concentrated on understanding how the complexity of the interacting structure between different neurons, proteins, or species influences the functioning of their respective systems. It is well established that many biological networks are constructed in a highly hierarchical way with two main properties: short average paths that join two apparently distant nodes (neuronal, species, or protein patches) and a high proportion of nodes in modular aggregations. Although several hypotheses have been proposed so far, still little is known about the relation of the modules with the dynamical activity in such biological systems. Here we show that network modularity is a key ingredient for the formation of self-organizing patterns of functional activity, independently of the topological peculiarities of the structure of the modules. In particular, we propose a self-organizing mechanism which explains the formation of macroscopic spatial patterns, which are homogeneous within modules. This may explain how spontaneous order in biological networks follows their modular structural organization. We test our results on real-world networks to confirm the important role of modularity in creating macroscale patterns.

Dominance, sharing, and assessment in an iterated Hawk-Dove game.

Animals use a wide variety of strategies to reduce or avoid aggression in conflicts over resources. These strategies range from sharing resources without outward signs of conflict to the development of dominance hierarchies, in which initial fighting is followed by the submission of subordinates. Although models have been developed to analyse specific strategies for resolving conflicts over resources, little work has focused on trying to understand why particular strategies are more likely to arise in certain situations. In this paper, we use a model based on an iterated Hawk-Dove game to analyse how resource holding potentials (RHPs) and other factors affect whether sharing, dominance relationships, or other behaviours are evolutionarily stable. We find through extensive numerical simulations that sharing is stable only when the cost of fighting is low and the animals in a contest have similar RHPs, whereas dominance relationships are stable in most other situations. We also explore what happens when animals are unable to assess each other's RHPs without fighting, and we compare a range of strategies for contestants using simulations. We find (1) that the most successful strategies involve a limited period of assessment followed by a stable relationship in which fights are avoided and (2) that the duration of assessment depends both on the costliness of fighting and on the difference between the animals' RHPs. Along with our direct work on modelling and simulations, we develop extensive software to facilitate further testing. It is available at https://bitbucket.org/CameronLHall/dominancesharingassessmentmatlab/.

The Human Cytomegalovirus Nonstructural Glycoprotein UL148 Reorganizes the Endoplasmic Reticulum.

Human cytomegalovirus (HCMV) encodes an endoplasmic reticulum (ER)-resident glycoprotein, UL148, which activates the unfolded protein response (UPR) but is fully dispensable for viral replication in cultured cells. Hence, its previously ascribed roles in immune evasion and modulation of viral cell tropism are hypothesized to cause ER stress. Here, we show that UL148 is necessary and sufficient to drive the formation of prominent ER-derived structures that on average occupy 5% of the infected cell cytoplasm. The structures are sites where UL148 coalesces with cellular proteins involved in ER quality control, such as HRD1 and EDEM1. Electron microscopy revealed that cells infected with wild-type but not UL148-null HCMV show prominent accumulations of densely packed ruffled ER membranes which connect to distended cisternae of smooth and partially rough ER. During ectopic expression of UL148-green fluorescent protein (GFP) fusion protein, punctate signals traffic to accumulate at conspicuous structures. The structures exhibit poor recovery of fluorescence after photobleaching, which suggests that their contents are poorly mobile and do not efficiently exchange with the rest of the ER. Small-molecule blockade of the integrated stress response (ISR) prevents the formation of puncta, leading to a uniform reticular fluorescent signal. Accordingly, ISR inhibition during HCMV infection abolishes the coalescence of UL148 and HRD1 into discrete structures, which argues that UL148 requires the ISR to cause ER reorganization. Given that UL148 stabilizes immature forms of a receptor binding subunit for a viral envelope glycoprotein complex important for HCMV infectivity, our results imply that stress-dependent ER remodeling contributes to viral cell tropism.IMPORTANCE Perturbations to endoplasmic reticulum (ER) morphology occur during infection with various intracellular pathogens and in certain genetic disorders. We identify that a human cytomegalovirus (HCMV) gene product, UL148, profoundly reorganizes the ER during infection and is sufficient to do so when expressed on its own. Our results reveal that UL148-dependent reorganization of the ER is a prominent feature of HCMV-infected cells. Moreover, we find that this example of virally induced organelle remodeling requires the integrated stress response (ISR), a stress adaptation pathway that contributes to a number of disease states. Since ER reorganization accompanies roles of UL148 in modulation of HCMV cell tropism and in evasion of antiviral immune responses, our results may have implications for understanding the mechanisms involved. Furthermore, our findings provide a basis to utilize UL148 as a tool to investigate organelle responses to stress and to identify novel drugs targeting the ISR.

A model for one-dimensional morphoelasticity and its application to fibroblast-populated collagen lattices.

The mechanical behaviour of solid biological tissues has long been described using models based on classical continuum mechanics. However, the classical continuum theories of elasticity and viscoelasticity cannot easily capture the continual remodelling and associated structural changes in biological tissues. Furthermore, models drawn from plasticity theory are difficult to apply and interpret in this context, where there is no equivalent of a yield stress or flow rule. In this work, we describe a novel one-dimensional mathematical model of tissue remodelling based on the multiplicative decomposition of the deformation gradient. We express the mechanical effects of remodelling as an evolution equation for the effective strain, a measure of the difference between the current state and a hypothetical mechanically relaxed state of the tissue. This morphoelastic model combines the simplicity and interpretability of classical viscoelastic models with the versatility of plasticity theory. A novel feature of our model is that while most models describe growth as a continuous quantity, here we begin with discrete cells and develop a continuum representation of lattice remodelling based on an appropriate limit of the behaviour of discrete cells. To demonstrate the utility of our approach, we use this framework to capture qualitative aspects of the continual remodelling observed in fibroblast-populated collagen lattices, in particular its contraction and its subsequent sudden re-expansion when remodelling is interrupted.

The magneto-elastica: from self-buckling to self-assembly.

Spherical neodymium-iron-boron magnets are permanent magnets that can be assembled into a variety of structures owing to their high magnetic strength. A one-dimensional chain of these magnets responds to mechanical loadings in a manner reminiscent of an elastic rod. We investigate the macroscopic mechanical properties of assemblies of ferromagnetic spheres by considering chains, rings and chiral cylinders of magnets. Based on energy estimates and simple experiments, we introduce an effective magnetic bending stiffness for a chain of magnets and show that, used in conjunction with classic results for elastic rods, it provides excellent estimates for the buckling and vibration dynamics of magnetic chains. We then use this estimate to understand the dynamic self-assembly of a cylinder from an initially straight chain of magnets.

Do overweight and obese individuals select a "moderate intensity" workload when asked to do so?

The purpose of this study was (1) to determine if overweight/obese individuals (age 26-50 y) would self-select moderate exercise intensity when asked to do so and (2) to determine how this self-selected workload compared to exercising at a workload (60% peak aerobic capacity) that is known to provide cardioprotective health benefits. Oxygen consumption (VO(2)) and energy expenditure were measured in 33 men/women (BMI ≥ 27 kg/m(2)) who completed two 30 min walking bouts: (1) self-selected walking pace on an indoor track and (2) prescribed exercise pace (60% VO(2) peak) on a treadmill. The data revealed that (1) the prescribed intensity was 6% higher than the self-selected pace and elicited a higher energy expenditure (P < 0.05) than the self-selected pace (+83 kJ); (2) overweight subjects walked at a slightly lower percentage of VO(2) peak than the obese subjects (P < 0.05); (3) men walked at a lower percentage of VO(2) peak than the women (P < 0.05). In conclusion when asked to walk at a moderate intensity, overweight/obese individuals tended to select a lower workload in the "moderate intensity" range which could be maintained for 30 min; however, a higher intensity which would be more cardioprotective could not be maintained for 30 min by most individuals.

A fibrocontractive mechanochemical model of dermal wound closure incorporating realistic growth factor kinetics.

Fibroblasts and their activated phenotype, myofibroblasts, are the primary cell types involved in the contraction associated with dermal wound healing. Recent experimental evidence indicates that the transformation from fibroblasts to myofibroblasts involves two distinct processes: The cells are stimulated to change phenotype by the combined actions of transforming growth factor ß (TGFß) and mechanical tension. This observation indicates a need for a detailed exploration of the effect of the strong interactions between the mechanical changes and growth factors in dermal wound healing. We review the experimental findings in detail and develop a model of dermal wound healing that incorporates these phenomena. Our model includes the interactions between TGFß and collagenase, providing a more biologically realistic form for the growth factor kinetics than those included in previous mechanochemical descriptions. A comparison is made between the model predictions and experimental data on human dermal wound healing and all the essential features are well matched.

A two-compartment mechanochemical model of the roles of transforming growth factor ß and tissue tension in dermal wound healing.

The repair of dermal tissue is a complex process of interconnected phenomena, where cellular, chemical and mechanical aspects all play a role, both in an autocrine and in a paracrine fashion. Recent experimental results have shown that transforming growth factor -ß (TGFß) and tissue mechanics play roles in regulating cell proliferation, differentiation and the production of extracellular materials. We have developed a 1D mathematical model that considers the interaction between the cellular, chemical and mechanical phenomena, allowing the combination of TGFß and tissue stress to inform the activation of fibroblasts to myofibroblasts. Additionally, our model incorporates the observed feature of residual stress by considering the changing zero-stress state in the formulation for effective strain. Using this model, we predict that the continued presence of TGFß in dermal wounds will produce contractures due to the persistence of myofibroblasts; in contrast, early elimination of TGFß significantly reduces the myofibroblast numbers resulting in an increase in wound size. Similar results were obtained by varying the rate at which fibroblasts differentiate to myofibroblasts and by changing the myofibroblast apoptotic rate. Taken together, the implication is that elevated levels of myofibroblasts is the key factor behind wounds healing with excessive contraction, suggesting that clinical strategies which aim to reduce the myofibroblast density may reduce the appearance of contractures.

Intracellular flow in optic nerve axons: a mechanism for cell death in glaucoma.

PURPOSE: In glaucoma, elevated intraocular pressure causes a progressive loss of retinal ganglion cells and results in optic neuropathy. The authors propose a potential mechanism for cell death, whereby elevated intraocular pressure causes fluid to permeate axonal membranes, creating a passive intracellular fluid flow within the axons. It is hypothesized that this intracellular flow locally depletes the adenosine triphosphate (ATP) concentration, disrupting axonal transport and leading to cell death. METHODS: A mathematical model was developed that takes into account the biomechanical principles underpinning the proposed hypothesis, and was solved to determine the implications of the mechanism. RESULTS: The model suggests that the raised intraocular pressures present in glaucoma are adequate to produce significant intracellular fluid flow. In the periphery of the optic nerve head, this flow may be sufficient to disrupt the diffusion of ATP and hence interrupt active axonal transport. CONCLUSIONS: The mathematical model demonstrates that it is physically plausible that a passive intracellular fluid flow could significantly contribute to the pathophysiology of the retinal ganglion cell axon in glaucoma.

Energy expenditure of walking and running: comparison with prediction equations.

PURPOSE: This study established the published prediction equations for the energy expenditure of walking and running compared with the measured values. To make this comparison we first determined whether differences exist in energy expenditure for 1600 m of walking versus running, and whether energy expenditure differences occur due to being on the track or treadmill. METHODS: Energy was measured via indirect calorimetry in 24 subjects while walking (1.41 m.s(-1)) and running (2.82 m.s(-1)) 1600 m on the treadmill. A subgroup also performed the 1600-m run/walk on the track. The measured energy expenditures were compared with published prediction equations. RESULTS: Running required more energy (P < 0.01) for 1600 m than walking (treadmill: running 481 +/- 20.0 kJ, walking 340 +/- 14 kJ; track: running 480 +/- 23 kJ, walking 334 +/- 14 kJ) on both the track and treadmill. Predictions using the ACSM or Leger equations for running, and the Pandolf equation for walking, were similar to the actual energy expenditures for running and walking (total error: ACSM: -20 and 14.4 kJ, respectively; Legers walking: -10.1 kJ; Pandolf walking: -10.0 kJ). An overestimation (P < 0.01) for 1600 m was found with the McArdle's table for walking and running energy expenditure and with van der Walt's prediction for walking energy expenditure, whereas the Epstein equation underestimated running energy expenditure (P < 0.01). CONCLUSION: Running has a greater energy cost than walking on both the track and treadmill. For running, the Leger equation and ACSM prediction model appear to be the most suitable for the prediction of running energy expenditure. The ACSM and Pandolf prediction equation also closely predict walking energy expenditure, whereas the McArdle's table or the equations by Epstein and van der Walt were not as strong predictors of energy expenditure.