Central Artery Hemodynamics in Angiotensin II-Induced Hypertension and Effects of Anesthesia.

Systemic hypertension is a strong risk factor for cardiovascular, neurovascular, and renovascular diseases. Central artery stiffness is both an initiator and indicator of hypertension, thus revealing a critical relationship between the wall mechanics and hemodynamics. Mice have emerged as a critical animal model for studying effects of hypertension and much has been learned. Regardless of the specific mouse model, data on changes in cardiac function and hemodynamics are necessarily measured under anesthesia. Here, we present a new experimental-computational workflow to estimate awake cardiovascular conditions from anesthetized data, which was then used to quantify effects of chronic angiotensin II-induced hypertension relative to normotension in wild-type mice. We found that isoflurane anesthesia had a greater impact on depressing hemodynamics in angiotensin II-infused mice than in controls, which led to unexpected results when comparing anesthetized results between the two groups of mice. Through comparison of the awake simulations, however, in vivo relevant effects of angiotensin II-infusion on global and regional vascular structure, properties, and hemodynamics were found to be qualitatively consistent with expectations. Specifically, we found an increased in vivo vascular stiffness in the descending thoracic aorta and suprarenal abdominal aorta, leading to increases in pulse pressure in the distal aorta. These insights allow characterization of the impact of regionally varying vascular remodeling on hemodynamics and mouse-to-mouse variations due to induced hypertension.

Forty years of Helicobacter pylori infection and changes in findings at esophagogastroduodenoscopy.

BACKGROUND: It is 40 years since the discovery of Helicobacter pylori infection. Over that time major changes have occurred in esophagogastroduodenoscopy (EGD) findings. The aim of this review is to describe these changes, and the important role H. pylori infection has played in their evolution. METHODS: References were identified through searches of PubMed using the search terms-endoscopy time trends, peptic ulcer disease, gastroesophageal reflux disease, upper gastrointestinal cancer, gastric polyps, H. pylori, eosinophilic gastrointestinal disorders, and celiac disease, from 1970 through December 2021. RESULTS: The prevalence of H. pylori infection has fallen and consequently, H. pylori-positive peptic ulcer disease has become rare. Gastroesophageal reflux disease is now the commonest disorder diagnosed at EGD, and Barrett's esophagus has increased in parallel. Cancer of the distal stomach has fallen while esophageal adenocarcinoma and reflux-related cardia cancer have risen. Gastric polyps have changed from hyperplastic and adenomas to sporadic fundic gland polyps. Antimicrobial resistance has made H. pylori infection more difficult to eradicate. Eosinophilic gastrointestinal disorders, particularly eosinophilic esophagitis, have emerged as important new allergic disorders. Celiac disease has changed and increased. CONCLUSIONS: EGD findings appear to have changed from features suggesting a H. pylori-positive "phenotype" 40 years ago to a H. pylori-negative "phenotype" today. These changes have major implications for the management of gastrointestinal disorders.

New computational approach to shunt design in congenital heart palliation.

Shunts are commonly used to redirect blood to pulmonary arteries in procedures that palliate congenital cardiovascular defects. Previous clinical studies and hemodynamic simulations reveal a critical role of shunt diameter in balancing flow to pulmonary versus systemic vessels, but the biomechanical process of creating the requisite anastomosis between the shunt and host vessel has received little attention. Here, we report a new Lagrange multiplier-based finite element approach that represents the shunt and host vessels as individual structures and predicts the anastomosis geometry and attachment force that result when the shunt is sutured at an incision in the host, followed by pressurization. Simulations suggest that anastomosis orifice opening increases markedly with increasing length of the host incision and moderately with increasing blood pressure. The host artery is further predicted to conform to common stiff synthetic shunts, whereas more compliant umbilical vessel shunts should conform to the host, with orifice area transitioning between these two extremes via a Hill-type function of shunt stiffness. Moreover, a direct relationship is expected between attachment forces and shunt stiffness. This new computational approach promises to aid in surgical planning for diverse vascular shunts by predicting in vivo pressurized geometries.

Ex vivo biomechanical characterization of umbilical vessels: Possible shunts in congenital heart palliation.

Children born with congenital heart defects typically undergo staged palliative surgeries to reconstruct the circulation to improve transport of deoxygenated blood to the lungs. As part of the first surgery, a temporary shunt (Blalock-Thomas-Taussig) is often created in neonates to connect a systemic and a pulmonary artery. Standard-of-care shunts are synthetic, which can lead to thrombosis, and much stiffer than the two host vessels, which can cause adverse mechanobiological responses. Moreover, the neonatal vasculature can undergo significant changes in size and structure over a short period, thus constraining the use of a non-growing synthetic shunt. Recent studies suggest that autologous umbilical vessels could serve as improved shunts, but there has not been a detailed biomechanical characterization of the four primary vessels - subclavian artery, pulmonary artery, umbilical vein, and umbilical artery. Herein, we biomechanically phenotype umbilical veins and arteries from prenatal mice (E18.5) and compare them to subclavian and pulmonary arteries harvested at two critical postnatal developmental ages (P10, P21). Comparisons include age-specific physiological conditions and simulated 'surgical-like' shunt conditions. Results suggest that the intact umbilical vein is a better choice as a shunt than the umbilical artery due to concerns with lumen closure and constriction related intramural damage in the latter. Yet, decellularization of umbilical arteries may be a viable alternative, with the possibility of host cellular infiltration and subsequent remodeling. Given recent efforts using autologous umbilical vessels as Blalock-Thomas-Taussig shunts in a clinical trial, our findings highlight aspects of the associated biomechanics that deserve further investigation.

CineCT platform for in vivo and ex vivo measurement of 3D high resolution Lagrangian strains in the left ventricle following myocardial infarction and intramyocardial delivery of theranostic hydrogel.

Myocardial infarction (MI) produces acute changes in strain and stiffness within the infarct that can affect remote areas of the left ventricle (LV) and drive pathological remodeling. We hypothesized that intramyocardial delivery of a hydrogel within the MI region would lower wall stress and reduce adverse remodeling in Yorkshire pigs (n = 5). 99mTc-Tetrofosmin SPECT imaging defined the location and geometry of induced MI and border regions in pigs, and in vivo and ex vivo contrast cine computed tomography (cineCT) quantified deformations of the LV myocardium. Serial in vivo cineCT imaging provided data in hearts from control pigs (n = 3) and data from pigs (n = 5) under baseline conditions before MI induction, post-MI day 3, post-MI day 7, and one hour after intramyocardial delivery of a hyaluronic acid (HA)-based hydrogel with shear-thinning and self-healing properties to the central infarct area. Isolated, excised hearts underwent similar cineCT imaging using an ex vivo perfused heart preparation with cyclic LV pressurization. Deformations were evaluated using nonlinear image registration of cineCT volumes between end-diastole (ED) and end-systole (ES), and 3D Lagrangian strains were calculated from the displacement gradients. Post-MI day 3, radial, circumferential, maximum principal, and shear strains were reduced within the MI region (p < 0.04) but were unchanged in normal regions (p > 0.6), and LV end diastolic volume (LV EDV) increased (p = 0.004), while ejection fraction (EF) and stroke volume (SV) decreased (p < 0.02). Post-MI day 7, radial strains in MI border zones increased (p = 0.04) and dilation of LV EDV continued (p = 0.052). There was a significant negative linear correlation between regional radial and maximum principal/shear strains and percent infarcted tissue in all hearts (R2 > 0.47, p < 0.004), indicating that cineCT strain measures could predict MI location and degree of injury. Post-hydrogel day 7 post-MI, LV EDV was significantly reduced (p = 0.009), EF increased (p = 0.048), and radial (p = 0.021), maximum principal (p = 0.051), and shear strain (p = 0.047) increased within regions bordering the infarct. A smaller strain improvement within the infarct and normal regions was also noted on average along with an improvement in SV in 4 out of 5 hearts. CineCT provides a reliable method to assess regional changes in strains post-MI and the therapeutic effects of intramyocardial hydrogel delivery.

Constrained Mixture Models of Soft Tissue Growth and Remodeling - Twenty Years After.

Soft biological tissues compromise diverse cell types and extracellular matrix constituents, each of which can possess individual natural configurations, material properties, and rates of turnover. For this reason, mixture-based models of growth (changes in mass) and remodeling (change in microstructure) are well-suited for studying tissue adaptations, disease progression, and responses to injury or clinical intervention. Such approaches also can be used to design improved tissue engineered constructs to repair, replace, or regenerate tissues. Focusing on blood vessels as archetypes of soft tissues, this paper reviews a constrained mixture theory introduced twenty years ago and explores its usage since by contrasting simulations of diverse vascular conditions. The discussion is framed within the concept of mechanical homeostasis, with consideration of solid-fluid interactions, inflammation, and cell signaling highlighting both past accomplishments and future opportunities as we seek to understand better the evolving composition, geometry, and material behaviors of soft tissues under complex conditions.

Epidemiology of periodontal disease in dogs in the UK primary-care veterinary setting.

OBJECTIVES: Periodontal disease is a frequent diagnosis of dogs and can have severe negative impacts on welfare. It was hypothesised that breeds with skull shapes that differ most in conformation from the moderate mesocephalic skull shape have higher odds of periodontal disease. MATERIALS AND METHODS: The cohort study included a random sample of dogs under primary veterinary care in 2016 from the VetCompass Programme database. Risk factor analysis used random effects multivariable logistic regression modelling. RESULTS: The study included a random sample of 22,333 dogs. The 1-year period prevalence for diagnosis with periodontal disease was 12.52% (95% CI: 12.09 to 12.97). Eighteen breeds showed increased odds compared with crossbred dogs. Breeds with the highest odds included Toy Poodle (odds ratio 3.97, 95% confidence intervals 2.21 to 7.13), King Charles Spaniel (odds ratio 2.63, 95% confidence interval 1.50 to 4.61), Greyhound (odds ratio 2.58, 95% confidence interval 1.75 to 3.80) and Cavalier King Charles Spaniel (odds ratio 2.39, 95% confidence interval 1.85 to 3.09). Four breeds showed reduced odds compared with crossbreds. Brachycephalic breeds had 1.25 times the odds (95% confidence interval 1.11 to 1.42) of periodontal disease compared with mesocephalic breeds. Spaniel types had 1.63 times the odds (95% confidence interval 1.42 to 1.87) compared with non-spaniel types. Increasing adult bodyweight was associated with progressively decreasing odds of periodontal disease. CLINICAL SIGNIFICANCE: The high prevalence identified in this study highlights periodontal disease as a priority welfare concern for predisposed breeds. Veterinarians can use this information to promote improved dental care in predisposed dogs, especially as these dogs age.

Biomechanical consequences of compromised elastic fiber integrity and matrix cross-linking on abdominal aortic aneurysmal enlargement.

Abdominal aortic aneurysms (AAAs) are characterized histopathologically by compromised elastic fiber integrity, lost smooth muscle cells or their function, and remodeled collagen. We used a recently introduced mouse model of AAAs that combines enzymatic degradation of elastic fibers and blocking of lysyl oxidase, and thus matrix cross-linking, to study progressive dilatation of the infrarenal abdominal aorta, including development of intraluminal thrombus. We quantified changes in biomaterial properties and biomechanical functionality within the aneurysmal segment as a function of time of enlargement and degree of thrombosis. Towards this end, we combined multi-modality imaging with state-of-the art biomechanical testing and histology to quantify regional heterogeneities for the first time and we used a computational model of arterial growth and remodeling to test multiple hypotheses, suggested by the data, regarding the degree of lost elastin, accumulation of glycosaminoglycans, and rates of collagen turnover. We found that standard histopathological findings can be misleading, while combining advanced experimental and computational methods revealed that glycosaminoglycan accumulation is pathologic, not adaptive, and that heightened collagen deposition is ineffective if not cross-linked. In conclusion, loss of elastic fiber integrity can be a strong initiator of aortic aneurysms, but it is the rate and effectiveness of fibrillar collagen remodeling that dictates enlargement. STATEMENT OF SIGNIFICANCE: Precise mechanisms by which abdominal aortic aneurysms enlarge remain unclear, but a recent elastase plus ß-aminopropionitrile mouse model provides new insight into disease progression. As in the human condition, the aortic degeneration and adverse remodeling are highly heterogeneous in this model. Our multi-modality experiments quantify and contrast the heterogeneities in geometry and biomaterial properties, and our computational modeling shows that standard histopathology can be misleading. Neither accumulating glycosaminoglycans nor frustrated collagen synthesis slow disease progression, thus highlighting the importance of stimulating adaptive collagen remodeling to limit lesion enlargement.

Differential biomechanical responses of elastic and muscular arteries to angiotensin II-induced hypertension.

Elastic and muscular arteries are distinguished by their distinct microstructures, biomechanical properties, and smooth muscle cell contractile functions. They also exhibit differential remodeling in aging and hypertension. Although regional differences in biomechanical properties have been compared, few studies have quantified biaxial differences in response to hypertension. Here, we contrast passive and active changes in large elastic and medium- and small-sized muscular arteries in adult mice in response to chronic infusion of angiotensin over 14 days. We found a significant increase in wall thickness, both medial and adventitial, in the descending thoracic aorta that associated with trends of an increased collagen:elastin ratio. There was adventitial thickening in the small-sized mesenteric artery, but also significant changes in elastic lamellar structure and contractility. An increased contractile response to phenylephrine coupled with a reduced vasodilatory response to acetylcholine in the mesenteric artery suggested an increased contractile state in response to hypertension. Overall reductions in the calculated gradients in pulse wave velocity and elastin energy storage capability from elastic-to-muscular arteries suggested a possible transfer of excessive pulsatile energy into the small-sized muscular arteries resulting in significant functional consequences in response to hypertension.

Adventitial remodeling protects against aortic rupture following late smooth muscle-specific disruption of TGFß signaling.

Altered signaling through transforming growth factor-beta (TGFß) increases the risk of aortic dissection in patients, which has been confirmed in mouse models. It is well known that altered TGFß signaling affects matrix turnover, but there has not been a careful examination of associated changes in structure-function relations. In this paper, we present new findings on the rupture potential of the aortic wall following late postnatal smooth muscle cell (SMC)-specific disruption of type I and II TGFß receptors in a mouse model with demonstrated dissection susceptibility. Using a combination of custom computer-controlled biaxial tests and quantitative histology and immunohistochemistry, we found that loss of TGFß signaling in SMCs compromises medial properties but induces compensatory changes in the adventitia that preserve wall strength above that which is needed to resist in vivo values of wall stress. These findings emphasize the different structural defects that lead to aortic dissection and rupture - compromised medial integrity and insufficient adventitial strength, respectively. Relative differences in these two defects, in an individual subject at a particular time, likely reflects the considerable phenotypic diversity that is common in clinical presentations of thoracic aortic dissection and rupture. There is, therefore, a need to move beyond examinations of bulk biological assays and wall properties to cell- and layer-specific studies that delineate pathologic and compensatory changes in wall biology and composition, and thus the structural integrity of the aortic wall that can dictate differences between life and death.

Social Susceptibility to Multiple Air Pollutants in Cardiovascular Disease.

INTRODUCTION: Cardiovascular disease (CVD) is the leading cause of death in the United States, and substantial research has linked ambient air pollution to elevated rates of CVD etiology and events. Much of this research identified increased effects of air pollution in lower socioeconomic position (SEP) communities, where pollution exposures are also often higher. The complex spatial confounding between air pollution and SEP makes it very challenging, however, to disentangle the impacts of these very different exposure types and to accurately assess their interactions. The specific causal components (i.e., specific social stressors) underlying this SEP-related susceptibility remain unknown, because there are myriad pathways through which poverty and/or lower-SEP conditions may influence pollution susceptibility - including diet, smoking, coexposures in the home and occupational environments, health behaviors, and healthcare access. Growing evidence suggests that a substantial portion of SEP-related susceptibility may be due to chronic psychosocial stress - given the known wide-ranging impacts of chronic stress on immune, endocrine, and metabolic function - and to a higher prevalence of unpredictable chronic stressors in many lower-SEP communities, including violence, job insecurity, and housing instability. As such, elucidating susceptibility to pollution in the etiology of CVD, and in the risk of CVD events, has been identified as a research priority. This interplay among social and environmental conditions may be particularly relevant for CVD, because pollution and chronic stress both impact inflammation, metabolic function, oxidative stress, hypertension, atherosclerosis, and other processes relevant to CVD etiology. Because pollution exposures are often spatially patterned by SEP, disentangling their effects - and quantifying any interplay - is especially challenging. Doing so, however, would help to improve our ability to identify and characterize susceptible populations and to improve our understanding of how community stressors may alter responses to multiple air pollutants. More clearly characterizing susceptible populations will improve our ability to design and target interventions more effectively (and cost-effectively) and may reveal greater benefits of pollution reduction in susceptible communities, strengthening cost-benefit and accountability analyses, ultimately reducing the disproportionate burden of CVD and reducing health disparities. METHODS: In the current study, we aimed to quantify combined effects of multiple pollutants and stressor exposures on CVD events, using a number of unique datasets we have compiled and verified, including the following. 1. Poverty metrics, violent crime rates, a composite socioeconomic deprivation index (SDI), an index of racial and economic segregation, noise disturbance metrics, and three composite spatial factors produced from a factor analysis of 27 community stressors. All indicators have citywide coverage and were verified against individual reports of stress and stressor exposure, in citywide focus groups and surveys. 2. Spatial surfaces for multiple pollutants from the New York City (NYC) Community Air Survey (NYCCAS), which monitored multiple pollutants year-round at 150 sites and used land use regression (LUR) modeling to estimate fine-scale (100-m) intra-urban spatial variance in fine particles (PM2.5), nitrogen dioxide (NO2), sulfur dioxide (SO2), and ozone (O3). 3. Daily data and time-trends derived from all U.S. Environmental Protection Agency (EPA) Air Quality System (AQS) monitors in NYC for 2005-2011, which we combined with NYCCAS surfaces to create residence- and day-specific spatiotemporal exposure estimates. 4. Complete data on in- and out-patient unscheduled CVD events presented in NYC hospitals for 2005-2011 (n = 1,113,185) from the New York State (NYS) Department of Health's Statewide Planning and Research Cooperative System (SPARCS). In the study, we quantified relationships between multiple pollutant exposures and both community CVD event rates and individual risk of CVD events in NYC and tested whether pollution-CVD associations varied by community SEP and social stressor exposures. We hypothesized (1) that greater chronic community-level SEP, stressor, and pollution exposures would be associated with higher community CVD rates; (2) that spatiotemporal variations in multiple pollutants would be associated with excess risk of CVD events; and (3) that pollution-CVD associations would be stronger in communities of lower SEP or higher stressor exposures. RESULTS: To first understand the separate and combined associations with CVD for both stressors and pollutants measured at the same spatial and temporal scale of resolution, we used ecological cross-sectional models to examine spatial relationships between multiple chronic pollutant and stressor exposures and age-adjusted community CVD rates. Using census-tract-level annual averages (n = 2,167), we compared associations with CVD rates for multiple pollutant concentrations and social stressors. We found that associations with community CVD rates were consistently stronger for social stressors than for pollutants, in terms of both magnitude and significance. We note, however, that this result may be driven by the relatively greater variation (on a proportional basis) for stressors than for pollutants in NYC. We also tested effect modification of pollutant-CVD associations by each social stressor and found evidence of stronger associations for NO2, PM2.5, and wintertime SO2 with CVD rates, particularly across quintiles of increasing community violence or assault rates (P trend < 0.0001). To examine individual-level associations between spatiotemporal exposures to multiple pollutants and the risk of CVD events, across multiple lag days, we examined the combined effects of multiple pollutant exposures, using spatiotemporal (day- and residence-specific) pollution exposure estimates and hospital data on individual CVD events in case-crossover models, which inherently adjust for nontime-varying individual confounders (e.g., sex and race) and comorbidities. We found consistent significant relationships only for same-day pollutant exposures and the risk of CVD events, suggesting very acute impacts of pollution on CVD risk. Associations with CVD were positive for NO2, PM2.5, and SO2, as hypothesized, and we found inverse associations for O3 (a secondary pollutant chemically decreased ["scavenged"] by fresh emissions that, in NYC, displays spatial and temporal patterns opposite those of NO2). Finally, to test effect modification by chronic community social stressors on the relationships between spatiotemporal pollution measures and the risk of CVD events, we used individual-level case-crossover models, adding interaction terms with categorical versions of each social stressor. We found that associations between NO2 and the risk of CVD events were significantly elevated only in communities with the highest exposures to social stressors (i.e., in the highest quintiles of poverty, socioeconomic deprivation, violence, or assault). The largest positive associations for PM2.5 and winter SO2 were generally found in the highest-stressor communities but were not significant in any quintile. We again found inverse associations for O3, which were likewise stronger for individuals living in communities with greater stressor exposures. CONCLUSIONS: In ecological models, we found stronger relationships with community CVD rates for social stressors than for pollutant exposures. In case-crossover analyses, higher exposures to NO2, PM2.5, and SO2 were associated with greater excess risk of CVD events but only on the case day (there were no consistent significant lagged-day effects). In effect-modification analyses at both the community and individual level, we found evidence of stronger pollution-CVD associations in communities with higher stressor exposures. Given substantial spatial confounding across multiple social stressors, further research is needed to disentangle these effects in order to identify the predominant social stressors driving this observed differential susceptibility.

Multi-view digital image correlation systems for in vitro testing of arteries from mice to humans.

Background: Digital image correlation (DIC) methods are increasingly used for non-contact optical assessment of geometry and deformation in soft tissue biomechanics, thus providing the full-field strain estimates needed for robust inverse material characterization. Despite the well-known flexibility and ease of use of DIC, issues related to spatial resolution and depth-of-field remain challenging in studies of quasi-cylindrical biological samples such as arteries. Objective: After demonstrating that standard surrounding multi-view DIC systems are inappropriate for such usage, we submit that both the optical setup and the data analysis need to be specifically designed with respect to the size of the arterial sample of interest. Accordingly, we propose novel and optimized DIC systems for two distinct ranges of arterial diameters: less than 2.5 mm (murine arteries) and greater than 10 mm (human arteries). Methods: We designed, set up, and validated a four-camera panoramic-DIC system for testing murine arteries and a multi-biprism DIC system for testing human arteries. Both systems enable dynamic 360-deg measurements with refraction correction over the entire surface of submerged samples in their native geometries. Results: Illustrative results for 3D shape and full-surface deformation fields were obtained for a mouse infrarenal aorta and a latex cylinder of size similar to the human infrarenal aorta. Conclusion: Results demonstrated the feasibility and accuracy of both proposed methods in providing quantitative information on the regional behavior of arterial samples tested in vitro under physiologically relevant loading.

Numerical knockouts-In silico assessment of factors predisposing to thoracic aortic aneurysms.

Myriad risk factors-including uncontrolled hypertension, aging, and diverse genetic mutations-contribute to the development and enlargement of thoracic aortic aneurysms. Detailed analyses of clinical data and longitudinal studies of murine models continue to provide insight into the natural history of these potentially lethal conditions. Yet, because of the co-existence of multiple risk factors in most cases, it has been difficult to isolate individual effects of the many different factors or to understand how they act in combination. In this paper, we use a data-informed computational model of the initiation and progression of thoracic aortic aneurysms to contrast key predisposing risk factors both in isolation and in combination; these factors include localized losses of elastic fiber integrity, aberrant collagen remodeling, reduced smooth muscle contractility, and dysfunctional mechanosensing or mechanoregulation of extracellular matrix along with superimposed hypertension and aortic aging. In most cases, mild-to-severe localized losses in cellular function or matrix integrity give rise to varying degrees of local dilatations of the thoracic aorta, with enlargement typically exacerbated in cases wherein predisposing risk factors co-exist. The simulations suggest, for the first time, that effects of compromised smooth muscle contractility are more important in terms of dysfunctional mechanosensing and mechanoregulation of matrix than in vessel-level control of diameter and, furthermore, that dysfunctional mechanobiological control can yield lesions comparable to those in cases of compromised elastic fiber integrity. Particularly concerning, therefore, is that loss of constituents such as fibrillin-1, as in Marfan syndrome, can compromise both elastic fiber integrity and mechanosensing.

Bonamia exitiosa in farmed native oysters Ostrea angasi in Australia: optimal epidemiological qPCR cut-point and clinical disease risk factors.

Bonamiosis has developed as a problem in Australian native oysters Ostrea angasi since the parasite Bonamia spp. was first detected in Port Phillip Bay, Victoria, in the early 1990s. At that time, large-scale mortalities in both farmed and wild oysters saw the demise of the pilot native oyster culture industry. More recent attempts to farm the species resulted in subclinical infections that progressed over time to clinical disease. The aim of this work was to establish what environmental factors result in the clinical manifestation of disease; determine the diagnostic sensitivity and diagnostic specificity of histopathological examination and a quantitative polymerase chain reaction (qPCR) test for the diagnosis of B. exitiosa infection in clinically diseased farmed native oysters; and calculate the optimal qPCR threshold cycle (CT) epidemiological cut-point for classification of positive and negative cases. After applying a range of stressors to tank-held oysters, results indicated a 58% increased risk (95% CI: 16%, 99%) of a Bonamia-infected oyster dying if the oyster was held at a higher temperature (p = 0.048). Starving and tumbling oysters, in isolation, was not significantly associated with clinical bonamiosis, but a Bonamia-infected oyster was at the greatest risk of death when increased water temperature was combined with both starvation and increased motion (p = 0.02; odds ratio = 3.47). The diagnostic sensitivity and specificity of the World Organisation for Animal Health qPCR protocol were calculated for increasing CT value cut-points from ≤25 to ≤40, with an optimal cut-point identified at ≤34.5 (specificity: 92.2; 95% posterior credible intervals [PCI]: 76.2, 99.8; Sensitivity: 93.5; 95% PCI: 84.7, 99.1).

Paradoxical aortic stiffening and subsequent cardiac dysfunction in Hutchinson-Gilford progeria syndrome.

Hutchinson-Gilford progeria syndrome (HGPS) is an ultra-rare disorder with devastating sequelae resulting in early death, presently thought to stem primarily from cardiovascular events. We analyse novel longitudinal cardiovascular data from a mouse model of HGPS (LmnaG609G/G609G) using allometric scaling, biomechanical phenotyping, and advanced computational modelling and show that late-stage diastolic dysfunction, with preserved systolic function, emerges with an increase in the pulse wave velocity and an associated loss of aortic function, independent of sex. Specifically, there is a dramatic late-stage loss of smooth muscle function and cells and an excessive accumulation of proteoglycans along the aorta, which result in a loss of biomechanical function (contractility and elastic energy storage) and a marked structural stiffening despite a distinctly low intrinsic material stiffness that is consistent with the lack of functional lamin A. Importantly, the vascular function appears to arise normally from the low-stress environment of development, only to succumb progressively to pressure-related effects of the lamin A mutation and become extreme in the peri-morbid period. Because the dramatic life-threatening aortic phenotype manifests during the last third of life there may be a therapeutic window in maturity that could alleviate concerns with therapies administered during early periods of arterial development.

Computer-Controlled Biaxial Bioreactor for Investigating Cell-Mediated Homeostasis in Tissue Equivalents.

Soft biological tissues consist of cells and extracellular matrix (ECM), a network of diverse proteins, glycoproteins, and glycosaminoglycans that surround the cells. The cells actively sense the surrounding ECM and regulate its mechanical state. Cell-seeded collagen or fibrin gels, so-called tissue equivalents, are simple but powerful model systems to study this phenomenon. Nevertheless, few quantitative studies document the stresses that cells establish and maintain in such gels; moreover, most prior data were collected via uniaxial experiments whereas soft tissues are mainly subject to multiaxial loading in vivo. To begin to close this gap between existing experimental data and in vivo conditions, we describe here a computer-controlled bioreactor that enables accurate measurements of the evolution of mechanical tension and deformation of tissue equivalents under well-controlled biaxial loads. This device allows diverse studies, including how cells establish a homeostatic state of biaxial stress and if they maintain it in response to mechanical perturbations. It similarly allows, for example, studies of the impact of cell and matrix density, exogenous growth factors and cytokines, and different types of loading conditions (uniaxial, strip-biaxial, and biaxial) on these processes. As illustrative results, we show that NIH/3T3 fibroblasts establish a homeostatic mechanical state that depends on cell density and collagen concentration. Following perturbations from this homeostatic state, the cells were able to recover biaxial loading similar to homeostatic. Depending on the precise loads, however, they were not always able to fully maintain that state.

Modeling lamellar disruption within the aortic wall using a particle-based approach.

Aortic dissections associate with medial degeneration, thus suggesting a need to understand better the biophysical interactions between the cells and matrix that constitute the middle layer of the aortic wall. Here, we use a recently extended "Smoothed Particle Hydrodynamics" formulation to examine potential mechanisms of aortic delamination arising from smooth muscle cell (SMC) dysfunction or apoptosis, degradation of or damage to elastic fibers, and pooling of glycosaminoglycans (GAGs), with associated losses of medial collagen in the region of the GAGs. First, we develop a baseline multi-layered model for the healthy aorta that delineates medial elastic lamellae and intra-lamellar constituents. Next, we examine stress fields resulting from the disruption of individual elastic lamellae, lost SMC contractility, and GAG production within an intra-lamellar space, focusing on the radial transferal of loading rather than on stresses at the tip of the delaminated tissue. Results suggest that local disruptions of elastic lamellae transfer excessive loads to nearby intra-lamellar constituents, which increases cellular vulnerability to dysfunction or death. Similarly, lost SMC function and accumulations of GAGs increase mechanical stress on nearby elastic lamellae, thereby increasing the chance of disruption. Overall these results suggest a positive feedback loop between lamellar disruption and cellular dropout with GAG production and lost medial collagen that is more pronounced at higher distending pressures. Independent of the initiating event, this feedback loop can catastrophically propagate intramural delamination.

Musculoskeletal injuries in real tennis.

Introduction: Real tennis is a growing, unique, and well-established sport. To date, there has been no epidemiological data on real tennis injuries. The primary aim of this retrospective study is to record the incidence and document any trends in real tennis musculoskeletal injuries, so as to improve injury awareness of common and possibly preventable injuries. Methods: A surveillance questionnaire e-mailed to 2,036 Tennis & Rackets Association members to retrospectively capture injuries sustained by amateur and professional real tennis players over their playing careers. Results: A total of 485 (438 males and 47 females) questionnaires were fully completed over 4 weeks. A total of 662 musculoskeletal injuries were recorded with a mean of 1.4 injuries per player (range 0-7). The incidence of sustaining an acute real tennis musculoskeletal injury is 0.4/1000 hrs. The three main anatomical locations reported injured were elbow 15.6% (103/662), knee 11.6% (77/662), and face 10.0% (66/662). The most common structures reported injured were muscle 24% (161/661), tendon 23.4% (155/661), ligament 7.0% (46/661), soft tissue bruising 6.5% (43/661), and eye 6.2% (41/661). The majority of the upper limb injuries were gradual onset (64.7%, 143/221), and the lower limb injuries were sudden onset (72.0%, 188/261). Conclusion: This study uniquely provides valuable preliminary data on the incidence and patterns of musculoskeletal injuries in real tennis players. In addition, it highlights a number of reported eye injuries. The study is also a benchmark for future prospective studies on academy and professional real tennis players.

Arterial Stiffness: Different Metrics, Different Meanings.

Findings from basic science and clinical studies agree that arterial stiffness is fundamental to both the mechanobiology and the biomechanics that dictate vascular health and disease. There is, therefore, an appropriately growing literature on arterial stiffness. Perusal of the literature reveals, however, that many different methods and metrics are used to quantify arterial stiffness, and reported values often differ by orders of magnitude and have different meanings. Without clear definitions and an understanding of possible inter-relations therein, it is increasingly difficult to integrate results from the literature to glean true understanding. In this paper, we briefly review methods that are used to infer values of arterial stiffness that span studies on isolated cells, excised intact vessels, and clinical assessments. We highlight similarities and differences and identify a single theoretical approach that can be used across scales and applications and thus could help to unify future results. We conclude by emphasizing the need to move toward a synthesis of many disparate reports, for only in this way will we be able to move from our current fragmented understanding to a true appreciation of how vascular cells maintain, remodel, or repair the arteries that are fundamental to cardiovascular properties and function.