Subject-specific multiscale modeling of aortic valve biomechanics.

A Finite Element workflow for the multiscale analysis of the aortic valve biomechanics was developed and applied to three physiological anatomies with the aim of describing the aortic valve interstitial cells biomechanical milieu in physiological conditions, capturing the effect of subject-specific and leaflet-specific anatomical features from the organ down to the cell scale. A mixed approach was used to transfer organ-scale information down to the cell-scale. Displacement data from the organ model were used to impose kinematic boundary conditions to the tissue model, while stress data from the latter were used to impose loading boundary conditions to the cell level. Peak of radial leaflet strains was correlated with leaflet extent variability at the organ scale, while circumferential leaflet strains varied over a narrow range of values regardless of leaflet extent. The dependency of leaflet biomechanics on the leaflet-specific anatomy observed at the organ length-scale is reflected, and to some extent emphasized, into the results obtained at the lower length-scales. At the tissue length-scale, the peak diastolic circumferential and radial stresses computed in the fibrosa correlated with the leaflet surface area. At the cell length-scale, the difference between the strains in two main directions, and between the respective relationships with the specific leaflet anatomy, was even more evident; cell strains in the radial direction varied over a relatively wide range ([Formula: see text]) with a strong correlation with the organ length-scale radial strain ([Formula: see text]); conversely, circumferential cell strains spanned a very narrow range ([Formula: see text]) showing no correlation with the circumferential strain at the organ level ([Formula: see text]). Within the proposed simulation framework, being able to account for the actual anatomical features of the aortic valve leaflets allowed to gain insight into their effect on the structural mechanics of the leaflets at all length-scales, down to the cell scale.

Mass-spring models for the simulation of mitral valve function: Looking for a trade-off between reliability and time-efficiency.

Patient-specific finite element (FE) models can assess the impact of mitral valve (MV) repair on the complex MV anatomy and function. However, FE excessive time requirements hamper their use for surgical planning; mass-spring models (MSMs) represent a more approximate approach but can provide almost real-time simulations. On this basis, we implemented MSMs of three healthy MVs from cardiac magnetic resonance (cMR) imaging to simulate the systolic MV closure, including the in vivo papillary muscles and annular kinematics, and the anisotropic and non-linear mechanical response of MV tissues. To test MSM reliability we compared the systolic peak configurations computed by MSMs and FE: mismatches by less than twice the in-plane cMR image resolution were detected over 75% of the leaflets' surface, independently of the MSM mesh refinement and of the specific MV anatomy. Data on MSMs time-efficiency and data from the comparison of MSMs vs. FE models suggest that MSM could represent a suitable trade-off between almost real-time simulations and reliability when computing MV systolic configuration, with the potential to be used in a clinical setting either as a support to the decisional process or as a virtual training tool.

Towards the improved quantification of in vivo abnormal wall shear stresses in BAV-affected patients from 4D-flow imaging: Benchmarking and application to real data.

Bicuspid aortic valve (BAV), i.e. the fusion of two aortic valve cusps, is the most frequent congenital cardiac malformation. Its progression is often characterized by accelerated leaflet calcification and aortic wall dilation. These processes are likely enhanced by altered biomechanical stimuli, including fluid-dynamic wall shear stresses (WSS) acting on both the aortic wall and the aortic valve. Several studies have proposed the exploitation of 4D-flow magnetic resonance imaging sequences to characterize abnormal in vivo WSS in BAV-affected patients, to support prognosis and timing of intervention. However, current methods fail to quantify WSS peak values. On this basis, we developed two new methods for the improved quantification of in vivo WSS acting on the aortic wall based on 4D-flow data. We tested both methods separately and in combination on synthetic datasets obtained by two computational fluid-dynamics (CFD) models of the aorta with healthy and bicuspid aortic valve. Tests highlighted the need for data spatial resolution at least comparable to current clinical guidelines, the low sensitivity of the methods to data noise, and their capability, when used jointly, to compute more realistic peak WSS values as compared to state-of-the-art methods. The integrated application of the two methods on the real 4D-flow data from a preliminary cohort of three healthy volunteers and three BAV-affected patients confirmed these indications. In particular, quantified WSS peak values were one order of magnitude higher than those reported in previous 4D-flow studies, and much closer to those computed by highly time- and space-resolved CFD simulations.

A novel approach to the quantification of aortic root in vivo structural mechanics.

Understanding aortic root in vivo biomechanics can help in elucidating key mechanisms involved in aortic root pathologies and in the outcome of their surgical treatment. Numerical models can provide useful quantitative information. For this to be reliable, detailed aortic root anatomy should be captured. Also, since the aortic root is never unloaded throughout the cardiac cycle, the modeled geometry should be consistent with the in vivo loads acting on it. Achieving such consistency is still a challenge, which was tackled only by few numerical studies. Here we propose and describe in detail a new approach to the finite element modeling of aortic root in vivo structural mechanics. Our approach exploits the anatomical information yielded by magnetic resonance imaging by reconstructing the 3-dimensional end-diastolic geometry of the aortic root and makes the reconstructed geometry consistent with end-diastolic loading conditions through the estimation of the corresponding prestresses field. We implemented our approach through a semiautomated modeling pipeline, and we applied it to quantify aortic root biomechanics in 4 healthy participants. Computed results highlighted that including prestresses into the model allowed for pressurizing the aortic root to the end-diastolic pressure while matching the image-based ground truth data. Aortic root dynamics, tissues strains, and stresses computed at relevant time points through the cardiac cycle were consistent with a broad set of data from previous computational and in vivo studies, strongly suggesting the potential of the method. Also, results highlighted the major role played by the anatomy in driving aortic root biomechanics.

Left ventricular modelling: a quantitative functional assessment tool based on cardiac magnetic resonance imaging.

We present the development and testing of a semi-automated tool to support the diagnosis of left ventricle (LV) dysfunctions from cardiac magnetic resonance (CMR). CMR short-axis images of the LVs were obtained in 15 patients and processed to detect endocardial and epicardial contours and compute volume, mass and regional wall motion (WM). Results were compared with those obtained from manual tracing by an expert cardiologist. Nearest neighbour tracking and finite-element theory were merged to calculate local myocardial strains and torsion. The method was tested on a virtual phantom, on a healthy LV and on two ischaemic LVs with different severity of the pathology. Automated analysis of CMR data was feasible in 13/15 patients: computed LV volumes and wall mass correlated well with manually extracted data. The detection of regional WM abnormalities showed good sensitivity (77.8%), specificity (85.1%) and accuracy (82%). On the virtual phantom, computed local strains differed by less than 14 per cent from the results of commercial finite-element solver. Strain calculation on the healthy LV showed uniform and synchronized circumferential strains, with peak shortening of about 20 per cent at end systole, progressively higher systolic wall thickening going from base to apex, and a 10° torsion. In the two pathological LVs, synchronicity and homogeneity were partially lost, anomalies being more evident for the more severely injured LV. Moreover, LV torsion was dramatically reduced. Preliminary testing confirmed the validity of our approach, which allowed for the fast analysis of LV function, even though future improvements are possible.

Evaluating the acceptability and feasibility of the I Promise Program: a driving program for families with young new drivers.

OBJECTIVES: To evaluate the acceptability and feasibility of the I Promise Program (IPP), a driving program developed for families with young new drivers (YNDs). DESIGN, SETTING, AND SUBJECTS: The IPP consists of a contract between parents and YNDs and a rear window decal (sticker). Program acceptability was assessed through four focus groups with 40 young new drivers (YND), two with 19 parents of YNDs, and two with 15 community members. To determine whether the program's design, materials, and procedures were working as planned, 51 families participated in a six month pilot project. Telephone and in-person interviews were conducted at months 1 and 6, respectively. RESULTS: Participants had problems with the acceptability of the program's underlying message; content, format, and language of the materials; program cost; and proposed participant incentives. Thirty eight (75%) families completed the six month pilot. Most YNDs (75%) and parents (85%) identified the contract as a useful communication tool. Despite positive initial reactions, 50% of YNDs did not recall the content of the contract after six months. Sixty eight percent of families had problems with the decal (for example, did not stay affixed, colors faded) and only 17% of YNDs reported a lasting impact on their driving. Only 20% of families chose to continue in the program after the pilot. CONCLUSIONS: These results highlight the importance of formative and process evaluation in the development of a new prevention strategy to assess a strategy's acceptability and feasibility. In response to participants' feedback, revisions made to the program's materials and delivery model included making its two key components-the contract and decal-available online, independent of each other, and free of charge.

Adherence of Candida albicans to epithelial cells from normal and cancerous urinary bladders.

Patients with malignancies are at high risk to develop infections by Candida albicans. We have compared the adherence of C. albicans isolated from urine cultures to bladder epithelial cells obtained from healthy volunteers and patients with cancer of the bladder. The mean number of C. albicans adhering per epithelial cell from areas infiltrated from cancer was significantly higher as compared to cells obtained from intact areas of cancerous bladders and from normal bladders. The increased adherence of C. albicans to cancerous epithelial cells suggests that malignancies are associated with alterations of the epithelial cell surface which render the cells more susceptible to colonization by C. albicans. The increased colonization may predispose these patients to C. albicans infections.

In vivo potentiation of polymorphonuclear leukocyte function by ciprofloxacin.

Ciprofloxacin was administered to 10 healthy volunteers at a dose of 250 mg orally. Serum and polymorphonuclear leukocytes (PMNLs) were obtained from all subjects before the administration of the drug and 12 hours after the administration. In addition serum was obtained from all subjects at 24 and 48 hours after ciprofloxacin administration. All sera and PMNLs were used for the chemotactic, phagocytic and killing determinations of the PMNLs. The results demonstrated that serum obtained 12 hours after the administration of ciprofloxacin potentiates PMNL chemotactic activity (chemotactic index (CI) = 33.0 +/- 4.2 microns (means +/- S.D.)) as compared to the chemotactic activity generated by serum obtained prior to administration of the drug, CI = 20.4 +/- 4.4 microns (p < 0.01). Serum obtained 24 and 48 hours after ciprofloxacin administration did not stimulate PMNL function. The administration of ciprofloxacin did not have any direct influence on the PMNLs in terms of their chemotactic response. Furthermore, serum obtained after the administration of ciprofloxacin markedly enhanced PMNL phagocytosis and killing of all organisms tested. Ciprofloxacin also acted directly on the PMNLs and increased their bactericidal activity. These results demonstrate that ciprofloxacin potentiates PMNL function in vivo which may be of potential clinical benefit.

Transient improvement of polymorphonuclear leukocyte function by splenectomy in beta-thalassemia.

Host defense mechanisms in transfusion-dependent non-splenectomized patients with beta-thalassemia were studied. Polymorphonuclear leukocytes (PMNLs) of non-splenectomized patients responded poorly to zymosan generated chemotactic factors. Chemotactic indices were 22.1 microns +/- 2.8 (mean +/- S.D.) using zymosan activated serum (ZAS) as the attractant in comparison to 20.4 microns +/- 2.6 when fresh untreated serum was used. In contrast, chemotactic indices of normal PMNLs increased from 21.1 microns to 33.6 microns +/- 3.1 in response to ZAS. Normal PMNL responses to a mixture of normal ZAS and thalassemic serum were inhibited; the mean chemotactic index was 18.1 microns +/- 5.1 with use of ZAS alone. Splenectomy temporarily reverses these alterations. Adherence to nylon wool of PMNLs suspended in fresh thalassemic serum prior to splenectomy was 3.1% +/- 1.1 (mean +/- S.D.); 20 days after splenectomy adherence increased to 14.0% +/- 2.8 (P = 0.0001) and remained at this level for 90 days. At 120 and 150 days after splenectomy adherence decreased to 1.5% +/- 0.8 and 1.0% +/- 0.85 respectively. Splenectomy also transiently abrogated the failure of zymosan to generate chemotactic factors in thalassemic serum.

Effects of methylprednisolone and dexamethasone on polymorphonuclear leukocyte adherence in vivo.

It has been proposed that corticosteroids may be effective in the treatment of shock and the adult respiratory distress syndrome (ARDS) by inhibiting complement-induced granulocyte aggregation and by disaggregating granulocyte aggregates in vitro. In the present investigation we have examined the effects of sera from patients who had received comparable doses of methylprednisolone (MP) and dexamethasone (DEX) on the adherence of polymorphonuclear leukocytes (PMNs). Sera obtained from patients that had received MP markedly reduced PMN adherence with maximum effect noted by 8 h. In contrast, sera from patients receiving DEX had no effect on PMN adherence. The results of this study indicate that MP may be more effective in the treatment of septic shock and other conditions associated with microvascular leukostasis.

Interaction of subminimal inhibitory concentrations of clindamycin and gram-negative aerobic organisms: effects on adhesion and polymorphonuclear leukocyte function.

The effect of pre-incubation of Pseudomonas aeruginosa, Klebsiella pneumoniae and Proteus mirabilis with sub-inhibitory concentrations (sub MICs) of clindamycin on the adherence of these organisms was studied. Culturing these organisms in the presence of clindamycin (4 mg/l) resulted in significant enhancement of adherence for Ps. aeruginosa and Pr. mirabilis and decreased adherence for K. pneumoniae. Furthermore, the effect of pre-exposure to clindamycin on polymorphonuclear leukocyte (PMNLs) function against these organisms was determined. Filtrates of Pr. mirabilis pre-exposed to clindamycin promoted PMNL chemotaxis. No effect on chemotaxis was noted with the filtrates of clindamycin treated Ps. aeruginosa and K. pneumoniae. PMNL phagocytosis for all the organisms was increased after they were pre-exposed to clindamycin.

Enhancement of polymorphonuclear leukocyte function against gram-positive aerobic organisms grown in the presence of lincomycin.

The effect of pre-incubating Staphylococcus aureus, Streptococcus pneumoniae and Streptococcus pyogenes with subinhibitory concentrations of lincomycin was studied with respect to polymorphonuclear leukocyte function against these organisms. Culturing the above organisms in the presence of lincomycin (1/4 MIC) resulted in a significant enhancement of polymorphonuclear leukocyte chemotaxis, phagocytosis and bactericidal activity against these organisms.

Effects of subinhibitory concentrations of cefotaxime on adhesion and polymorphonuclear leukocyte function with gram-negative bacteria.

The effect of pre-incubation of Escherichia coli, Pseudomonas aeruginosa, Proteus mirabilis and Klebsiella pneumoniae with subinhibitory concentrations of cefotaxime on adherence and polymorphonuclear leukocyte function against these organisms was studied. Culturing the above organisms in the presence of cefotaxime (1/4 MIC) resulted in reduced adherence of Pseudomonas aeruginosa and Proteus mirabilis. Furthermore pre-incubation of all organisms with sub MICs of cefotaxime resulted in significant enhancement of polymorphonuclear leukocyte chemotaxis, phagocytosis and bactericidal activity against these organisms.