Mitral Valve Imaging and Biomechanics: A Workflow Towards Computational Modeling and Validation

The mitral valve serves a critical role in healthy cardiac function by ensuring the unidirectional flow of oxygenated blood from the left atrium into the left ventricle. It experiences the highest pressures found within the heart and its closure is the result of a complex interaction of several different structures that, furthermore, are unique to each individual. Despite the valve’s vital role however, the specific function of these constituent structures is not fully understood. This, confounded by its asymmetric, personalized nature, make surgical interventions for the mitral valve far less effective than for its neighboring aortic valve. Efforts to overcome this have been made through the lens of computational simulation, in which the valve is studied virtually and procedures may be planned. The quality and reliability of these simulation results are only as good as the inputs that the simulation model receives. This study proposes and evaluates a workflow by which high-quality biomechanical inputs are obtained for computational input and validation. To account for individual variation, all steps are performed on the same valve such that a direct correspondence is made between geometry, stress/load distribution and the resulting coaptation. Ultrasound in vivo measurements are made so that custom tailored mounting hardware can be manufactured. This hardware is used to support the valve in a physiologically appropriate manner for µCT imaging in both the open and closed configurations. Scanning within a fluid medium, to prevent tissue desiccation and other detrimental effects, is made possible through a DiceCT tissue staining procedure. High resolution, 3D imagery is obtained for the open valve whereas only a relatively quick set of projection images is obtained for the closed configuration. Registration between open and closed imagery is accomplished by localizing aluminum oxide fiducial markers that are bound to the leaflet surface. Subsequent image analysis is performed to isolate the tissue and place the data in the proper format for computational use. The valve is then closed under known pressure while chordal forces/strains are simultaneously recorded to provide loading conditions. The effectiveness of the workflow is illustrated through two animal experiments. Incomplete results were obtained from the first experiment as the tissue degraded significantly during a prolonged period of µCT downtime. The second experiment resulted in good quality ultrasound imagery, leading to the creation of customized mounting hardware, yet the remainder of the process was still in progress at the final stages of this document. Computational modeling is still ongoing, yet some preliminary results are presented which show the geometry from the first animal experiment tending towards closure

Mitral Valve Imaging and Biomechanics: A Workflow Towards Computational Modeling and Validation

The mitral valve serves a critical role in healthy cardiac function by ensuring the unidirectional flow of oxygenated blood from the left atrium into the left ventricle. It experiences the highest pressures found within the heart and its closure is the result of a complex interaction of several different structures that, furthermore, are unique to each individual. Despite the valve’s vital role however, the specific function of these constituent structures is not fully understood. This, confounded by its asymmetric, personalized nature, make surgical interventions for the mitral valve far less effective than for its neighboring aortic valve. Efforts to overcome this have been made through the lens of computational simulation, in which the valve is studied virtually and procedures may be planned. The quality and reliability of these simulation results are only as good as the inputs that the simulation model receives. This study proposes and evaluates a workflow by which high-quality biomechanical inputs are obtained for computational input and validation. To account for individual variation, all steps are performed on the same valve such that a direct correspondence is made between geometry, stress/load distribution and the resulting coaptation. Ultrasound in vivo measurements are made so that custom tailored mounting hardware can be manufactured. This hardware is used to support the valve in a physiologically appropriate manner for µCT imaging in both the open and closed configurations. Scanning within a fluid medium, to prevent tissue desiccation and other detrimental effects, is made possible through a DiceCT tissue staining procedure. High resolution, 3D imagery is obtained for the open valve whereas only a relatively quick set of projection images is obtained for the closed configuration. Registration between open and closed imagery is accomplished by localizing aluminum oxide fiducial markers that are bound to the leaflet surface. Subsequent image analysis is performed to isolate the tissue and place the data in the proper format for computational use. The valve is then closed under known pressure while chordal forces/strains are simultaneously recorded to provide loading conditions. The effectiveness of the workflow is illustrated through two animal experiments. Incomplete results were obtained from the first experiment as the tissue degraded significantly during a prolonged period of µCT downtime. The second experiment resulted in good quality ultrasound imagery, leading to the creation of customized mounting hardware, yet the remainder of the process was still in progress at the final stages of this document. Computational modeling is still ongoing, yet some preliminary results are presented which show the geometry from the first animal experiment tending towards closure

KSU Jazz Ensemble with special guest The Atlanta Youth Jazz Orchestra

Kennesaw State University School of Music presents Jazz Ensemble with special guest Atlanta Youth Jazz Orchestra.https://digitalcommons.kennesaw.edu/musicprograms/1753/thumbnail.jp

From Models to Implementations - Distributed Algorithms using Maude

Maude is an equational and rewriting logic specification tool. It allows a unique and simple way of specifying concurrent programs and lends itself nicely to verification. This senior thesis focuses specifically on patterns for creating distributed algorithms in Maude, and after applying these patterns to several classical algorithms, it builds up to the consensus algorithm Raft, which has not previous been implemented. Maude has limited support for communication between processes on separate machines. This paper develops a “middleware” that enables a straightforward approach for transforming a model into an implementation, allowing correct-by-construction working implementations of distributed systems. The design and usage of this middleware will be examined, especially with the use of case studies. Ideally, this will allow easier development of future distributed systems in Maude, without having to worry about socket-level coding.Ope

High Resolution Imaging of the Mitral Valve in the Natural State with 7 Tesla MRI

Imaging techniques of the mitral valve have improved tremendously during the last decade, but challenges persist. The delicate changes in annulus shape and papillary muscle position throughout the cardiac cycle have significant impact on the stress distribution in the leaflets and chords, thus preservation of anatomically accurate positioning is critical. The aim of this study was to develop an in vitro method and apparatus for obtaining high-resolution 3D MRI images of porcine mitral valves in both the diastolic and systolic configurations with physiologically appropriate annular shape, papillary muscle positions and orientations, specific to the heart from which the valve was harvested. Positioning and mounting was achieved through novel, customized mounting hardware consisting of papillary muscle and annulus holders with geometries determined via pre-mortem ultrasonic intra-valve measurements. A semi-automatic process was developed and employed to tailor Computer Aided Design models of the holders used to mount the valve. All valve mounting hardware was 3D printed using a stereolithographic printer, and the material of all fasteners used were brass for MRI compatibility. The mounted valves were placed within a clear acrylic case, capable of holding a zero-pressure and pressurized liquid bath of a MRI-compatible fluid. Obtaining images from the valve submerged in liquid fluid mimics the natural environment surrounding the valve, avoiding artefacts due to tissue surface tension mismatch and gravitational impact on tissue shape when not neutrally buoyant. Fluid pressure was supplied by reservoirs held at differing elevations and monitored and controlled to within ±1mmHg to ensure that the valves remained steady. The valves were scanned in a 7 Tesla MRI system providing a voxel resolution of at least 80μm. The systematic approach produced 3D datasets of high quality which, when combined with physiologically accurate positioning by the apparatus, can serve as an important input for validated computational models

IgG light chain-independent secretion of heavy chain dimers: consequence for therapeutic antibody production and design

Rodent monoclonal antibodies with specificity towards important biological targets are developed for therapeutic use by a process of humanisation. This process involves the creation of molecules, which retain the specificity of the rodent antibody but contain predominantly human coding sequence. Here we show that some humanised heavy chains can fold, form dimers and be secreted even in the absence of light chain. Quality control of recombinant antibody assembly in vivo is thought to rely upon folding of the heavy chain CH1 domain. This domain acts as a switch for secretion, only folding upon interaction with the light chain CL domain. We show that the secreted heavy-chain dimers contain folded CH1 domains and contribute to the heterogeneity of antibody species secreted during the expression of therapeutic antibodies. This subversion of the normal quality control process is dependent upon the heavy chain variable domain, is prevalent with engineered antibodies and can occur when only the Fab fragments are expressed. This discovery will impact on the efficient production of both humanised antibodies as well as the design of novel antibody formats

The novel mu-opioid antagonist, GSK1521498, reduces ethanol consumption in C57BL/6J mice.

RATIONALE Using the drinking-in-the-dark (DID) model, we compared the effects of a novel mu-opioid receptor antagonist, GSK1521498, with naltrexone, a licensed treatment of alcohol dependence, on ethanol consumption in mice. OBJECTIVE We test the ability of GSK1521498 to reduce alcohol consumption and compare its intrinsic efficacy to that of naltrexone by comparing the two drugs at doses matched for equivalent receptor occupancy. METHODS Thirty-six C57BL/6J mice were tested in a DID procedure. In 2-day cycles, animals experienced one baseline, injection-free session, and one test session when they received two injections, one of test drug and one placebo. All animals received GSK1521498 (0, 0.1, 1 and 3 mg/kg, i.p., 30 min pre-treatment) and naltrexone (0, 0.1, 1 and 3 mg/kg, s.c. 10 min pre-treatment) in a cross-over design. Receptor occupancies following the same doses were determined ex vivo in separate groups by autoradiography, using [3H]DAMGO. Binding in the region of interest was measured integrally by computer-assisted microdensitometry and corrected for non-specific binding. RESULTS Both GSK1521498 and naltrexone dose-dependently decreased ethanol consumption. When drug doses were matched for 70-75 % receptor occupancy, GSK1521498 3 mg/kg, i.p., caused a 2.5-fold greater reduction in alcohol consumption than naltrexone 0.1 mg/kg, s.c. Both GSK1521498 and naltrexone significantly reduced sucrose consumption at a dose of 1 mg/kg but not 0.1 mg/kg. In a test of conditioned taste aversion, GSK1521498 (3 mg/kg) reduced sucrose consumption 24 h following exposure to a conditioning injection. CONCLUSIONS Both opioid receptor antagonists reduced alcohol consumption but GK1521498 has higher intrinsic efficacy than naltrexone

Lung cancer diagnosis and staging with endobronchial ultrasound-guided transbronchial needle aspiration compared with conventional approaches: an open-label, pragmatic, randomised controlled trial

SummaryBackgroundThe diagnosis and staging of lung cancer is an important process that identifies treatment options and guides disease prognosis. We aimed to assess endobronchial ultrasound-guided transbronchial needle aspiration as an initial investigation technique for patients with suspected lung cancer.MethodsIn this open-label, multicentre, pragmatic, randomised controlled trial, we recruited patients who had undergone a CT scan and had suspected stage I to IIIA lung cancer, from six UK centres and randomly assigned them to either endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) or conventional diagnosis and staging (CDS), for further investigation and staging. If a target node could not be accessed by EBUS-TBNA, then endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) was allowed as an alternative procedure. Randomisation was stratified according to the presence of mediastinal lymph nodes measuring 1 cm or more in the short axis and by recruiting centre. We used a telephone randomisation method with permuted blocks of four generated by a computer. Because of the nature of the intervention, masking of participants and consenting investigators was not possible. The primary endpoint was the time-to-treatment decision after completion of the diagnostic and staging investigations and analysis was by intention-to-diagnose. This trial is registered with ClinicalTrials.gov, number NCT00652769.FindingsBetween June 10, 2008, and July 4, 2011, we randomly allocated 133 patients to treatment: 66 to EBUS-TBNA and 67 to CDS (one later withdrew consent). Two patients from the EBUS-TBNA group underwent EUS-FNA. The median time to treatment decision was shorter with EBUS-TBNA (14 days; 95% CI 14–15) than with CDS (29 days; 23–35) resulting in a hazard ratio of 1·98, (1·39–2·82, p<0·0001). One patient in each group had a pneumothorax from a CT-guided biopsy sample; the patient from the CDS group needed intercostal drainage and was admitted to hospital.InterpretationTransbronchial needle aspiration guided by endobronchial ultrasound should be considered as the initial investigation for patients with suspected lung cancer, because it reduces the time to treatment decision compared with conventional diagnosis and staging techniques.FundingUK Medical Research Council