Validating a prediction modeling tool for left ventricular outflow tract (LVOT) obstruction after transcatheter mitral valve replacement (TMVR).

OBJECTIVE: Demonstrate proof-of-concept validation of a computed tomography (CT) computer-aided design prediction modeling tool to identify patients at risk for left ventricular outflow tract (LVOT) obstruction in transcatheter mitral valve replacement (TMVR). BACKGROUND: LVOT obstruction is a significant and even fatal consequence of TMVR. METHODS: From August 2013 to August 2017, 38 patients in 5 centers underwent TMVR with compassionate use of balloon-expandable valves for severe mitral valve dysfunction because of degenerative surgical mitral ring, bioprosthesis, or severe native mitral stenosis from to severe mitral annular calcification. All patients had preprocedural CT scans performed for anatomic screening, intraprocedural TEE and invasive hemodynamics performed. Preprocedural prediction modeling was performed utilizing computer-aided design (CAD) of the neo-LVOT post-TMVR. Post-TMVR CT scans were obtained and compared to pre-TMVR LVOT modeling datasets for validation. RESULTS: All patients underwent successful TMVR without device embolization. Seven of the 38 patients experienced LVOT obstruction, defined as an increase of ≥10 mmHg LVOT peak gradient post-TMVR. Anatomic screening using CT was validated in 20/38 patients as preprocedural predicted neo-LVOT surface area correlated well with post-TMVR measurements (R2 = 0.8169, P < 0.0001). A receiver operating curve curve found a predicted neo-LVOT surface area of ≤ 189.4 mm2 to have 100% sensitivity and 96.8% specificity for predicting TMVR-induced LVOT obstruction. CONCLUSION: CAD design and CT postprocessing are indispensable tools in predicting LVOT obstruction and necessary for anatomic screening in percutaneous TMVR.

Prospective, randomized comparison of 3-dimensional computed tomography guidance versus TEE data for left atrial appendage occlusion (PRO3DLAAO).

BACKGROUND: Preliminary data comparing 3-dimensional computed tomography (3D-CT) to transesophageal echocardiography (TEE) for left atrial appendage occlusion (LAAO) indicates that 3D-CT provides more accurate measurements and improves case planning. Therefore, we conducted a pilot study comparing 3D-CT to TEE in occluder selection accuracy and procedural efficiency. METHODS: From May 2016 to February 2017, 24 patients were prospectively randomized to undergo LAAO using either TEE or 3D-CT. The primary endpoint was device accuracy while the secondary endpoints included # devices per case, # guide catheters used per case, # fluoroscopy angles used, procedure time, fluoroscopy time, radiation dose, and major adverse events (stroke, MI, device embolization, perforation, death). RESULTS: Procedure success was 100% and 92% for the 3D-CT and 2D-TEE cohorts respectively. Accuracy for 1st device selection 92% and 27% (P = .01) for 3D-CT and 2D-TEE respectively but with intra-procedural upsizing in the 2D-TEE cohort, the 2D-TEE cohort accuracy increased to 64% while the 3D-CT groups 92% was accurate (P = .33). Case planning using 3D-CT was significantly more efficient with respect to device utilization (CT 1.33 ± 0.7 vs. 2D-TEE 2.5 ± 1.2 P = .01), guide catheters (CT 1 vs. 2D-TEE 1.7 ± 0.8 P = .01) and procedure time (3D-CT 55 ± 17 min vs. 2D-TEE 73 ± 24 min P < .05). One major adverse event, a stroke occurred in the 2D-TEE group. CONCLUSION: In this single-center pilot study, CT guided LAAO case planning was associated with improved device selection accuracy and procedural efficiency. This study data supports the notion that comprehensive 3D assessment significantly simplifies LAAO, minimizing the time and number of steps needed.

MIT CAACB Risk Assessment Case Study: Assessing Virus Cross-Contamination Risk between Two Simultaneous Processes in an Open Biomanufacturing Facility.

Some members of MIT's Consortium on Adventitious Agent Contamination in Biomanufacturing (CAACB) previously published content on the "Quality Risk Management in the Context of Viral Contamination", which described tools, procedures, and methodologies for assessing and managing the risk of a potential virus contamination in cell culture processes. To address the growing industry interest in moving manufacturing toward open ballrooms with functionally closed systems and to demonstrate how the ideas of risk management can be leveraged to perform a risk assessment, CAACB conducted a case study exercise of these new manufacturing modalities. In the case study exercise, a cross-functional team composed of personnel from many of CAACB's industry membership collaboratively assessed the risks of viral cross-contamination between a human and non-human host cell system in an open manufacturing facility. This open manufacturing facility had no walls to provide architectural separation of two processes occurring simultaneously, specifically a recombinant protein perfusion cell culture process using the human cell line, HEK-293 (Process 1) and a downstream postviral filtration unit operation (Process 2) of a recombinant protein produced in CHO cells. This viral risk assessment focused on cross-contamination of the Process 2 filtration unit operation after the Process 1 perfusion bioreactor was contaminated with a virus that went undetected. The workflow for quality risk management that is recommended by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) was followed, which included identifying and mapping the manufacturing process, defining the risk question, risk evaluation, and risk control. The case study includes a completed Failure Mode and Effects Analysis (FMEA) to provide descriptions of the specific risks and corresponding recommended risk reduction actions.

An application for relating Legionella shower water monitoring results to estimated health outcomes.

Exposure models are useful tools for relating environmental monitoring data to expected health outcomes. The objective of this study was to (1) compare two Legionella shower exposure models, and (2) develop a risk calculator tool for relating environmental monitoring data to estimated Legionella infection risks and Legionnaires' Disease (LD) illness risks. Legionella infection risks for a single shower event were compared using two shower Legionella exposure models. These models varied in their description of partitioning of Legionella in aerosols and aerosol deposition in the lung, where Model 1 had larger and fewer aerosol ranges than Model 2. Model 2 described conventional vs. water efficient showers separately, while Model 1 described exposure for an unspecified shower type (did not describe it as conventional or water efficient). A Monte Carlo approach was used to account for variability and uncertainty in these aerosolization and deposition parameters, Legionella concentrations, and the dose-response parameter. Methods for relating infection risks to illness risks accounting for demographic differences were used to inform the risk calculator web application ("app"). Model 2 consistently estimated higher infection risks than Model 1 for the same Legionella concentration in water and estimated deposited doses with less variability. For a 7.8-min shower with a Legionella concentration of 0.1 CFU/mL, the average infection risks estimated using Model 2 were 4.8 × 10-6 (SD=3.0 × 10-6) (conventional shower) and 2.3 × 10-6 (SD=1.7 × 10-6) (water efficient). Average infection risk estimated by Model 1 was 1.1 × 10-6 (SD=9.7 × 10-7). Model 2 was used for app development due to more conservative risk estimates and less variability in estimated dose. While multiple Legionella shower models are available for quantitative microbial risk assessments (QMRAs), they may yield notably different infection risks for the same environmental microbial concentration. Model comparisons will inform decisions regarding their integration with risk assessment tools. The development of risk calculator tools for relating environmental microbiology data to infection risks will increase the impact of exposure models for informing water treatment decisions and achieving risk targets.

Three-Dimensional Printing for Planning of Structural Heart Interventions.

Three-dimensional (3D) printing is a process leading to the creation of a physical 3D model used for teaching, patient education, device evaluation, and procedural planning. 3D printed models of patient-specific anatomy can be generated from 3D transesophageal, cardiac MRI, or cardiac computed tomographic datasets. This article discusses the potential advantages of 3D printing, reviews the different modalities to acquire a 3D dataset, and highlights the application of 3D printing to enhance patient screening and procedural planning in structural heart intervention.

Application of 3-Dimensional Computed Tomographic Image Guidance to WATCHMAN Implantation and Impact on Early Operator Learning Curve: Single-Center Experience.

OBJECTIVES: The aim of this study was to examine the impact of 3-dimensional (3D) computed tomographic (CT) guided procedural planning for left atrial appendage (LAA) occlusion on the early operator WATCHMAN learning curve. BACKGROUND: Traditional WATCHMAN implantation is dependent on 2-dimensional transesophageal echocardiographic (TEE) sizing and intraprocedural guidance. METHODS: LAA occlusion with the WATCHMAN device was performed in 53 patients. Pre-procedural case plans were generated from CT studies with recommended device size, catheter selection, and C-arm angle for deployment. RESULTS: All 53 patients underwent successful LAA occlusion with the WATCHMAN. Three-dimensional CT LAA maximal-width sizing was 2.7 ± 2.2 mm and 2.3 ± 3.0 mm larger than 2-dimensional and 3D TEE measurements, respectively (p ≤ 0.0001). By CT imaging, device selection was 100% accurate. There were 4 peri-WATCHMAN leaks (<4.5 mm) secondary to accessory LAA pedunculations. By 2-dimensional TEE maximal-width measurements alone, 62.3% (33 of 53) would have required larger devices. Using 3D TEE maximal-width measurements, 52.8% of cases (28 of 53) would have required larger devices. Three-dimensional TEE length would have inappropriately excluded 10 patients from WATCHMAN implantation. Compared with the average of 1.8 devices used per implantation attempt in PROTECT AF (WATCHMAN Left Atrial Appendage System for Embolic Protection in Patients With Atrial Fibrillation) (82% success rate), the present site averaged 1.245 devices per implantation attempt (100% success rate). There were no intraprocedural screen failures and no major adverse cardiac events. CONCLUSIONS: Three-dimensional CT image case planning provides a comprehensive and customized patient-specific LAA assessment that appears to be accurate and may possibly facilitate reducing the early WATCHMAN implantation learning curve.

Sleep hygiene practices in a population-based sample of insomniacs.

STUDY OBJECTIVES: The present study was designed to assess selected aspects of sleep hygiene from a population-based sample of individuals with insomnia compared to age- and sex-matched controls. DESIGN: A random-sample phone survey of 258 individuals meeting Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition-based criteria for insomnia was compared to age- and sex-matched normal sleepers on specific measures of sleep hygiene. Sleep hygiene practices measured included cigarette smoking, smoking near bedtime, alcohol use, caffeine use, napping, time in bed, and reported likelihood of sleeping in on weekends. SETTING: Detroit tricounty population. PARTICIPANTS: 258 individuals 18 to 65 years old with insomnia and 258 age- and sex-matched controls. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: Insomniacs reported poorer sleep hygiene, as evidenced by an increase in prevalence of smoking close to bedtime and increased use of alcohol. They also reported more naps per week and sleeping in on days not worked. Caffeine use did not differ between groups. Time in bed was also comparable between insomniacs and controls. CONCLUSION: Insomniacs do engage in specific poor sleep hygiene practices, such as smoking and drinking alcohol just before bedtime. These particular aspects of sleep hygiene may be important components that exacerbate or perpetuate insomnia.

Virulence of Listeria monocytogenes Propagated in NaCl Containing Media at 4, 25 and 37°C.

Virulence, as determined in a mouse model, and virulence factor activities of catalase (CA), superoxide dismutase (SOD) and listeriolysin O (LLO), was examined in Listeria monocytogenes 10403S. Cells were propagated in media containing various concentrations of sodium chloride (NaCl) at 4, 25 and 37°C. Strain 10403S exhibited significant increases in CA activity and LLO when grown in media containing 428 mM of NaCl at 37°C. The CA activities at 4 and 25°C were significantly less, and the cells exhibited similar increases and decreases as cells grown at 37°C. When comparing the growth temperatures, the CA activity decreased as the growth temperature decreased. The SOD activity was significantly increased only when cells were propagated in media containing either 428 or 1,112 mM of NaCl. The SOD activity increased as the growth temperature decreased. No LLO activity was detected when cells were grown at 4 and 25°C. The production of these enzymes appeared to be thermoregulated. In addition, approximate lethal dose (ALD50) values were determined after intragastric (i.g.) and intraperitoneal (i.p.) infection. Each method of infection indicated that LLO was required for virulence, while growth in salt containing media, growth at 4°C, or the production of higher levels of CA, SOD and LLO did not appear to influence the virulence of L. monocytogenes .

Discrete and continuous mathematical models of DNA branch migration.

DNA junctions, known as Holliday junctions, are intermediates in genetic recombination between DNAs. In this structure, two double-stranded DNA helices with similar sequence are joined at a branch point. The branch point can move along these helices when strands with the same sequence are exchanged. Such branch migration is modeled as a random walk. First, we model this process discretely, such that the motion of the branch is represented as transfer between discrete compartments. This is useful in analysing the results of DNA branch migration on junction comprised of synthetic oligonucleotides. The limit in which larger numbers of smaller steps go to continuous motion of the branch is also considered. We show that the behavior of the continuous system is very similar to that of the discrete system when there are more than just a few compartments. Thus, even branch migration on oligonucleotides can be viewed as a continuous process. One consequence of this is that a step size must be assumed when determining rate constants of branch migration. We compare migration where forward and backward movements of the branch are equally probable to biased migration where one direction is favored over the other. In the latter case larger differences between the discrete and continuous cases are predicted, but the differences are still small relative to the experimental error associated with experiments to measure branch migration in oligonucleotides.

Catalase, Superoxide Dismutase and Listeriolysin O Production by Listeria monocytogenes in Broth Containing Acetic and Hydrochloric Acids.

Cells of Listeria monocytogenes 10403S were propagated at 37°C in media acidified with either acetic or hydrochloric acid to determine the effect on the production of catalase (CA), superoxide dismutase (SOD) and listeriolysin O (LLO). The CA and LLO activities decreased while SOD activity increased as the pH of the growth media was decreased. Comparison of the acids indicated that neither acid caused significant differences in enzyme production except for SOD activity at pH 5.7. These results suggest that growth of L. monocytogenes in acid environments may influence the production of these enzymes, while growth in strong acids versus weak acids may not be significantly different.