Isolation and Phenotypic Characterization of Virulent Bacteriophages Against Multidrug-Resistant Escherichia coli and Its Phage-Resistant Variant from Sewage Sources.

Purpose: The use of lytic bacteriophages for the control or elimination of pathogenic multidrug-resistant (MDR) bacteria is the promising alternative. However, the emergence of resistant bacterial variants after phage application may challenge its therapeutic benefit. In this study, we aimed to isolate candidate phages from sewage samples against two MDR Escherichia coli as well as their phage-resistant variant. Methods: MDR E. coli isolates (n = 10) obtained from Jimma Medical Center that had been properly identified and stored were used to isolate bacteriophages. Two lytic coliphages were isolated from hospital sewage samples following standard protocols. Upon single phage infection, phage-resistant variant quickly evolved serving as a new host for the isolation of a third lytic phage. This virulent phage's lytic activity against both its host and the wild host was investigated. The host infectivity of the various cocktails was assessed, and each phage's biological properties were studied. Results: Out of the first round of phage isolation process, two lytic phages were identified as VBO-E. coli 4307 and VBW-E. coli 4194. When exposed to VBO-E. coli 4307, the wild-type E. coli 4307 developed resistant variants. A third phage (VBA-E. coli 4307R) was isolated specific to this resistant variant (E. coli 4307R) under optimum condition. For VBO-E. coli 4307, VBW-E. coli 4194, and VBA-E. coli 4307R, the plaque assays generated under comparable conditions were 2.13 × 1010 PFU mL-1, 9.17 × 1012 PFU mL-1, and 3.3 × 1010 PFU mL-1, respectively. These phages have nearly identical stability and lytic ability but differ greatly in their host ranges for VBA-E. coli 4307R. Conclusion: While the wild-type MDR pathogen could easily evolve resistance when exposed to a single phage infection by VBO-E. coli 4307, it is still possible to isolate a novel bacteriophage from environmental samples that is effective against the phage-resistant variants. This indicates that it is possible to manage the effects of phage resistance pathogens even if they are MDR.

Objectively Quantifying Pediatric Psychiatric Severity Using Artificial Intelligence, Voice Recognition Technology, and Universal Emotions: Pilot Study for Artificial Intelligence-Enabled Innovation to Address Youth Mental Health Crisis.

BACKGROUND: Providing Psychotherapy, particularly for youth, is a pressing challenge in the health care system. Traditional methods are resource-intensive, and there is a need for objective benchmarks to guide therapeutic interventions. Automated emotion detection from speech, using artificial intelligence, presents an emerging approach to address these challenges. Speech can carry vital information about emotional states, which can be used to improve mental health care services, especially when the person is suffering. OBJECTIVE: This study aims to develop and evaluate automated methods for detecting the intensity of emotions (anger, fear, sadness, and happiness) in audio recordings of patients' speech. We also demonstrate the viability of deploying the models. Our model was validated in a previous publication by Alemu et al with limited voice samples. This follow-up study used significantly more voice samples to validate the previous model. METHODS: We used audio recordings of patients, specifically children with high adverse childhood experience (ACE) scores; the average ACE score was 5 or higher, at the highest risk for chronic disease and social or emotional problems; only 1 in 6 have a score of 4 or above. The patients' structured voice sample was collected by reading a fixed script. In total, 4 highly trained therapists classified audio segments based on a scoring process of 4 emotions and their intensity levels for each of the 4 different emotions. We experimented with various preprocessing methods, including denoising, voice-activity detection, and diarization. Additionally, we explored various model architectures, including convolutional neural networks (CNNs) and transformers. We trained emotion-specific transformer-based models and a generalized CNN-based model to predict emotion intensities. RESULTS: The emotion-specific transformer-based model achieved a test-set precision and recall of 86% and 79%, respectively, for binary emotional intensity classification (high or low). In contrast, the CNN-based model, generalized to predict the intensity of 4 different emotions, achieved test-set precision and recall of 83% for each. CONCLUSIONS: Automated emotion detection from patients' speech using artificial intelligence models is found to be feasible, leading to a high level of accuracy. The transformer-based model exhibited better performance in emotion-specific detection, while the CNN-based model showed promise in generalized emotion detection. These models can serve as valuable decision-support tools for pediatricians and mental health providers to triage youth to appropriate levels of mental health care services. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR1-10.2196/51912.

Bacterial contamination of single and multiple-dose parenteral injection vials after opening and antibiotic susceptibility of isolates at Jimma Medical Center, Jimma, Southwest Ethiopia.

Background: Single- or multiple-dose vials are prone to bacterial contamination after improper handling and can be potential reservoirs of microorganisms that could be transmitted to the patient through the parenteral route. The present study aims to assess the magnitude of the problem and associated factors at Jimma Medical Center (JMC), Jimma, Southwest Ethiopia. Methods: A cross-sectional study design was conducted at JMC from July 2021 to October 2021. A total of 384 parental medications and nurse interviews that were administered in 11 wards and 3 intensive care units were included. Samples were processed and identified by conventional bacterial culture methods. Results: The overall prevalence of vial contamination due to aerobic bacteria was 21 (5.5%) among multiple-dose vials and none of the single-dose vials. The highest level of contamination (8, 38.1%) was found in the paediatric ward. Pseudomonas aeruginosa and Klebsiella pneumoniae were the most common microorganisms identified vial contamination, 6 cases (28.5%) and 5 cases (23.8%) respectively Multidrug resistance was identified in 95.2% of the isolates, with all Gram-negative isolates showing a multidrug resistance against the tested antibiotics. In multivariate logistic regression analysis, vial contamination was strongly associated with reuse of syringe and/or needle, the environment where medication was handled, and the storage conditions. Conclusion: In this study, the prevalence of vial contamination was high. The bacterial isolates from vials were also resistant to commonly prescribed antimicrobial drugs. Healthcare professionals must strictly adhere to basic infection control practices as per standard guidelines to reduce the risk of infection from contaminated vials.

Detecting Clinically Relevant Emotional Distress and Functional Impairment in Children and Adolescents: Protocol for an Automated Speech Analysis Algorithm Development Study.

BACKGROUND: Even before the onset of the COVID-19 pandemic, children and adolescents were experiencing a mental health crisis, partly due to a lack of quality mental health services. The rate of suicide for Black youth has increased by 80%. By 2025, the health care system will be short of 225,000 therapists, further exacerbating the current crisis. Therefore, it is of utmost importance for providers, schools, youth mental health, and pediatric medical providers to integrate innovation in digital mental health to identify problems proactively and rapidly for effective collaboration with other health care providers. Such approaches can help identify robust, reproducible, and generalizable predictors and digital biomarkers of treatment response in psychiatry. Among the multitude of digital innovations to identify a biomarker for psychiatric diseases currently, as part of the macrolevel digital health transformation, speech stands out as an attractive candidate with features such as affordability, noninvasive, and nonintrusive. OBJECTIVE: The protocol aims to develop speech-emotion recognition algorithms leveraging artificial intelligence/machine learning, which can establish a link between trauma, stress, and voice types, including disrupting speech-based characteristics, and detect clinically relevant emotional distress and functional impairments in children and adolescents. METHODS: Informed by theoretical foundations (the Theory of Psychological Trauma Biomarkers and Archetypal Voice Categories), we developed our methodology to focus on 5 emotions: anger, happiness, fear, neutral, and sadness. Participants will be recruited from 2 local mental health centers that serve urban youths. Speech samples, along with responses to the Symptom and Functioning Severity Scale, Patient Health Questionnaire 9, and Adverse Childhood Experiences scales, will be collected using an Android mobile app. Our model development pipeline is informed by Gaussian mixture model (GMM), recurrent neural network, and long short-term memory. RESULTS: We tested our model with a public data set. The GMM with 128 clusters showed an evenly distributed accuracy across all 5 emotions. Using utterance-level features, GMM achieved an accuracy of 79.15% overall, while frame selection increased accuracy to 85.35%. This demonstrates that GMM is a robust model for emotion classification of all 5 emotions and that emotion frame selection enhances accuracy, which is significant for scientific evaluation. Recruitment and data collection for the study were initiated in August 2021 and are currently underway. The study results are likely to be available and published in 2024. CONCLUSIONS: This study contributes to the literature as it addresses the need for speech-focused digital health tools to detect clinically relevant emotional distress and functional impairments in children and adolescents. The preliminary results show that our algorithm has the potential to improve outcomes. The findings will contribute to the broader digital health transformation. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/46970.

Neisseria meningitidis carriage rate, antibiotic susceptibility profile, and associated factors among prisoners at Jimma zonal correction facility in Jimma Town, Southwestern Ethiopia: a cross-sectional study.

BACKGROUND: Neisseria meningitidis causes severe life-threatening meningococcal disease with a case fatality rate of 10-15% even with proper treatment. In Ethiopia, particularly in our study area, inadequate information is found on meningococcal disease. So, this study aimed to assess N. meningitidis carriage rate, antibiotic susceptibility profile, and associated factors among prisoners in Jimma Town, Southwestern Ethiopia. METHODS: A cross-sectional study was conducted in Jimma town, Southwest Ethiopia, from May to October 2019. A stratified sampling technique was used and proportional allocation was done. A total of 550 oropharyngeal swabs were collected, processed, isolated, and identified N. meningitidis using standard microbiological techniques. Antibiotics susceptibility test was done for isolates using the disk diffusion method. Data on demographic and associated factors for carriage were collected using a structured questionnaire. Data were summarized using frequency, percentage, graph, and table. A logistic regression model was used to see the association between the dependent and independent variables. Variables with a p-value < 0.25 during bivariate analysis were included in multivariate analysis to identify factors significantly associated with the meningococcal carriage and, a p-value < 0.05 was considered statistically significant. RESULT: Out of the 550 study participants, 76(13.8%) with (CI: 7.20-18.20) were found carriers of N meningitidis. The predominant isolates were non-serogroupable 26(34.2%) and serogroup W/Y 22(28.9%), respectively. N. meningitidis isolates showed highest sensitivity to chloramphenicol 74(97.4%). Meningococcal carriage rate was significantly associated with being age group of 16-20 years; having respiratory symptoms within 3 months and active cigarette smoking within 3 months. CONCLUSIONS: The majority of participants harbor most of the serogroups responsible for invasive cases of meningococcal disease. Respiratory symptoms, active cigarette smoking, and age group of 16-20 years increased the risk of N. meningitidis pharyngeal carriage rate. This study suggests providing better health education to control respiratory symptoms, smoking, and providing antibiotic prophylaxis for prisoners.

Does cotrimoxazole prophylaxis in HIV patients increase the drug resistance of pneumococci? A comparative cross-sectional study in southern Ethiopia.

BACKGROUND: Infections caused by antibiotic-resistant bacteria results in high rates of morbidity and mortality. Although the prolonged cotrimoxazole (CTX) prophylaxis is arguably associated with the risk of increasing drug resistance in the common pathogens, information regarding its impact on Streptococci pneumoniae / pneumococcus is very limited. OBJECTIVE: This study was conducted to investigate the effect of cotrimoxazole prophylaxis on nasopharyngeal colonization rate and antimicrobial resistance using Streptococci pneumoniae (pneumococcus) as an indicator organism among HIV patients in Arba Minch, Ethiopia. MATERIALS AND METHODS: A comparative cross-sectional study was designed and conducted among HIV patients attending the Anti-Retroviral Treatment (ART) clinic of Arba Minch General Hospital (AMGH) from April 01 to August 31, 2018. A total of 252 participants were systematically selected and clustered into two study groups based on their CTX prophylaxis status, one taking CTX prophylaxis, and the second one, the control group (without prophylaxis). A structured questionnaire was used to collect socio-demographic and clinical data from patients. A nasopharyngeal swab was collected and cultured for pneumococcal isolation and identification in accordance with standard microbiological techniques. An antibiotics sensitivity test was performed according to the CLSI guidelines. Data were analyzed using the Statistical package for social science (SPSS) version 20. The primary outcome was determined using logistic regression analysis. RESULTS: Of the 252 enrolled HIV patients (mean age (37.38± 9.03 years), 144 (57.14%) were males. The overall, nasopharyngeal colonization rate of S. pneumoniae was 13.5% (95% CI: 8.4-15.6). Asymptomatic pneumococcal carriage rates among patients on CTX prophylaxis and the control group were 16.3%, and 10.3% respectively (p-value = 0.03). Regarding the risk factors analyzed, CTX prophylaxis (AOR: 2.2; 95% CI: 1.05-4.9) and gender (AOR: 2.5; 95% CI: 1.09-5.93) were significantly associated with pneumococcal colonization, showing a male preponderance. Cotrimoxazole-resistant pneumococci were 85.7% vs. 47.4% in the prophylaxis group and the control group respectively and it was statistically significant (AOR: 6.7; 95% CI: 1.3-36). Percentages of multi-drug resistant isolates in these two groups were 38.09 and 15.38 respectively (p-value = 0.04). Among the CTX resistant pneumococci isolates, 85% were also found to be co-resistant towards penicillin and was statistically significant. CONCLUSION: The percentage prevalence of nasopharyngeal pneumococci colonization was higher in patients taking CTX prophylaxis. It was noted that CTX prophylaxis eventually results in the selection of cotrimoxazole resistance and multi-drug resistance in pneumococci. There is evidence of existing cross-resistance between cotrimoxazole and penicillin antibiotics. Therefore, CTX prophylaxis must be administered judiciously. Surveillance for antimicrobial susceptibility is warranted where the prophylaxis is common.

Enhanced identification of Group B streptococcus in infants with suspected meningitis in Ethiopia.

Meningitis is one of the top ten causes of death among Ethiopian infants. Group B streptococcus (GBS) has emerged as a leading cause of meningitis in neonates and young infants, resulting in high mortality. Despite this, there is no report on GBS associated meningitis in Ethiopia where infant meningitis is common. Hence, the aim of this study was to determine the proportion of GBS associated meningitis among Ethiopian infants. PCR was prospectively used to detect GBS in culture-negative cerebrospinal fluid (CSF) samples, which were collected from infants suspected for meningitis, at Tikur Anbessa specialized hospital, Ethiopia, over a one-year period. GBS was detected by PCR in 63.9% of culture-negative CSF samples. Out of the 46 GBS positive infants, 10.9% (n = 5) of them died. The late onset of GBS (LOGBS) disease was noted to have a poor outcome with 3 LOGBS out of 5 GBS positive samples collected from patients with the final outcome of death. PCR was advantageous in the identification of GBS in culture-negative CSF samples. GBS was detected in 64% of the CSF samples from infants with meningitis compared with zero-detection rate by culture.

In Vitro Biofilm Formation and Antibiotic Susceptibility Patterns of Bacteria from Suspected External Eye Infected Patients Attending Ophthalmology Clinic, Southwest Ethiopia.

BACKGROUND: Ocular disease with its complications is a major public health problem which has significant impacts on the quality of life particularly in developing countries. An eye infection due to bacterial agents can lead to reduced vision and blindness. This study was aimed to assess the antimicrobial susceptibility pattern and biofilm-forming potential of bacteria isolated from suspected external eye infected patients in Jimma. METHOD: A cross-sectional facility-based study was conducted on 319 suspect patients with external eye infections from March to June 2017 at Jimma University Medical Center (JUMC) Ophthalmology Department in Ethiopia. External ocular specimens were collected and standard operating procedures were followed to handle and culture throughout the study period. Antimicrobial susceptibility was determined by the disk diffusion method according to CLSI guidelines. Microtiter (96 wells) plate method was used to screen biofilm formation by ELISA reader at 570 nm. RESULTS: Out of 319 study participants with an external eye infection, the prevalence of bacterial pathogens was 46.1%. The predominant bacterial isolates were coagulase-negative staphylococcus (CoNS) (27.7%) followed by Staphylococcus aureus (19.7%). Among Gram-negative groups, Pseudomonas aeruginosa (6.8%) was the leading isolate. Increased antimicrobial resistance was observed for tetracycline (64%), erythromycin (66.7%), and penicillin (77.1%). Amoxicillin-clavulanic acid, ciprofloxacin, and gentamicin were the most effective drugs for external eye infections due to susceptibility ranging from 70 to 100% among both Gram-negative and Gram-positive groups. Methicillin-resistant S. aureus (MRSA) accounted for 13.8%. Multidrug resistance (MDR) accounted for 68.7%. The overall biofilm formation rate of bacterial ocular pathogens was 66.1%, where P. aeruginosa (40%), CoNS (34.1%), and S. aureus (31%) formed strong biofilm phenotype. CONCLUSION: The prevalence rate of bacterial isolates was high. Almost all bacterial isolates were resistant to at least one or more drugs. MDR pathogens were observed increasingly among biofilm formers or vice versa.

Methicillin-resistant Staphylococcus aureus carriage among medical students of Jimma University, Southwest Ethiopia.

OBJECTIVES: Infections caused by methicillin-resistant Staphylococcus aureus (MRSA) are often difficult to manage due to its resistance to multiple antibiotics. This study aimed to determine the nasal carriage of MRSA and its antimicrobial susceptibility patterns among medical students at the Jimma University medical center (JUMC), Southwest Ethiopia. METHODS: An institution based cross-sectional study was conducted at the JUMC from May to August; 2016. A total of 371 participants were systematically selected. Demographic data was collected using pre-designed questionnaire. Nasal swabs were collected following standard microbiological methods. MRSA was detected using cefoxitin (30µg) disc (Oxoid, UK); and antimicrobial susceptibility tests were performed by disc diffusion method. RESULTS: A total of 371 students were included. Of these, 84.9% (315/371) were males. The overall prevalence of nasal carriage of S. aureus and MRSA among medical students at JUMC were 22.1% (82/371) and 8.4 % (31/371), respectively. The carriage rate of MRSA among medical intern (20% (16/80)) was higher compared with clinical year-I (3.6% (6/166)) and year-II (7.2% (9/125)) students. Resistance against trimethoprim-sulfamethoxazole, tetracycline and ciprofloxacin were 83.9%, 64.5% and 51.6%, respectively. Longer stay in hospital was significantly associated with the acquisition of MRSA (X2 = 6.93, P value = 0.031). CONCLUSION: The prevalence of nasal carriage of MRSA was high. Longer stay in hospital environment was associated with the acquisition of MRSA. These findings suggest that infection control efforts focusing the performance of antimicrobial stewardship could have a significant impact on MRSA incidence in this setting.

Ventricular Assist Device Implantation Configurations Impact Overall Mechanical Circulatory Support System Thrombogenic Potential.

Ventricular assist devices (VADs) became in recent years the standard of care therapy for advanced heart failure with hemodynamic compromise. With the steadily growing population of device recipients, various postimplant complications have been reported, mostly associated with the hypershear generated by VADs that enhance their thrombogenicity by activating platelets. Although VAD design optimization can significantly improve its thromboresistance, the implanted VAD need to be evaluated as part of a system. Several clinical studies indicated that variability in implantation configurations may contribute to the overall system thrombogenicity. Numerical simulations were conducted in the HeartAssist 5 (HA5) and HeartMate II (HMII) VADs in the following implantation configurations: 1) inflow cannula angles: 115° and 140° (HA5); 2) three VAD circumferential orientations: 0°, 30°, and 60° (HA5 and HMII); and 3) 60° and 90° outflow graft anastomotic angles with respect to the ascending aorta (HA5). The stress accumulation of the platelets was calculated along flow trajectories and collapsed into a probability density function, representing the "thrombogenic footprint" of each configuration-a proxy to its thrombogenic potential (TP). The 140° HA5 cannula generated lower TP independent of the circumferential orientation of the VAD. Sixty-degree orientation generated the lowest TP for the HA5 versus 0° for the HMII. An anastomotic angle of 60° resulted in lower TP for HA5. These results demonstrate that optimizing the implantation configuration reduces the overall system TP. Thromboresistance can be enhanced by combining VAD design optimization with the surgical implantation configurations for achieving better clinical outcomes of implanted VADs.

Progression of abdominal aortic aneurysm towards rupture: refining clinical risk assessment using a fully coupled fluid-structure interaction method.

Rupture of abdominal aortic aneurysm (AAA) is associated with high mortality rates. Risk of rupture is multi-factorial involving AAA geometric configuration, vessel tortuosity, and the presence of intraluminal pathology. Fluid structure interaction (FSI) simulations were conducted in patient based computed tomography scans reconstructed geometries in order to monitor aneurysmal disease progression from normal aortas to non-ruptured and contained ruptured AAA (rAAA), and the AAA risk of rupture was assessed. Three groups of 8 subjects each were studied: 8 normal and 16 pathological (8 non-ruptured and 8 rAAA). The AAA anatomical structures segmented included the blood lumen, intraluminal thrombus (ILT), vessel wall, and embedded calcifications. The vessel wall was described with anisotropic material model that was matched to experimental measurements of AAA tissue specimens. A statistical model for estimating the local wall strength distribution was employed to generate a map of a rupture potential index (RPI), representing the ratio between the local stress and local strength distribution. The FSI simulations followed a clear trend of increasing wall stresses from normal to pathological cases. The maximal stresses were observed in the areas where the ILT was not present, indicating a potential protective effect of the ILT. Statistically significant differences were observed between the peak systolic stress and the peak stress at the mean arterial pressure between the three groups. For the ruptured aneurysms, where the geometry of intact aneurysm was reconstructed, results of the FSI simulations clearly depicted maximum wall stress at the a priori known location of rupture. The RPI mapping indicated several distinct regions of high RPI coinciding with the actual location of rupture. The FSI methodology demonstrates that the aneurysmal disease can be described by numerical simulations, as indicated by a clear trend of increasing aortic wall stresses in the studied groups, (normal aortas, AAAs and rAAAs). Ultimately, the results demonstrate that FSI wall stress mapping and RPI can be used as a tool for predicting the potential rupture of an AAA by predicting the actual rupture location, complementing current clinical practice by offering a predictive diagnostic tool for deciding whether to intervene surgically or spare the patient from an unnecessary risky operation.

Thromboresistance comparison of the HeartMate II ventricular assist device with the device thrombogenicity emulation- optimized HeartAssist 5 VAD.

Approximately 7.5 × 106 patients in the US currently suffer from end-stage heart failure. The FDA has recently approved the designations of the Thoratec HeartMate II ventricular assist device (VAD) for both bridge-to-transplant and destination therapy (DT) due to its mechanical durability and improved hemodynamics. However, incidence of pump thrombosis and thromboembolic events remains high, and the life-long complex pharmacological regimens are mandatory in its VAD recipients. We have previously successfully applied our device thrombogenicity emulation (DTE) methodology for optimizing device thromboresistance to the Micromed Debakey VAD, and demonstrated that optimizing device features implicated in exposing blood to elevated shear stresses and exposure times significantly reduces shear-induced platelet activation and significantly improves the device thromboresistance. In the present study, we compared the thrombogenicity of the FDA-approved HeartMate II VAD with the DTE-optimized Debakey VAD (now labeled HeartAssist 5). With quantitative probability density functions of the stress accumulation along large number of platelet trajectories within each device which were extracted from numerical flow simulations in each device, and through measurements of platelet activation rates in recirculation flow loops, we specifically show that: (a) Platelets flowing through the HeartAssist 5 are exposed to significantly lower stress accumulation that lead to platelet activation than the HeartMate II, especially at the impeller-shroud gap regions (b) Thrombus formation patterns observed in the HeartMate II are absent in the HeartAssist 5 (c) Platelet activation rates (PAR) measured in vitro with the VADs mounted in recirculation flow-loops show a 2.5-fold significantly higher PAR value for the HeartMate II. This head to head thrombogenic performance comparative study of the two VADs, one optimized with the DTE methodology and one FDA-approved, demonstrates the efficacy of the DTE methodology for drastically reducing the device thrombogenic potential, validating the need for a robust in silico/in vitro optimization methodology for improving cardiovascular devices thromboresistance.

Simulation of platelets suspension flowing through a stenosis model using a dissipative particle dynamics approach.

Stresses on blood cellular constituents induced by blood flow can be represented by a continuum approach down to the µm level; however, the molecular mechanisms of thrombosis and platelet activation and aggregation are on the order of nm. The coupling of the disparate length and time scales between molecular and macroscopic transport phenomena represents a major computational challenge. In order to bridge the gap between macroscopic flow scales and the cellular scales with the goal of depicting and predicting flow induced thrombogenicity, multi-scale approaches based on particle methods are better suited. We present a top-scale model to describe bulk flow of platelet suspensions: we employ dissipative particle dynamics to model viscous flow dynamics and present a novel and general no-slip boundary condition that allows the description of three-dimensional viscous flows through complex geometries. Dissipative phenomena associated with boundary layers and recirculation zones are observed and favorably compared to benchmark viscous flow solutions (Poiseuille and Couette flows). Platelets in suspension, modeled as coarse-grained finite-sized ensembles of bound particles constituting an enclosed deformable membrane with flat ellipsoid shape, show self-orbiting motions in shear flows consistent with Jeffery's orbits, and are transported with the flow, flipping and colliding with the walls and interacting with other platelets.

Toward optimization of a novel trileaflet polymeric prosthetic heart valve via device thrombogenicity emulation.

Aortic stenosis is the most prevalent and life-threatening form of valvular heart disease. It is primarily treated via open-heart surgical valve replacement with either a tissue or a mechanical prosthetic heart valve (PHV), each prone to degradation and thrombosis, respectively. Polymeric PHVs may be optimized to eliminate these complications, and they may be more suitable for the new transcatheter aortic valve replacement procedure and in devices like the total artificial heart. However, the development of polymer PHVs has been hampered by persistent in vivo calcification, degradation, and thrombosis. To address these issues, we have developed a novel surgically implantable polymer PHV composed of a new thermoset polyolefin called cross-linked poly(styrene-block-isobutylene-block-styrene), or xSIBS, in which key parameters were optimized for superior functionality via our device thrombogenicity emulation methodology. In this parametric study, we compared our homogeneous optimized polcymer PHV to a prior composite polymer PHV and to a benchmark tissue valve. Our results show significantly improved hemodynamics and reduced thrombogenicity in the optimized polymer PHV compared to the other valves. These results indicate that our new design may not require anticoagulants and may be more durable than its predecessor, and validate the improvement, toward optimization, of this novel polymeric PHV design.

Biomechanical factors in coronary vulnerable plaque risk of rupture: intravascular ultrasound-based patient-specific fluid-structure interaction studies.

OBJECTIVES: The aim of this study was to elucidate the mechanisms and underlying biomechanical factors that may play a role in the risk of rupture of vulnerable plaques (VPs) by studying patient-based geometries of coronary arteries reconstructed from intravascular ultrasound (IVUS) imaging utilizing fluid-structure interaction (FSI) numerical simulations. BACKGROUND: According to recent estimates, coronary artery disease is responsible for one in six deaths in the USA, and causes about one million heart attacks each year. Among these, the rupture of coronary VPs followed by luminal blockage is widely recognized as a major cause of sudden heart attacks; most importantly, the patients may appear as asymptomatic under routine screening before the occurrence of the index event. MATERIALS AND METHODS: FSI simulations of patient-based geometries of coronary arteries reconstructed from IVUS imaging were performed to establish the dependence of the risk of rupture of coronary VP on biomechanical factors, such as the fibrous cap thickness, presence of microcalcification in the fibrous cap, arterial anisotropy, and hypertension. RESULTS: Parametric FSI simulations indicated that mechanical stresses (von Mises stresses) increase exponentially with the thinning of the fibrous cap as well as with increasing levels of hypertension. The inclusion of a microcalcification in the fibrous cap considerably increases the risk of rupture of VP , with an ∼two-fold stress increase in the VP stress burden. Furthermore, the stress-driven reorientation and biochemical degradation of the collagen fibers in the vessel wall because of atherosclerosis (studied with an anisotropic fibrous cap 65° fiber reorientation angle) results in a 30% increase in the stress levels as compared with simulations with isotropic material models, clearly indicating that the latter, which are commonly used in such studies, underestimate the risk of rupture of VP. CONCLUSION: The results indicate that IVUS-based patient-specific FSI simulations for mapping the wall stresses, followed by analysis of the biomechanical risk factors, may be used as an additional diagnostic tool for clinicians to estimate the plaque burden and determine the proper treatment and intervention.

The Syncardia(™) total artificial heart: in vivo, in vitro, and computational modeling studies.

The SynCardia(™) total artificial heart (TAH) is the only FDA-approved TAH in the world. The SynCardia(™) TAH is a pneumatically driven, pulsatile system capable of flows of >9L/min. The TAH is indicated for use as a bridge to transplantation (BTT) in patients at imminent risk of death from non-reversible bi-ventricular failure. In the Pivotal US approval trial the TAH achieved a BTT rate of >79%. Recently a multi-center, post-market approval study similarly demonstrated a comparable BTT rate. A major milestone was recently achieved for the TAH, with over 1100 TAHs having been implanted to date, with the bulk of implantation occurring at an ever increasing rate in the past few years. The TAH is most commonly utilized to save the lives of patients dying from end-stage bi-ventricular heart failure associated with ischemic or non-ischemic dilated cardiomyopathy. Beyond progressive chronic heart failure, the TAH has demonstrated great efficacy in supporting patients with acute irreversible heart failure associated with massive acute myocardial infarction. In recent years several diverse clinical scenarios have also proven to be well served by the TAH including severe heart failure associated with advanced congenital heart disease. failed or burned-out transplants, infiltrative and restrictive cardiomyopathies and failed ventricular assist devices. Looking to the future a major unmet need remains in providing total heart support for children and small adults. As such, the present TAH design must be scaled to fit the smaller patient, while providing equivalent, if not superior flow characteristics, shear profiles and overall device thrombogenicity. To aid in the development of a new "pediatric," TAH an engineering methodology known as "Device Thrombogenicity Emulation (DTE)", that we have recently developed and described, is being employed. Recently, to further our engineering understanding of the TAH, as steps towards next generation designs we have: (1) assessed of the degree of platelet reactivity induced by the present clinical 70 cc TAH using a closed loop platelet activity state assay, (2) modeled the motion of the TAH pulsatile mobile diaphragm, and (3) performed fluid-structure interactions and assessment of the flow behavior through inflow and outflow regions of the TAH fitted with modern bi-leaflet heart valves. Developing a range of TAH devices will afford biventricular replacement therapy to a wide range of patients, for both short and long-term therapy.

Fluid structure interaction with contact surface methodology for evaluation of endovascular carotid implants for drug-resistant hypertension treatment.

Drug-resistant hypertensive patients may be treated by mechanical stimulation of stretch-sensitive baroreceptors located in the sinus of carotid arteries. To evaluate the efficacy of endovascular devices to stretch the carotid sinus such that the induced strain might trigger baroreceptors to increase action potential firing rate and thereby reduce systemic blood pressure, numerical simulations were conducted of devices deployed in subject-specific carotid models. Two models were chosen--a typical physiologic carotid and a diminutive atypical physiologic model representing a clinically worst case scenario--to evaluate the effects of device deployment in normal and extreme cases, respectively. Based on the anatomical dimensions of the carotids, two different device sizes were chosen out of five total device sizes available. A fluid structure interaction (FSI) simulation methodology with contact surface between the device and the arterial wall was implemented for resolving the stresses and strains induced by device deployment. Results indicate that device deployment in the carotid sinus of the physiologic model induces an increase of 2.5% and 7.5% in circumferential and longitudinal wall stretch, respectively, and a maximum of 54% increase in von Mises arterial stress at the sinus wall baroreceptor region. The second device, deployed in the diminutive carotid model, induces an increase of 6% in both circumferential and longitudinal stretch and a 50% maximum increase in von Mises stress at the sinus wall baroreceptor region. Device deployment has a minimal effect on blood-flow patterns, indicating that it does not adversely affect carotid bifurcation hemodynamics in the physiologic model. In the smaller carotid model, deployment of the device lowers wall shear stress at sinus by 16% while accelerating flow entering the external carotid artery branch. Our FSI simulations of carotid arteries with deployed device show that the device induces localized increase in wall stretch at the sinus, suggesting that this will activate baroreceptors and subsequently may control hypertension in drug-resistant hypertensive patients, with no consequential deleterious effects on the carotid sinus hemodynamics.

Device thrombogenicity emulation: a novel method for optimizing mechanical circulatory support device thromboresistance.

Mechanical circulatory support (MCS) devices provide both short and long term hemodynamic support for advanced heart failure patients. Unfortunately these devices remain plagued by thromboembolic complications associated with chronic platelet activation--mandating complex, lifelong anticoagulation therapy. To address the unmet need for enhancing the thromboresistance of these devices to extend their long term use, we developed a universal predictive methodology entitled Device Thrombogenicity Emulation (DTE) that facilitates optimizing the thrombogenic performance of any MCS device--ideally to a level that may obviate the need for mandatory anticoagulation. DTE combines in silico numerical simulations with in vitro measurements by correlating device hemodynamics with platelet activity coagulation markers--before and after iterative design modifications aimed at achieving optimized thrombogenic performance. DTE proof-of-concept is demonstrated by comparing two rotary Left Ventricular Assist Devices (LVADs) (DeBakey vs HeartAssist 5, Micromed Houston, TX), the latter a version of the former following optimization of geometrical features implicated in device thrombogenicity. Cumulative stresses that may drive platelets beyond their activation threshold were calculated along multiple flow trajectories and collapsed into probability density functions (PDFs) representing the device 'thrombogenic footprint', indicating significantly reduced thrombogenicity for the optimized design. Platelet activity measurements performed in the actual pump prototypes operating under clinical conditions in circulation flow loops--before and after the optimization with the DTE methodology, show an order of magnitude lower platelet activity rate for the optimized device. The robust capability of this predictive technology--demonstrated here for attaining safe and cost-effective pre-clinical MCS thrombo-optimization--indicates its potential for reducing device thrombogenicity to a level that may significantly limit the extent of concomitant antithrombotic pharmacotherapy needed for safe clinical device use.

Patient based abdominal aortic aneurysm rupture risk prediction combining clinical visualizing modalities with fluid structure interaction numerical simulations.

Fluid structure interaction (FSI) simulations of patient-specific fusiform non-ruptured and contained ruptured Abdominal Aortic Aneurysm (AAA) geometries were conducted. The goals were: (1) to test the ability of our FSI methodology to predict the location of rupture, by correlating the high wall stress regions with the rupture location, (2) estimate the state of the pathological condition by calculating the ruptured potential index (RPI) of the AAA and (3) predict the disease progression by comparing healthy and pathological aortas.

The effect of angulation in abdominal aortic aneurysms: fluid-structure interaction simulations of idealized geometries.

Abdominal aortic aneurysm (AAA) represents a degenerative disease process of the abdominal aorta that results in dilation and permanent remodeling of the arterial wall. A fluid structure interaction (FSI) parametric study was conducted to evaluate the progression of aneurysmal disease and its possible implications on risk of rupture. Two parametric studies were conducted using (i) the iliac bifurcation angle and (ii) the AAA neck angulation. Idealized streamlined AAA geometries were employed. The simulations were carried out using both isotropic and anisotropic wall material models. The parameters were based on CT scans measurements obtained from a population of patients. The results indicate that the peak wall stresses increased with increasing iliac and neck inlet angles. Wall shear stress (WSS) and fluid pressure were analyzed and correlated with the wall stresses for both sets of studies. An adaptation response of a temporary reduction of the peak wall stresses seem to correlate to a certain extent with increasing iliac angles. For the neck angulation studies it appears that a breakdown from symmetric vortices at the AAA inlet into a single larger vortex significantly increases the wall stress. Our parametric FSI study demonstrates the adaptation response during aneurysmal disease progression and its possible effects on the AAA risk of rupture. This dependence on geometric parameters of the AAA can be used as an additional diagnostic tool to help clinicians reach informed decisions in establishing whether a risky surgical intervention is warranted.