All Publications


  • A regulated multiscale closed-loop cardiovascular model, with applications to hemorrhage and hypertension. International journal for numerical methods in biomedical engineering Canuto, D. n., Chong, K. n., Bowles, C. n., Dutson, E. P., Eldredge, J. D., Benharash, P. n. 2018

    Abstract

    A computational tool is developed for simulating the dynamic response of the human cardiovascular system to various stressors and injuries. The tool couples zero-dimensional models of the heart, pulmonary vasculature, and peripheral vasculature to one-dimensional models of the major systemic arteries. To simulate autonomic response, this multiscale circulatory model is integrated with a feedback model of the baroreflex, allowing control of heart rate, cardiac contractility, and peripheral impedance. The performance of the tool is demonstrated in two scenarios: neurogenic hypertension by sustained stimulation of the sympathetic nervous system, and an acute 10 percent hemorrhage from the left femoral artery. This article is protected by copyright. All rights reserved.

    View details for DOI 10.1002/cnm.2975

    View details for PubMedID 29500858

  • Vascular Complications in the Sapien 3 Era: Continued Role of Transapical Approach to TAVR. Seminars in thoracic and cardiovascular surgery Toppen, W. n., Suh, W. n., Aksoy, O. n., Benharash, P. n., Bowles, C. n., Shemin, R. J., Kwon, M. n. 2018

    Abstract

    With the introduction of the latest generation Sapien 3 transcatheter aortic valve, there has been a reduction in the usage of transapical (TA) approach for TAVRs in many centers. However, despite the smaller sheath size and more stream-lined delivery system, vascular complications continue to occur, especially in patients with peripheral vascular disease. Thus, our institution has maintained a stringent TA protocol aiming to prevent these complications. We hypothesize that this protocol has helped to reduce vascular complications and improve outcomes at our institution even in the Sapien 3 era.All TAVR procedures done at our institution were considered for analysis. Patients were grouped according to whether their procedure was done before (Pre-S3) or after (S3) the introduction of the Sapien 3 valve as well as whether they underwent a transapical or transfemoral (TF) approach. Femoral artery intraluminal diameter of <7.5mm in the Pre-S3 era and <5.5mm in the S3 era with circumferential calcifications triggered TA approach consideration. Vascular complications included vascular perforation, dissection, flow-limiting stenosis, unplanned vascular surgery, significant post-procedural bleeding, hematoma at access site, and retroperitoneal bleed. Welch's t-test of unequal variance and chi-squared tests were used as appropriate. An alpha of <0.05 was considered significant.275 total patients were included in the analysis (121 Pre-S3, 154 S3). TA approach was utilized in 45% of Pre-S3 Era vs. 15% in the S3 Era (p<0.001). Within the S3 era, 131 underwent TF approach compared to 23 undergoing TA. TA and TF patients were similar in all preoperative characteristics except hypertension. Mortality was significantly lower in the S3 era (0% vs 4% in the pre-S3 era, p=0.02). Overall rates of vascular complications were similar between the Pre-S3 and S3 eras (16% vs 14%, p=0.63). Overall adverse outcomes were similar between TA and TF groups. TA patients saw significantly longer intensive care unit (ICU) and total hospital stay.Our results show that despite a smaller sheath size, vascular complications continue at a similar rate into the Sapien 3 era. This occurred in the setting of an ongoing aggressive TA utilization in select patients, specifically those with peripheral vascular disease. Maintaining this approach is likely a large contributor to both our current success and reduced mortality.

    View details for DOI 10.1053/j.semtcvs.2018.02.032

    View details for PubMedID 29522810

  • The impact of migration and antimicrobial resistance on the transmission dynamics of typhoid fever in Kathmandu, Nepal: A mathematical modelling study. PLoS neglected tropical diseases Saad, N. J., Bowles, C. C., Grenfell, B. T., Basnyat, B., Arjyal, A., Dongol, S., Karkey, A., Baker, S., Pitzer, V. E. 2017; 11 (5)

    Abstract

    A substantial proportion of the global burden of typhoid fever occurs in South Asia. Kathmandu, Nepal experienced a substantial increase in the number of typhoid fever cases (caused by Salmonella Typhi) between 2000 and 2003, which subsequently declined but to a higher endemic level than in 2000. This epidemic of S. Typhi coincided with an increase in organisms with reduced susceptibility against fluoroquinolones, the emergence of S. Typhi H58, and an increase in the migratory population in Kathmandu.We devised a mathematical model to investigate the potential epidemic drivers of typhoid in Kathmandu and fit this model to weekly data of S. Typhi cases between April 1997 and June 2011 and the age distribution of S. Typhi cases. We used this model to determine if the typhoid epidemic in Kathmandu was driven by heightened migration, the emergence of organisms with reduced susceptibility against fluoroquinolones or a combination of these factors.Models allowing for the migration of susceptible individuals into Kathmandu alone or in combination with the emergence of S. Typhi with reduced susceptibility against fluoroquinolones provided a good fit for the data. The emergence of organisms with reduced susceptibility against fluoroquinolones organisms alone, either through an increase in disease duration or increased transmission, did not fully explain the pattern of S. Typhi infections.Our analysis is consistent with the hypothesis that the increase in typhoid fever in Kathmandu was associated with the migration of susceptible individuals into the city and aided by the emergence of reduced susceptibility against fluoroquinolones. These data support identifying and targeting migrant populations with typhoid immunization programmes to prevent transmission and disease.

    View details for DOI 10.1371/journal.pntd.0005547

    View details for PubMedID 28475605

    View details for PubMedCentralID PMC5435358

  • Current Methods and Advances in Simulation of Hemorrhage after Trauma. The American surgeon Bowles, C. n., Canuto, D. n., Teran, J. n., Dutson, E. n., Plurad, D. n., Eldredge, J. n., Benharash, P. n. 2017; 83 (10): 1137–41

    Abstract

    As animal models fall out of favor, there is demand for simulators to train medical personnel in the management of trauma and hemorrhage. Realism is essential to the development of simulators for training in the management of trauma and hemorrhage, but is difficult to achieve because it is difficult to create models that accurately represent bleeding organs. We present a simulation platform that uses real-time mathematical modeling of hemodynamics after hemorrhage and trauma and visually represents the injury described by the model. Using patient-specific imaging, 3D-mesh representations of the liver were created and merged with an anatomically accurate vascular tree. By using anatomically accurate representations of the vasculature, we were able to model the cardiovascular response to hemorrhage in a specific artery. The incorporation of autonomic tone allowed for the calculation of bleeding rate and aortic pressures. The 3D-mesh representation of the liver allowed us to simulate blood flow from the liver after trauma. For the first time, we have successfully incorporated tissue modeling and fluid dynamics with a model of the cardiovascular system to create a simulator. These simulations may aid in the creation of realistic virtual environments for training.

    View details for PubMedID 29391111

  • Are nonemergent cardiac operations performed during off-time associated with worse outcome? The Journal of surgical research Ou, R. n., Ramos, G. n., Bowles, C. n., Juo, Y. Y., Shemin, R. J., Benharash, P. n. 2017; 218: 348–52

    Abstract

    With the implementation of value-based health care, it is of increasing interest to understand whether performing elective surgeries during off-time impacts surgical outcomes. The objective of this study was to evaluate the impact of start times on nonemergent cardiac operations.The institutional Society of Thoracic Surgeons was used to identify all adult nonemergent cardiac operations performed between January 2008 and December 2015 at our institution. "Off-time" is defined as either operation "late starts," that is, an incision time after 3 PM and before 7 AM, or procedures occurring during the weekends. Univariate and multivariate logistic regression analyses were performed to examine its impact on in-hospital mortality and major adverse events. Available cost data were directly obtained from the departmental BIOME database.Of the 3406 cardiac operations included in the study, 2933 (86.1%) were normal-start and 473 (13.9%) were off-time-start operations. After adjusting for patient and operative characteristics, late operating room start times were not associated with increased in-hospital mortality (P = 0.28, confidence interval [CI] 95% = 0.99-1.03), readmissions (P = 0.21, CI 95% = 0.99-1.07), or major adverse events (P = 0.07, CI 95% = 1.00-1.12). In addition, there was no significant impact on total hospital cost (9.0% increase, P = 0.07).These findings suggest that late operating room start times are not associated with increased mortality or other complications in a tertiary-care academic medical center. Our findings should be considered during operative scheduling to optimize resource distribution and patient care strategies.

    View details for DOI 10.1016/j.jss.2017.06.065

    View details for PubMedID 28985872

  • Use of preoperative aspirin in combined coronary and valve operations SURGERY Kashani, R., Bowles, C., Sareh, S., Toppen, W., Ou, R., Shemin, R., Benharash, P. 2016; 160 (6): 1612-1618

    Abstract

    The aim of this study was to determine the relationship between preoperative aspirin use and postoperative outcomes in patients undergoing combined coronary artery bypass grafting and valve operations.All combined coronary artery bypass grafting and valve procedures from 2008 to 2015 at our institution were identified. After exclusions, patients were stratified according to those that received preoperative aspirin and those who did not. Propensity score methodology was used to match the 2 groups using baseline and operative characteristics. Logistic regression models were then developed to assess differences in postoperative outcomes between groups.Of the 563 patients identified, 534 met inclusion criteria: preoperative aspirin = 327 (61.2%), no preoperative aspirin = 207 (38.8%). After propensity matching, 194 patient pairs were analyzed, with no significant differences in preoperative characteristics. No significant differences were observed between the preoperative aspirin and no preoperative aspirin groups in rates of 30-day mortality (3.6% vs 4.1%, P = 1.00), major adverse cardiovascular events (23.2% vs 24.2%, P = .91), or 30-day readmission (12.4% vs 11.9%, P = 1.00), among others.Preoperative aspirin use in patients undergoing combined coronary artery bypass grafting and valve operations was not associated with significant differences in major postoperative outcomes. Large-scale, randomized trials are needed to better establish the role of preoperative aspirin in this population.

    View details for DOI 10.1016/j.surg.2016.07.034

    View details for Web of Science ID 000389157400025

    View details for PubMedID 27590618

  • Accounting for Behavior in Treatment Effects: New Applications for Blind Trials PLOS ONE Chassang, S., Snowberg, E., Seymour, B., Bowles, C. 2015; 10 (6)

    Abstract

    The double-blind randomized controlled trial (DBRCT) is the gold standard of medical research. We show that DBRCTs fail to fully account for the efficacy of treatment if there are interactions between treatment and behavior, for example, if a treatment is more effective when patients change their exercise or diet. Since behavioral or placebo effects depend on patients' beliefs that they are receiving treatment, clinical trials with a single probability of treatment are poorly suited to estimate the additional treatment benefit that arises from such interactions. Here, we propose methods to identify interaction effects, and use those methods in a meta-analysis of data from blinded anti-depressant trials in which participant-level data was available. Out of six eligible studies, which included three for the selective serotonin re-uptake inhibitor paroxetine, and three for the tricyclic imipramine, three studies had a high (>65%) probability of treatment. We found strong evidence that treatment probability affected the behavior of trial participants, specifically the decision to drop out of a trial. In the case of paroxetine, but not imipramine, there was an interaction between treatment and behavioral changes that enhanced the effectiveness of the drug. These data show that standard blind trials can fail to account for the full value added when there are interactions between a treatment and behavior. We therefore suggest that a new trial design, two-by-two blind trials, will better account for treatment efficacy when interaction effects may be important.

    View details for DOI 10.1371/journal.pone.0127227

    View details for Web of Science ID 000355979500029

    View details for PubMedID 26062024

    View details for PubMedCentralID PMC4465691

  • Predicting the Impact of Vaccination on the Transmission Dynamics of Typhoid in South Asia: A Mathematical Modeling Study PLOS NEGLECTED TROPICAL DISEASES Pitzer, V. E., Bowles, C. C., Baker, S., Kang, G., Balaji, V., Farrar, J. J., Grenfell, B. T. 2014; 8 (1)

    Abstract

    Modeling of the transmission dynamics of typhoid allows for an evaluation of the potential direct and indirect effects of vaccination; however, relevant typhoid models rooted in data have rarely been deployed.We developed a parsimonious age-structured model describing the natural history and immunity to typhoid infection. The model was fit to data on culture-confirmed cases of typhoid fever presenting to Christian Medical College hospital in Vellore, India from 2000-2012. The model was then used to evaluate the potential impact of school-based vaccination strategies using live oral, Vi-polysaccharide, and Vi-conjugate vaccines. The model was able to reproduce the incidence and age distribution of typhoid cases in Vellore. The basic reproductive number (R 0) of typhoid was estimated to be 2.8 in this setting. Vaccination was predicted to confer substantial indirect protection leading to a decrease in the incidence of typhoid in the short term, but (intuitively) typhoid incidence was predicted to rebound 5-15 years following a one-time campaign.We found that model predictions for the overall and indirect effects of vaccination depend strongly on the role of chronic carriers in transmission. Carrier transmissibility was tentatively estimated to be low, consistent with recent studies, but was identified as a pivotal area for future research. It is unlikely that typhoid can be eliminated from endemic settings through vaccination alone.

    View details for DOI 10.1371/journal.pntd.0002642

    View details for Web of Science ID 000337977300038

    View details for PubMedID 24416466

    View details for PubMedCentralID PMC3886927

  • Gastrointestinal Dysfunction Following Hemolytic Uremic Syndrome DIGESTIVE DISEASES AND SCIENCES Bowles, C., Ancker, M., Triadafilopoulos, G. 2011; 56 (8): 2241-2243

    View details for DOI 10.1007/s10620-011-1733-8

    View details for Web of Science ID 000293296100007

    View details for PubMedID 21559739