Publications by authors named "Johanna Van Zyl"

18 Publications

  • Page 1 of 1

Liver stiffness and prediction of cardiac outcomes in patients with acute decompensated heart failure.

Clin Transplant 2021 Nov 24:e14545. Epub 2021 Nov 24.

Baylor Scott & White Research Institute, Baylor University Medical Center, Dallas, TX, USA.

Background: In acute decompensated heart failure (ADHF), noninvasive markers that predict morbidity and mortality are limited. Liver stiffness measurement (LSM) increases with hepatic fibrosis; however it may be falsely elevated in patients with ADHF in the absence of liver disease. We investigated whether elevated LSM predicts cardiac outcomes in ADHF.

Methods: In a prospective study, we examined 52 ADHF patients without liver disease between 2016 and 2017. Patients underwent liver 2D shear wave elastography (SWE) and were followed for 12 months to assess the outcomes of left ventricular assist device (LVAD), heart transplant (HT) or death.

Results: The median LSM was elevated in patients who received an LVAD or HT within 30-days compared to those who did not (median [IQR]: 55.6 [22.5 - 63.4] vs 13.8 [9.5 - 40.3] kPa, p = 0.049). Moreover, the risk of composite outcome was highest in the 3rd tertile (>39.8 kPa compared to 1 and 2 combined, HR 2.83, 95% CI 1.20- 6.67, p = 0.02). Each 1-kPa increase in LSM was associated with a 1%-increase in the incidence rate of readmissions (IRR 1.01, 95% CI 1.00-1.02, p = 0.01).

Conclusions: LSM may serve as a novel noninvasive tool to determine LVAD, HT or death in patients with ADHF. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1111/ctr.14545DOI Listing
November 2021

Urinary Cell-Cycle Arrest Biomarkers as Early Predictors of Acute Kidney Injury After Ventricular Assist Device Implantation or Cardiac Transplantation.

J Cardiothorac Vasc Anesth 2021 Oct 16. Epub 2021 Oct 16.

Medical City Heart Hospital, Dallas, TX; University of Maryland Medical Center, Baltimore, Maryland.

Objectives: Acute kidney injury (AKI) remains a leading source of morbidity and mortality after cardiothoracic surgery. Insulin-like growth factor-binding protein 7 (IGFBP7), and tissue inhibitor of metalloproteinases-2 (TIMP-2), are novel early-phase renal biomarkers that have been validated as sensitive predictors of AKI. Here the authors studied the efficacy of these biomarkers for predicting AKI after left ventricular assist device (LVAD) implantation and cardiac transplantation.

Design/setting/participants/interventions: This was a prospective study of 73 patients undergoing LVAD implantation (n = 37) or heart transplant (n = 36) from 2016 to 2017 at the authors' center. TIMP-2 and IGFBP7 were measured with the NephroCheck Test on urine samples before surgery and one-to-six hours after surgery. NephroCheck scores were assessed as predictors of moderate/severe AKI (Kidney Disease International Global Outcomes 2/3 creatinine criteria) within 48 hours of surgery, and the association with survival to one year was investigated.

Measurements And Main Results: The LVAD and transplant cohorts overall were similar in demographics and baseline creatinine (p > 0.05), with the exception of having more African-American patients in the LVAD arm (p = 0.003). Eleven (30%) LVAD and 16 (44%) transplant patients developed moderate/severe AKI. Overall, AKI was associated with postsurgery NephroCheck (odds ratio [95% confidence interval] for 0.1 mg/dL increase: 1.36 [1.04-1.79]; p = 0.03), but not with baseline NephroCheck (p = 0.92). When analyzed by cohort, this effect remained for LVAD (1.68 [1.05-2.71]; p = 0.03) but not for transplant (p = 0.15). Receiver operating characteristic analysis showed postoperative NephroCheck to be superior to baseline creatinine in LVAD (p = 0.046). Furthermore, an increase of 0.1 mg/dL in postoperative NephroCheck was associated with a 10% increase in the risk of mortality (adjusted hazard ratio: 1.11 [1.01-1.21]; p = 0.04) independent of age and body mass index.

Conclusion: Assessment of TIMP-2 and IGFBP7 within six hours after surgery appeared effective at predicting AKI in patients with LVADs. Larger studies are warranted to validate these findings.
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http://dx.doi.org/10.1053/j.jvca.2021.10.013DOI Listing
October 2021

Keep Your Move in the Tube® Method and Self-Confidence After Coronary Artery Bypass Graft Surgery.

J Cardiopulm Rehabil Prev 2021 Nov;41(6):438-440

Department of Cardiothoracic Surgery, Baylor University Medical Center, Dallas, Texas.

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http://dx.doi.org/10.1097/HCR.0000000000000648DOI Listing
November 2021

Improvement in Metabolic Co-Morbidities after Implantation of CardioMEMS in Patients with Heart Failure with Preserved Ejection Fraction Phenotype.

J Clin Med 2021 Sep 22;10(19). Epub 2021 Sep 22.

Department of Cardiology, St. Francis Hospital, Roslyn, New York, NY 10001, USA.

Background: Heart failure with preserved ejection fraction (HFpEF) patients often have other comorbidities, including obesity, dyslipidemia, hypertension, and diabetes, comprising the metabolic syndrome. The impacts of hemodynamic monitoring via CardioMEMS on these co-morbidities remain unknown.

Methods: A retrospective analysis of 29 patients with HFpEF (EF 45% or greater) and CardioMEMS was performed at a single center. Weight, body mass index (BMI), systolic blood pressures (SBP), high-density lipoprotein (HDL), triglycerides (TGL), hemoglobin A1C (HbA1c), and pulmonary artery diastolic pressures (PADP) were assessed at baseline and six months post-implant. Paired -tests and the Wilcoxon signed-rank test were used, as appropriate, to test differences between time points.

Results: These patients were 69% female, with a mean age of 73 years, and 62% had non-ischaemic cardiomyopathies (NICM). At the time of CardioMEMS implantation, average PADP was 20.1 mmHg ± 5.7, weight was 102.6 kg ± 22.7, BMI was 38.0 kg/m ± 8.3, SBP was 135 mmHg ± 19, HDL was 42.4 mg/dL ± 11.3, and median TGL was 130 mg/dL (100, 180). At six months we witnessed a decrease by 20.9% in PADP to 15.9 mmHg ± 5.8, ( < 0.001). In addition, the following was noted: weight decreased by 2.5% to 100.0 kg ± 23.2, ( = 0.006), BMI reduced by 2.6% to 37.0 ± 8.2, ( = 0.002), SBP decreased by 6.7% to 126 mmHg ± 16 ( < 0.001), HDL increased by 10.8% to 47 mg/dL ± 11.9 ( < 0.001), and TGL decreased by 15.4% to 110 mg/dL (105, 135) ( = 0.001). 62% of patients were diabetic with no significant improvements in HbA1C values at the 6-month follow-up.

Conclusion: The utilization of CardioMEMS to optimize PADP results in an improvement in the comorbidities associated with the metabolic syndrome. Further studies are warranted to validate these findings and delineate clinical significance.
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http://dx.doi.org/10.3390/jcm10194308DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8509547PMC
September 2021

De novo tacrolimus extended-release tablets (LCPT) versus twice-daily tacrolimus in adult heart transplantation: Results of a single-center non-inferiority matched control trial.

Clin Transplant 2021 Sep 16:e14487. Epub 2021 Sep 16.

Baylor Scott & White Research Institute, Baylor Scott & White Health, Dallas, Texas, USA.

Extended-release tacrolimus for prophylaxis of allograft rejection in orthotopic heart transplant (OHT) recipients is currently not FDA-approved. One such extended-release formulation of tacrolimus known as LCPT allows once-daily dosing and improves bioavailability compared to immediate-release tacrolimus (IR-tacrolimus). We compared the efficacy and safety of LCPT to IR-tacrolimus applied de novo in adult OHT recipients. Twenty-five prospective recipients on LCPT at our center from 2017 to 2019 were matched 1:2 with historical control recipients treated with IR-tacrolimus based on age, gender, and baseline creatinine. The primary composite outcome of death, acute cellular rejection, and/or new graft dysfunction within 1 year was compared using non-inferiority analysis. LCPT demonstrated non-inferiority to IR-tacrolimus, with a primary outcome risk reduction of 20% (90% CI: -40%, -.5%; non-inferiority P = .001). Tacrolimus trough levels peaked at 2-3 months and were higher in LCPT (median 14.5 vs. 12.7 ng/ml; P = .03) with similar dose levels (LCPT vs. IR-tacrolimus: .08 vs. .09 mg/kg/day; P = .33). Cardiovascular-related readmissions were reduced by 62% (P = .046) in LCPT patients. The complication rate per transplant admission and all-cause readmission rate did not differ significantly. These results suggest that LCPT is non-inferior in efficacy to IR-tacrolimus with a similar safety profile and improved bioavailability in OHT.
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http://dx.doi.org/10.1111/ctr.14487DOI Listing
September 2021

Pneumothorax and Pneumomediastinum in COVID-19 Suggest a Pneumocystic Pathology.

Mayo Clin Proc Innov Qual Outcomes 2021 Oct 25;5(5):827-834. Epub 2021 Aug 25.

Baylor Scott & White Research Institute, Dallas, TX.

Objective: To determine whether the apparent excess incidence of pneumothorax and pneumomediastinum in patients with coronavirus disease 2019 (COVID-19) is explained adequately by iatrogenic causes vs reflecting sequelae of severe acute respiratory syndrome coronavirus 2 infection.

Patients And Methods: We retrospectively reviewed patients within our health care system from March 15, 2020, through May 31, 2020, who had a diagnosis of pneumothorax or pneumomediastinum during hospitalization for confirmed COVID-19 infection with attention to timing of pneumothorax and pneumomediastinum; presence, laterality, and placement, or attempts at central lines; and presence of mechanical ventilation before the event.

Results: We report clinical data and outcomes from 9 hospitalized patients with COVID-19 who developed pneumothorax and/or pneumomediastinum among more than 1200 hospitalized patients admitted within our hospital system early in the pandemic. Many events were inexplicable by iatrogenic needle injury, including 1 spontaneous case without central line access or mechanical ventilation. One occurred before central line placement, 2 in patients with only a peripherally inserted central line, and 1 contralateral to a classic central line. Three of these 9 patients died of complications of COVID-19 during their hospital stay.

Conclusion: With COVID-19 affecting the peripheral lung pneumocytes, patients are vulnerable to develop pneumothorax or pneumomediastinum irrespective of their central line access site. We hypothesize that COVID-19 hyperinflammation, coupled with the viral tropism that includes avid involvement of peripheral lung pneumocytes, induces a predisposition to peripheral bronchoalveolar communication and consequent viral hyperinflammatory-triggered pneumothorax and pneumomediastinum.
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http://dx.doi.org/10.1016/j.mayocpiqo.2021.05.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8385307PMC
October 2021

Impact of risk-stratified mycophenolate dosing in heart transplantation.

Clin Transplant 2021 Nov 6;35(11):e14445. Epub 2021 Aug 6.

Department of Pharmacy, Baylor University Medical Center, Dallas, Texas, USA.

Mycophenolate mofetil (MMF), the prodrug of mycophenolic acid, is a highly effective immunosuppressive agent in heart transplant therapy. While the FDA approved dose is 1500 mg twice daily, dosing is often reduced due to dose-dependent adverse effects. However, empiric MMF dose reductions may lead to sub-therapeutic dosing and impair clinical outcomes. Our single center protocolized a risk-stratified approach based on age and weight to dose 500 mg twice daily or 1000 mg twice daily to patients after heart transplantation. This retrospective single-center study analyzed 140 consecutive heart transplant patients who were initiated on our risk-stratified MMF protocol post-transplant. The analysis revealed that the composite rate of biopsy-proven rejection, graft loss, or mortality at 1-year post-transplantation was similar between the two groups. Incidence of neutropenia, thrombocytopenia, infection, cardiac allograft vasculopathy, or acute kidney injury by 1-year also showed similar results between the two groups. Risk-stratification of MMF dosing appears to be a safe and effective strategy after heart transplantation.
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http://dx.doi.org/10.1111/ctr.14445DOI Listing
November 2021

Long-term outcomes of patients with primary graft dysfunction after cardiac transplantation.

Eur J Cardiothorac Surg 2021 Nov;60(5):1178-1183

Baylor University Medical Center, Dallas, TX, USA.

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Objectives: The International Society of Heart and Lung Transplantation (ISHLT) criteria for primary graft dysfunction (PGD) after cardiac transplantation have been shown to stratify patient outcomes up to 1 year after transplantation, but scarce data are available regarding outcomes beyond the 1st year. We sought to characterize survival of patients with PGD following cardiac transplantation beyond the 1st year.

Methods: A retrospective review of consecutive patients undergoing isolated cardiac transplantation at a single centre between 2012 and 2015 was performed. Patients were diagnosed with none, mild, moderate or severe PGD by the ISHLT criteria. Survival was ascertained from the United Network for Organ Sharing database and chart review. Kaplan-Meier curves were plotted to compare survival. The hazard ratio for mortality associated with PGD severity was estimated using Cox-proportional hazards modelling, with a pre-specified conditional survival analysis at 90 days.

Results: A total of 257 consecutive patients underwent cardiac transplantation during the study period, of whom 73 (28%) met ISHLT criteria for PGD: 43 (17%) mild, 12 (5%) moderate and 18 (7%) severe. Patients with moderate or severe PGD had decreased survival up to 5 years after transplantation (log-rank P < 0.001). Landmark analyses demonstrated that patients with moderate or severe PGD were at increased risk of mortality during the first 90-days after transplantation as compared to those with none or mild PGD [hazard ratio (95% confidence interval) 18.9 (7.1-50.5); P < 0.001], but this hazard did not persist beyond 90-days in survivors (P = 0.64).

Conclusions: A diagnosis of moderate or severe PGD is associated with increased mortality up to 5 years after cardiac transplantation. However, patients with moderate or severe PGD who survive to post-transplantation day 90 are no longer at increased risk for mortality as compared to those with none or mild PGD.
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http://dx.doi.org/10.1093/ejcts/ezab177DOI Listing
November 2021

Impact of antimicrobial selection for prophylaxis of left ventricular assist device surgical infections.

J Card Surg 2021 Sep 2;36(9):3052-3059. Epub 2021 Jun 2.

Baylor Annette C. and Harold C. Simmons Transplant Institute, Baylor University Medical Center, Dallas, Texas, USA.

Background: Surgical site infections (SSIs) after left ventricular assist device (LVAD) implantation are associated with high mortality, while surgical prophylaxis is variable.

Methods: This retrospective study included adult patients who underwent LVAD implantation at a single center. We compared outcomes in patients who received narrow antimicrobial prophylaxis (cefazolin, vancomycin, or both) to those who received broad antimicrobial prophylaxis (any antimicrobial combination targeting gram-positive and gram-negative organisms not included in the narrow group) at 30-day and 1-year postimplantation. Cox-proportional hazards models and log-rank tests were used for survival analysis.

Results: Among the 39 and 65 patients comprising narrow and broad groups respectively, there was no difference in rate of SSI at 30 days (6.2% vs. 12.8%, p = .290) and 1 year (16.9% vs. 25.6%, p = .435). Comparing narrow to broad prophylaxis, the risk of mortality (hazard ratio [HR] = 0.44, 95% confidence interval [CI] = 0.15-1.35, logrank p = .14), and composite of mortality and infection was reduced (HR = 0.92, 95% CI = 0.45-1.88, logrank p = .83), but did not reach statistical significance. Most culture positive infections were due to gram-positive bacteria (70%) and the most common organisms were the Staphylococcus spp (47%). There were no significant differences in the rate of SSI at 1-year (p = 1.00) and mortality (p = .33) by device type.

Conclusions: The rates of infection and all-cause mortality were not different between patients who received narrow or broad prophylaxis. This highlights an opportunity for institutions to narrow their surgical infection prophylaxis protocols to primarily cover gram-positive organisms.
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http://dx.doi.org/10.1111/jocs.15682DOI Listing
September 2021

Dynamic albumin values as clinical surrogate for COVID-19 therapeutics.

J Investig Med 2021 08 28;69(6):1260. Epub 2021 May 28.

Baylor Scott & White Research Institute, Baylor Scott & White Health, Dallas, Texas, USA

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http://dx.doi.org/10.1136/jim-2021-001895DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8172265PMC
August 2021

Distal versus proximal radial artery access for cardiac catheterization and intervention: Design and rationale of the DIPRA trial.

Cardiovasc Revasc Med 2021 Apr 15. Epub 2021 Apr 15.

Interventional Cardiology and Structural Heart Disease, The Heart Hospital - Plano, Baylor Scott & White Health, United States of America.

Background: Radial artery (RA) catheterization is the access of choice over femoral artery access for most interventional vascular procedures given its safety and faster patient recovery. There has been growing interest in distal radial artery (dRA) access as an alternative to the conventional proximal radial artery (pRA) access. Preserving the RA is important which serves as a potential conduit for future coronary artery bypass surgery, dialysis conduit or preserve the artery for future cardiovascular procedures. The dRA runs in close proximity to the radial nerve, which raises the concern of potential detrimental effects on hand function.

Study Design: The Distal versus Proximal Radial Artery Access for cardiac catheterization and intervention (DIPRA) trial is a prospective, randomized, parallel-controlled, open-label, single center study evaluating the outcomes of hand function and effectiveness of dRA compared to pRA access in patients undergoing cardiac catheterization. The eligible subjects will be randomized to dRA and pRA access in a (1:1) fashion. The primary end point is an evaluation of hand function at one and twelve months follow-up. Secondary end points include rates of access site hematoma, access site bleeding, other vascular access complications, arterial access success rate, and RA occlusion at one and twelve months follow up.

Conclusion: Effects of dRA on hand function remains unknown and it's use questionable in the presence of a widely accepted pRA. DIPRA trial is designed to determine the safety and effectiveness of dRA for diagnostic and interventional cardiovascular procedures compared to the standard of care pRA.
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http://dx.doi.org/10.1016/j.carrev.2021.04.001DOI Listing
April 2021

Potency of vancomycin against Mycobacterium tuberculosis in the hollow fiber system model.

J Glob Antimicrob Resist 2021 03 26;24:403-410. Epub 2021 Jan 26.

Department of Pulmonary Immunology, University of Texas Health Science Center at Tyler, Tyler, TX, USA; Quantitative Preclinical and Clinical Sciences Department, Praedicare Inc., Dallas, TX, USA; Lung Infection and Immunity Unit, Division of Pulmonology and UCT Lung Institute, Department of Medicine, University of Cape Town, Cape Town, South Africa. Electronic address:

Objectives: To determine whether an inhaled vancomycin formulation resulting in high intrapulmonary 24-h area under the concentration-time curve (AUC) could be optimised for tuberculosis treatment. We also explored vancomycin synergy and antagonism with d-cycloserine and benzylpenicillin.

Methods: We determined MICs of two Mycobacterium tuberculosis (Mtb) laboratory strains (H37Ra and H37Rv) and two drug-susceptible and nine multidrug resistant clinical strains. Second, in the hollow fiber system model of TB [HFS-TB] using Mtb H37Ra strain, we recapitulated vancomycin intrapulmonary pharmacokinetics of eight doses administered twice daily over 28 days, mimicking a 6-h half-life. Using the HFS-TB, vancomycin was tested in combination with d-cycloserine and benzylpenicillin to determine synergy or antagonism between drugs targeting the same pathway.

Results: Vancomycin MICs were 12 and 48 mg/L in drug-susceptible clinical isolates but >96 mg/L in all MDR isolates.In the HFS-TB, vancomycin killed 3.9 ± 0.6 log CFU/mL Mtb. The EC was calculated as AUC/MIC of 184.6 ± 106.5. Compared with day 0, 1.0 and 2.0 log CFU/mL kill was achieved by AUC/MIC of 168 and 685, respectively. Acquired vancomycin resistance developed to all vancomycin doses tested in the HFS-TB. In the HFS-TB, vancomycin was antagonistic to benzylpenicillin, which works downstream to glycopeptides in peptidoglycan synthesis, but synergistic with d-cycloserine, which inhibits upstream d-Ala-d-Ala ligase and alanine racemase.

Conclusion: Our proof-of-concept studies show that vancomycin optimal exposure target for Mtb kill could be achieved via inhalational drug delivery. Addition of drugs synergistic with vancomycin, e.g. d-cycloserine, may lower the vancomycin concentrations required to kill Mtb.
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http://dx.doi.org/10.1016/j.jgar.2021.01.005DOI Listing
March 2021

ALLY in fighting COVID-19: magnitude of albumin decline and lymphopenia (ALLY) predict progression to critical disease.

J Investig Med 2021 03 11;69(3):710-718. Epub 2021 Jan 11.

Baylor Scott & White Research Institute, Baylor Scott and White Health, Dallas, Texas, USA

The global severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic leading to coronavirus disease 2019 (COVID-19) is straining hospitals. Judicious resource allocation is paramount but difficult due to the unpredictable disease course. Once hospitalized, discerning which patients may progress to critical disease would be valuable for resource planning. Medical records were reviewed for consecutive hospitalized patients with COVID-19 in a large healthcare system in Texas. The main outcome was progression to critical disease within 10 days from admission. Albumin trends from admission to 7 days were analyzed using mixed-effects models, and progression to critical disease was modeled by multivariable logistic regression of laboratory results. Risk models were evaluated in an independent group. Of 153 non-critical patients, 28 (18%) progressed to critical disease. The rate of decrease in mean baseline-corrected () albumin was -0.08 g/dL/day (95% CI -0.11 to -0.04; p<0.001) or four times faster, in those who progressed compared with those who did not progress. A model of albumin combined with lymphocyte percentage predicting progression to critical disease was validated in 60 separate patients (sensitivity, 0.70; specificity, 0.74). ALLY (delta albumin and lmphocyte percentage) is a simple tool to identify patients with COVID-19 at higher risk of disease progression when: (1) a 0.9 g/dL or greater albumin drop from baseline within 5 days of admission or (2) baseline lymphocyte of ≤10% is observed. The ALLY tool identified >70% of hospitalized cases that progressed to critical COVID-19 disease. We recommend prospectively tracking albumin. This is a globally applicable tool for all healthcare systems.
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http://dx.doi.org/10.1136/jim-2020-001525DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7802390PMC
March 2021

A system-wide extracorporeal membrane oxygenation quality collaborative improves patient outcomes.

J Thorac Cardiovasc Surg 2020 Oct 27. Epub 2020 Oct 27.

Baylor University Medical Center, Baylor Scott & White Health, Dallas, Tex. Electronic address:

Objective: Extracorporeal membrane oxygenation (ECMO) use in adult patient populations has grown rapidly with wide variation in practices and outcomes. We evaluated the impact on patient outcomes, resource use, and costs of an initiative to coordinate and standardize best practices across ECMO programs within a large integrated health care system.

Methods: The ECMO Collaborative Project brought clinicians and service-line leaders from 4 programs within a single health care system together with operational subject matter experts tasked with developing and implementing standardized guidelines, order sets, and an internal database to support an automated quarterly report card. Patient outcomes, resource use, and financial measures were compared for the 16 months before (January 2017 to April 2018; "precollaborative," n = 185) versus the 14 months after (November 2018 to December 2019, "postcollaborative," n = 243) a 6-month implementation and blanking period. Subset analyses were performed for venoarterial ECMO, venovenous ECMO, and extracorporeal cardiopulmonary resuscitation.

Results: Survival to discharge/transfer increased significantly (in-hospital mortality hazard ratio, 0.75; 95% confidence interval [95% CI], 0.58-0.99) for the postcollaborative versus the precollaborative period (107/185, 57.8% vs 113/243, 46.5%, P = .03), predominantly due to improvement among patients receiving venoarterial ECMO (hazard ratio, 0.61; 95% CI, 0.41-0.91). The percentage of patients successfully weaned from ECMO increased from 58.9% (109/185) to 70% (170/243), P = .02. Complication rates decreased by 40% (incidence rate ratio, 0.60; 95% CI, 0.49-0.72). No significant changes were observed in ECMO duration, intensive care unit or hospital length of stay, or cost-per-case; payment-per-case and contribution-margin-per-case both decreased significantly.

Conclusions: The ECMO Collaborative Project improved survival to discharge/transfer, weaning rates and complications, without additional costs, through coordination and standardization across ECMO programs within a health care system.
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http://dx.doi.org/10.1016/j.jtcvs.2020.10.079DOI Listing
October 2020

Usefulness of Thoracic Aortic Calcium to Predict 1-Year Mortality After Transcatheter Aortic Valve Implantation.

Am J Cardiol 2021 02 2;140:103-109. Epub 2020 Nov 2.

Service de Cardiologie, Hôpital Croix-Rousse and Hôpital Lyon Sud, Hospices Civils de Lyon, Lyon, France; CREATIS UMR5220; INSERM U1044; INSA-15, Université de Lyon, Lyon, France.

In patients who underwent transcatheter aortic valve implantation (TAVI), vascular disease is associated with increased risk of mortality. Thoracic aortic calcification (TAC), an objective surrogate of vascular disease, could be a predictor of mortality after TAVI. We aimed to analyze the association between TAC burden and 1-year all-cause mortality in patients who underwent TAVI in a US population. From July 2015 through July 2017, a retrospective review of TAVI procedures was performed at Baylor Scott & White-The Heart Hospital, Plano, Texas. Patients were analyzed for comorbidities, cardiac risk factors, and 30-day and 1-year all-cause mortality. Restricted cubic splines analysis was used to define low, moderate, and high TAC categories. The association between TAC and survival was evaluated using unadjusted and adjusted Cox models. A total of 431 TAVI procedures were performed, of which TAC was measured in 374 (81%) patients. Median (interquartile range) age was 82 (77, 87) years, and 51% were male. Median (interquartile range) STS PROM was 5.6 (4.1, 8.2) %. Overall 30-day and 1-year all-cause mortality was 1% and 10%, respectively. TAC was categorized as low (<1.6 cm), moderate (1.6 to 2.9 cm), and high (>2.9 cm). At 1 year, all-cause mortality was 16% in patients with high TAC compared with 6% in the low and moderate TAC categories (p = 0.008). Unadjusted and adjusted Cox regression analysis showed a significant increase in mortality for patients with high TAC compared with low TAC (hazard ratio 2.98, 95% confidence interval [1.34-6.63]), but not significant compared with moderate TAC group. TAC is a predictor of late mortality after TAVI. In conclusion, adding TAC to preoperative evaluation may provide an objective, reproducible, and potentially widely available tool that can help in shared decision-making.
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http://dx.doi.org/10.1016/j.amjcard.2020.10.045DOI Listing
February 2021

Evaluation of Ceftriaxone Plus Avibactam in an Intracellular Hollow Fiber Model of Tuberculosis: Implications for the Treatment of Disseminated and Meningeal Tuberculosis in Children.

Pediatr Infect Dis J 2020 12;39(12):1092-1100

From the Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Baylor University Medical Center.

Background: Ceftazidime-avibactam is an effective agent for the treatment of tuberculosis (TB) but requires frequent administration because of a short half-life. Due to a longer half-life, ceftriaxone could allow intermittent dosing.

Methods: First, we identified the MIC of ceftriaxone with 15 mg/L avibactam in 30 clinical Mycobacterium tuberculosis isolates. Next, 2 ceftriaxone exposure-effect studies in the intracellular hollow fiber model of TB (HFS-TB) that mimics disseminated disease in young children, were performed. Ceftriaxone was administered once or twice daily for 28 days to explore percentage of time that the concentration persisted above MIC (%TMIC) ranging from 0 to 100%. In a third HFS-TB experiment, the "double cephalosporin" regimen of ceftazidime-ceftriaxone-avibactam was examined and analyzed using Bliss Independence.

Conclusion: The MIC99 of the clinical strains was 32 mg/L, in the presence of 15 mg/L avibactam. Ceftriaxone %TMIC <42 had no microbial effect in the HFS-TB, %TMIC >54% demonstrated a 4.1 log10 colony-forming units per milliliter M. tuberculosis kill, while %TMIC mediating Emax was 68%. The "double cephalosporin" combination was highly synergistic. Monte Carlo experiments of 10,000 subjects identified the optimal ceftriaxone dose as 100 mg/kg twice a day.

Conclusion: The combination of ceftriaxone-avibactam at 100 mg/kg could achieve Emax in >90% of children. The ceftriaxone potent activity M. tuberculosis could potentially shorten therapy in children with disseminated TB.
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http://dx.doi.org/10.1097/INF.0000000000002857DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7654946PMC
December 2020

Duration of pretomanid/moxifloxacin/pyrazinamide therapy compared with standard therapy based on time-to-extinction mathematics.

J Antimicrob Chemother 2020 02;75(2):392-399

Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Baylor University Medical Center, Dallas, TX, USA.

Objectives: Animal models have suggested that the combination of pretomanid with pyrazinamide and moxifloxacin (PaMZ) may shorten TB therapy duration to 3-4 months. Here, we tested that in the hollow-fibre system model of TB (HFS-TB).

Methods: A series of HFS-TB experiments were performed to compare the kill rates of the PaMZ regimen with the standard three-drug combination therapy. HFS-TB experiments were performed with bacilli in log-phase growth treated for 28 days, intracellular bacilli treated daily for 28 days and semi-dormant Mycobacterium tuberculosis treated with daily therapy for 56 days for sterilizing effect. Next, time-to-extinction equations were employed, followed by morphism transformation and Latin hypercube sampling, to determine the proportion of patients who achieved a time to extinction of 3, 4 or 6 months with each regimen.

Results: Using linear regression, the HFS-TB sterilizing effect rates of the PaMZ regimen versus the standard-therapy regimen during the 56 days were 0.18 (95% credible interval=0.13-0.23) versus 0.15 (95% credible interval=0.08-0.21) log10 cfu/mL/day, compared with 0.16 (95% credible interval=0.13-0.18) versus 0.11 (95% credible interval=0.09-0.13) log10 cfu/mL/day in the Phase II clinical trial, respectively. Using time-to-extinction and Latin hypercube sampling modelling, the expected percentages of patients in which the PaMZ regimen would achieve sterilization were 40.37% (95% credible interval=39.1-41.34) and 72.30% (95% credible interval=71.41-73.17) at 3 and 4 months duration of therapy, respectively, versus 93.67% (95% credible interval=93.18-94.13) at 6 months for standard therapy.

Conclusions: The kill rates of the PaMZ regimen were predicted to be insufficient to achieve cure in less than 6 months in most patients.
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http://dx.doi.org/10.1093/jac/dkz460DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6966096PMC
February 2020

Minocycline Immunomodulates via Sonic Hedgehog Signaling and Apoptosis and Has Direct Potency Against Drug-Resistant Tuberculosis.

J Infect Dis 2019 02;219(6):975-985

Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Dallas, Texas.

Drug-resistant tuberculosis represents a global emergency, requiring new drugs. We found that minocycline was highly potent in laboratory strains of Mycobacterium tuberculosis and that 30 drug-susceptible and multidrug/extensively drug-resistant clinical strains were susceptible to clinically achievable concentrations. In the hollow fiber system model, lung concentration-time profiles of 7 mg/kg/day human-equivalent minocycline dose achieved bacterial kill rates equivalent to those of first-line antituberculosis agents. Minocycline killed extracellular bacilli directly. Minocycline also killed intracellular bacilli indirectly, via concentration-dependent granzyme A-driven apoptosis. Moreover, minocycline demonstrated dose-dependent antiinflammatory activity and downregulation of extracellular matrix-based remodeling pathways and, thus, could protect patients from tuberculosis immunopathology. In RNA sequencing of repetitive samples from the hollow fiber system and in independent protein abundance experiments, minocycline demonstrated dose-dependent inhibition of sonic hedgehog-patched-gli signaling. These findings have implications for improved lung remodeling and for dual immunomodulation and direct microbial kill-based treatment shortening regimens for drug-susceptible and drug-resistant latent and active M. tuberculosis infection.
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http://dx.doi.org/10.1093/infdis/jiy587DOI Listing
February 2019
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