Dr. O'Brien is a native of Menlo Park, CA. He attended medical school at Columbia University College of Physicians and Surgeons. At Columbia he was elected to both Alpha Omega Alpha and Gold Humanism Honors Societies. He completed an Internal Medicine residency as well as fellowship in Cardiovascular Medicine at Stanford University. In his third year of fellowship, he was selected Chief Cardiology Fellow.
He is currently a post-doctoral fellow performing regenerative medicine research, specifically studying the role of exosomes in treating cardiomyopathy. In addition to his basic science research, he is also involved in human clinical trials investigating the role of stem cells in treating various forms of cardiomyopathy.
Honors & Awards
Timothy E Beckett Award, Stanford University Department of Internal Medicine (2020)
Chief Fellow, Stanford University Division of Cardiovascular Medicine (2018)
Gerald Reaven Basic Science Research Award, Stanford University Division of Cardiovascular Medicine (2018)
Outstanding Clinical Fellow Award, Stanford University Division of Cardiovascular Medicine (2017)
Ruth L Kirschstein National Research Service Award, National Institutes Of Health (2017)
Timothy E Beckett Award, Stanford University Department of Internal Medicine (2016)
Johnson and Johnson Global Health Scholar, Stanford University Department of Internal Medicine (2014)
Alpha Omega Alpha Honors Society, Columbia University College of Physicians and Surgeons (2012)
Gold Humanism Honor Society, Columbia University College of Physicians and Surgeons (2012)
Benjamin H Kean Travel Fellowship in Tropical Medicine, American Society of Tropical Medicine and Hygiene (2011)
Howard Hughes Medical Research Fellow, Howard Hughes Medical Institute (2010)
Cum Laude, University of Pennsylvania (2005)
Elliot Stellar Chance Research Award, University of Pennsylvania Department of Biological Basis of Behavior (2005)
Fellowship, Stanford Hospital and Clinics, Critical Care Medicine (2020)
Fellowship, Stanford Hospital and Clinics, Cardiovascular Medicine (2018)
Residency, Stanford Hospital and Clinics, Internal Medicine (2015)
Internship, Stanford Hospital and Clinics, Internal Medicine (2013)
Doctor of Medicine, Columbia University (2012)
Bachelor of Arts, University of Pennsylvania (2005)
Mitochondria-Rich Extracellular Vesicles From Autologous Stem Cell-Derived Cardiomyocytes Restore Energetics of Ischemic Myocardium.
Journal of the American College of Cardiology
2021; 77 (8): 1073–88
Mitochondrial dysfunction results in an imbalance between energy supply and demand in a failing heart. An innovative therapy that targets the intracellular bioenergetics directly through mitochondria transfer may be necessary.The purpose of this study was to establish a preclinical proof-of-concept that extracellular vesicle (EV)-mediated transfer of autologous mitochondria and their related energy source enhance cardiac function through restoration of myocardial bioenergetics.Human-induced pluripotent stem cell-derived cardiomyocytes (iCMs) were employed. iCM-conditioned medium was ultracentrifuged to collect mitochondria-rich EVs (M-EVs). Therapeutic effects of M-EVs were investigated using in vivo murine myocardial infarction (MI) model.Electron microscopy revealed healthy-shaped mitochondria inside M-EVs. Confocal microscopy showed that M-EV-derived mitochondria were transferred into the recipient iCMs and fused with their endogenous mitochondrial networks. Treatment with 1.0 × 108/ml M-EVs significantly restored the intracellular adenosine triphosphate production and improved contractile profiles of hypoxia-injured iCMs as early as 3 h after treatment. In contrast, isolated mitochondria that contained 300× more mitochondrial proteins than 1.0 × 108/ml M-EVs showed no effect after 24 h. M-EVs contained mitochondrial biogenesis-related messenger ribonucleic acids, including proliferator-activated receptor γ coactivator-1α, which on transfer activated mitochondrial biogenesis in the recipient iCMs at 24 h after treatment. Finally, intramyocardial injection of 1.0 × 108 M-EVs demonstrated significantly improved post-MI cardiac function through restoration of bioenergetics and mitochondrial biogenesis.M-EVs facilitated immediate transfer of their mitochondrial and nonmitochondrial cargos, contributing to improved intracellular energetics in vitro. Intramyocardial injection of M-EVs enhanced post-MI cardiac function in vivo. This therapy can be developed as a novel, precision therapeutic for mitochondria-related diseases including heart failure.
View details for DOI 10.1016/j.jacc.2020.12.060
View details for PubMedID 33632482
Cardiogenic Shock: Reflections at the Crossroad Between Perfusion, Tissue Hypoxia, and Mitochondrial Function.
The Canadian journal of cardiology
2020; 36 (2): 184–96
Cardiogenic shock is classically defined by systemic hypotension with evidence of hypoperfusion and end organ dysfunction. In modern practice, however, these metrics often incompletely describe cardiogenic shock because patients present with more advanced cardiovascular disease and greater degrees of multiorgan dysfunction. Understanding how perfusion, congestion, and end organ dysfunction contribute to hypoxia at the cellular level are central to the diagnosis and management of cardiogenic shock. Although, in clinical practice, increased lactate level is often equated with hypoxia, several other factors might contribute to an elevated lactate level including mitochondrial dysfunction, impaired hepatic and renal clearance, as well as epinephrine use. To this end, we present the evidence underlying the value of lactate to pyruvate ratio as a potential discriminator of cellular hypoxia. We will then discuss the physiological implications of hypoxia and congestion on hepatic, intestinal, and renal physiology. Organ-specific susceptibility to hypoxia is presented in the context of their functional architecture. We discuss how the concepts of contractile reserve, fluid responsiveness, tissue oxygenation, and cardiopulmonary interactions can help personalize the management of cardiogenic shock. Finally, we highlight the limitations of using lactate for tailoring therapy in cardiogenic shock.
View details for DOI 10.1016/j.cjca.2019.11.020
View details for PubMedID 32036863
Electrical Storm in COVID-19.
JACC. Case reports
2020; 2 (9): 1256–60
COVID-19 is a global pandemic caused by SARS-CoV-2. Infection is associated with significant morbidity and mortality. Individuals with pre-existing cardiovascular disease or evidence of myocardial injury are at risk for severe disease and death. Little is understood about the mechanisms of myocardial injury or life-threatening cardiovascular sequelae. (Level of Difficulty: Intermediate.).
View details for DOI 10.1016/j.jaccas.2020.05.032
View details for PubMedID 32835266
View details for PubMedCentralID PMC7259914
Disruptive Modifications to Cardiac Critical Care Delivery During the Covid-19 Pandemic: An International Perspective.
Journal of the American College of Cardiology
The COVID-19 pandemic has presented a major unanticipated stress on our workforce, organizational structure, systems of care, and critical resource supply. In order to ensure provider safety, maximize efficiency, and optimize patient outcomes, health systems need to be agile. Critical care cardiologists may be uniquely positioned to treat the numerous respiratory and cardiovascular complications of the SARS-CoV-2 virus and support clinicians without critical care training who may be suddenly asked to care for critically ill patients. This manuscript draws upon the experiences of colleagues from heavily impacted regions of the United States and Europe as well as lessons learned from military mass casualty medicine. We offer pragmatic suggestions on how to implement scalable models for critical care delivery, cultivate educational tools for team training, and embrace technologies such as telemedicine to enable effective collaboration despite social distancing imperatives.
View details for DOI 10.1016/j.jacc.2020.04.029
View details for PubMedID 32305402
View details for PubMedCentralID PMC7161519
MICROVESICLES LARGER THAN 200NM RESCUE CARDIOMYOCYTES FROM DOXORUBICIN INJURY IN A PATIENT-SPECIFIC MODEL OF ANTHRACYCLINE INDUCED CARDIOMYOPATHY
ELSEVIER SCIENCE INC. 2019: 688
View details for Web of Science ID 000460565900688
EXOSOMES FROM HUMAN INDUCED PLURIPOTENT STEM CELL-DERIVED CARDIOMYOCYTES (ICMS) AND MESENCHYMAL STEM CELLS (MSCS) RECOVER HEART FUNCTION IN PORCINE ACUTE MYOCARDIAL INFARCTION (MI) MODEL
ELSEVIER SCIENCE INC. 2021: 19
View details for Web of Science ID 000647487500020
The Use of Factor Eight Inhibitor Bypass Activity (FEIBA) for the Treatment of Perioperative Hemorrhage in Left Ventricular Assist Device Implantation.
Journal of cardiothoracic and vascular anesthesia
OBJECTIVE: To test the hypothesis that factor eight inhibitor bypassing activity (FEIBA) can be used to control bleeding following left ventricular assist device (LVAD) implantation without increasing the 14-day composite thrombotic outcome of pump thrombus, ischemic cerebrovascular accidents, pulmonary embolism, and deep venous thrombosis.DESIGN: Retrospective cohort study.SETTING: Academic hospital.PARTICIPANTS: Three hundred nineteen consecutive patients who underwent LVAD implantation (December 1, 2009 to December 30, 2018).INTERVENTION: FEIBA administered to control perioperative hemorrhage.MEASUREMENTS AND MAIN RESULTS: The 82 patients (25.7%) in the FEIBA cohort had more risk factors for perioperative hemorrhage, such as lower preoperative platelet count (169 ± 66 v 194 ± 68 * 103/mL, p = 0.004), prior cardiac surgery (36.6% v 21.9%, p = 0.008), and longer cardiopulmonary bypass (CPB) time (100.3 v 75.2 minutes, p = 0.001) than the 237 controls. After 16.6 units (95% CI: 14.3-18.9) of blood products were given, 992 units (95% CI: 821-1163) of FEIBA were required to control bleeding in the FEIBA cohort. Compared to the controls, there were no differences in the 14-day composite thrombotic outcome (11.0% v 7.6%, p = 0.343) or mortality rate (3.7% v 1.3%, p = 0.179). Multivariate logistical regression identified preoperative international normalized ratio (odds ratio [OR]: 1.30, 95% CI: 1.04-1.62) and CPB time (OR: 1.11, 95% CI: 1.02-1.20) as risk factors for 14-day thrombotic events, but FEIBA usage was not associated with an increased risk.CONCLUSIONS: In this retrospective cohort study, the use of FEIBA (1,000 units, 13 units/kg) to control perioperative hemorrhage following LVAD implantation was not associated with increases in mortality or composite thrombotic outcome.
View details for DOI 10.1053/j.jvca.2021.04.030
View details for PubMedID 34034934
A Phase II Study of Autologous Mesenchymal Stromal Cells and c-kit Positive Cardiac Cells, Alone or in Combination, in Patients with Ischemic Heart Failure: The CCTRN CONCERT-HF Trial.
European journal of heart failure
AIMS: CONCERT-HF is an NHLBI-sponsored, double-blind, placebo-controlled, Phase II trial designed to determine whether treatment with autologous bone marrow-derived mesenchymal stromal cells (MSCs) and c-kit positive cardiac cells (CPCs), given alone or in combination, is feasible, safe, and beneficial in patients with heart failure (HF) caused by ischemic cardiomyopathy.METHODS AND RESULTS: Patients were randomized (1:1:1:1) to transendocardial injection of MSCs combined with CPCs, MSCs alone, CPCs alone, or placebo, and followed for 12months. Seven centers enrolled 125 participants with left ventricular ejection fraction (LVEF) of 28.6±6.1% and scar size 19.4±5.8%, in NYHA class II or III. The proportion of major adverse cardiac events (MACE) was significantly decreased by CPCs alone (-22% vs. placebo, P=0.043). Quality of life (MLHFQ score) was significantly improved by MSCs alone (P=0.050) and MSCs+CPCs (P=0.023) vs. placebo. LVEF, LV volumes, scar size, 6-min walking distance, and peak VO2 did not differ significantly among groups.CONCLUSIONS: This is the first multicenter trial assessing CPCs and a combination of two cell types from different tissues in HF patients. The results show that treatment is safe and feasible. Even with maximal guideline-directed therapy, both CPCs and MSCs were associated with improved clinical outcomes (MACE and quality of life, respectively) in ischemic HF without affecting LV function or structure, suggesting possible systemic or paracrine cellular mechanisms. Combining MSCs with CPCs was associated with improvement in both these outcomes. These results suggest potential important beneficial effects of CPCs and MSCs and support further investigation in HF patients.
View details for DOI 10.1002/ejhf.2178
View details for PubMedID 33811444
Worldwide Survey of COVID-19 Associated Arrhythmias.
Circulation. Arrhythmia and electrophysiology
Background - COVID-19 has led to over 1 million deaths worldwide and has been associated with cardiac complications including cardiac arrhythmias. The incidence and pathophysiology of these manifestations remain elusive. In this worldwide survey of patients hospitalized with COVID-19 who developed cardiac arrhythmias, we describe clinical characteristics associated with various arrhythmias, as well as global differences in modulations of routine electrophysiology practice during the pandemic. Methods - We conducted a retrospective analysis of patients hospitalized with COVID-19 infection worldwide with and without incident cardiac arrhythmias. Patients with documented atrial fibrillation (AF), atrial flutter (AFL), supraventricular tachycardia (SVT), non-sustained or sustained ventricular tachycardia (VT), ventricular fibrillation (VF), atrioventricular block (AVB), or marked sinus bradycardia (HR<40bpm) were classified as having arrhythmia. De-identified data was provided by each institution and analyzed. Results - Data was collected for 4,526 patients across 4 continents and 12 countries, 827 of whom had an arrhythmia. Cardiac comorbidities were common in patients with arrhythmia: 69% had hypertension, 42% diabetes mellitus, 30% had heart failure and 24% coronary artery disease. Most had no prior history of arrhythmia. Of those who did develop an arrhythmia, the majority (81.8%) developed atrial arrhythmias, 20.7% developed ventricular arrhythmias, and 22.6% had bradyarrhythmia. Regional differences suggested a lower incidence of AF in Asia compared to other continents (34% vs. 63%). Most patients in in North America and Europe received hydroxychloroquine, though the frequency of hydroxychloroquine therapy was constant across arrhythmia types. Forty-three percent of patients who developed arrhythmia were mechanically ventilated and 51% survived to hospital discharge. Many institutions reported drastic decreases in electrophysiology procedures performed. Conclusions - Cardiac arrhythmias are common and associated with high morbidity and mortality among patients hospitalized with COVID-19 infection. There were significant regional variations in the types of arrhythmias and treatment approaches.
View details for DOI 10.1161/CIRCEP.120.009458
View details for PubMedID 33554620
miR-106a-363 cluster in extracellular vesicles promotes endogenous myocardial repair via Notch3 pathway in ischemic heart injury.
Basic research in cardiology
2021; 116 (1): 19
Endogenous capability of the post-mitotic human heart holds great promise to restore the injured myocardium. Recent evidence indicates that the extracellular vesicles (EVs) regulate cardiac homeostasis and regeneration. Here, we investigated the molecular mechanism of EVs for self-repair. We isolated EVs from human iPSC-derived cardiomyocytes (iCMs), which were exposed to hypoxic (hEVs) and normoxic conditions (nEVs), and examined their roles in in vitro and in vivo models of cardiac injury. hEV treatment significantly improved the viability of hypoxic iCMs in vitro and cardiac function of severely injured murine myocardium in vivo. Microarray analysis of the EVs revealed significantly enriched expression of the miR-106a-363 cluster (miR cluster) in hEVs vs. nEVs. This miR cluster preserved survival and contractility of hypoxia-injured iCMs and maintained murine left-ventricular (LV) chamber size, improved LV ejection fraction, and reduced myocardial fibrosis of the injured myocardium. RNA-Seq analysis identified Jag1-Notch3-Hes1 as a target intracellular pathway of the miR cluster. Moreover, the study found that the cell cycle activator and cytokinesis genes were significantly up-regulated in the iCMs treated with miR cluster and Notch3 siRNA. Together, these results suggested that the miR cluster in the EVs stimulated cardiomyocyte cell cycle re-entry by repressing Notch3 to induce cell proliferation and augment myocardial self-repair. The miR cluster may represent an effective therapeutic approach for ischemic cardiomyopathy.
View details for DOI 10.1007/s00395-021-00858-8
View details for PubMedID 33742276
Allogeneic Mesenchymal Cell Therapy in Anthracycline-Induced Cardiomyopathy Heart Failure Patients: The CCTRN SENECA Trial.
2020; 2 (4): 581–95
BACKGROUND: Anthracycline-induced cardiomyopathy (AIC) may be irreversible with a poor prognosis, disproportionately affecting women and young adults. Administration of allogeneic bone marrow-derived mesenchymal stromal cells (allo-MSCs) is a promising approach to heart failure (HF) treatment.OBJECTIVES: SENECA (Stem Cell Injection in Cancer Survivors) was a phase 1 study of allo-MSCs in AIC.METHODS: Cancer survivors with chronic AIC (mean age 56.6 years; 68% women; NT-proBNP 1,426 pg/ml; 6 enrolled in an open-label, lead-in phase and 31 subjects randomized 1:1) received 1 * 108 allo-MSCs or vehicle transendocardially. Primary objectives were safety and feasibility. Secondary efficacy measures included cardiac function and structure measured by cardiac magnetic resonance imaging (CMR), functional capacity, quality of life (Minnesota Living with Heart Failure Questionnaire), and biomarkers.RESULTS: A total of 97% of subjects underwent successful study product injections; all allo-MSC-assigned subjects received the target dose of cells. Follow-up visits were well-attended (92%) with successful collection of endpoints in 94% at the 1-year visit. Although 58% of subjects had non-CMR compatible devices, CMR endpoints were successfully collected in 84% of subjects imaged at 1 year. No new tumors were reported. There were no significant differences between allo-MSC and vehicle groups with regard to clinical outcomes. Secondary measures included 6-min walk test (p = 0.056) and Minnesota Living with Heart Failure Questionnaire score (p = 0.048), which tended to favor the allo-MSC group.CONCLUSIONS: In this first-in-human study of cell therapy in patients with AIC, transendocardial administration of allo-MSCs appears safe and feasible, and CMR was successfully performed in the majority of the HF patients with devices. This study lays the groundwork for phase 2 trials aimed at assessing efficacy of cell therapy in patients with AIC.
View details for DOI 10.1016/j.jaccao.2020.09.001
View details for PubMedID 33403362
MITOCHONDRIA CONTAINING EXTRACELLULAR VESICLES FROM AUTOLOGOUS INDUCED PLURIPOTENT STEM CELL DERIVED CARDIOMYOCYTES RESTORE BIOENERGETICS IN ISCHEMIC MYOCARDIUM
ELSEVIER SCIENCE INC. 2020: 3659
View details for Web of Science ID 000522979103444
Meta-analysis of short- and long-term efficacy of mononuclear cell transplantation in patients with myocardial infarction.
American heart journal
2019; 220: 155–75
BACKGROUND: Mononuclear cells (MNCs) have been tested in clinical trials across multiple cardiovascular pathologies with mixed results. Major adverse cardiac events (MACE) and markers of cardiovascular capacity have been particularly challenging to interpret because of small size. This meta-analysis is aimed to assess the efficacy of MNC therapy in randomized clinical trials to identify the markers of efficiency that could influence future trial design.METHODS: PubMed, Embase, Cochrane library, and ClinicalTrials.gov were searched from inception through November 8, 2018. Changes in left ventricular ejection fraction (LVEF) and infarct size from baseline to follow-up were selected as primary outcomes. Changes in the left ventricular end-systolic volume, left ventricular end-diastolic volume, brain natriuretic peptide/N-terminal pro-B-type natriuretic peptide, 6-minute walk test, New York Heart Association class, and MACE incidences were considered secondary outcomes.RESULTS: In short-term follow-up, patients treated with MNCs demonstrated a significant increase in absolute LVEF of 2.21% (95% CI 1.59-2.83; P < .001; I2 = 32%) and 6.01% (95% CI 4.45-7.57; P < .001; I2 = 0%) in acute myocardial infarction (AMI) and ischemic cardiomyopathy studies, respectively. This effect was sustained in long-term follow-up. MNC therapy significantly reduced left ventricular end-systolic volume; however, infarct size, 6-minute walk test, New York Heart Association class, and MACE rates were comparable.CONCLUSIONS: MNC therapy may convey a modest but sustained increase in LVEF in ischemic cardiomyopathy patients, supporting further investigation. AMI trials, however, demonstrated minimal improvement in LVEF of unclear clinical significance, suggesting a limited role for MNC therapy in AMI.
View details for DOI 10.1016/j.ahj.2019.09.005
View details for PubMedID 31821904
Large-Scale Assessment of a Smartwatch to Identify Atrial Fibrillation.
The New England journal of medicine
2019; 381 (20): 1909–17
BACKGROUND: Optical sensors on wearable devices can detect irregular pulses. The ability of a smartwatch application (app) to identify atrial fibrillation during typical use is unknown.METHODS: Participants without atrial fibrillation (as reported by the participants themselves) used a smartphone (Apple iPhone) app to consent to monitoring. If a smartwatch-based irregular pulse notification algorithm identified possible atrial fibrillation, a telemedicine visit was initiated and an electrocardiography (ECG) patch was mailed to the participant, to be worn for up to 7 days. Surveys were administered 90 days after notification of the irregular pulse and at the end of the study. The main objectives were to estimate the proportion of notified participants with atrial fibrillation shown on an ECG patch and the positive predictive value of irregular pulse intervals with a targeted confidence interval width of 0.10.RESULTS: We recruited 419,297 participants over 8 months. Over a median of 117 days of monitoring, 2161 participants (0.52%) received notifications of irregular pulse. Among the 450 participants who returned ECG patches containing data that could be analyzed - which had been applied, on average, 13 days after notification - atrial fibrillation was present in 34% (97.5% confidence interval [CI], 29 to 39) overall and in 35% (97.5% CI, 27 to 43) of participants 65 years of age or older. Among participants who were notified of an irregular pulse, the positive predictive value was 0.84 (95% CI, 0.76 to 0.92) for observing atrial fibrillation on the ECG simultaneously with a subsequent irregular pulse notification and 0.71 (97.5% CI, 0.69 to 0.74) for observing atrial fibrillation on the ECG simultaneously with a subsequent irregular tachogram. Of 1376 notified participants who returned a 90-day survey, 57% contacted health care providers outside the study. There were no reports of serious app-related adverse events.CONCLUSIONS: The probability of receiving an irregular pulse notification was low. Among participants who received notification of an irregular pulse, 34% had atrial fibrillation on subsequent ECG patch readings and 84% of notifications were concordant with atrial fibrillation. This siteless (no on-site visits were required for the participants), pragmatic study design provides a foundation for large-scale pragmatic studies in which outcomes or adherence can be reliably assessed with user-owned devices. (Funded by Apple; Apple Heart Study ClinicalTrials.gov number, NCT03335800.).
View details for DOI 10.1056/NEJMoa1901183
View details for PubMedID 31722151
Routine Indwelling Urethral Catheterization in Acute Heart Failure Patients Is Associated With Increased Urinary Tract Complications Without Improved Heart Failure Outcomes
2018; 82 (6): 1632-+
Indwelling urethral catheters (IUC) are routinely inserted for the purpose of monitoring urine output in patients with acute heart failure (AHF). The benefit of IUC in patients capable of complying with urine collection protocols is unclear, and IUC carry multiple risks. This study describes the impact of IUC on AHF treatment.Methods and Results:A total of 540 records were retrospectively analyzed. After exclusion criteria were applied, 316 patients were propensity matched to establish groups of 100 AHF patients who either did (IUC(+)) or did not receive an IUC (IUC(-)) upon admission. Hospital length of stay (9 vs. 7 days), in-hospital urinary complications (24 vs. 5%), and 1-year urinary tract infection rate (17 vs. 6%; HR, 3.145; 95% CI: 1.240-7.978) were significantly higher in the IUC(+) group (P<0.05 for all). There were no differences in 30-day rehospitalization (6 vs. 6%; HR, 0.981; 95% CI: 0.318-3.058; P=0.986) or major adverse cardiac/cerebrovascular events at 1 year (37 vs. 32%, HR, 1.070; 95% CI: 0.636-1.799; P=0.798).Based on this retrospective analysis, the routine use of IUC may increase length of stay and UTI complications in AHF patients without reducing the risk for major cardiovascular and cerebrovascular events or 30-day rehospitalization rate.
View details for PubMedID 29593145
Alternative Therapies for Chronic Hepatitis B Patients With Partial Virological Response to Standard Entecavir Monotherapy.
Journal of clinical gastroenterology
2016; 50 (4): 338-344
Entecavir (ETV) is a first-line, oral antinucleoside agent for the treatment of chronic hepatitis B patients. Despite its high potency, some patients may still be viremic after prolonged therapy with ETV monotherapy. Long-term outcome data comparing maintained ETV monotherapy to alternative therapies in persistently viremic patients are limited. Our goal was to compare complete viral suppression (CVS) rates [hepatitis B DNA (HBV DNA)<40 to 60 IU/mL] with alternative therapies to continued ETV monotherapy in ETV partial responders.This is a retrospective cohort study consisting of 86 consecutive treatment-naive, ETV=0.5 mg partial responders (detectable HBV DNA after ≥12 mo on ETV) who maintained ETV=0.5 mg daily (n=29) or switched to either ETV=1.0 mg daily (n=32) or ETV/tenofovir (TDF)=0.5 mg/300 mg (n=25) in 3 US GI/liver clinics from January 2005 to January 2012. Patients were identified by International Classification of Diseases, Ninth Revision query and data were collected by individual chart review. For those who remained on ETV=0.5 mg, comparison at regimen "switch time" was done using values at 12 months from initial ETV therapy. Rates of CVS were evaluated using Kaplan-Meier methods. Multivariate Cox proportional hazard models were used to estimate hazard ratio (HR) relating to potential predictors to the desirable outcomes of CVS.In all therapy groups, the majority of patients were Asian (93.1% to 100.0%), male (64.0% to 68.8%), and hepatitis B e antigen-positive (95.8% to 100.0%) and had similar baseline alanine aminotransferase (ALT) levels. However, baseline HBV DNA (7.0 vs. 7.9 vs. 7.8 log10 IU/mL, P=0.05) and HBV DNA at regimen switch point (2.9 vs. 3.7 vs. 3.6 log10 IU/mL, P=0.0014) were lower in the ETV=0.5 mg cohort compared with those switched to ETV=1.0 mg or ETV/TDF, respectively. The ETV=0.5 mg cohort also had the shortest duration of ETV=0.5 mg therapy before switch (11.8 vs. 13.5 vs. 19.2 mo, P<0.0001). After the switch point, more patients on ETV/TDF achieved CVS compared with those on ETV=0.5 mg or ETV=1.0 mg at month 6 (77.3% vs. 13.8% vs. 9.4%), month 12 (86.4% vs. 40.5% vs. 25.0%), and month 18 (100% vs. 70.2% vs. 33.3%). Compared with the ETV=0.5 mg and ETV=1.0 mg groups, the ETV/TDF group also had higher rates of ALT normalization at month 6 (73.0% vs, 46.4% vs. 63.0%), month 12 (79.7% vs. 69.5% vs. 77.9%), and month 18 (100.0% vs. 69.5% vs. 86.8%), respectively. The multivariate analyses, inclusive of baseline age and treatment duration on initial therapy with ETV=0.5 mg, indicated that the ETV/TDF combination (HR=12.19, P<0.0001) was independently and positively associated with CVS, whereas high HBV DNA levels at baseline (HR=0.77, P=0.02) and at switch point (HR=0.46, P=0.002) were negatively associated with CVS. ETV=1.0 mg dose was not a predictor for CVS compared with ETV=0.5 mg.Following adjustments for HBV DNA levels and prior treatment duration, ETV/TDF combination therapy independently predicted superior viral suppression and ALT normalization in partial responders to ETV=0.5 mg daily compared with ETV=0.5 mg or ETV=1.0 mg monotherapy. In patients who continued to be viremic after 12 months of ETV=0.5 mg, one third were still viremic after another 18 months on the same therapy. Alternative therapies should be considered for these patients.
View details for DOI 10.1097/MCG.0000000000000455
View details for PubMedID 26646801
Hurdles to clinical translation of human induced pluripotent stem cells
JOURNAL OF CLINICAL INVESTIGATION
2015; 125 (7): 2551-2557
Human pluripotent stem cells are known to have the capacity to renew indefinitely, being intrinsically able to differentiate into many different cell types. These characteristics have generated tremendous enthusiasm about the potential applications of these cells in regenerative medicine. However, major challenges remain with the development and testing of novel experimental stem cell therapeutics in the field. In this Review, we focus on the nature of the preclinical challenges and discuss potential solutions that could help overcome them. Furthermore, we discuss the use of allogeneic versus autologous stem cell products, including a review of their respective advantages and disadvantages, major clinical requirements, quality standards, time lines, and costs of clinical grade development.
View details for DOI 10.1172/JCI80575
View details for Web of Science ID 000357553300002
View details for PubMedID 26132109
View details for PubMedCentralID PMC4563685
Current treatment guidelines for chronic hepatitis B and their applications.
Journal of clinical gastroenterology
2014; 48 (9): 773-783
Treatment practices for patients with chronic hepatitis B (CHB) varies across the world and several professional associations have issued treatment recommendations. This synopsis aims to review the major principles of CHB and its management, and to systematically summarize and compare the recommendations of the major treatment guidelines by: the Asian-Pacific Association for the Study of the Liver, the US Panel, the European Association for the Study of the Liver, and the American Association for the Study of the Liver.Treatment recommendations were summarized separately for hepatitis B e antigen (HBeAg)-positive and HBeAg-negative patients.Treatment for CHB is recommended on the basis of a variety of host and viral factors, and the ultimate goal of treatment is the prevention of decompensated liver disease, hepatocellular carcinoma, cirrhosis, and premature death. Despite updates and improvements in these guidelines during the past decade, greater patient and physician education as well as better noninvasive markers to identify high-risk patients are still needed. Significant improvements in the application of current practice guidelines, however, can be made by relatively simple educational efforts, and new molecular and genomic techniques may hold promise for more accurate selection of high-risk patients for further therapeutic interventions in a near future.
View details for DOI 10.1097/MCG.0000000000000130
View details for PubMedID 24859715
Evidence for Pyronaridine as a Highly Effective Partner Drug for Treatment of Artemisinin-Resistant Malaria in a Rodent Model
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
2014; 58 (1): 183-195
The increasing prevalence in Southeast Asia of Plasmodium falciparum infections with delayed parasite clearance rates, following treatment of malaria patients with the artemisinin derivative artesunate, highlights an urgent need to identify which of the currently available artemisinin-based combination therapies (ACTs) are most suitable to treat populations with emerging artemisinin resistance. Here, we demonstrate that the rodent Plasmodium berghei SANA strain has acquired artemisinin resistance following drug pressure, as defined by reduced parasite clearance and early recrudescence following daily exposure to high doses of artesunate or the active metabolite dihydroartemisinin. Using the SANA strain and the parental drug-sensitive N strain, we have interrogated the antimalarial activity of five ACTs, namely, artemether-lumefantrine, artesunate-amodiaquine, artesunate-mefloquine, dihydroartemisinin-piperaquine, and the newest combination artesunate-pyronaridine. By monitoring parasitemia and outcome for 30 days following initiation of treatment, we found that infections with artemisinin-resistant P. berghei SANA parasites can be successfully treated with artesunate-pyronaridine used at doses that are curative for the parental drug-sensitive N strain. No other partner drug combination was as effective in resolving SANA infections. Of the five partner drugs tested, pyronaridine was also the most effective at suppressing the recrudescence of SANA parasites. These data support the potential benefit of implementing ACTs with pyronaridine in regions affected by artemisinin-resistant malaria.
View details for DOI 10.1128/AAC.01466-13
View details for Web of Science ID 000329581100023
View details for PubMedID 24145526
Risk Factors and Characterization of Plasmodium Vivax-Associated Admissions to Pediatric Intensive Care Units in the Brazilian Amazon
2012; 7 (4)
Plasmodium vivax is responsible for a significant proportion of malaria cases worldwide and is increasingly reported as a cause of severe disease. The objective of this study was to characterize severe vivax disease among children hospitalized in intensive care units (ICUs) in the Western Brazilian Amazon, and to identify risk factors associated with disease severity.In this retrospective study, clinical records of 34 children, 0-14 years of age hospitalized in the 11 public pediatric and neonatal ICUs of the Manaus area, were reviewed. P. falciparum monoinfection or P. falciparum/P. vivax mixed infection was diagnosed by microscopy in 10 cases, while P. vivax monoinfection was confirmed in the remaining 24 cases. Two of the 24 patients with P. vivax monoinfection died. Respiratory distress, shock and severe anemia were the most frequent complications associated with P. vivax infection. Ninety-one children hospitalized with P. vivax monoinfections but not requiring ICU were consecutively recruited in a tertiary care hospital for infectious diseases to serve as a reference population (comparators). Male sex (p = 0.039), age less than five years (p = 0.028), parasitemia greater than 500/mm(3) (p = 0.018), and the presence of any acute (p = 0.023) or chronic (p = 0.017) co-morbidity were independently associated with ICU admission. At least one of the WHO severity criteria for malaria (formerly validated for P. falciparum) was present in 23/24 (95.8%) of the patients admitted to the ICU and in 17/91 (18.7%) of controls, making these criteria a good predictor of ICU admission (p = 0.001). The only investigated criterion not associated with ICU admission was hyperbilirubinemia (p = 0.513)].Our study points to the importance of P. vivax-associated severe disease in children, causing 72.5% of the malaria admissions to pediatric ICUs. WHO severity criteria demonstrated good sensitivity in predicting severe P. vivax infection in this small case series.
View details for DOI 10.1371/journal.pone.0035406
View details for Web of Science ID 000305345000064
View details for PubMedID 22523591
Pfatp6 molecular profile of Plasmodium falciparum isolates in the western Brazilian Amazon
Anti-malarial drug resistance has emerged as one of the biggest challenges confronting the worldwide effort to control malaria. The appearance of chloroquine and multi-drug resistance had devastating effects on therapeutic efficacy of former first-line agents. Artemisinin has proven to be an excellent therapeutic alternative to fill the void in chemotherapeutic options left by resistance mechanisms. At the time of introduction, no resistance to artemisinins had been recorded, and artemisinins demonstrated excellent parasite reduction rates. In an attempt to protect artemisinin efficacy, the World Health Organization (WHO) made artemisinin-based combination therapy (ACT) its official first-line treatment recommendation for uncomplicated Plasmodium falciparum in 2006. In Brazil, artemether/lumefantrine became the Brazilian Malaria Control Programme's official treatment recommendation in 2007. The sarco/endoplasmic reticulum Ca2+ - ATPase ortholog of P. falciparum (pfatp6) has been suggested as one of the targets of artemisinins. Consequently, pfatp6 gene polymorphisms are being investigated as markers of artemisinin resistance elsewhere. The goal of this work was to describe the molecular profile of pfatp6 in P. falciparum isolates from different localities in the Amazonas State.DNA polymorphisms of the pfatp6 gene in 80 P. falciparum isolates from 11 municipalities of the Amazonas State (Western Brazilian Amazon), before and after the introduction of ACT in the Brazilian anti-malarial guidelines, were analysed by automatic sequencing. Mutations in the pfatp6 gene were searched using Mutation Surveyor v3.25 software.The P. falciparum pfatp6 gene presented polymorphisms at codons 37, 630 and 898. The R37K mutation was found in 16% of the samples, A630S in 32% and I898I in 52%. No S769N mutation, however, was detected in the analysed samples.Despite the small number of samples, data presented here provide baseline information about polymorphisms of pfatp6 gene before and after exposure to ACT in a low transmission area, which will help to infer drug selection pressure in this area in the future.
View details for DOI 10.1186/1475-2875-11-111
View details for Web of Science ID 000304046700001
View details for PubMedID 22487143
- In vitro and in vivo activity of frenolicin B against Plasmodium falciparum and P berghei JOURNAL OF ANTIBIOTICS 2011; 64 (12): 799-801
Recent clinical and molecular insights into emerging artemisinin resistance in Plasmodium falciparum
CURRENT OPINION IN INFECTIOUS DISEASES
2011; 24 (6): 570-577
Artemisinin-based combination therapies (ACTs) have been deployed globally with remarkable success for more than 10 years without having lost their malaria treatment efficacy. However, recent reports from the Thai-Cambodian border reveal evidence of emerging resistance to artemisinins. The latest published clinical and molecular findings are summarized herein.Clinical studies have identified delayed parasite clearance time as the most robust marker of artemisinin resistance. Resistance has only been documented from South-east Asia and has been observed in isolates that show no significant decrease in drug susceptibility in vitro. Genetic investigations have yet to uncover robust molecular markers. In-vitro studies have identified parasite quiescence or dormancy mechanisms that protect early 'ring-stage' intra-erythrocytic parasites against short-term artemisinin exposure. This might be achieved by reducing the rate of hemoglobin degradation, important for artemisinin bioactivation.Should ACTs fail, no suitable alternatives exist as first-line treatments of P. falciparum malaria. Intensified efforts are essential to monitor the spread of resistance, define therapeutic and operational strategies to counter its impact, and understand its molecular basis. Success in these areas is critical to ensuring that recent gains in reducing the burden of malaria are not lost.
View details for DOI 10.1097/QCO.0b013e32834cd3ed
View details for Web of Science ID 000296496800008
View details for PubMedID 22001944
In Vivo and In Vitro Antimalarial Properties of Azithromycin-Chloroquine Combinations That Include the Resistance Reversal Agent Amlodipine
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
2011; 55 (7): 3115-3124
Evidence of emerging Plasmodium falciparum resistance to artemisinin-based combination therapies, documented in western Cambodia, underscores the continuing need to identify new antimalarial combinations. Given recent reports of the resurgence of chloroquine-sensitive P. falciparum parasites in Malawi, after the enforced and prolonged withdrawal of this drug, and indications of a possible synergistic interaction with the macrolide azithromycin, we sought to further characterize chloroquine-azithromycin combinations for their in vitro and in vivo antimalarial properties. In vitro 96-h susceptibility testing of chloroquine-azithromycin combinations showed mostly additive interactions against freshly cultured P. falciparum field isolates obtained from Mali. Some evidence of synergy, however, was apparent at the fractional 90% inhibitory concentration level. Additional in vitro testing highlighted the resistance reversal properties of amlodipine for both chloroquine and quinine. In vivo experiments, using the Peters 4-day suppressive test in a P. yoelii mouse model, revealed up to 99.9% suppression of parasitemia following treatment with chloroquine-azithromycin plus the R enantiomer of amlodipine. This enantiomer was chosen because it does not manifest the cardiac toxicities observed with the racemic mixture. Pharmacokinetic/pharmacodynamic analyses in this rodent model and subsequent extrapolation to a 65-kg adult led to the estimation that 1.8 g daily of R-amlodipine would be required to achieve similar efficacy in humans, for whom this is likely an unsafe dose. While these data discount amlodipine as an additional partner for chloroquine-based combination therapy, our studies continue to support azithromycin as a safe and effective addition to antimalarial combination therapies.
View details for DOI 10.1128/AAC.01566-10
View details for Web of Science ID 000291687900007
View details for PubMedID 21464242