scholarly journals Age-Dependent Myocardial Dysfunction in Critically Ill Patients: Role of Mitochondrial Dysfunction

2019 ◽  
Vol 20 (14) ◽  
pp. 3523 ◽  
Author(s):  
Andrew J. Lautz ◽  
Basilia Zingarelli
Keyword(s):  
Septic Shock ◽  
Cardiac Arrest ◽  
Mitochondrial Dysfunction ◽  
Nitrosative Stress ◽  
Mitochondrial Permeability Transition ◽  
Myocardial Dysfunction ◽  
Ischemia Reperfusion ◽  
Systolic Dysfunction ◽  
Future Research ◽  
Age Dependent

Myocardial dysfunction is common in septic shock and post-cardiac arrest but manifests differently in pediatric and adult patients. By conventional echocardiographic parameters, biventricular systolic dysfunction is more prevalent in children with septic shock, though strain imaging reveals that myocardial injury may be more common in adults than previously thought. In contrast, diastolic dysfunction in general and post-arrest myocardial systolic dysfunction appear to be more widespread in the adult population. A growing body of evidence suggests that mitochondrial dysfunction mediates myocardial depression in critical illness; alterations in mitochondrial electron transport system function, bioenergetic production, oxidative and nitrosative stress, uncoupling, mitochondrial permeability transition, fusion, fission, biogenesis, and autophagy all may play key pathophysiologic roles. In this review we summarize the epidemiologic and clinical phenotypes of myocardial dysfunction in septic shock and post-cardiac arrest and the multifaceted manifestations of mitochondrial injury in these disease processes. Since neonatal and pediatric-specific data for mitochondrial dysfunction remain sparse, conclusive age-dependent differences are not clear; instead, we highlight what evidence exists and identify gaps in knowledge to guide future research. Finally, since focal ischemic injury (with or without reperfusion) leading to myocardial infarction is predominantly an atherosclerotic disease of the elderly, this review focuses specifically on septic shock and global ischemia-reperfusion injury occurring after resuscitation from cardiac arrest.

scholarly journals Melatonin in Mitochondrial Dysfunction and Related Disorders

2011 ◽  
Vol 2011 ◽  
pp. 1-16 ◽  
Author(s):  
Venkatramanujam Srinivasan ◽  
D. Warren Spence ◽  
Seithikurippu R. Pandi-Perumal ◽  
Gregory M. Brown ◽  
Daniel P. Cardinali
Keyword(s):  
Septic Shock ◽  
Electron Transport ◽  
Mitochondrial Dysfunction ◽  
Neurodegenerative Disorders ◽  
Nitrosative Stress ◽  
Mitochondrial Permeability Transition ◽  
Ischemia Reperfusion ◽  
No Production ◽  
Lethal Effects ◽  
Respiratory Complex

Mitochondrial dysfunction is considered one of the major causative factors in the aging process, ischemia/reperfusion (I/R), septic shock, and neurodegenerative disorders like Parkinson's disease (PD), Alzheimer's disease (AD), and Huntington's disease (HD). Increased free radical generation, enhanced mitochondrial inducible nitric oxide (NO) synthase activity, enhanced NO production, decreased respiratory complex activity, impaired electron transport system, and opening of mitochondrial permeability transition pore all have been suggested as factors responsible for impaired mitochondrial function. Melatonin, the major hormone of the pineal gland, also acts as an antioxidant and as a regulator of mitochondrial bioenergetic function. Both in vitro and in vivo, melatonin was effective for preventing oxidative stress/nitrosative stress-induced mitochondrial dysfunction seen in experimental models of PD, AD, and HD. In addition, melatonin is known to retard aging and to inhibit the lethal effects of septic shock or I/R lesions by maintaining respiratory complex activities, electron transport chain, and ATP production in mitochondria. Melatonin is selectively taken up by mitochondrial membranes, a function not shared by other antioxidants. Melatonin has thus emerged as a major potential therapeutic tool for treating neurodegenerative disorders such as PD or AD, and for preventing the lethal effects of septic shock or I/R.

scholarly journals Baicalin Improves Cardiac Outcome and Survival by Suppressing Drp1-Mediated Mitochondrial Fission after Cardiac Arrest-Induced Myocardial Damage

2021 ◽  
Vol 2021 ◽  
pp. 1-14
Author(s):  
Jun Wu ◽  
Hui Chen ◽  
Jiahong Qin ◽  
Nan Chen ◽  
Shiqi Lu ◽  
...  
Keyword(s):  
Cardiac Arrest ◽  
Mitochondrial Dysfunction ◽  
Myocardial Injury ◽  
Myocardial Dysfunction ◽  
Ischemia Reperfusion ◽  
Mitochondrial Fission ◽  
Specific Inhibitor ◽  
Myocardial Damage ◽  
Spontaneous Circulation ◽  
Flavonoid Compound

Myocardial injury after cardiac arrest (CA) often results in severe myocardial dysfunction and death involving mitochondrial dysfunction. Here, we sought to investigate whether baicalin, a natural flavonoid compound, exerts cardioprotection against CA-induced injury via regulating mitochondrial dysfunction. We subjected the rats to asphyxia CA after a daily baicalin treatment for 4 weeks. After the return of spontaneous circulation, baicalin treatment significantly improved cardiac function performance, elevated survival rate from 35% to 75%, prevented necrosis and apoptosis in the myocardium, which was accompanied by reduced phosphorylation of Drp1 at serine 616, inhibited Drp1 translocation to the mitochondria and mitochondrial fission, and improved mitochondrial function. In H9c2 cells subjected to simulated ischemia/reperfusion, increased phosphorylation of Drp1 at serine 616 and subsequently enhanced mitochondrial Drp1 translocation as well as mitochondrial fission, augmented cardiomyocyte death, increased reactive oxygen species production, released cytochrome c from mitochondria and injured mitochondrial respiration were efficiently improved by baicalin and Drp1 specific inhibitor with Mdivi-1. Furthermore, overexpression of Drp1 augmented excessive mitochondrial fission and abolished baicalin-afforded cardioprotection, indicating that the protective impacts of baicalin are linked to the inhibition of Drp1. Altogether, our findings disclose for the first time that baicalin offers cardioprotection against ischemic myocardial injury after CA by inhibiting Drp1-mediated mitochondrial fission. Baicalin might be a prospective therapy for the treatment of post-CA myocardial injury.

Abstract 12933: Myocardial Dysfunction After In-Hospital Cardiac Arrest in COVID-19 Patients

Circulation ◽  
2021 ◽  
Vol 144 (Suppl_2) ◽  
Author(s):  
Abhishek Bhardwaj ◽  
Mahmoud Alwakeel ◽  
Siddharth Dugar ◽  
sudhir krishnan ◽  
Xiaofeng Wang ◽  
...  
Keyword(s):  
Cardiac Arrest ◽  
Median Time ◽  
Systolic Function ◽  
Myocardial Dysfunction ◽  
Systolic Dysfunction ◽  
Cleveland Clinic ◽  
Case Series ◽  
Apache Ii Score ◽  
Lv Function ◽  
Hospital Cardiac Arrest

Introduction: Post resuscitation myocardial dysfunction (PRMD) is common after out-of-hospital cardiac arrest. While PRMD is a known cause of post-resuscitation circulatory failure, few studies have reported associations between PRMD and neurologic outcome or survival. Further, little is known about PRMD after in-hospital cardiac arrest (IHCA) nor on the incidence and prognosis of PRMD in COVID-19 IHCA. We sought to evaluate the incidence of PRMD in a multicenter cohort of resuscitated COVID-19 IHCA patients. Study Population and Methods: We included adult patients (≥18 y) admitted to multiple hospitals of Cleveland Clinic Health System. Patients who attained ROSC with an initial echocardiogram (EC) in the 72 hours post-arrest were included. Data were extracted from a data registry and electronic medical records. Results: From 03/2020-10/2020, 58 patients with COVID-19 had IHCA. ROSC was noted in 35 patients (60.3%), 27 (46.6%) were alive at 24 h and 13 patients (22.4%) survived to hospital discharge. Of the 35 patients who had ROSC, 14 patients (40%) had an EC within 72 h. The median age of this cohort was 67 y (IQR 47 - 73); 71% were male, and median BMI of 28 (IQR 27 - 34), and admission APACHE II score was 13 (IQR 11 - 19). One third of the patients (36%) were mechanically ventilated before arrest and 43% were on vasopressors. Initial arrest rhythms were: PEA/Asystole, 79%; and VF/VT, 21%. Most patients (93%) received manual chest compression with median CPR duration of 5 min (IQR 2 - 10). The median time of obtaining first EC post-ROSC in these 14 patients was 22 hours (IQR 6 - 62). 7/14 (50%) of the patient had systolic dysfunction on initial EC (6 had global dysfunction, 1 with regional wall motion abnormality, and 4/7 had combined LV and RV systolic dysfunction). 5/14 patients had a follow up EC with a median time of 43 days. 2/5 had normal initial EC and 3 out of these 5 patients who initially had PMRD showed complete recovery in their LV and RV systolic function. Conclusion: We report a case series of PRMD in COVID-19 patients who experienced IHCA. We found that PMRD is seen in half of the patients. Most patients with PMRD recovered to normal RV and LV function, consistent with prior studies of non-COVID-19 arrest EC.

Abstract 87: Cyclosporin A does not Prevent Myocardial Dysfunction after Resuscitation from Cardiac Arrest in Rats

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Iyad M Ayoub ◽  
Jeejabai Radhakrishnan ◽  
Raúl J Gazmuri
Keyword(s):  
Cardiac Arrest ◽  
Cyclosporin A ◽  
Chest Compression ◽  
Rat Model ◽  
Mitochondrial Permeability Transition ◽  
Myocardial Dysfunction ◽  
Left Ventricular ◽  
List Type ◽  
Ischemia And Reperfusion ◽  
Biphasic Waveform

Objective: We have previously reported in a rat model of VF and closed-chest resuscitation that cytochrome c is released into the bloodstream after resuscitation from cardiac arrest attaining plasma levels inversely proportional to survival. Recent evidence indicates that release of cytochrome c during ischemia and reperfusion may be a manifestation of prolonged opening of the mitochondrial permeability transition pore (mPTP). In this study, we investigated whether cyclosporin A (CsA, an inhibitor of mPTP opening) can prevent post-resuscitation (PR) myocardial dysfunction and improve survival. Methods: VF was electrically induced and left untreated for 10 mins. Resuscitation was attempted by 8 mins of chest compression followed by biphasic waveform defibrillation. Rats were randomized to received a bolus CsA (10 mg/kg) five minutes before inducing VF (n=6), immediately before starting chest compression (n=6), or to receive vehicle control before inducing VF (n=3) or before starting chest compression (n=3). CsA-treated (n=12) and vehicle-treated (n=6) rats were pooled for this analysis after noticing no differences between subgroups. Resuscitated rats were monitored for up to 6 hours. Results: All rats were successfully resuscitated. Treatment with CsA did not improve PR myocardial function (Table ). Survival time was comparable between CsA-treated (321±67 mins) and vehicle-treated (331±67 mins) rats. Conclusions: In our rat model of VF and resuscitation, CsA failed to prevent PR myocardial dysfunction and improve survival. These data contrast with numerous studies demonstrating a protective effect in isolated heart models of ischemia and reperfusion. Two possible explanations are the mPTP does not open in this unique setting of cardiac arrest and resuscitation, and the optimal in vivo dose of CsA needs to be determined as the protective effects of CsA are dose dependent. Hemodynamic and Left Ventricular Function

Abstract 10773: Curcumin Improves the Outcomes of Cardiopulmonary Resuscitation in a Rat Model of Cardiac Arrest

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Zhengfei Yang ◽  
Jiangang Wang ◽  
Lu Yin ◽  
Shen Zhao ◽  
Ziren Tang ◽  
...  
Keyword(s):  
Cardiac Arrest ◽  
Placebo Group ◽  
Rat Model ◽  
Myocardial Function ◽  
Ischemia Reperfusion Injury ◽  
Myocardial Dysfunction ◽  
Ischemia Reperfusion ◽  
Sprague Dawley ◽  
Successful Resuscitation ◽  
Pre Treatment

Introduction: Curcumin has been proven to provide potent protection of vital organs against regional ischemia reperfusion injury. In this study, we investigated the effects of curcumin on the outcomes of CPR in a rat model of cardiac arrest. Hypothesis: Curcumin reduces the severity of post-CPR myocardial dysfunction and prolong the duration of survival. Method: Sixteen male Sprague-Dawley rats weighing between 450-550g were randomized into two groups: 1) Placebo; 2) Curcumin (100 mg/kg) pre-treatment. Ventricular fibrillation (VF) was induced. After 8 mins of VF, CPR was initiated for 8 mins and defibrillation was then attempted. Myocardial function was measured by echocardiography at baseline and hourly for 4 hours following successful resuscitation. The duration of survival was observed for total 72 hours. Result: Six animals in the placebo group and seven in the curcumin group were successfully resuscitated. Post-resuscitation myocardial function was significantly impaired in all animals. However, myocardial function gradually improved 4 hours after resuscitation and was significantly better in the animals pre-treated with curcumin (Figure). Significantly shorter duration of survival of 40±29 hours was observed in the placebo group. Conclusion: In a rat model of cardiac arrest, curcuminim proves post-resuscitation myocardial dysfunction and prolongs the duration of survival.

Characterization of Myocardial Dysfunction in Fluid- and Catecholamine-Refractory Pediatric Septic Shock and Its Clinical Significance

2016 ◽  
Vol 34 (1) ◽  
pp. 17-25 ◽  
Author(s):  
Feifei Z. Williams ◽  
Ritu Sachdeva ◽  
Curtis D. Travers ◽  
Karen H. Walson ◽  
Kiran B. Hebbar
Keyword(s):  
Septic Shock ◽  
Intensive Care ◽  
Clinical Significance ◽  
Cold Shock ◽  
Myocardial Dysfunction ◽  
Systolic Dysfunction ◽  
Severity Of Illness ◽  
Left Ventricular ◽  
Hospital Length Of Stay ◽  
Z Score

Purpose: Myocardial dysfunction is a known complication in patients with pediatric septic shock (PSS); however, its clinical significance remains unclear. The purpose of this study was to characterize left ventricular (LV) and right ventricular (RV) dysfunction and their prevalence in patients with PSS using echocardiography (echo) and to investigate their associations with the severity of illness and clinical outcomes. Methods: Retrospective chart review between 2010 and 2015 from 2 tertiary care pediatric intensive care units. Study included 78 patients (mean age 9.3 ± 7 years) from birth up to 21 years who fulfilled criteria for fluid- and catecholamine-refractory septic shock. Echocardiographic parameters of systolic, diastolic, and global function were measured offline. They were correlated with admission Pediatric Risk of Mortality III (PRISM III) and Pediatric Logistic Organ Dysfunction scores, vasoactive–inotrope score (VIS), β-type natriuretic peptide (BNP), lactate, type of shock, duration of mechanical ventilation (MV), intensive care unit and hospital length of stay, and mortality. Results: Overall, 28-day mortality was 26%, and 88% patients required MV. Prevalence of LV dysfunction was 72% and RV dysfunction was 63%. LV systolic dysfunction (fractional shortening z score <−2) was significantly associated with PRISM III, VIS, and BNP. RV systolic dysfunction (tricuspid annular plane systolic excursion z score <−2) was significantly associated with cold shock. LV and RV diastolic dysfunction did not have any significant clinical associations. No echocardiographic measures were associated with mortality. Conclusion: Myocardial dysfunction is highly prevalent in PSS but is not associated with mortality. LV systolic dysfunction is associated with a higher severity of illness, use of vasoactives, and BNP, whereas RV systolic dysfunction is associated with cold shock. Further studies are needed to determine the utility of echo in the bedside management of patients with PSS.

scholarly journals Pediatric Cardiac Arrest

2020 ◽  
Author(s):  
Priscilla Yu ◽  
Ivie D. Esangbedo ◽  
Lakshmi Raman ◽  
Cindy Darnell Bowens
Keyword(s):  
Cardiac Arrest ◽  
Ischemia Reperfusion Injury ◽  
Myocardial Dysfunction ◽  
Ischemia Reperfusion ◽  
Temperature Management ◽  
Patient Centered ◽  
Recent Developments ◽  
Cpr Quality ◽  
Current Guidelines

This chapter will focus on four important topics in pediatric cardiac arrest. We will highlight recent developments in pediatric CPR quality, medications used in cardiac arrest, ECPR, and post-cardiac arrest care (PCAC) and discuss the existing literature behind AHA guidelines and gaps in knowledge. Optimization of CPR quality is critical during cardiac arrest. We will summarize literature regarding current guidelines which target provider-centered goals and discuss evidence behind patient-centered goals. We will also discuss the evidence behind drugs used in the PALS guidelines. In cases of refractory cardiac arrest, ECMO can be lifesaving; however, there are still many gaps in our knowledge of this field. We will summarize the literature regarding determination of candidacy, cannulation strategies, resuscitation practices during ECPR, and outcomes. After a cardiac arrest, PCAC is crucial to minimize further injury from post-cardiac arrest syndrome (PCAS). The main goals of PCAC are to prevent further brain injury, treat myocardial dysfunction, and systemic ischemia/reperfusion injury. We will discuss AHA guidelines on oxygenation and ventilation goals, targeted temperature management, hemodynamic monitoring, and neuromonitoring.

Abstract 297: Mitochondrial Cyclophilin D as a Target for Cardiac Arrest Resuscitation: Insight From Knockout Mice

Circulation ◽  
2018 ◽  
Vol 138 (Suppl_2) ◽  
Author(s):  
Martin Cour ◽  
Vincent Jahandiez ◽  
Bruno Pillot ◽  
Michel Ovize ◽  
Laurent Argaud
Keyword(s):  
Cardiac Arrest ◽  
Therapeutic Hypothermia ◽  
Knockout Mice ◽  
Myocardial Dysfunction ◽  
Ischemia Reperfusion ◽  
Cardiac Massage ◽  
Cyclophilin D ◽  
Short Term ◽  
Term Survival

Introduction: Solid evidence support that cyclophilin D (CypD), which promotes the lethal opening of the mitochondrial permeability transition pore (mPTP), is involved in the pathogenesis of ischemia-reperfusion injury, including after cardiac arrest (CA). However, a recent trial (CYRUS study) showed that cyclosporine A, the reference mPTP inhibitor (via its binding to CypD), failed to limit the severity of the post-CA syndrome, raising the question of whether CypD is a viable target for protection in CA. Therefore, we aimed to reassess the role of CypD in CA resuscitation using CypD knockout mice. Hypothesis: We hypothesized that CypD is a target of interest for CA treatment. Methods: Wild type (WT) or CypD knockout (CypD -/- ) mice underwent 5 minutes of asphyxia-induced CA followed by cardiopulmonary resuscitation. Additional mice were treated with therapeutic hypothermia (32-34°C) as the gold standard intervention to confer protection after CA. In a first set of experiments, animals were euthanized after 2 hours of reperfusion for biochemical and mitochondrial assays. In a second set of experiments, animals were observed for up to 7 days for survival and neurological status. Results: All animals underwent similar durations of asphyxia before CA. Rate of ROSC was significantly higher in CypD -/- group (with a shorter cardiac massage duration) compared to WT group (p<0.05). CA-induced myocardial dysfunction and increase in plasma levels of troponin were both attenuated by CypD deletion (p<0.05 versus WT) without additional benefits of hypothermia. CypD -/- mice exhibited significantly less brain damage than WT. CypD deletion prevented both CA-induced mPTP opening and respiration impairment in isolated brain mitochondria (p<0.05 versus WT). Short-term survival (24 hours) was significantly higher in CypD -/- than WT mice (p<0.05). Only therapeutic hypothermia significantly improved both short-term and neurological intact survival at day 7 after CA compared to WT (p<0.05). Conclusions: Our results suggest that CypD remains a potential major target to improve resuscitability and early but not long-term outcomes. Supplementary interventions, such as therapeutic hypothermia, are needed to enhance long-term recovery.

Abstract 107: Mitochondrial Dysfunction Mediated Myocardial Stunning Following Resuscitation From Cardiac Arrest

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Willard W Sharp ◽  
Lin Piao ◽  
Yong Fang ◽  
David G Beiser ◽  
James K Liao ◽  
...  
Keyword(s):  
Cardiac Arrest ◽  
Myocardial Stunning ◽  
Mitochondrial Dynamics ◽  
Myocardial Dysfunction ◽  
Ischemia Reperfusion ◽  
Myocardial Necrosis ◽  
Spontaneous Circulation ◽  
Contractile Dysfunction ◽  
Myocardial Contractile ◽  
Induced Changes

Rationale: Severe myocardial contractile dysfunction following resuscitation from cardiac arrest (CA) is a major contributor to CA mortality. The pathophysiology and etiology of this dysfunction is not known and there are no pharmacological therapies known to improve outcomes. Previously, we demonstrated that Dynamin related protein 1 (Drp1) is activated and recruited to the mitochondria during CA and that the Drp1 inhibitor Mdivi-1 improves post CA survival. Objective: To determine the effects of CA length on myocardial and mitochondrial function. We also sought to determine the effects of Mdivi-1 on post CA outcomes. Methods and Results: Asystolic cardiac arrest (CA) was induced in mice by IV injection of 0.08 mg/g KCL. CPR begun at 4, 8, 12, and 16 minutes post-cardiac arrest had rates of return of spontaneous circulation (ROSC) of 100%(12/12), 93%(14/15), 71%(10/14), and 44% (4/9) and 2-hour survival of 100%(12/12), 67%(10/15), 50%(7/14), and 11%(1/9). Transthoracic echocardiography 15 min post-resuscitation demonstrated percent fractional shortening of 36±4% (Sham,n=6), 30±4% (4 minCA,n=11), 24±5% (8minCA,n=10), 15±2% (12minCA,n=12). In surviving animals, myocardial dysfunction persisted for 2 hours post-resuscitation, but slowly recovered to baseline by 72 hours. No evidence of myocardial necrosis, inflammation, or apoptosis was noted following resuscitation. Progressive increases in mitochondrial derived reactive oxygen species (ROS) during CA was observed by MitoSOX red myocardial tissue staining. Mitochondria isolated from 12 min CA hearts demonstrated decreased substrate coupled and uncoupled respiration. Mdivi-1, a mitochondrial inhibitor of division (fission), improved survival and neurological scores in mice following an 8 min cardiac arrest compared to controls. Conclusions: Severe, time dependent myocardial stunning (contractile dysfunction in the absence of irreversible injury) was observed following asystolic cardiac arrest. This myocardial stunning was associated with mitochondrial injury and improved by an inhibitor of Drp1. Strategies targeting ischemia/reperfusion-induced changes in mitochondrial dynamics hold promise for improving myocardial function and survival following cardiac arrest.

scholarly journals Myocardial Dysfunction and Shock after Cardiac Arrest

2015 ◽  
Vol 2015 ◽  
pp. 1-14 ◽  
Author(s):  
Jacob C. Jentzer ◽  
Meshe D. Chonde ◽  
Cameron Dezfulian
Keyword(s):  
Cardiac Arrest ◽  
Ischemia Reperfusion Injury ◽  
Systolic Function ◽  
Myocardial Dysfunction ◽  
Ischemia Reperfusion ◽  
Left Ventricular Systolic Function ◽  
Left Ventricular ◽  
Contributing Factors ◽  
Vasopressor Support ◽  
Cytokine Activation

Postarrest myocardial dysfunction includes the development of low cardiac output or ventricular systolic or diastolic dysfunction after cardiac arrest. Impaired left ventricular systolic function is reported in nearly two-thirds of patients resuscitated after cardiac arrest. Hypotension and shock requiring vasopressor support are similarly common after cardiac arrest. Whereas shock requiring vasopressor support is consistently associated with an adverse outcome after cardiac arrest, the association between myocardial dysfunction and outcomes is less clear. Myocardial dysfunction and shock after cardiac arrest develop as the result of preexisting cardiac pathology with multiple superimposed insults from resuscitation. The pathophysiology involves cardiovascular ischemia/reperfusion injury and cardiovascular toxicity from excessive levels of inflammatory cytokine activation and catecholamines, among other contributing factors. Similar mechanisms occur in myocardial dysfunction after cardiopulmonary bypass, in sepsis, and in stress-induced cardiomyopathy. Hemodynamic stabilization after resuscitation from cardiac arrest involves restoration of preload, vasopressors to support arterial pressure, and inotropic support if needed to reverse the effects of myocardial dysfunction and improve systemic perfusion. Further research is needed to define the role of postarrest myocardial dysfunction on cardiac arrest outcomes and identify therapeutic strategies.

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