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Neuroprotection of the Young Brain Arun K Gupta Consultant in Anaesthesia and NeuroCritical Care Director of Postgraduate Education Cambridge University.

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Presentation on theme: "Neuroprotection of the Young Brain Arun K Gupta Consultant in Anaesthesia and NeuroCritical Care Director of Postgraduate Education Cambridge University."— Presentation transcript:

1 Neuroprotection of the Young Brain Arun K Gupta Consultant in Anaesthesia and NeuroCritical Care Director of Postgraduate Education Cambridge University Health Partners

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3 JOURNAL OF NEUROTRAUMA Volume 19, Number 5, 2002 © Mary Ann Liebert, Inc. Clinical Trials in Head Injury RAJ K. NARAYAN 1† MARY ELLEN MICHEL, 2,† and THE CLINICAL TRIALS IN HEAD INJURY STUDY GROUP INCLUDING ‡ : Beth Ansell, 3 Alex Baethmann,4 Anat Biegon, 5,* Michael B. Bracken, 6,* M. Ross Bullock, 7,* Sung C. Choi, 7,* Guy L. Clifton, 8,* Charles F. Contant, 9,* William M. Coplin, 10 W. Dalton Dietrich, 11 Jamshid Ghajar 12,* Sean M. Grady, 13 Robert G. Grossman, 9 Edward D. Hall, 14,* William Heetderks, 15 David A. Hovda, 16 Jack Jallo,17 Russell L. Katz, 18,* Nachshon Knoller, 19,* Patrick M. Kochanek, 20 Andrew I. Maas, 21,* Jeannine Majde, 22 Donald W. Marion, 20 Anthony Marmarou, 7,* Lawrence F. Marshall 23,* Tracy K. McIntosh, 3,* Emmy Miller,8 Noel Mohberg, 24 J. Paul Muizelaar, 25,* Lawrence H. Pitts, 26 Peter Quinn, 12 Gad Riesenfeld,27 Claudia S. Robertson, 9,* Kenneth I. Strauss, 28 Graham Teasdale, 29,* Nancy Temkin, 30,* Ronald Tuma, 28 Charles Wade 31,* Michael D. Walker, 15 Michael Weinrich, 3 John Whyte, 17,* Jack Wilberger, 32 A. Byron Young, 33,* and Lorraine Yurkewicz 34,* ABSTRACT Traumatic brain injury (TBI) remains a major public health problem globally. In the United States the incidence of closed head injuries admitted to hospitals is conservatively estimated to be 200 per 100,000 population, and the incidence of penetrating head injury is estimated to be 12 per 100,000, the highest of any developed country in the world. This yields an approximate number of 500,000 new cases each year, a sizeable proportion of which demonstrate signficant long-term disabilities. Unfor- tunately, there is a paucity of proven therapies for this disease. For a variety of reasons, clinical trials for

4 JOURNAL OF NEUROTRAUMA Volume 19, Number 5, 2002 © Mary Ann Liebert, Inc. Clinical Trials in Head Injury RAJ K. NARAYAN 1† MARY ELLEN MICHEL, 2,† and THE CLINICAL TRIALS IN HEAD INJURY STUDY GROUP INCLUDING ‡ : Beth Ansell, 3 Alex Baethmann,4 Anat Biegon, 5,* Michael B. Bracken, 6,* M. Ross Bullock, 7,* Sung C. Choi, 7,* Guy L. Clifton, 8,* Charles F. Contant, 9,* William M. Coplin, 10 W. Dalton Dietrich, 11 Jamshid Ghajar 12,* Sean M. Grady, 13 Robert G. Grossman, 9 Edward D. Hall, 14,* William Heetderks, 15 David A. Hovda, 16 Jack Jallo,17 Russell L. Katz, 18,* Nachshon Knoller, 19,* Patrick M. Kochanek, 20 Andrew I. Maas, 21,* Jeannine Majde, 22 Donald W. Marion, 20 Anthony Marmarou, 7,* Lawrence F. Marshall 23,* Tracy K. McIntosh, 3,* Emmy Miller,8 Noel Mohberg, 24 J. Paul Muizelaar, 25,* Lawrence H. Pitts, 26 Peter Quinn, 12 Gad Riesenfeld,27 Claudia S. Robertson, 9,* Kenneth I. Strauss, 28 Graham Teasdale, 29,* Nancy Temkin, 30,* Ronald Tuma, 28 Charles Wade 31,* Michael D. Walker, 15 Michael Weinrich, 3 John Whyte, 17,* Jack Wilberger, 32 A. Byron Young, 33,* and Lorraine Yurkewicz 34,* ABSTRACT Traumatic brain injury (TBI) remains a major public health problem globally. In the United States the incidence of closed head injuries admitted to hospitals is conservatively estimated to be 200 per 100,000 population, and the incidence of penetrating head injury is estimated to be 12 per 100,000, the highest of any developed country in the world. This yields an approximate number of 500,000 new cases each year, a sizeable proportion of which demonstrate signficant long-term disabilities. Unfor- tunately, there is a paucity of proven therapies for this disease. For a variety of reasons, clinical trials for

5 PET evidence of heterogeneity following severe head injury Coles et al. JCBFM 2004

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7 PreNCCU Severe disability /PVS NCCU * * :p < 0.05 * * Dead Favourable outcome Percentage of patients in outcome category Making a marginal difference Patel et al. Intensive Care Med 2002

8 Defining Therapeutic Targets ICPICP CPPCPP Cerebral Blood FlowCerebral Blood Flow Cerebral Oxygenation and metabolismCerebral Oxygenation and metabolism Brain ActivityBrain Activity

9 ICP Threshold 2007 BTF Guideline 20-25mmHg 20-25mmHg

10 ICP- accepted limits Adults <20mmHgAdults <20mmHg Children < 15 mmHgChildren < 15 mmHg Infants 5-10 mmHgInfants 5-10 mmHg

11 Does ICP Monitoring affect Outcome? Lack of Prospective RCTLack of Prospective RCT Improved outcome with interventions to reduce ICPImproved outcome with interventions to reduce ICP

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13 CPP and outcome CPP>70mmHg (mean 83) resulted in 29% mortality 59% good recovery or moderate disability – significantly improved outcome compared to historical controls (Rosner -J Neurosurg 1996)CPP>70mmHg (mean 83) resulted in 29% mortality 59% good recovery or moderate disability – significantly improved outcome compared to historical controls (Rosner -J Neurosurg 1996) Hypotension independent predictor of poor outcome (Chestnut- Acta Neurochir 1993)Hypotension independent predictor of poor outcome (Chestnut- Acta Neurochir 1993)

14 Vessel diameter CBF (ml/100g/min) 50 (MAP) CPP CBV(ml/100g) CVR 4.0  CPP Cerebral vasodilatation  CBV  ICP  CPP Cerebral vasoconstriction  CBV  ICP

15 The Alternative view Lund Approach-Lund Approach- Optimising CPP to lower CPP (50mmHg) reported mortality of 8% with 80% good recovery or moderate disability at 6 months (Grande J Trauma 1997, Eker Crit Care Med 1998) Optimising CPP to lower CPP (50mmHg) reported mortality of 8% with 80% good recovery or moderate disability at 6 months (Grande J Trauma 1997, Eker Crit Care Med 1998) CPP target mmHgCPP target mmHg

16 Modified 2007 BTF guidelines: -CPP 50-70mmHg but aim for 60mmHg -Paediatric patients CPP> 40mmHg

17 ICP- accepted limits ICP CPP ICP CPP Adults <20mmHg 60-70mmHgAdults <20mmHg 60-70mmHg Children < 15 mmHg 50-60mmHgChildren < 15 mmHg 50-60mmHg Infants 5-10 mmHg 40-50mmHgInfants 5-10 mmHg 40-50mmHg

18 Individualising monitoring Pressure Reactivity Index (PRx)Pressure Reactivity Index (PRx) Index correlating averaged changes in ICP with ABP changes (-1 to +1). Index correlating averaged changes in ICP with ABP changes (-1 to +1). –ve value = normally reactive vascular bed –ve value = normally reactive vascular bed + ve value correlates to poor outcome (Czosnyka 1997, Ballestreri 2004)

19 “Optimal CPP” varies between patients In a retrospective analysis 66% of patients show a zone of best vascular responseIn a retrospective analysis 66% of patients show a zone of best vascular response CPP OPT varied between 50 and 110 mmHgCPP OPT varied between 50 and 110 mmHg Management at or close to CPP OPT associated with better outcomesManagement at or close to CPP OPT associated with better outcomes CPP OPT Steiner et al. Crit Care Med. 2002

20 Hyperventilation for ICP Control Traditional therapy for ICP controlTraditional therapy for ICP control Emerging concern about ischaemia in first 24hrs after injury Bouma 1991, Marion 1991, Robertson 1992Emerging concern about ischaemia in first 24hrs after injury Bouma 1991, Marion 1991, Robertson 1992 Evidence suggesting hypocapnic vasoconstriction may worsen ischaemiaEvidence suggesting hypocapnic vasoconstriction may worsen ischaemia Obrist1984, Cruz 1991, Muizelaar 1991,Sheinberg 1992 Obrist1984, Cruz 1991, Muizelaar 1991,Sheinberg 1992 Use of prophylactic hyperventilation (PaCO 2 < 35 mmHg) not recommended in first 24 hours after severe TBIUse of prophylactic hyperventilation (PaCO 2 < 35 mmHg) not recommended in first 24 hours after severe TBI J Neurotrauma 13;11: 1996 J Neurotrauma 13;11: 1996

21 PaCO 2 (mm Hg) CBV CBF CBF and CBV (% of value at 40 mm Hg) At 40 mm Hg CBF = 55ml/100g/min CBV = 3.6 ml/100g

22 0ml/100g/min60 Acute head injury (6 hrs post impact) Areas in red show regions with critically low blood flow Hyperventilation PaCO2: 3.3 kPa (25 mmHg) Normal ventilation PaCO2: 5.0 kPa (38 mmHg) Wolfson Brain Imaging Centre University of Cambridge

23 SjO 2 (%) Percent brain volume with OEF >75% R 2 =.627; p < Coles et al. JCBFM 2004

24 Severe Head Injury 3 studies in 1993 suggested improved outcome 3 studies in 1993 suggested improved outcome Marion et al. J Neurosurg 1993.Marion et al. J Neurosurg HI pts, GCS <8, 32-33°C 40 HI pts, GCS <8, 32-33°C Shiozaki et al. J Neurosurg 1993Shiozaki et al. J Neurosurg HI pts, GCS <8 (50% vs18% survival) 33HI pts, GCS <8 (50% vs18% survival) Clifton et al J Neurotrauma 1993Clifton et al J Neurotrauma HI pts GCS <8, 16% fall in poor outcome. 44HI pts GCS <8, 16% fall in poor outcome.

25 The New England Journal of Medicine Vol 344, No.8. February 2001; LACK OF EFFECT OF INDUCTION OF HYPOTHERMIA AFTER ACUTE BRAIN INJURY Guy L Clifton MD, Emmy R Miller PhD, RN, Sung C Choi PhD, Harvey S Levin PhD, Stephen McCauley, PhD, Kenneth R Smith Jr, MD, J Paul Muizelaar MD,PhD, Franklin C Wagner Jr, MD, Donald W Marion MD, Thomas G Luerssen MD, Randall Chestnut MD and Michael Schwartz MD.

26 The New England Journal of Medicine Vol 344, No.8. February 2001; LACK OF EFFECT OF INDUCTION OF HYPOTHERMIA AFTER ACUTE BRAIN INJURY Guy L Clifton MD, Emmy R Miller PhD, RN, Sung C Choi PhD, Harvey S Levin PhD, Stephen McCauley, PhD, Kenneth R Smith Jr, MD, J Paul Muizelaar MD,PhD, Franklin C Wagner Jr, MD, Donald W Marion MD, Thomas G Luerssen MD, Randall Chestnut MD and Michael Schwartz MD.

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31 ICP TCD Laser Doppler SjVO2 Brain tissue oxygen Near infrared Microdialysis Multimodality monitoring

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33 Meta Analysis of Brain Oxygen and Outcome in TBI 64% unfavourable when PbtO 2 < 10 mmHg64% unfavourable when PbtO 2 < 10 mmHg 27% favourable when PbtO 2 < 10 mmHg27% favourable when PbtO 2 < 10 mmHg Overall PbtO 2 <10 mmHg associated withOverall PbtO 2 <10 mmHg associated with - worse outcome (Rel Risk 2.00; 95%CI ) - higher mortality (Rel Risk 2..34; 95%CI )

34 August 2011 Favourable Unfavourable ICP/CPP 42% 58% PbtO2 61% 39%

35 Principles of microdialysis

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37 Favourable vs. Unfavourable outcome p=0.026 p=0.033 LactateL/P ratio Timofeev et al Brain 2011

38 “Tighter” glycemic control is Associated with reduced brain glucose and higher frequency of increased L/P ratio

39 Preliminary data from “normal brain” ● - median brain glucose mmol/L

40 Percent of abnormally low glucose values <1.0 mmol/L<0.5 mmol/L

41 Glucose dilemma in brain injury High levels of plasma glucose are associated with increased mortality following brain injuryHigh levels of plasma glucose are associated with increased mortality following brain injury Ample animal evidence exists of detrimental role of high glucose in ischaemia / brain injury. Possible mechanisms -- lactic acidosis, inflammation, osmotic effects...Ample animal evidence exists of detrimental role of high glucose in ischaemia / brain injury. Possible mechanisms -- lactic acidosis, inflammation, osmotic effects...vs Glucose is the main substrate for the brainGlucose is the main substrate for the brain High glucose just reflects the response to trauma and severity of injury?High glucose just reflects the response to trauma and severity of injury? Increased glucose levels may be aimed at compensation of increased demands.Increased glucose levels may be aimed at compensation of increased demands. Low cerebral glucose levels are associated with worse outcome (Vespa et al, 2003)Low cerebral glucose levels are associated with worse outcome (Vespa et al, 2003)

42 Menzel et al Response to oxygen challenge

43 OEF histogram distribution from a single patient at baseline FiO 2 (black) and hyperoxia (grey). The leftward shift with hyperoxia implies a correction of ischaemia with a measurable reduction in the ischaemic brain volume (IBV) (grey hatched area). Nortje et al – Crit Care Med 2008

44 Metabolic responses to hyperoxia Box and whisker plots show the significant increase in CMRO 2 (**p <.01, Wilcoxon Signed Rank Test), and the absence of significant changes in the other 15 O-PET parameters. The central lines in the boxes denote the median values, the upper and lower edges the 75 th and 25 th percentiles, the error bars the 90 th and 10 th percentiles and the closed circles the data points outside these percentiles. (CBF, cerebral blood flow; CBV, cerebral blood volume; OEF, oxygen extraction fraction; CMRO 2, cerebral metabolic rate for oxygen; B, baseline FiO 2 ; H, hyperoxia). Nortje et al – Crit Care Med 2008

45 Other Intervention Trials Rescue ICPRescue ICP ProTECT IIIProTECT III THAPCATHAPCA STICH 2STICH 2 STICH traumaSTICH trauma STASHSTASH

46 Monitoring Based Trials P bt O 2 targeted therapyP bt O 2 targeted therapy Hyperoxia therapyHyperoxia therapy Brain Glucose optimisationBrain Glucose optimisation Identification of relevant biomarkersIdentification of relevant biomarkers ICP/CPP outcome studiesICP/CPP outcome studies

47 CENTER TBI- (n~20,000) Improve characterization and classification of TBI, with inclusion of emerging technologies.Improve characterization and classification of TBI, with inclusion of emerging technologies. Improve health care delivery and treatment for TBI by identification of the most effective clinical interventionsImprove health care delivery and treatment for TBI by identification of the most effective clinical interventions High quality data acquisitionHigh quality data acquisition NeuroimagingNeuroimaging BiomarkersBiomarkers GeneticsGenetics

48 Protecting the Brain-Conclusions Optimising Physiology Good general Intensive Care Careful use of interventions Multimodal monitoring if available

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50 Specialist Neuro-Intensive Care TARN data ( ) Odds of death after head injury (age and severity adjusted) was 2.14times greater in non Neuro Units Odds of death after head injury (age and severity adjusted) was 2.14times greater in non Neuro Units

51 Project Impact 42 ICU’s 40,000 patients 3 years Crit Care Med 2001; 29

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55 ICP- What Threshold? 73 pts- prospective trial showing improved outcome when ICP controlled at 20mmHg with pentobarbital Eisenberg et al pts- prospective trial showing improved outcome when ICP controlled at 20mmHg with pentobarbital Eisenberg et al 1988 Regression Analysis of 1030 TBI pts showed 20mmHg correlated with outcome Marmarou et al 1991Regression Analysis of 1030 TBI pts showed 20mmHg correlated with outcome Marmarou et al pt prospective study showed no difference between 20-25mmHg Ratanalert et al pt prospective study showed no difference between 20-25mmHg Ratanalert et al 2004

56 CPP Threshold? Retrospective review of 393 patients (Hypothermia study)- Outcome worse when CPP 70mmHg (Clifton et al 2002)Retrospective review of 393 patients (Hypothermia study)- Outcome worse when CPP 70mmHg (Clifton et al 2002) Retrospective review of 427 patients (Selfotel study)- No affect on Outcome when CPP>60mmHg (Juul et al 2000)Retrospective review of 427 patients (Selfotel study)- No affect on Outcome when CPP>60mmHg (Juul et al 2000) Prospective outcome study of 131 pts- when autoregulation not intact outcome better at CPP 50-60mmHg (Howell 2005)Prospective outcome study of 131 pts- when autoregulation not intact outcome better at CPP 50-60mmHg (Howell 2005)

57 Lewin W. Recent developments in the nursing of head injuries. Nursing Mirror 1957

58 Prevention of secondary ischemic insults after severe head injury [Feature Articles] Robertson, Claudia S. MD, FCCM; Valadka, Alex B. MD; Hannay, H. Julia PhD; Contant, Charles F. PhD; Gopinath, Shankar P. MD; Cormio, Manuela MD; Uzura, Masahiko MD; Grossman, Robert G. MD Critical Care Medicine 1999 ;27(10) Recovery CBF-Targeted(%) ICP Targeted (%) p value 3 Month scores.554 Good recovery/ 29 (31.9) 30 (37.0) moderate disability Severe Disability 28 (30.8) 27 (33.3) Vegetative/dead 34 (37.4) 24 (29.6) Six month scores.491 Good recovery/ 33 (39.8) 35 (49.3) moderate disability Severe Disability 20 (24.1) 14 (19.7) Vegetative/dead 30 (36.1) 22 (31.0)

59 B CD Timofeev et al. Brain- 2011N=223 P= P=0.01

60 Optimal CPP within subject fluctuations The CPP OPT does not only differ from patient to patient. As the patient’s state changes during the stay in the ICU the optimal CPP seems to fluctuate. Setting the calculation window to 6-8 hour provides enough data to capture the CPP OPT curve and yet it is short enough to provide feedback for the intensivists. 8 hours CPP OPT calculation period

61 Critical Care Medicine 2012

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63 Jugular Bulb Common Facial Vein Jugular venous cannula Internal Jugular Vein

64 III 20% mannitol 2ml/kg X 3 or till plasma 320 mosm/l 5% NaCl 2ml/kg (repeat if Na < 155 mmol/l, Posm < 320) PAC, volume,vasoactives: trial of  CPP ( mmHg) Temp ~ 35 o C, Daily lipid screen if still on propofol EEG: ? fits -> Institute or escalate antiepileptic therapy Reduce PaCO 2 to ~ 4.0 kPa providing SjO 2 stays >> 55% Consider 0.3M THAM 1-2 ml/kg if chronically  PaCO 2 Temp 33 o C (discontinue propofol commence midazolam) CPP 25 (Check probe, ? re-CT) Addenbrooke’s NCCU: ICP/CPP management algorithm II Consider decompressive craniectomy as an alternative to medical therapy for uncontrolled intracranial hypertension

65 SjO 2 and Outcome SjO 2 and Outcome Robertson et al 1995 – 177 TBI patientsRobertson et al 1995 – 177 TBI patients SjO 2 < 50% in 39% patients Episodes Good Severe dis Death 0 44% 35% 21% >

66 Licox- Clarke Electrode

67 Direct measurement of brain tissue pO 2 (PbO 2 ) Normoxic Hypoxic (>/< 1.3 kPa) Vascular – tissue pO 2 gradient = PvO 2 – PbO 2 Gupta et al. J Neurosurg 2002; Menon et al. Crit Care Med 2004 End-capillary (venous) pO 2 from OEF (PvO 2 )

68 Table 1. Proportions of monitoring time belonging to each tissue state category Tissue StateTissue state 1 Low pH bt and low O 2 Tissue state 2 Low pH bt and normal P bt O 2 Tissue state 3 Normal pH bt and low P bt O 2 Tissue state 4 Normal pH bt and normal P bt O 2 Overall2.6%(68)16%(426)13.4%(356)68%(1815) Pericontusional brain tissue 3.8%(40)15%(157)16.6%(173)64.6%(675) Less injured brain tissue 1.7%(28)16.6%(269)11.3%(183) 70.4%(1140)

69 Critical Care Medicine 2009; 37:

70 Studies included in Analysis

71 August 2011

72 Neurocritical Care 2011

73 August 2011 Favourable Unfavourable ICP/CPP 42% 58% PbtO2 61% 39%

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75 J Neurotrauma 2007

76 Consensus Meeting on Microdialysis in Neurointensive Care. Intensive Care Med 2004;Nov 10: Bellander BM, Cantais E, Enblad P, Hutchinson P, Nordstrom CH, Robertson C, Sahuquillo J, Smith M, Stocchetti N, Ungerstedt U, Unterberg A, Olsen NV.

77 What next? Individualisation of therapyIndividualisation of therapy Identification of biomarkersIdentification of biomarkers Refining monitoring targetsRefining monitoring targets Better Data acquisition- Research NetworksBetter Data acquisition- Research Networks Genomics, Pharmacogenomics and ProteomicsGenomics, Pharmacogenomics and Proteomics

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79 Conventional imaging of TBI based on Marshall Grading of CT

80 ~ 6 weeks~6 months~1 year ~ 2 days~ 1 week Control Superior Inferior LeftRight Posterior Anterior Euler Delta Crossings (EuDX) algorithm, DiPy (Diffusion Imaging in Python)

81 TBI, 38 year old male, GCS 3 15 months post injury Control, 36 year old male FLAIR GE

82 Percent of LP values > 25 and >40 > 25>40

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84 Control seizures Prophylactic treatment if: previous epileptic on treatmentprevious epileptic on treatment compound skull fracturecompound skull fracture Treat if: witnessed fitswitnessed fits EEG evidenceEEG evidence ICP, documentation of fits not possible, other measures to ICP ineffective ICP, documentation of fits not possible, other measures to ICP ineffective

85 Therapy load with iv Phenytoin 15 mg / kgload with iv Phenytoin 15 mg / kg (at < 50 mg / min) maintenance mg / kg / 24 hrsmaintenance mg / kg / 24 hrs in 3 divided iv doses or single oral dose If persistent fits: valporate / carbamazepine / clonazepam / chlormethiazole If still uncontrolled: thiopentone

86 Hyperosmolar therapy Mannitol 20%Mannitol 20% Hypertonic Saline (5%, 7.5%)Hypertonic Saline (5%, 7.5%) Maintain osmolality < 320mmol

87 Vespa et al – CCM 2012

88 Brain glucose levels Wilcoxon paired test Glucose

89 Timofeev et al JCBFM 2013

90 Timofeev et al Brain 2011


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