Severe Sepsis and Severe Sepsis and

Septic ShockSeptic ShockJohn C. Marshall, MD FRCSCJohn C. Marshall, MD FRCSC

December 2, 2008December 2, 2008

St. Michael’s HospitalSt. Michael’s Hospital University of TorontoUniversity of Toronto

HippocratesHippocrates460 – 370 BC460 – 370 BC

SepsisSepsis

PepsisPepsis

Louis PasteurLouis Pasteur1822 - 18951822 - 1895

Fermentation Fermentation caused by living caused by living

organismsorganisms

Germ theoryGerm theoryof diseaseof disease

Richard PfeifferRichard Pfeiffer

An extract of An extract of the cell wall of the cell wall of Vibrio choleraVibrio cholera::

EndotoxinEndotoxin

- 1894- 1894

- - MMWRMMWR 48:621,1999 48:621,1999

Rates of Sepsis, U.S. 1979 - 2001Rates of Sepsis, U.S. 1979 - 2001

- Martin, - Martin, N Engl J MedN Engl J Med 348:1546, 2003 348:1546, 2003

EpidemiologyEpidemiology

• 750,000 cases a year750,000 cases a year

• 211,000 deaths annually211,000 deaths annually

- Angus et al Crit. Care Med. 29:1303, 2001- Angus et al Crit. Care Med. 29:1303, 2001

Mortality of SepsisMortality of Sepsis

- Martin, - Martin, N Engl J MedN Engl J Med 348:1546, 2003 348:1546, 2003

Microbiology of SepsisMicrobiology of Sepsis

- Martin, - Martin, N Engl J MedN Engl J Med 348:1546, 2003 348:1546, 2003

SepsisSepsis

“ “ The presence of pus-forming The presence of pus-forming organisms in the bloodstream….organisms in the bloodstream….

- - Stedman’s Dictionary, 1974Stedman’s Dictionary, 1974

“ “ The systemic host response to The systemic host response to invasive infection…”invasive infection…”

- ACCP/SCCM, 1992- ACCP/SCCM, 1992

InfectionInfectionSepsisSepsis

Systemic InflammatorySystemic InflammatoryResponse SyndromeResponse Syndrome

SIRSSIRSTraumaTrauma

PancreatitisPancreatitis

BurnsBurns

ACCP/SCCM Consensus Conference 1991ACCP/SCCM Consensus Conference 1991

SepsisSepsis The systemic host The systemic host response to infectionresponse to infection

Severe SepsisSevere Sepsis Sepsis + organ Sepsis + organ dysfunctiondysfunction

Septic ShockSeptic Shock Sepsis + Sepsis + hemodynamic hemodynamic instabilityinstability

- Bone et al - Bone et al Crit Care Med Crit Care Med 22:864, 199222:864, 1992

Sepsis Syndrome Sepsis Syndrome

• 24 year old man with penetrating 24 year old man with penetrating injury to coloninjury to colon

• 86 year old woman with CHF and 86 year old woman with CHF and Enterococcal UTIEnterococcal UTI

• 51 year old man with COPD 51 year old man with COPD exacerbation; exacerbation; CandidaCandida in sputum in sputum

How doesHow does

sepsis kill?sepsis kill?

LipopolysaccharideLipopolysaccharide (Endotoxin)(Endotoxin)

Susceptibility to LPS is Susceptibility to LPS is

Transferred with Bone Marrow CellsTransferred with Bone Marrow Cells

C3H HeJ C3H HeJ

(Resistant)(Resistant)C3H HeN C3H HeN

(Sensitive)(Sensitive)

- Michalek, - Michalek, J.Infect.Dis.J.Infect.Dis. 141:55, 1980 141:55, 1980

Susceptibility to LPS is Susceptibility to LPS is

Transferred with Bone Marrow CellsTransferred with Bone Marrow Cells

C3H HeJ C3H HeJ

(Resistant)(Resistant)C3H HeN C3H HeN

(Sensitive)(Sensitive)IRRADIATION IRRADIATION

CROSSOVER BONE MARROW TRANSPLANTCROSSOVER BONE MARROW TRANSPLANT

+ + LPSLPS

- Michalek, - Michalek, J.Infect.Dis.J.Infect.Dis. 141:55, 1980 141:55, 1980

Susceptibility to LPS is Susceptibility to LPS is

Transferred with Bone Marrow CellsTransferred with Bone Marrow Cells

C3H HeJ C3H HeJ

(Resistant)(Resistant)C3H HeN C3H HeN

(Sensitive)(Sensitive)

HeN Marrow DieHeN Marrow Die

HeJ Marrow LiveHeJ Marrow Live

IRRADIATION IRRADIATION

CROSSOVER BONE MARROW TRANSPLANTCROSSOVER BONE MARROW TRANSPLANT

+ + LPSLPS

- Michalek, - Michalek, J.Infect.Dis.J.Infect.Dis. 141:55, 1980 141:55, 1980

TLR2TLR2 Lipoteichoic acid, Bacterial Lipoteichoic acid, Bacterial lipoprotein, Injured tissue lipoprotein, Injured tissue

TLR3TLR3 Double-stranded RNADouble-stranded RNATLR4TLR4 Endotoxin, elastase, heparan, Endotoxin, elastase, heparan,

HSP60HSP60TLR5TLR5 FlagellinFlagellinTLR6TLR6 MycoplasmaMycoplasma lipopeptide lipopeptideTLR7TLR7 Imiquod, viral DNAImiquod, viral DNATLR8TLR8 Viral DNA, single-strand RNAViral DNA, single-strand RNATLR9TLR9 Bacterial DNABacterial DNA

Toll-like ReceptorsToll-like Receptors

CD14CD14

LPSLPS

Activation of NFB by LPS

MD

-2

Ubiquitination + degradation

NucleusNucleus

CytoplasmCytoplasm

TRAF6TRAF6

TAK1/TAB1TAK1/TAB1

NIKNIK

IKKIKK/IKK/IKK

p50p50 p65p65

IIBBpp pp

IRAKIRAK

TLR4TLR4

NFNFBB

MyD88MyD88

TLR4TLR4CD14CD14

EndotoxinEndotoxin

IRAKIRAKMyD88MyD88

TRAF2TRAF2

NFkBNFkB

MAP Kinases: MAP Kinases: Erk, p38, JnkErk, p38, JnkPI3 KinasePI3 Kinase

Pro-inflammatory genes:Pro-inflammatory genes:IL-1, TNFIL-1, TNF

PAF, Nitric oxide, PAF, Nitric oxide, CoagulationCoagulation

Tissue ischemia,Tissue ischemia,Cell necrosis, Cell necrosis,

apoptosisapoptosis

Mediators ofMediators ofLethality in Murine EndotoxemiaLethality in Murine Endotoxemia

CytokinesCytokines IL-1, IL-12, IL-18 TNF, IFNIL-1, IL-12, IL-18 TNF, IFN, TGF, TGFββ, , LIF,MIF, G-CSF, LIF,MIF, G-CSF, HMGB-1, MIP-1HMGB-1, MIP-1αα, , MFP-14, LBP, PTH-RPMFP-14, LBP, PTH-RPIL-1ra, IL-4, IL-10, IL-13, IFNIL-1ra, IL-4, IL-10, IL-13, IFNαα, , HGF, LIF, CRP, MCP-1, HGF, LIF, CRP, MCP-1, BPI, CAP18, TSG-14, VLDL, VIP, C3, C4, melatoninBPI, CAP18, TSG-14, VLDL, VIP, C3, C4, melatonin

ReceptorsReceptors TNFr p55, IL-1r, PAFr, LECAM-1, TREM-1, LDLr, TNFr p55, IL-1r, PAFr, LECAM-1, TREM-1, LDLr, CD11a, CD14CD11a, CD14VIPr, Adenosine A3rVIPr, Adenosine A3r

Non-proteinsNon-proteins PAF, PLAPAF, PLA22

Vitamin B12, Vitamin D3Vitamin B12, Vitamin D3

Signal Signal hck, COX-2, p38, jnk, NFhck, COX-2, p38, jnk, NFκκB, iNOS, caspase-3B, iNOS, caspase-3

transductiontransduction Stat4, Stat6, IStat4, Stat6, IκκB, HSP70, hemoxygenaseB, HSP70, hemoxygenase

CoagulationCoagulation PAI 1, Tissue FactorPAI 1, Tissue Factor

FactorsFactors TFPI, APCTFPI, APC

- Marshall - Marshall Nature Rev Drug Disc Nature Rev Drug Disc 2:391, 20032:391, 2003

“…“….. .. The major limiting The major limiting

factor after injury in patients factor after injury in patients

who do not have brain injury who do not have brain injury

is not so much a system, but is not so much a system, but

rather a combination of rather a combination of

events that can best be called events that can best be called

multiple systems failure….”multiple systems failure….”

- A.E. Baue, - A.E. Baue, Arch Surg Arch Surg 110:779-781, 1975110:779-781, 1975

The Multiple Organ The Multiple Organ Dysfunction Dysfunction

Syndrome (MODS)Syndrome (MODS)

Treatment of SepsisTreatment of Sepsis

• Intravenous fluidsIntravenous fluids

• Vasoactive drugsVasoactive drugs

• AntibioticsAntibiotics

• Surgical source controlSurgical source control

• Organ system supportOrgan system support

• ??? Therapy targeting biologic ??? Therapy targeting biologic

mediatorsmediators

Sepsis Management GuidelinesSepsis Management Guidelines

International Sepsis ForumInternational Sepsis Forum

Intensive Care MedicineIntensive Care Medicine27 (Suppl) 200127 (Suppl) 2001

www.sepsisforum.orgwww.sepsisforum.org

Surviving Sepsis CampaignSurviving Sepsis Campaign

ESICM/SCCM/ISFESICM/SCCM/ISF

Early Goal-directed TherapyEarly Goal-directed Therapyfor Septic Shockfor Septic Shock

StandardStandard Goal-DirectedGoal-Directed (N=133) (N=130)(N=133) (N=130)

MVOMVO22 65.3 65.3++11.411.4 70.4 70.4++10.7*10.7*

APACHE II 15.9APACHE II 15.9++6.4 13.06.4 13.0++6.3*6.3*

Mortality 46.5% 30.5%*Mortality 46.5% 30.5%* * p<0.02* p<0.02 - Rivers, - Rivers, N Engl J MedN Engl J Med 345:1368, 2001 345:1368, 2001

Ventilation with lower tidal volumes as compared Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury with traditional tidal volumes for acute lung injury

and the acute respiratory distress syndromeand the acute respiratory distress syndrome

Mortality (%)Mortality (%)

ControlsControls 39.839.8

Volume-limitedVolume-limited 31.0*31.0*

ARDSNet; NEJM 342:1301, 2000

*P=0.007

sTNFR1 sTNFR2 IL-1ra

Ser

um

Lev

els

(ng

/ml)

0

10

20

30

40

50

60

70

Conventional

Protective

**

**

p<0.001p<0.001

Mechanical Ventilation Evokes Mechanical Ventilation Evokes a Systemic Cytokine Responsea Systemic Cytokine Response

- Ranieri, - Ranieri, JAMAJAMA 282:54, 1999 282:54, 1999

TLR4TLR4CD14CD14

EndotoxinEndotoxin

IRAKIRAKMyD88MyD88

TRAF2TRAF2

NFkBNFkB

MAP Kinases: MAP Kinases: Erk, p38, JnkErk, p38, JnkPI3 KinasePI3 Kinase

Pro-inflammatory genes:Pro-inflammatory genes:IL-1, TNFIL-1, TNF

PAF, Nitric oxide, PAF, Nitric oxide, CoagulationCoagulation

Tissue ischemia,Tissue ischemia,Cell necrosis, Cell necrosis,

apoptosisapoptosis

Endotoxin Activity Level(ICU Patients)

0.0 0.2 0.4 0.6 0.8 1.0

Nu

mb

er

of

Su

bje

cts

0

10

20

30

40

50

60

70

Endotoxin Activity (ICU Patients)Endotoxin Activity (ICU Patients)

Randomized Trial of HA-1A in SepsisRandomized Trial of HA-1A in Sepsis

All patients 43% 39% 0.24All patients 43% 39% 0.24

Gram negative 49% 32% 0.014Gram negative 49% 32% 0.014

Gm -ve shock 57% 33% 0.017Gm -ve shock 57% 33% 0.017

Placebo HA-1A p.Placebo HA-1A p.MortalityMortality

- Ziegler, - Ziegler, N.Engl.J.Med. N.Engl.J.Med. 324:429, 1991324:429, 1991

Followup Study of HA-1AFollowup Study of HA-1A(2199 Patients)(2199 Patients)

All patients 36% 38% 0.19All patients 36% 38% 0.19

Gram negative 32% 33% 0.86Gram negative 32% 33% 0.86

Gram positive 37% 41% 0.07Gram positive 37% 41% 0.07

Placebo HA-1A p.Placebo HA-1A p.14 Day Mortality14 Day Mortality

- McCloskey, - McCloskey, Ann.Intern.Med.Ann.Intern.Med. 121:1, 1994 121:1, 1994

TNFTNFαα

TNFTNFββ (lymphotoxin)(lymphotoxin)

• 26 kDa cell surface molecule26 kDa cell surface molecule

• 17 kDa secreted molecule17 kDa secreted molecule

• Two receptors TNFR1 (p55), TNFR2 (p75)Two receptors TNFR1 (p55), TNFR2 (p75)

Time (Hours)Time (Hours)

0 5 10 15 20

Cy

tok

ine

lev

els

(p

g/m

l)C

yto

kin

e le

vel

s (

pg

/ml)

0

50

100

150

200

250TNFIL-1

IL-6

The Cytokine Response toThe Cytokine Response toEndotoxin ChallengeEndotoxin Challenge

Gentamicin 0/6

Gentamicin + Bay x1351 6/6

- Hinshaw, Circ Shock 30:279, 1990

Survival of Baboons FollowingSurvival of Baboons FollowingChallenge with Challenge with E. coliE. coli

Median (pg/ml) RangeMedian (pg/ml) Range

TNFTNF 83 83 7 – 57,151 7 – 57,151

IL-6IL-6 965 965 8 – 1,553,435 8 – 1,553,435

IL-8IL-8 2130 2130 16 – 651,338 16 – 651,338

Cytokine Levels in Human SepsisCytokine Levels in Human Sepsis

- MONARCS, Unpublished- MONARCS, Unpublished

Anti-TNF AntibodiesAnti-TNF Antibodies8 Studies; 6500 patients8 Studies; 6500 patients

28 Day Mortality28 Day Mortality

Odds Ratio: 0.93 (0.87-0.99)Odds Ratio: 0.93 (0.87-0.99)

p=0.02p=0.02

Neutralization of Pro-InflammatoryNeutralization of Pro-InflammatoryCytokines in SepsisCytokines in Sepsis

Absolute Risk Reduction (%)Absolute Risk Reduction (%)-40 -20 0 20 40 60

S. pneumoniaeS. pneumoniae

Grp. B Strep.Grp. B Strep.

S. aureusS. aureus

CLPCLP

E. coliE. coli

LPSLPS N=256N=256

N=56N=56

N=23N=23

N=14N=14

N=10N=10

N=21N=21

Influence of Infectious Challenge onInfluence of Infectious Challenge onResponse to Neutralization of TNFResponse to Neutralization of TNFαα

- Lorente & Marshall, - Lorente & Marshall, ShockShock 24 (Suppl):107, 2005 24 (Suppl):107, 2005

Absolute Risk Reduction (%)Absolute Risk Reduction (%)

-40-40 -30-30 -20-20 -10-10 00 1010 2020 3030

M. tuberculosisM. tuberculosis

ListeriaListeria

CandidaCandida

SalmonellaSalmonella N=11N=11

N=14N=14

N=10N=10

N=11N=11

- Lorente & Marshall, - Lorente & Marshall, ShockShock 24 (Suppl):107, 2005 24 (Suppl):107, 2005

Nature 2000;404:518

Protein CProtein C

• Hepatic synthesisHepatic synthesis

• Activated by thrombin:thrombomodulinActivated by thrombin:thrombomodulin

• Inhibits Factors Va, VIIIaInhibits Factors Va, VIIIa

Actions of Activated Protein CActions of Activated Protein C

• Anti-thrombotic:Anti-thrombotic: Inhibits Inhibits

microvascular coagulopathymicrovascular coagulopathy

• Anti-inflammatory: Anti-inflammatory: EPCR EPCR

transduces anti-inflammatory signaltransduces anti-inflammatory signal

• Anti-apoptotic: Anti-apoptotic: Inhibits endothelial Inhibits endothelial

cell apoptosiscell apoptosis

rhAPC Reduces Mortality in SepsisrhAPC Reduces Mortality in Sepsis

-Bernard et al; -Bernard et al; NEJM NEJM 344:649, 2001344:649, 2001

Bleeding ComplicationsBleeding Complications

PlaceboPlacebo 2.0%2.0%

rhAPCrhAPC 3.5%3.5%

P=0.06P=0.06

- Davidson et al; - Davidson et al; N Engl J Med N Engl J Med 347:1036, 2002347:1036, 2002

Corticosteroids in Septic ShockCorticosteroids in Septic Shock

Placebo Steroids p.Placebo Steroids p.

MortalityMortality 63% 53% 0.02 63% 53% 0.02

Shock Reversal 40% 57% 0.001Shock Reversal 40% 57% 0.001

Non-responders to corticotropin Non-responders to corticotropin (N = 229)(N = 229)

-Annane et al -Annane et al JAMAJAMA 288:862, 2002 288:862, 2002

Day of Study

Per

cen

t S

urv

ivin

g

0

20

40

60

80

100

0 7 14 21 280 7 14 21 28

PlaceboPlacebo

L-NMMAL-NMMAp<0.001p<0.001WilcoxonWilcoxon

Effects of L-NMMA on SurvivalEffects of L-NMMA on Survivalin Septic Shockin Septic Shock

- Lopez, - Lopez, Crit Care MedCrit Care Med 32:21, 2004 32:21, 2004

0 1 2 3 4 5 60 1 2 3 4 5 6

Study Drug BetterStudy Drug Better

All dosesAll doses

<5 mg/kg/hr<5 mg/kg/hr

> 5mg/kg/hr> 5mg/kg/hr

Dose-dependent Effects of L-NMMADose-dependent Effects of L-NMMAon Survivalon Survival

- Lopez, - Lopez, Crit Care MedCrit Care Med 32:21, 2004 32:21, 2004

Mortality Reduction in Human SepsisMortality Reduction in Human Sepsis

TargetTarget RRR (%) RRR (%)

EndotoxinEndotoxin 6 6

TNFTNF 9 9

IL-1IL-1 15 15

Activated Protein C 20 Activated Protein C 20

SteroidsSteroids 16 16

Survival of Baboons FollowingSurvival of Baboons FollowingChallenge with Challenge with E. coli E. coli

GentamicinGentamicin 0/6 0/6

Gentamicin + Bay x1351Gentamicin + Bay x1351 6/6 6/6

- Hinshaw et al, - Hinshaw et al, Circ Shock 30:279, 1990Circ Shock 30:279, 1990

Sepsis SyndromeSepsis Syndrome(Bone et al; 1987)(Bone et al; 1987)

Suspected or proven infection, in Suspected or proven infection, in association with:association with:

• TachycardiaTachycardia• TachypneaTachypnea• Hyper- or hypothermiaHyper- or hypothermia• Dysfunction of one or more organsDysfunction of one or more organs

Staging in Oncology Stratifies by:Staging in Oncology Stratifies by:

• Risk of adverse outcomeRisk of adverse outcome

• Potential to benefit from Potential to benefit from therapytherapy

The PIRO Staging SystemThe PIRO Staging System

• Pre-existing conditionsPre-existing conditions

• InsultInsult

• ResponseResponse

• Organ dysfunctionOrgan dysfunction

SCCM/ESICM Conference, Dec. 2001SCCM/ESICM Conference, Dec. 2001

““Genetic and environmental influences Genetic and environmental influences on premature death in adult adoptees”on premature death in adult adoptees”

- Sorensen TI et al; - Sorensen TI et al; N Engl J MedN Engl J Med 318:727, 1988 318:727, 1988

• 960 Danish families960 Danish families

• Children born 1924 – 1926Children born 1924 – 1926

• Early adoption into biologically Early adoption into biologically

unrelated familyunrelated family

• Early deaths in children and parentsEarly deaths in children and parents

Risk of Death: Risk of Death: Cause of Death of Adoptive ParentCause of Death of Adoptive Parent

RRRR 95% CI95% CI

All causesAll causes 1 1

Natural causesNatural causes 1 1

InfectionInfection 1 1

CardiovascularCardiovascular 3.023.02 0.72 – 12.8 0.72 – 12.8

CancerCancer 5.165.16 1.20 – 22.2 1.20 – 22.2

- Sorensen et al - Sorensen et al N Engl J MedN Engl J Med 318:727, 1988 318:727, 1988

Risk of Death: Risk of Death: Cause of Death of Biologic ParentCause of Death of Biologic Parent

RRRR 95% CI95% CI

All causesAll causes 1.711.71 1.14 – 2.57 1.14 – 2.57

Natural causesNatural causes 1.981.98 1.25 – 3.12 1.25 – 3.12

InfectionInfection 5.815.81 2.47 – 13.7 2.47 – 13.7

CardiovascularCardiovascular 4.524.52 1.32 – 15.4 1.32 – 15.4

CancerCancer 1.191.19 0.16 – 8.99 0.16 – 8.99

- Sorensen et al - Sorensen et al N Engl J MedN Engl J Med 318:727, 1988 318:727, 1988

InsultInsult

• Infection – primary, secondary, Infection – primary, secondary,

tertiarytertiary

• EndotoxinEndotoxin

• Injury, ischemiaInjury, ischemia

Followup Study of HA-1AFollowup Study of HA-1A(2199 Patients)(2199 Patients)

All patients 36% 38% 0.19All patients 36% 38% 0.19

Gram negative 32% 33% 0.86Gram negative 32% 33% 0.86

Gram positive 37% 41% 0.07Gram positive 37% 41% 0.07

Placebo HA-1A p.Placebo HA-1A p.14 Day Mortality14 Day Mortality

- McCloskey, - McCloskey, Ann.Intern.Med.Ann.Intern.Med. 121:1, 1994 121:1, 1994

Corticosteroids in Septic ShockCorticosteroids in Septic Shock

Placebo Steroids p.Placebo Steroids p.

MortalityMortality 63% 53% 0.02 63% 53% 0.02

Shock Reversal 40% 57% 0.001Shock Reversal 40% 57% 0.001

Non-responders to corticotropin Non-responders to corticotropin (N = 229)(N = 229)

-Annane et al -Annane et al JAMAJAMA 288:862, 2002 288:862, 2002

Source Control MortalitySource Control Mortality

Adequate 126 (23.1%) Adequate 126 (23.1%) (N=545)(N=545)

Inadequate 48 (39.7%)* Inadequate 48 (39.7%)* (N=121)(N=121)

* p<0.001* p<0.001

Impact of Source Control inImpact of Source Control inPatients with Low IL-6 LevelsPatients with Low IL-6 Levels

Source Control MortalitySource Control Mortality

Adequate 177 (42.3%) Adequate 177 (42.3%) (N=419)(N=419)

Inadequate 40 (47.1%)* Inadequate 40 (47.1%)* (N=85)(N=85)

* p=0.49* p=0.49

Impact of Source Control inImpact of Source Control inPatients with Patients with High High IL-6 LevelsIL-6 Levels

Baseline MOD Score

0-4 5-8 9-12 13-16 17-20 21-24

28 D

ay M

ort

ali

ty (

Per

cen

t)

0

20

40

60

80

100

PlaceboAfelimomab

*

Impact of Baseline Organ Dysfunction onImpact of Baseline Organ Dysfunction onResponse to Therapy with ~TNF AntibodyResponse to Therapy with ~TNF Antibody

*p = 0.003*p = 0.003 OR: 0.51OR: 0.51(0.32 - 0.80)(0.32 - 0.80)

.5 .6 .7 .8 .9 1.0 1.1 1.2 1.3 1.4.5 .6 .7 .8 .9 1.0 1.1 1.2 1.3 1.4

16901690

418418

543543

432432

235235

6161

Response to Drotrecogin Response to Drotrecogin αα as a as aFunction of Number of Organ FailuresFunction of Number of Organ Failures

All patientsAll patients

One OFOne OF

2 OF2 OF

3 OF3 OF

4 OF4 OF

5 OF5 OF

Challenges for Challenges for

Sepsis ResearchSepsis Research

• DescriptionDescription What is the disease?What is the disease?

• Staging Staging Who should be treated, with what?Who should be treated, with what?

• MarkersMarkers How do we titrate therapy?How do we titrate therapy?

• OrganizationOrganization Sepsis societiesSepsis societies

• Education Education * Clinicians and health care workers* Clinicians and health care workers

* Public* Public

Thank you!Thank you!