Diabetes EpidemicDiabetes Epidemic

Newsweek, September 4,Newsweek, September 4, 20002000

Newsweek, September 4,Newsweek, September 4, 20002000 Time, September 4, 2000Time, September 4, 2000Time, September 4, 2000Time, September 4, 2000

Definition Definition

Diabetes is a heterogeneous group of diseases, Diabetes is a heterogeneous group of diseases, characterized by a state of chronic characterized by a state of chronic hyperglycemia, resulting from a diversity of hyperglycemia, resulting from a diversity of etiologies, environmental and genetic, acting etiologies, environmental and genetic, acting jointlyjointly

Diabetes is a metabolic Diabetes is a metabolic disease characterized by disease characterized by

hyperglycemiahyperglycemiaresulting from defects in resulting from defects in insulin secretion, insulin insulin secretion, insulin

action, or Both.action, or Both.

(American Diabetes Association 2004).(American Diabetes Association 2004).

Disease burden of DM per hourDisease burden of DM per hour

• New Cases – 4,100

• Deaths – 810

• Amputations – 230

• Kidney Failure – 120

• Blindness - 55

Derived from NIDDK, National Diabetes Statistics fact sheet. HHS, NIH, 2005.

Diabetes means:Diabetes means:

2 x the risk of high blood pressure2 x the risk of high blood pressure 2 to 4 x the risk of heart disease2 to 4 x the risk of heart disease 2 to 4 x the risk of stroke2 to 4 x the risk of stroke #1 cause of adult blindness #1 cause of adult blindness #1 cause of kidney failure#1 cause of kidney failure Causes more than 60% of non-Causes more than 60% of non-

traumatic lower-limb amputations traumatic lower-limb amputations each yeareach year

NIDDK, National Diabetes Statistics fact sheet. HHS, NIH, 2010.NIDDK, National Diabetes Statistics fact sheet. HHS, NIH, 2010.

Global Prevalence of Diabetes Mellitus

2000 – 171 million

2030 – 366 million

2003 2025

Global Projections for the Diabetes Global Projections for the Diabetes Epidemic:2003-2025Epidemic:2003-2025

Diabetes Atlas Committee. Diabetes Atlas 2nd Edition: IDF 2003.

NORTH AMERICA

23.0 M36.2 M57.0%

19.2 M39.4 M105%

MIDDLE EAST48.4 M58.6 M21%

EUROPE

43.0 M 75.8 M

79%

WP

39.3 M81.6 M

108%

ASIA

7.1M15.0 M111%

AFR

14.2 M26.2 M85%

SOUTH AMERICA

World

2003 = 194 M2025 = 333 M

72%

Estimated Number of People with DiabetesEstimated Number of People with Diabetes in 2000 and 2030 (and % change) in 2000 and 2030 (and % change)

Wild, S et al.: Global prevalence of diabetes: Estimates for 2000 and projections for 2030 Diabetes Care 2004. In press

+176%

+26%

-13%

Estimated Number of People with Diabetes in Estimated Number of People with Diabetes in 2000 and 2030 (and % change)2000 and 2030 (and % change)

Wild, S et al.: Global prevalence of diabetes: Estimates for 2000 and projections for 2030 Diabetes Care 2004 In press

+308%

+247%

+189%

Estimated Number of People with Estimated Number of People with Diabetes in 2000 and 2030Diabetes in 2000 and 2030

Wild, S et al.: Global prevalence of diabetes: Estimates for 2000 and projections for 2030 Diabetes Care 2004 In press

+242%

+212%

+75%

Global Burden of Diabetes MellitusGlobal Burden of Diabetes Mellitus

3.2 million deaths/yr attributable to complications of 3.2 million deaths/yr attributable to complications of diabetes.diabetes.

Leading cause of non traumatic amputation, adult blindness Leading cause of non traumatic amputation, adult blindness and chronic renal failure.and chronic renal failure.

Cardiovascular disease increased 2-5 timesCardiovascular disease increased 2-5 times

Direct costs range from 2.5% to 15% of annual health care Direct costs range from 2.5% to 15% of annual health care budgets.budgets.

Diabetes in PakistanDiabetes in Pakistan

Currently Pakistan is 7th in World according to WHO estimates with 7 million peoples with Diabetes and Expected to 4th in world with 15 million peoples by year 2025 representing 2 fold increase.

(WHO, 1998 Diabetes Atlas 2003)

Etiological Classification of DiabetesEtiological Classification of Diabetes

I. Type-1 Diabetes

II. Type-2 Diabetes

III. Other Specific Types

A. Genetic defects of Beta cell function.

B. Genetic defect in Insulin Action.

C. Diseases of Exocrine Pancreas.

D. Endocrinopathies.

E. Drug or Chemical induced.

F. Infections.

G. Uncommon forms of Immune Mediated.

H. Other Genetic Syndromes associated with Diabetes.

IV. Gestational Diabetes Mellitus (GDM)(Diabetes Care, Vol 27, 2004)

Type 1 DiabetesType 1 Diabetes Formally know as IDDMFormally know as IDDM

Beta cell destruction – autoimmune Beta cell destruction – autoimmune

Tend to be under 40 yearsTend to be under 40 years

Tend to present with ketones and weight lossTend to present with ketones and weight loss

Usually LeanUsually Lean

Markers of autoimmunity – islet cell antibodiesMarkers of autoimmunity – islet cell antibodies

Family history positive in 10% of casesFamily history positive in 10% of cases

30-50% concordance in identical twins30-50% concordance in identical twins

Type 2 DiabetesType 2 Diabetes Formally known NIDDMFormally known NIDDM Disorder of insulin action and insulin Disorder of insulin action and insulin

secretionsecretion Usually obeseUsually obese Usually over 50 years – but coming Usually over 50 years – but coming

down!down! No markers of autoimmunityNo markers of autoimmunity Family history positive in 30% of Family history positive in 30% of

casescases Nearly 100% concordance in identical Nearly 100% concordance in identical

twinstwins

Common symptoms of Diabetes Common symptoms of Diabetes MellitusMellitus

Polyuria / NocturiaPolyuria / Nocturia

Excessive thirst and appetiteExcessive thirst and appetite

Weight LossWeight Loss

LethargyLethargy

Blurred VisionBlurred Vision

Skin infectionsSkin infections

Vaginal infectionsVaginal infections

Definition of Type-2 DiabetesDefinition of Type-2 Diabetes

Individual with type-2 diabetes lose the ability to produce sufficient quantities of insulin to maintain normoglycemia in the face of various degrees of Insulin Resistance.

High Risk Group for DevelopingHigh Risk Group for Developing Type-2 DM Type-2 DM

1. Obese

2. Family history of Type-2 Diabetes.

3. Age > 45.

4. Ethnicity.

5. Existing CAD, CVA, PVD, HTN.

6. Women with GDM or delivers Large Babies.

7. Women with PCOs.

8. Those with IFG and IGT Group.

Insulin ResistanceInsulin Resistance

An impaired response of a cell, tissue, organ or system, to either exogenous or endogenous insulin.

Or

State in which a given concentration of insulin produces a less than expected biological effect

It is either:

Pre receptor

Receptor

Post Receptor

Metabolic SyndromeMetabolic Syndrome

Insulin Resistance Syndrome (Metabolic Syndrome X)

Insulin Resistance & DiabetesInsulin Resistance & Diabetes

As many as 92% people

with type -2 diabetes have

insulin resistance.

Ref: Diabetes Care 1999, 22 (4)

Metabolic SyndromeMetabolic Syndrome

1. Abdominal Obesity

Diagnostic Criteria

2. Triglycerides >150mg/dl

3.HDL – Cholesterol

4.Blood Pressure

5.FBS

NCEP ATP lll (2001)

Hyperglycaemia

Euglycaemia

InsulinResistance

Insulin Action InsulinConcentration

-cell Failure

InsulinResistance

Type 2 Diabetes

-cellDysfunction

Normal IGT ± Obesity Diagnosis oftype 2 diabetes

Progression oftype 2 diabetes

Diabetes Care 1992;15:318-68

Developmental StagesDevelopmental Stages

100

-C

ell

Fu

nct

ion

(%

)*

PostprandialHyperglycemia

IGT† Type 2DiabetesPhase I Type 2

DiabetesPhase II

Type 2 DiabetesPhase III

25

75

0

50

-12 -10 -6 -2 0 2 6 10 14Years From Diagnosis

Patients treated with insulin, metformin, sulfonylureas‡

Lebovitz HE. Diabetes Rev. 1999;7:139-153.

UKPDS: UKPDS: -Cell Loss Over Time-Cell Loss Over Time

ADA Diagnostic CriteriaADA Diagnostic Criteria

Ref: ADA Clinical Practice Recommendation 2004

Normal Normal Glucose Glucose

ToleranceTolerance

Impaired Impaired Glucose Glucose

ToleranceTolerance

Diabetes Diabetes Mellitus Mellitus

Fasting Fasting Plasma Plasma Glucose Glucose (mg/dl)(mg/dl)

<100<100 100-125100-125 ≥ ≥ 126126

Two hours Two hours after after

Glucose Glucose load.load.

(mg/dl)(mg/dl)

<140<140 ≥ ≥ 140-199140-199 ≥ ≥ 200200

SymptomsSymptoms

Frequent urinationFrequent urination Excessive thirstExcessive thirst Extreme hunger or Extreme hunger or

constant eatingconstant eating Unexplained weight Unexplained weight

loss loss Presence of glucose Presence of glucose

in the urinein the urine

Tiredness or fatigue Tiredness or fatigue Changes in vision Changes in vision Numbness or Numbness or

tingling in the tingling in the extremitiesextremities

Slow-healing Slow-healing wounds or sores wounds or sores

Abnormally high Abnormally high frequency of frequency of infection infection

Many people have Many people have no symptomsno symptoms

Diabetic ComplicationsDiabetic Complications

1. Metabolic Complication Ketoacidosis

Hyperosmolar nonketotic syndrome

Hypoglycemia

2.Macrovascular ComplicationsCardiovascular disease

Cerebrovascular disease

Peripheral vascular disease

3.Microvascular Complications

Diabetic neuropathy

Diabetic retinopathy

Diabetic nephropathy Diabetologia 2002; 45: S13-S17

Chronic complications of diabetes at diagnosisChronic complications of diabetes at diagnosis

Retinopathy:

Nephropathy:

Polyneuropathy:

Erectile dysfunction:

21%

3%

11%

20%

Macrovascular:

Abnormal ECG:

Myocardial infarction:

Stroke or TIA:

Intermittant

claudication:

Absent foot pulses:

Ischaemic skin

changes to feet:

18%

1%

1%

3%

13%

6%

50% of newly presenting patients with type 2 diabetes

already have one or more complications at diagnosis(UKPDS) United Kingdom Prospective Diabetes Study. Diabetes Research 1990; 13:1-11.

Based on failure, consider:Higher order combination therapy . . .

Stepwise Management of Type 2Stepwise Management of Type 2Diabetes: Treat-to-Failure ApproachDiabetes: Treat-to-Failure Approach

Monotherapy… wait for failure

Combination therapy… wait for failure

Diet, exercise, lifestyle…wait for failure

Slide provided by Steve Edelman, MD.

Priorities of Care for Adults with Diabetes

CVD Risk

ASA, tobacco, ACEI/ARB, statin

CVD Risk

ASA, tobacco, ACEI/ARB, statin

© 2008 International Diabetes Center.

Diagnosis–PreventionDx Fasting Gluco se > 126 Casual > 200 + Symptoms

Prevent Pre-diabetes (IFG-I GT) & Me tabolic S yndrome

Diagnosis–PreventionDx Fasting Gluco se > 126 Casual > 200 + Symptoms

Prevent Pre-diabetes (IFG-I GT) & Me tabolic S yndrome

Self-Management Knowledge and SkillMonitoring Medication Problem sol ving Food plan & nutritionRisk reduction Living & copi ng Physical ac tivity

Hemoglobin A1C Target < 7.0%

SMBGPre 70-120 mg/ dL

2 hr. post < 160 mg/dL

(~ 50% of readings)

Blood Pressure(every visit)

Dxand Rx < 130/80

Annual Lipid ProfileLDL < 100HDL > 40

Trigs < 150

DM + CVDLDL < 70

Annual ScreeningNephropathy

Microalbumin screeningCalculated GFR

RetinopathyDilated retinal exam

NeuropathyNeuro and foot exam

Sexual health

Hospital careFoot care

Dental careImmunizations

GlucoseGlucose Hyp ertensionHyp ertensionLipidsLipids MicrovascularcomplicationsMicrovascularcomplications

Other essentialsof care

Other essentialsof care

TEAM APPROACH TO THE TREATMENT TEAM APPROACH TO THE TREATMENT OF THE DIABETIC PATIENTOF THE DIABETIC PATIENT

PhysicianPhysician

Fitness TrainerFitness Trainer

NurseNurseEducatorEducator

DieticianDietician

©2006. American College of Physicians. All Rights Reserved.

Optimizing glycemic control: the Optimizing glycemic control: the role of current treatmentsrole of current treatments

1UKPDS Group. Diabetologia 1991;34:877–890. 2Haffner S, et al. Diabetes Care 1999;22:562–568.3Baptist GallwitzRev Diabetic Stud (2006) 3:208-216.

• 50% of patients already have complications1

• Over 80% of patients are insulin resistant2

• Up to 50% of b-cell function has already been lost3

At diagnosis of type 2 diabetes:

The need to optimise type 2 diabetes management

EVERY 1%

reduction in HBA1C

Reduced Risk*

1%

Deaths from diabetes

Heart attacks

Microvascular complications

Peripheral vascular disorders

*p<0.0001

Intervention to effect better control Intervention to effect better control means fewer complicationsmeans fewer complications

- 37%

- 43%

- 14%

- 21%

UKPDS 35 BMJ 2000;321:405-412

•*Diet, only.•†Insulin or sulphonylurea + diet.•UKPDS, United Kingdom Prospective Diabetes Study; ADA, American Diabetes Association.

•Adapted from UKPDS Group. Lancet. 1998;352:837-853.

•Cross-sectional median values

Time From Randomization (years)Time From Randomization (years)

Conventional Treatment* (n=1138)Conventional Treatment* (n=1138)Intensive TreatmentIntensive Treatment†† (n=2729) (n=2729)

99

88

77

66

ADAADA targettarget

ADAADA actionactionsuggestedsuggested

0000 33 66 99 1212 1515

Med

ian

A1c (

%)

Med

ian

A1c (

%)

Type 2 Diabetes Is a Progressive Type 2 Diabetes Is a Progressive Disease: UKPDSDisease: UKPDS

Adapted from Stratton IM, et al. UKPDS 35. BMJ 2000; 321:405–412.

UKPDS: decreased risk of diabetes-related complications UKPDS: decreased risk of diabetes-related complications associated with a 1% decrease in A1Cassociated with a 1% decrease in A1C

Perc

en

tag

e d

ecr

ease

in

rela

tive r

isk

corr

esp

on

din

g t

o a

1%

decr

ease

in

Hb

A1

C

Any diabetes-related

endpoint

21%

All cause

mortality

14%

Stroke

12%

Peripheral vascular disease†

43%

Myocardial infarction

14%

Micro-vascular disease

37%

Cataract extraction

19%

Observational analysis from UKPDS study data

Goals of drug therapyGoals of drug therapy1.Reduce insulin resistance, and in 1.Reduce insulin resistance, and in

turn, the demands on the beta turn, the demands on the beta cellcell

2.Increase 2.Increase -cell function-cell function

3.Sustain glucose lowering3.Sustain glucose lowering

4.Safe & Economical4.Safe & Economical

5.Reduce CVD risk5.Reduce CVD risk

Sites of action of the current  and possible pharmacological Sites of action of the current  and possible pharmacological therapies for the treatment of type 2 diabetes.therapies for the treatment of type 2 diabetes.

EducationEducation

Structured Patients education is an Integral Part of the Management of type-2 diabetes

It Includes:

• Knowledge of Diabetes

• SMBG, Annual Review Examination.

• Foot Care

• Medical Nutrition Therapy

• Physical Activity

Through:

• Individual Counseling

• Group Counseling

• Self Help Group

• Literature , Brochure, Diet Chart, Electronics & Print Media & Internet.

Make Healthy Food ChoicesMake Healthy Food Choices

80% of heart disease, stroke & type 2 diabetes and 40% of cancer could be prevented through

Healthy dietRegular physical activityAvoidance of tobacco products

Preventive Strategies

Make Healthy Food ChoicesMake Healthy Food Choices

Make Healthy Food ChoicesMake Healthy Food Choices

Make Healthy Food ChoicesMake Healthy Food Choices

Diabetes and LifestyleDiabetes and Lifestyle

Lifestyle changes Lifestyle changes can mean the can mean the

difference difference between between

developing developing diabetes or notdiabetes or not

•Conclusions

• Glycaemic control significantly reduces diabetes complications

• Early glycaemic control is associated with a long-lasting ‘legacy’ effect, in reducing later complications (macro + microvascular)

• Implications for patient care

• Early intervention to achieve and maintain glycaemic targets is critical

• Treatment should be individualised, to maintain an optimal balance between the benefits and risks of an intensive glucose control

• Maintain HbA1c as close to normal as safely possible

26 million with Diabetes

79 millionwith Pre-Diabetes

Problem StatementProblem Statement

Iceberg Disease Increased prevalence in newly industrialized and

developing countries. Disease acquired in the most productive period of

their life. 20% of current global diabetic population resides

in the SEAR.

Undiagnosed or inadequately treated patients develop multiple chronic complications.

Lack of awareness about interventions for prevention and management of complications.

Epidemiological DeterminantsEpidemiological Determinants

AGENT FACTORSAGENT FACTORS

Pancreatic disorders

Defects in formn of insulin

Destruction of beta cells

Decreased insulin sensitivity

Genetic defects

Autoimmunity

AgeSexGenetic factorsGenetic markers – HLA-B8, B15, HLA

DR3 & DR4Immune mechanismsObesityMaternal diabetes

HOST FACTORSHOST FACTORS

Sedentary lifestyleDietDietary fiberMalnutritionAlcoholViral infectionsChemical agentsStressOthers

ENVIRONMENTAL FACTORSENVIRONMENTAL FACTORS

Prevention And CarePrevention And Care

PRIMARY PREVENTION Population Strategy High Risk Strategy

SECONDARY PREVENTION

TERTIARY PREVENTION

Screening for DMScreening for DM

TARGET POPULATION

Questionnaires used alone tend to work poorly;

Biochemical tests alone or in combination with assessment of risk factors are a better alternative.

G.C.T; Gold standard testHBA1c test

Diabetes and Obesity, Time to Act, p.33, IDF 2004

Study Year Interventions Outcome

DaQing (China)

1997 Diet, physical activity or both (control group: general)

Reduction in diabetes incidence 31% in diet group, 46% in physical activity and 42% in diet and physical activity compared to control group

Finnish Diabetes Prevention Study

2001 Diet and physical activity (control group: general advice)

Reduction by 58% of the risk of diabetes compared to control group

Diabetes Prevention Program (USA)

2002 Diet, physical activity, metformin and placebo

58% reduction in incidence of diabetes with lifestyle intervention, 31% with metformin

STOP-NIDDM

2002 Acarbose or placebo

32% patients randomised to acarbose and 42% randomised to placebo developed diabetes

Primary Prevention of Type 2 Diabetes Primary Prevention of Type 2 Diabetes

The Diabetes Prevention Program (DPP): The The Diabetes Prevention Program (DPP): The New Frontier: Lifestyle Modifications or New Frontier: Lifestyle Modifications or

MedicationMedication Goal: To prevent or delay the development of type 2 Goal: To prevent or delay the development of type 2

diabetes in persons with impaired glucose tolerance (IGT)diabetes in persons with impaired glucose tolerance (IGT)

High-risk individuals with IGT and elevated FPG (N=3234) High-risk individuals with IGT and elevated FPG (N=3234) randomized torandomized to

• PlaceboPlacebo

• Intensive lifestyle intervention; at least monthly contact Intensive lifestyle intervention; at least monthly contact with case managers with case managers

• Metformin titrated to 850 mg bidMetformin titrated to 850 mg bid Reduction at 2.8 yearsReduction at 2.8 years

• 58%58% in the intensive lifestyle intervention group in the intensive lifestyle intervention group• 31%31% in the metformin group in the metformin group

The Diabetes Prevention Program Research Group. Diabetes Care. 1999;22:623.NIDDK. http://www.niddk.nih.gov/welcome/releases/8_8_01.htm.

National Diabetes Prevention ProgramNational Diabetes Prevention Program

Goal:Goal: Systematically scale the translated Systematically scale the translated

model of the Diabetes Prevention model of the Diabetes Prevention Program (DPP) for high risk persons Program (DPP) for high risk persons in collaboration with community-in collaboration with community-based organizations that have based organizations that have necessary infrastructure, health necessary infrastructure, health payers, health care professionals, payers, health care professionals, public health, academia, and others public health, academia, and others to reduce the incidence of type 2 to reduce the incidence of type 2 diabetes in the United Statesdiabetes in the United States.

Goal:Goal: Systematically scale the translated Systematically scale the translated

model of the Diabetes Prevention model of the Diabetes Prevention Program (DPP) for high risk persons Program (DPP) for high risk persons in collaboration with community-in collaboration with community-based organizations that have based organizations that have necessary infrastructure, health necessary infrastructure, health payers, health care professionals, payers, health care professionals, public health, academia, and others public health, academia, and others to reduce the incidence of type 2 to reduce the incidence of type 2 diabetes in the United Statesdiabetes in the United States.

www.cdc.gov/diabetes/prevention

Type 2 diabetesType 2 diabetes, ,

the the metabolic syndromemetabolic syndrome

and and cardiovascular diseasecardiovascular disease

in Europein Europe

70%–80% of people with diabetes die of 70%–80% of people with diabetes die of cardiovascular disease.cardiovascular disease.

For each risk factor present, the risk of For each risk factor present, the risk of cardiovascular death is about three times greater cardiovascular death is about three times greater in people with diabetes as compared to people in people with diabetes as compared to people without the condition. without the condition.

Cardiovascular disease is the number one cause Cardiovascular disease is the number one cause of death in industrialized countries. It is also set of death in industrialized countries. It is also set to overtake infectious diseases as the most to overtake infectious diseases as the most common cause of death in many parts of the less common cause of death in many parts of the less developed world.developed world.

Diabetes and cardiovascular diseaseDiabetes and cardiovascular disease

The annual direct healthcare costs of diabetes The annual direct healthcare costs of diabetes worldwide, for people in the 20 – 79 age bracket, worldwide, for people in the 20 – 79 age bracket, is estimated to be at least 153 billion is estimated to be at least 153 billion international dollars. international dollars.

It is estimated that diabetes accounts for It is estimated that diabetes accounts for between 5% and 10% of total healthcare between 5% and 10% of total healthcare spending in most countries and up to 25% spending in most countries and up to 25% in some.in some.

If predictions of diabetes prevalence are fulfilled, If predictions of diabetes prevalence are fulfilled, total direct healthcare expenditure on diabetes total direct healthcare expenditure on diabetes worldwide will be between 213 billion and 396 worldwide will be between 213 billion and 396 billion international dollars in 2025.billion international dollars in 2025.

The cost of diabetes The cost of diabetes

Direct health care costs of diabetes are high and Direct health care costs of diabetes are high and risingrising

Direct health care costs of the metabolic Direct health care costs of the metabolic syndrome dominate health care budgetssyndrome dominate health care budgets

Preventing or delaying the onset of Preventing or delaying the onset of type 2 diabetes results in considerable type 2 diabetes results in considerable cost reductioncost reduction

Improving metabolic control can also reduce Improving metabolic control can also reduce health care resource usehealth care resource use

The cost of diabetesThe cost of diabetes

Implications for health systemsImplications for health systems

The human and economic costs of diabetes could The human and economic costs of diabetes could be significantly reduced by investing in be significantly reduced by investing in prevention, particularly early detection, in prevention, particularly early detection, in order to avoid the onset of diabetic complications.order to avoid the onset of diabetic complications.

At least 50% of all people with diabetes At least 50% of all people with diabetes are unaware of their condition.  are unaware of their condition. 

In some countries this figure may rise In some countries this figure may rise to 80%.to 80%.

Managing Diabetes and Managing Diabetes and Diabetic ComplicationsDiabetic Complications

CONCLUSIONSCONCLUSIONS A growing diabetes pandemic is unfolding with rapid A growing diabetes pandemic is unfolding with rapid

increases in the prevalence of type 2 diabetes.increases in the prevalence of type 2 diabetes.

effective interventions to prevent diabetes and its effective interventions to prevent diabetes and its complications is availablecomplications is available

diabetes education as an essential intervention.diabetes education as an essential intervention.

interventions at the level of the patient, provider, and interventions at the level of the patient, provider, and system that could help address the overall suboptimal system that could help address the overall suboptimal quality of diabetes care;quality of diabetes care;

Thank youThank you