Download Free Medical Cardiometabolic Syndrome PowerPoint Presentation

Cardiometabolic Syndrome PowerPoint Presentation

DOWNLOAD MEDICAL POWERPOINT PRESENTATION

About This Presentation

Description : Check out this medical PowerPoint presentation titled "Cardiometabolic Syndrome" by Dr. Nabil Sulaiman and Dr Dhafir A. Mahmood.

This medical PowerPoint presentation talks about ardiometabolic syndrome (CMS), also known as metabolic syndrome or insulin resistance syndrome. Ardiometabolic syndrome is a cluster of risk factors that increase the likelihood of developing cardiovascular disease and type 2 diabetes.

Tags : ardiometabolic syndrome, metabolic syndrome, insulin resistance syndrome, cardiovascular disease, type 2 diabetes, endocrinology, endocrinology PowerPoint presentation

Published on : Apr 18, 2023 | Views : 922 | Downloads : 3

Shareable Url :

Embed Code :

Comment

Transcript

Slide 1-

Cardiometabolic Syndrome Dr. Nabil Sulaiman HOD Family and Community Medicine, Sharjah University and University of Melbourne & Dr Dhafir A. Mahmood Consultant Endocrinologist Al- Qassimi & Al-Kuwait Hospital Sharjah
Slide 2-

Agenda History & Definition Clustering component of Metabolic Syndrome Cardiovascular disease worldwide Global cardiometabolic risks Abdominal obesity prevalence ( National & International ) Intra Abdominal Adiposity & associated risks Targeting Cardiometabolic Risk factors Multiple Risk Factor management A Critical Look at the Metabolic Syndrome
Slide 3-

Metabolic Syndrome (History) 1923 - Kylin first to describe the clustering of hypertension, hyperglycemia, hyperuricemia 1936 - Himsworth first reported Insulin insensitivity in diabetics 1965 - Yalow and Berson developed insulin assay and correlated insulin levels & glucose lowering effects in resistant and non-resistant individuals
Slide 4-

Metabolic Syndrome History (cont.) 1988 - Reaven in his Banting lecture at the ADA meeting coined the term Syndrome X and brought into focus the clustering of features of Metabolic Syndrome Reaven now prefers the name, Insulin-Resistance Syndrome - feels insulin resistance is the common denominator for Metabolic Syndrome Literature now extensive
Slide 5-

Other Names Used: Syndrome X Cardiometabolic Syndrome Cardiovascular Dysmetabolic Syndrome Insulin-Resistance Syndrome Metabolic Syndrome Beer Belly Syndrome Reaven’s Syndrome etc.
Slide 6-

Clustering of Components: Hypertension: BP. > 140/90 Dyslipidemia: TG > 150 mg/ dL ( 1.7 mmol/L ) HDL- C < 35 mg/ dL (0.9 mmol/L) Obesity (central): BMI > 30 kg/M2 Waist girth > 94 cm (37 inch) Waist/Hip ratio > 0.9 Impaired Glucose Handling: IR , IGT or DM FPG > 110 mg/dL (6.1mmol/L) 2hr.PG >200 mg/dL(11.1mmol/L) Microalbuninuria (WHO)
Slide 7-

Necessary Criteria to Make Diagnosis WHO: Impaired G handling + 2 other criteria. Also requires microalbuminuria - Albumen/ creatinine ratio >30 mg/gm creatinine IDF: Require central obesity plus two of the other abnormalities NCEP/ATP III: Require three or more of the five criteria
Slide 8-

What is cardiometabolic risk?* Global cardiometabolic risk represents the overall risk of developing type 2 diabetes and/or cardiovascular disease (including MI and stroke), which is due to a cluster of modifiable risk factors/markers These include classical risk factors such as smoking, high LDL, hypertension, elevated blood glucose and emerging risk factors closely related to abdominal obesity (especially intra-abdominal adiposity), such as insulin resistance, low HDL, high triglycerides and inflammatory markers Cardiometabolic risk is based on the concept of risk continuum * working definition MI: myocardial infarction; LDL: low-density lipoprotein; HDL: high-density lipoprotein
Slide 9-

Global cardiometabolic risk* Gelfand EV et al, 2006; Vasudevan AR et al, 2005 * working definition
Slide 10-

Despite therapeutic advances, CV disease remains the leading cause of death (USA) Number of deaths (thousands) % of all deaths(right axis) No. of deaths(left axis) % All deaths (male + female) National Center for Health Statistics, 2004 Data for 2002
Slide 11-

Substantial residual cardiovascular risk in statin-treated patients Placebo Statin Year of follow-up % patients 0 1 2 3 4 5 6 10 20 30 0 Risk reduction=24% (p<0.0001) The MRC/BHF Heart Protection Study Heart Protection Study Collaborative Group, 2002 19.8% of statin-treatedpatients had a majorcardiovascular event by 5 years
Slide 12-

Abdominal obesity has reached epidemic proportions worldwide Prevalence of abdominal obesity by region 1. Ford ES et al, 2003; 2 Haftenberger M et al, 2002; 3. Kim MH et al 2004; 4. Cameron AJ et al, 2003; 5. Puoane T et al, 2002
Slide 13-

Targeting Cardiometaboilc Risk Defining cardiometabolic Risk What is Abdominal Obesity ? Can be defined by Waist Circumference;
Slide 14-

Obesity: IDF: Central obesity - waist circumference >94 cm for Europid men, >80 Europid women with ethnicity specific values for other groups WHO: Waist-hip ratio >0.9 - men or >0.85 - women ATP III: Waist circumference >40 in. - men, > 35 in. - women
Slide 15-

Fat Topography In Type 2 Diabetic Subjects Intramuscular Intrahepatic Subcutaneous Intra- abdominal FFA* TNF-alpha* Leptin* IL-6 (CRP)* Tissue Factor* PAI-1* Angiotensinogen*
Slide 16-

Patients with abdominal obesity often present with one or more additional cardiovascular risk factors (NCEP ATP III criteria) Abdominal obesity is linked to multiple cardiometabolic risk factors National Cholesterol Education Panel/Adult Treatment Panel III, 2002 HDL: high-density lipoprotein; BP: blood pressure
Slide 17-

Targeting Cardiometaboilc Risk Defining cardiometabolic Risk 86% At least 1 additional CM risk factor 24% 2 or more additional CM risk factors
Slide 18-

Abdominal obesity and increased risk of cardiovascular events Dagenais GR et al, 2005 Adjusted relative risk 1 1 1 1.17 1.16 1.14 1.29 1.27 1.35 0.8 1 1.2 1.4 CVD death MI All-cause deaths Tertile 1 Tertile 2 Tertile 3 Men Women <95 95–103 >103 <87 87–98 >98 Waistcircumference (cm): The HOPE study Adjusted for BMI, age, smoking, sex, CVD disease, DM, HDL-cholesterol, total-C; CVD: cardiovascular disease; MI: myocardial infarction; BMI: body mass index; DM: diabetes mellitus; HDL: high-density lipoprotein cholesterol
Slide 19-

Abdominal obesity predicts adverse outcomes such as sudden death Quintile of SAD The Paris Prospective study Empana JP et al, 2004 Quintile 1 2 3 4 5 SAD (cm) 12–19 20–21 22–23 24 25–35 BMI (kg/m2) <23.2 23.2–24.9 25.0–26.6 26.7–28.4 28.5–47.7 SAD: sagittal abdominal diameter; BMI: body mass index
Slide 20-

Abdominal obesity increases the risk of developing type 2 diabetes <71 71–75.9 76–81 81.1–86 86.1–91 91.1–96.3 >96.3 24 20 16 12 8 4 0 Relative risk Waist circumference (cm) Carey VJ et al, 1997
Slide 21-

Abdominal obesity is linked to an increased risk of coronary heart disease Waist circumference has been shown to be independently associated with increased age-adjusted risk of CHD, even after adjusting for BMI and other cardiovascular risk factors Rexrode KM et al, 1998 CHD: coronary heart disease; BMI: body mass index
Slide 22-

Diabetes in the new millenniumInterdisciplinary problem Diabetes
Slide 23-

Diabetes in the new millenniumInterdisciplinary problem OBESITY
Slide 24-

Diabetes in the new millenniumInterdisciplinary problem DIAB ESITY
Slide 25-

Targeting Cardiometabolic Risk
Slide 26-

Intra-abdominal adiposity is a major contributor to increased cardiometabolic risk Kershaw EE et al, 2004; Lee YH et al, 2005; Boden G et al, 2002 Inflammation Insulin resistance Dyslipidaemia Increased cardiometabolic risk IAA = high risk fat IAA: intra-abdominal adiposity
Slide 27-

Abdominal obesity: a major underlying cause of acute myocardial infarction Yusuf S et al, 2004 aProportion of MI in the total population attributable to a specific risk factor; CVD: cardiovascular disease; BMI: body mass index; PAR: population attributable risk; MI: myocardial infarction Cardiometabolic risk factors in the INTERHEART Study PAR (%)a Abdominal obesity predicts the risk of CVD beyond BMI 0 20 40 60 18 Hypertension 10 Diabetes 20 Abdominal obesity 49 Abnormallipids
Slide 28-

Pouliot MC et al, 1992 IAA: intra-abdominal adiposity; significantly different from 1non-obese, 2obese with low intra-abdominal adiposity levels Non-obese Obese low IAA Obese high IAA Intra-abdominal adiposity and glucose metabolism
Slide 29-

Intra-abdominal adiposity is closely correlated with abdominal obesity To assess IAA, the simplest measure of abdominal obesity is waist circumference, which is strongly correlated with direct measurement of IAA by CT scan or MRI, considered to be the gold standard Després JP et al, 2001; Pouliot MC et al, 2004 300 200 100 0 r = 0.80 60 80 100 120 IAA Waist circumference (cm) IAA (cm2) IAA: intra-abdominal adiposity; CT: computed tomography; MRI: magnetic resonance imaging
Slide 30-

Waist Circumference
Slide 31-

Intra-abdominal adiposity and dyslipidaemia Pouliot MC et al, 1992 310 248 186 124 62 0 60 45 30 mg/dL mg/dL Triglycerides Lean HDL-cholesterol Visceral fat(obese subjects) Low High Lean Visceral fat(obese subjects) Low High HDL: high-density lipoprotein
Slide 32-

IAA: intra-abdominal adiposity; IL-6: interleukin-6; TNF-α: tumour necrosis factor-α; PAI-1: plasminogen activator inhibitor-1 Marette A, 2002 Properties of key adipokines
Slide 33-

Relationship between adiponectin levels and risk of myocardial infarction Pischon T et al, 2004 Relative risk (95% CI) Risk of MI for highest vs lowest quintile of adiponectin Adjusted for age;date of blooddraw; smoking + Adjusted for familyhistory; alcohol;exercise + Adjusted for HbA1C;CRP; HDL-cholesterol;LDL-cholesterol p<0.001 p<0.001 p=0.02 0.0 0.2 0.4 0.6 0.8 1.0 MI: myocardial infarction; HbA1c: haemoglobin A1c; CRP: C-reactive protein; HDL: high-density lipoprotein; LDL: low-density lipoprotein
Slide 34-

Targeting Cardiometaboilc Risk Defining cardiometabolic Risk Cardiovascular Disease Abdominal Obesity Glucose intolerance Insulin Resistance Dyslipedemia Hypertension
Slide 35-

Targeting Cardiometaboilc Risk Defining cardiometabolic Risk Major Unmet Clinical Need Classical Risk Factors Novel Risk Factors Cluster Risk Factors LDL-C BP Smoking DM-2 Insulin HDL-C TNF & IL-6 Abdominal Obesity Glucose PAI-1 TG Cardiovascular Disease
Slide 36-

Targeting Cardiometaboilc Risk Site of Action Mechanisms Addresses Adipose tissues Adiponectin Dyslipidemia Lipogeenesis Insulin resistance Muscle G uptake Insulin resistance Liver Lipogeenesis Dyslipidemia Insulin resistance GI tract Satiety signals Body weight Waist circumference Hypothalamus Food intake Body weight Waist circumference
Slide 37-

Linked Metabolic Abnormalities: Impaired glucose handling/ insulin resistance Atherogenic dyslipidemia Endothelial dysfunction Prothrombotic state Hemodynamic changes Proinflammatory state Excess ovarian testosterone production Sleep-disordered breathing
Slide 38-

Resulting Clinical Conditions: Type 2 diabetes Essential hypertension Polycystic ovary syndrome (PCOS) Nonalcoholic fatty liver disease Sleep apnea Cardiovascular Disease (MI, PVD, Stroke) Cancer (Breast, Prostate, Colorectal, Liver)
Slide 39-

Multiple Risk Factor Management Obesity Glucose Intolerance Insulin Resistance Lipid Disorders Hypertension Goals: Minimize Risk of Type 2 Diabetes and Cardiovascular Disease
Slide 40-

Glucose Abnormalities: IDF: FPG >100 mg/dL (5.6 mmol. L) or previously diagnosed type 2 diabetes WHO: Presence of diabetes, IGT, IFG, insulin resistance ATP III: FBS >110 mg/dL, <126 mg/dL (6.1-7.1 mmol/L ) (ADA: FBS >100 mg/dL [ 5.6 mmol/L ])
Slide 41-

Hypertension: IDF: BP >130/85 or on Rx for previously diagnosed hypertension WHO: BP >140/90 NCEP ATP III: BP >130/80
Slide 42-

Dyslipidemia: IDF: Triglycerides - >150mg/dL (1.7 mmol /L) HDL - <40 mg/dL (men), <50 mg/dL (women) WHO: Triglycerides - >150 mg/dL (1.7 mmol/L) HDL - <35 mg/dL (men), >39 mg/dL) women ATP III: Same as IDF
Slide 43-

Adipocytokines and Insulin Resistance Adipokines and Metabolic Syndrome
Slide 44-

INSULIN MODULATION OF ENDOTHELIAL ACTIVITIES
Slide 45-

ppt slide no 45 content not found
Slide 46-

Insulin Resistance: Hyperinsulinemic individuals are at risk for developing Diabetes, Dyslipidemia, Hypertension & ultimately Cardiovascular disease Patients with Metabolic Syndrome are 3.5 times as likely to die from Cardiovascular disease compared to normal people
Slide 47-

Screening/Public Health Approach Public Education Screening for at risk individuals: Blood Sugar/ HbA1c Lipids Blood pressure Tobacco use Body habitus Family history
Slide 48-

Life-Style Modification: Is it Important? Exercise Improves CV fitness, weight control, sensitivity to insulin, reduces incidence of diabetes Weight loss Improves lipids, insulin sensitivity, BP levels, reduces incidence of diabetes Goals: Brisk walking - 30 min./day 10% reduction in body wt.
Slide 49-

Smoking Cessation / Avoidance: A risk factor for development in children and adults Both passive and active exposure harmful A major risk factor for: insulin resistance and metabolic syndrome macrovascular disease (PVD, MI, Stroke) microvascular complications of diabetes pulmonary disease, etc.
Slide 50-

Diabetes Control - How Important? For every 1% rise in Hb A1c there is an 18% rise in risk of cardiovascular events & a 28% increase in peripheral arterial disease Evidence is accumulating to show that tight blood sugar control in both Type 1 and Type 2 diabetes reduces risk of CVD Goals: FBS - premeal <110, postmeal <180. HbA1c <7%
Slide 51-

Overcome Insulin Resistance/ Diabetes: Insulin Sensitizers: Biguanides - metformin PPAR α, γ & δ agonists – Glitazones, Gltazars Rosiglitazon, Pioglitazon Can be used in combination Insulin Secretagogues: Sulfonylurea - glipizide, glyburide, glimeparide, glibenclamide Meglitinides - repaglanide, netiglamide
Slide 52-

Insulin Insulin Analogues: Lyspro /Aspart /glulysine used with meals Glargine & Livemer as basal insulin Continuous Subcutaneous Insulin Infusion (CSII) NPH/Regular, NPH/logs - Mixed or in fixed combinations (70/30, 75/25, 50/50) Insulin combined with oral agents
Slide 53-

BP Control - How Important? MRFIT and Framingham Heart Studies: Conclusively proved the increased risk of CVD with long-term sustained hypertension Demonstrated a 10 year risk of cardiovascular disease in treated patients vs non-treated patients to be 0.40. 40% reduction in stroke with control of HTN Precedes literature on Metabolic Syndrome Goal: BP.<130/80
Slide 54-

Lipid Control - How Important? Multiple major studies show 24 - 37% reductions in cardiovascular disease risk with use of statins and fibrates in the control of hyperlipidemia. Goals: LDL <100 mg/dL (<3.0 mmol /l) (high risk <70 mg/dL- <2.6 mmol/L) TG <150 mg% (<1.7 mmol /l) HDL >40 mg% (>1.1 mmol /l)
Slide 55-

Medications: Hypertension: ACE inhibitors, ARBs Others - thiazides, calcium channel blockers, beta blockers, alpha blockers Central acting Alfa agonist : Moxolidin Dylipidemia: Statins, Fibrates, Niacin Platelet inhibitors: ASA, clopidogrel
Slide 56-

Antihypertensive Medications: Angiotensin -converting Enzyme Inhibitors (ACEI) Angiotensin II Receptor (ARB) Blockers Combination with Thiazides, Calcium Channel Blockers, Cardioselective Beta Blockers Target BP: <130/80
Slide 57-

A Critical Look at the Metabolic Syndrome Is it a Syndrome?* “…too much clinically important information is missing to warrant its designations as a syndrome.” Unclear pathogenesis, Insulin resistance may not underlie all factors, & is not a consistent finding in some definitions. CVD risks associated with metabolic syndrome has not shown to be greater than the sum of it’s individual components. *ADA & EASD
Slide 58-

A Critical Look at the Metabolic Syndrome “Until much needed research is completed, clinicians should evaluate and treat all CVD risk factors without regard to whether a patient meets the criteria for diagnosis of the ‘metabolic syndrome’.” The advice remains to treat individual risk factors when present & to prescribe therapeutic lifestyle changes & weight management for obese patients with multiple risk factors.
Slide 59-

Individual metabolic abnormalities among Qatari population according to gender (Musallam et al 08) Men (n = 405) Women (n=412) Variable n(%) n(%) p-Value ATP III Abdominal obesity 227(56.0) 308(74.8) <0.001 Hypertension 143(35.3) 156(37.9) 0.448 Diabetes 77(19.0) 107(26.0) 0.017 Hypertriglyceridemia 113(27.9) 83(20.1) 0.009 Low HDL 95(23.5) 121(29.4) 0.055
Slide 60-

Individual metabolic abnormalities among Qatari population according to gender Men (n = 405) Women (n=412) Variable n(%) n(%) p-Value None 88(21.7) 74(18.0) – One 103(25.4) 100(24.3) 0.033 Two 125(30.9) 111(26.9) – Three or more 89(22.0) 127(30.8) – No of components of ATP III
Slide 61-

Multivariate logistic regression analysis of factors associated with Metabolic Syndrome according to (ATP III criteria) Odds ratio 95% CI p-Value Age 1.07 1.05–1.09 <0.001 Female gender 1.86 1.30–2.67 0.001 Body Mass Index 1.05 1.02–1.07 <0.001 Fam his of DM 1.66 1.12–2.44 0.011 Smoking 3.27 1.63–6.55 0.001
Slide 62-

Prevalence of MeS in different Countries * Crude rates Mussallam et al. Int J Food Safety and PH 2008
Slide 63-

Prevalence of MeS in different Countries * Crude rates Mussallam et al. Int J Food Safety and PH 2008
Slide 64-

ppt slide no 64 content not found
Slide 65-

ppt slide no 65 content not found
Slide 66-

ppt slide no 66 content not found
Slide 67-

Thank You
Slide 68-

Determinants and dynamics of the CVD Epidemic in the developing Countries Data from South Asian Immigrant studies Excess, early, and extensive CHD in persons of South Asian origin The excess mortality has not been fully explained by the major conventional risk factors. Diabetes mellitus and impaired glucose tolerance highly prevalent. (Reddy KS, circ 1998). Central obesity, ↑triglycerides, ↓HDL with or without glucose intolerance, characterize a phenotype. genetic factors predispose to ↑lipoprotein(a) levels, the central obesity/glucose intolerance/dyslipidemia complex collectively labeled as the “metabolic syndrome”
Slide 69-

Determinants and dynamics of the CVD epidemic in the developing countries Other Possible factors Relationship between early life characteristics and susceptibility to NCD in adult hood ( Barker’s hypothesis) (Baker DJP,BMJ,1993) Low birth weight associated with increased CVD Poor infant growth and CVD relation Genetic–environment interactions (Enas EA, Clin. Cardiol. 1995; 18: 131–5) Amplification of expression of risk to some environmental changes esp. South Asian population) Thrifty gene (e.g. in South Asians)
Slide 70-

CVD epidemic in developing &developed countries. Are they same? Urban populations have higher levels of CVD risk factors related to diet and physical activity (overweight, hypertension, dyslipidaemia and diabetes) Tobacco consumption is more widely prevalent in rural population The social gradient will reverse as the epidemics mature. The poor will become progressively vulnerable to the ravages of these diseases and will have little access to the expensive and technology-curative care. The scarce societal resources to the treatment of these disorders dangerously depletes the resources available for the ‘unfinished agenda’ of infectious and nutritional disorders that almost exclusively afflict the poor
Slide 71-

Burden of CVD in Pakistan Coronary heart disease Mortality statistics Specific mortality data ideal for making comparisons with other countries are not available Inadequate and inappropriate death certification, and multiple concurrent causes of death
Slide 72-

Central obesity: a driving force for cardiovascular disease & diabetes “Balzac” by Rodin Front Back
Slide 73-

Developing A New Definition of the Metabolic Syndrome: IDF Objectives Needs: To identify individuals at high risk of developing cardiovascular disease (and diabetes) To be useful for clinicians To be useful for international comparisons
Slide 74-

The new IDF definition focusses on abdominal obesity rather than insulin resistance International Diabetes Federation (IDF) Consensus Definition 2005
Slide 75-

Why people physically inactive? Lack of awareness regarding the of physical activity for health fitness and prevention of diseases Social values and traditions regarding physical exercise (women, restriction). Non-availability public places suitable for physical activity (walking and cycling path, gymnasium). Modernization of life that reduce physical activity (sedentary life, TV, Computers, tel, cars).
Slide 76-

Insulin Resistance: Associated Conditions
Slide 77-

Prevalence of the Metabolic Syndrome Among US Adults NHANES 1988-1994 Age (years) Ford E et al. JAMA. 2002(287):356. 1999-2002 Prevalence by IDF vs. NCEP Definitions (Ford ES, Diabetes Care 2005; 28: 2745-9) (unadjusted, age 20+) NCEP : 33.7% in men and 35.4% in women IDF: 39.9% in men and 38.1% in women
Slide 78-

ppt slide no 78 content not found
Slide 79-

Prevention of CVD There is an urgent need to establish appropriate research studies, increase awareness of the CVD burden, and develop preventive strategies. Prevention and treatment strategies that have been proven to be effective in developed countries should be adapted for developing countries. Prevention is the best option as an approach to reduce CVD burden. Do we know enough to prevent this CVD Epidemic in the first place.
Slide 80-

The new IDF definition focusses on abdominal obesity rather than insulin resistance International Diabetes Federation (IDF) Consensus Definition 2005
Slide 81-

International Diabetes Federation (IDF) Consensus Definition 2005
Slide 82-

Treatment of Metabolic Syndrome: 2005
Slide 83-

Primary management for the Metabolic Syndrome is healthy lifestyle promotion. This includes: moderate calorie restriction (to achieve a 5-10% loss of body weight in the first year) moderate increases in physical activity change dietary composition to reduce saturated fat and total intake, increase fibre and, if appropriate, reduce salt intake. Recommendations for treatment
Slide 84-

Appropriate & aggressive therapy is essentialfor reducing patient risk of cardiovascular disease Lifestyle measures should be the first action Pharmacotherapy should have beneficial effects on Glucose intolerance/diabetes Obesity Hypertension Dyslipidaemia Ideally, treatment should address all of the components of the syndrome and not the individual components Management of the Metabolic Syndrome
Slide 85-

Summary: new IDF definition for the Metabolic Syndrome The new IDF definition addresses both clinical and research needs: provides a simple entry point for primary care physicians to diagnose the Metabolic Syndrome providing an accessible, diagnostic tool suitable for worldwide use, taking into account ethnic differences establishing a comprehensive ‘platinum standard’ list of additional criteria that should be included in epidemiological studies and other research into the Metabolic Syndrome
Slide 86-

ppt slide no 86 content not found
Slide 87-

Lifestyle modification Diet Exercise Weight loss Smoking cessation If a 1% reduction in HbA1c is achieved, you could expect a reduction in risk of: 21% for any diabetes-related endpoint 37% for microvascular complications 14% for myocardial infarction However, compliance is poor and most patients will require oral pharmacotherapy within a few years of diagnosis Stratton IM et al. BMJ 2000; 321: 405–412.