Evidence-Based Medicine: From Research to Clinical Practice

School

Monash University**We aren't endorsed by this school

Course

BMS 3052

Subject

Medicine

Date

Dec 12, 2024

Pages

Uploaded by AmbassadorUniverseQuail9

Research in medicine: Laboratory to bedside& CVDEvidence-based medicine and systemic reviews-EMB integrates: oClinical experienceoPatient values & preferencesoBest available research information -The 5A’s of evidence basic practice oASK: ask an answerable question P: Patient/participants/ population I: intervention/exposure C: comparison/controlO: outcomesoACCESS:locate the best evidenceoAPPRAISE: critically appraise the literatureoAPPLY:apply to the patient oASSES: reflect on the process/evaluate its efficacySystematic review: A comprehensive and structured way of analyzing and summarizing all available research on a particular topic which eliminates bias when answering a scientific question. This helps to identify what is known, what is not known, and where there are gaps in the research.-Efficient way to access the body of research oReduce time required for searching oCritical appraisal oInterpretation of resultsoIdentify gaps in the literature/future research -Reliable basis for decision making oHealth care oPolicy oFuture research -Types of systematic reviews oInterventionaloDiagnostic test accuracy oPrognostic

oMethodological oQualitative Biomedical challenges: -Values of biomedical research oImproving health oTraining the next generation of scientists: Funding biomedical research allow more scientists to stay in australia instead of going overseasoIncreasing knowledge oStrenghening the economy $2.17 return on investment oDeveloping new tenchogies products and industries -Most funding comes from the government 74%, which is driven by public opinion. This is much greater than america when a higher percentage of funding comes from private industries -Can biomedical research lead to reduction in health costs?: 74% of Australians agree. --Australia spends a smaller fraction of GDP on H&MR compared to other countries but has a higher life expectancy, indicating that the budget may be better spent.-Cost of medical care are expected to increased as the population ages, investment in H&MR may be able to counteract this

Why does it take so long from bench to bedside:? -Improving bench to bedside:oRemove red tape and improve processes, such as animal ethics, OH&S etc oOpen interactions among researcher, and more effective relations among companies, government, foundations, and universities. Competition for money. oIncrease resourcesoHave researcher/clinicians working in parallel oLess focus on mechanisms, understanding mechanisms can be timeconsuming. -Dubious and/or conflicting biomedical value, due to inappropriate commercial exploitation, and conflicting findings create public doubt -There are growing concern about the inability to replicate key scientific findings. oFalse positive date oLow statistical date oPoor experimental design oCherry picking data-Translation from animal models to humans oDisparate animal species and strains, with a variety of metabolic pathways and drug metabolites, leading to variation in efficacy and toxicity oVariation in drug dosing schedules and experimental desig, with uncertain relavence to human condition oDifferent models for inducing illness or injury, with varying similarityto the human condition; oSmall experimental groups with inadequate experimental significance

oSelection of outcome measures which being surrogates or precurosrof disease, are of uncertian relevance to the human clinical condition-Stigma of publishing negative data oResearchers are in competition for acquiring resources and funding,many are choosing not to publish non significant findings that have less scientific interest and fewer citationsoNegative findings are valuable because they allow us to critically evaluate and validate our current thinking and approach. Ethics:-Research integrity oPlagiarism oFalsifying/fabricating data

OKAYNot Okay oDuplicating results oInappropriate finance management oConcealing conflicts of interest oStealing other peoples research -Animal ethics oAnimal ethics committees must consider and evaluate requests to use animals for research or teaching activities on the basis of applicants responses to a comprehensive set of questionsThe justifications for the research Its likely impact on the animals Procedures for preventing or alleviating pain and distress oExperiments are tightly regulated (this includes strict documentation being kept) ooReduction Strategies that will result in fewer animals being used in research oRefinement Modification of experimental procedure to minimize pain oReplacement Methods with avoid or replace animal models

-AECs must consider and evaluate requests to use animals for research or teaching activities on the basis of applicants responses to comprehensive set of question including-Non-human primates: -Using stem cells for biomedical researchoIn Australia a researcher must obtain a licence from the NHMRC licencing committeeto use excess human IVF embryos for research, including the derivation of new embryonic stem cell lines oResearch using human tissue of any kind must be conducted under the highest ethical standards. oThe 2 polar views Research on human embryos created by any means, and at any age, as unethical, believing that human life begins when a human egg gains the ability to form an embryo Conversely, there are other with the strongly held view that embryonic stemcells hold the promise of sufficient benefit to human health to justify the useof human embryos for research purposes. oAmnion epithelial cells: cells that line the amniotic sac surrounding the developing foetus during pregnancy Are highly multipotent but not pluripotent unlike ESCs Are more widely regarded as being acceptable for research as they are usualy discarded either way. However, they may not fully appropriate for conducting certain studies that require pluripotency. Cardiovascular disease -health equity: systemic avoidable and often often unjust factors, structural practices and racism that create barrirs to opportunity and result in avoidable adverse health status and outcomes. -CVD deaths increase more in high income compared to low income countries .-Healthcare spending distributed unevenly – africa 1%, but has 18% of population.

-These health equities persist from womb to tomb. --Preventative interventions in elderly population has immediate risks but delayed benefits-Comorbidities and functional limitations are strong risk factors for complications and side effects further increase risk. -Due to reduced life expectancy, introducing an intervention may expose them to negative influence without sufficient time to see the benefits. -- for statin prescription those at higher risk are prescribed at a higher rate than those at lower risk -Misconceptions about benefit-harm trade off -Misjudgement for capacity to adhere to the treatment-Inattentiveness, because of other more pressing diseases -increased risk of cardiac arrest onbushfire days -Body must compromise betweenthermoregulation tissue perfusion tokey organs. -Diuretics betablockers can decreaseworkload of the heart. -However usage of diuretics in a hotenvironment increases fluid loss andthus risk of dehydration

Ischaemic stroke -Occlusion of cerebral blood vessel, due to a combination of blood clot or thrombus build upmore common-Haemorrhagic stroke is a result of ruptured cerebral blood vessel--1: identifies the type of stroke. -Hypertension is the number risk factor for stroke. -5. Options only work for ischaemic stroke, makes haemorrhagic worse -T-PA “clot buster: tissue plasminogen activator ocatalyses the conversion of the inactive protein plasminogen intothe active enzyme plasmin which breaks down the fibrin,the main protein that makes up blood clotsoDoes to reduce damage that has already been done,reduces future damage. oIncreases risk of haemorrhage if used after 4.5h afterstroke oSome situations can be given 9h post stroke if infarct region is predicted to expandand cause severe impairments, in which case the risk of TPA is outweighed by risk ofadditional damage.o10% of patients eligible for TPA, of which 30% is actually effective.i.e it is used in 3% of cases -Endovascular procedureoMechanical thrombectomy involves stent inserted to removeclot oOnly performed with occlusion of large artery oOnly done in hospitals in major cities due to the sophisticatedequipment needed. oMost patients receive TPA first-Tenecteplase: oFibrinolytic drug with higher fibrin specificityand longer half-live than t-PA (alteplase)

oIt is a genetically modified variant of alteplase, with 3 point mutations that enhanceits properties oTenecteplase reduces mortality rate compared to alteplase and leads to better 90day functional outcome compared to alteplase. -Cell death mechanisms following stroke: oExcitotoxicity(necrosis):causes 60% of cell death in a stroke. Peaks at 6hours Disappears within 24 hoursCauses most damage earlier during strokeInterventions targeted at excitotoxicity usually fail because most patientsreceive it too late. oNeuroinflammation Starts at 6H does not peak until 24h- 3days after strokeoApoptosis Does not peak until after 3 days and can last weeks -Hypothermia limits brain damage: oTargets variety of signalling mechanisms and reduces reactive oxygen species andreduces metabolism that reduces cell death as it lowers demand for oxygen andglucoseoLimits excitotoxicity by slowing down release of neurotransmitters like glutamateoReduces inflammation -Stem cell therapy for stroke oMesenchymal stem cells,neural stem cellsand induced pluripotent stem cells canbe used to differentiate into neural cells oThese replace damaged neurons oBone marrow stem cells: from patient themselvesIsolated and allowed to proliferate in vitroIntroduced back into patient via an arteryin the groin up to the brain Stem cells release a cocktail of chemicalthat trigger the growth of new brain tissuein damaged area. oHuman amnion epithelial cells hAECs lack tumorigenicity as they lacktelomerase and very low proliferation rate have unique proteins that have lowimmunogenicity as they are not detectedby the immune system can regulate the immune system andreduce damage causedoStem cell-derived exosomesNano-sized extracellular vesicles secretedby stem cells Contain substances that regulate neuro-regeneration or protection miRNA and siRNAs Lipids

Proteins Able to pass through smaller capillaries lungs as they are much smaller andBBBCan be injected at a higher dose, because exosomes can be stored at -60degrees for months, where as stem cells must be stored in liquid nitrogentakes about 8-12 hours to be ready for useAneurysm/ Haemorrhagic strokes-Aneurysms are bulging weak areas in the wall of an arteryoCan occur anywhere throughout the vascular system most common along the aortaand the brain oRupture is fatal if they rupture. o3 types: Cerebral Thoracic aortic aneurysm Abdominal aortic aneurysm -What causes aneurysms oA weakness in the blood vessel wall present from birth oHigh blood pressure weakening of blood vessels oPrevious aneurysm oRace: African American more likely oGender: women more likely oFatty plaques weaking blood vessel. oInherited diseases oTrauma oSTI oPKD -Cerebral aneurysms o15% oAn Unruptured ones may have no symptoms and could be discovered incidentally oSymptoms of a ruptured cerebral aneurysm include severe headache with rapidonset, neck pain, drowsiness, paralysis, seizures impaired speech and visual problemoSaccular aneurysm is the most common, and account for 80% to 90% of cases o--Saccular:rounded lobulated focal outpouchings arising at arterial bifurcations most commontype -Fusiform aneurysm:out-pouching of an arterial wall on both sides of the artery no neck orstem. More rare

-Giant:saccular, but much larger >2.5cm. high chance or rupture -Dissecting:wall of artery rips longitudinally. Occurs because bleeding into the weakenedwall. Most damaging because false lumen creates much larger area at risk of a rupture. -Aortic aneurysms oPrevalence of AA sharply increases with increasing age oRupture is associated with a high mortality 80% oSymptoms, include drop in blood pressure, coldness, loss ofcolour oScreening men over the age of 65 years reduces aneurysmsmortality .-Treatments of an aneurysm oRisks: Risk of haemorrhage: is it probable that it will rupture Size and locationAge and health of patient Family history-: have any aneurysms ruptured Surgical risks. oTreatment for non-ruptured Surgical clipping:place a clip to the neck of the aneurysm toprevent blood from flowing to it. More risky for older patientsEndovascular coiling: not as invasive: can be inserted throughfemoral artery, to fill space in the aneurysm. May not be ableto access some parts of the brain. -There are 2 types of Haemorrhagic stroke oSubarachnoid happens around the brain oIntracerebral: bleeding within the brain -Pharmacological treatments: osmotic agents oUsed to reduce edema, and intracranial pressure following haemorrhagic stroke oMannitol: sucrose solutionUsed to raise serum osmolarity (within vasculature)Plasma osmotic pressure is increased relative to spinal fluid Water flows from tissue with bleeding to blood \oAdverse effects:

10% develop edema: if mannitol solution gets into brains more water will bedrawn from solution to brain.Animal stroke models osome animal models are more appropriate than othersdepending on the research and study design -Middle cerebral artery occlusion: oPros:best mimics human stroke Surgery is performed in the neck of the animal toocclude MCAReperfusion and duration is controlledBlood flow is measured oCons: Variable infarct damage Su rgery is invasive: high mortality rate for animals -Photothrombotic stroke oPros: Induces a thrombus Minimal surgical interventionHighly reproducible infarct damage oCons: Little or no ischemic penumbra(surrounding area of the infarct that hasreduced blood flow that is not immediately an infarct, but can become oneif blood flow is not returned Unable to measure blood flow -Endothelin model oPros: conscious model: injection of a potent vasoconstrictor directly into the brainto reproduce stroke in a awake animal. reproducible infarct damage low mortality ocons induces Astro cytosis and facilitates axonal sproutingunable to measure blood flow changes lacks BBB breakdown-Autologous Blood injection model: oPros: Blood injected into the striatum to establish a haematoma Widely used modelGood reproducibility; relevant to ICH patients oCons: Does not simulate blood vessel rupture-Endovascular puncture model: oPros: Closely mimics SAH in the clinic Blood flow can be measured

oCon: Invasive surgery: Pulmonary hypertension -PulmonaryoPulmonary arteries constricted oRight ventricular hypertrophy -Systemic hypertension oLeft ventricular hypertrophy oSystemic arteries constricted -Pulmonary hypertensionwhen >20mmHg at rest oLeads to right ventricular hypertrophy oUltimately right heart failure and death -Symptoms:oShortness of br3eathoDifficulty breathing with exertionoDizziness oRapid breathing, rapid heart rate oEdema or swelling oChest pain-Risk factors include: oif two or more family have PH, or someone in genetic lineage has PH gene mutationrisk is more likelyoObesity and obstructive sleep apnea in combination oGender: more common in women, especially of child bearing ageopregnancyoaltitude oother diseases odrugs and toxins-thickening of smooth muscle layer of adventitia and endothelial layer.

-Lumen becomes small increasing resistance. -Type 2 pulmonary hypertension is caused by disorder of the left side of the heart(mitralvalve eg). Reflux of blood into the lungs.-Diagnosis:oECGoEchocardiogram oPulmonary function tests oRight heart catheterisation oPulmonary angiogram(measuring pressure within artery) -Causes of PAH

oIdiopathic(unsure about cause) oA progressive disease with no cure, patients will die from RV failure or require a lungtransplant -airway obstructioncauses -Poor ventilation =lower perfusion,vessels constrict.-Causes blood tofavour the sidewithbetterventilation so thatoxygen delivery isoptimised -Chronic hypoxia causes vasoconstriction but also smooth muscle hypertrophy compared tohypoxic pulmonary vasoconstriction -Oxygen: replaces the low oxygen in your blood-Anticoagulants or blood thinners: such as warfarin: decreases clot formation so blood flowsmore feely through blood vessels

-Diuretics:removes extra fluid from the tissues and bloodstream which reduces swelling andmakes breathing easier. -Inotropic agents: improves the heart’s pumping ability -Vasodilators: lowers pulmonary blood pressure and may improve the pumping ability of theright side of the heart -Endothelin-1 antagonists: helpsblock the action of endothelin-1 which causes narrowing oflong blood vessels -Sildenafil:relaxes pulmonary smooth muscle cells, which leads to dilation of the pulmonaryarteries. -Vasodilators are largely non-selective, so have side effects -Slow disease progression but not curative -Limited ability to reduce vascular and cardiac remodelling -Targeting the immune system: oResearch has suggested that inflammation and immunity is implicated in thepathogenesis of PH

Particularly with respect to pulmonary vascular remodelling andmaladaptive RV hypertrophy Targeting this may an alternative o-Polycythaemia(increase of RBC) wasnot the issue because administeringEPO compared to control in rats didnot increase hypertension despite asignificantincreaseinhaematocrit(proportion of bloodoccupies by RBCs) -CH-induced arterial remodelling doesnot reduce luminal diameter -Chronic hypoxia activates RhoA-Rhokinase pathway, which is independent ofCa2+ -Rho inhibitors have been shown to beeffective. Atherosclerosis

Lipoproteins: -Cylomicrons: oTransports dietary lipids from intestines to tissues -VLDL: very low density lipoproteins (triglyceride) unable to pass through blood vessel wall. oContains Apo-B-100-ligand for LDL re-uptake-LDL- low density lipoproteins (cholesterol) oDue to size easily penetrates vascular endothelium (contains ApoB-100) oTransports cholesterol from liver to peripheral tissues. oCan lead to buildup of cholesterol in the arteries, forming plaques and increasing the risk ofcardiovascular disease-HDL: high density lipoproteins (cholesterol); many species all contain apo-A-I (protective)oTransports triglycerides from liver to tissues ---Strong positive correlation between plasma [LDL] and atherosclerosis/ CHD (cholesterol-rich plaque) -Positive correlation between plaque lipoprotein a& CHD (reduced plasminogen favours increasedthrombosis) -Elevated plasma [HDL’ is protective (reverse cholesterol transport) -Endothelial cells maintain vasodilator as an anti-thrombogenic surface, prevents buildup ofcholesterol Atherosclerosis development Endogenous pathway: Cholesterol synthesized in the liver is transported to muscles and tissues viaVLDL. The triglycerides are then consumed by the cell leaving more cholesterol with the lipoprotein particle now called LDL which is high in cholesterol. LDL provides cholesterol into cells. LDL recirculates the blood stream untilit comes across LDL receptors. Bindingto LDL-rec on the surface of liver cells cause the uptake of cholesterol into cells,

1.Vascular cholesterol uptake by LDL receptors a.Excess LDLD infiltrates the artery b.Oxidised LDL induces adhesion molecule expression on endothelium c.Oxidised LDL phagocytosed by macrophages (now called foam cells)2.Monocyte recruitment into arterial wall a.Adhesion molecules facilitate entry of monocytesb.Differentiate into macrophage c.Macrophages release mediators creating inflammatory milleu3.Inflammation immune cell surveillance a.T cells infiltrate b.Activated T cells produce Th1 cytokines (IFNy , IL-1B, IL-6, TNF) c.Amplification of vascular inflammation d.Regulatory T cells oppose inflammation by release IL-10, TGF-B-The vulnerable plaque -(a) healthy blood vessel with endothelial lining, vascular smooth muscle cells and inflammatorycells kept outside-(b) infiltration of lipid into the artery-(c) migration of vascular smooth muscle cells to cover the plaque, and release collagen to strengthenthat wall . -(d) formation of the fibrous cap, vessel injury can cause rupture and rapid occlusion of the artery-C-reactive protein (CRP) ois an acute phase protein synthesised in liver and is stimulated by IL-6 from inflamed cells. oBinds to surface of dying cells; to promote phagocytosis oOften used as a marker/predictor of CVDHyperlipidaemia (dyslipidaemia) -Primary: ocholesterol (hypercholesterolaemia) oTriglycerides (hypertriglyceridemia) oOr both (mixed) -Caused by:oGenetic familial hypercholesterolaemia (FH) odefect in LDL receptor -Secondary:oDiabetes mellites, alcoholism liver diésasse drugsStatins :

-HMG-CoA reductase inhibitors prevent the synthesis of acetyl-CoA to cholesterol within hepatocytes-Reduces endogenous cholesterol in hepatocytes which promotes increased expression of LDLreceptors on hepatocytes disrupting feedback regulation -Increases LDL plasma clearance -Great reduction in LDL smaller reduction in triglycerides and increase in HDL, -Other effects such as improved endothelial function and plaque stabilisation -Primary prevention for cardiovascular disease including high risk elevated cholesterol high risk CHDwith/without elevated cholesterol-Used as a secondary prevention of myocardial infarction & stroke -Side effects may include GI disturbance, memory loss, muscle weakness although not in all patients.-Proprotein convertase subtilisin/kexin type 9 (PCSK9) oA circulating serine protease that binds to LDL rec; facilitates lysosomal degradation oReduces LDL rec recycling to cell surfaceoReduces LDL clearance which elevates circulating LDL Gain of function mutation revealed subjects with high LDLLoss of function mutation reveals subjects with low LDL oInhibition of PCSK9 has been proposed as a novel therapy o-

Coronary heart disease -= ischaemic heart disease; a umbrella term -Acute presentation oAngina radiating chest pain oAcute myocardial infarction (AMI; heart attack) oArrhythmias -Chronic disease oStable angina oHeart failure oArrhythmias -Acute coronary syndrome:oAny condition causing sudden, reduced blood flow to heart, includes the typeof chest pressure that you feel during a heart attack or pressure in your chestwhile you’re at rest or doing light physical activity (unstable angina). -Leading symptom for diagnosis is chest pain -Two groups of patients: oAcute chest pain and persistent (>20 min) ST-segment elevation. ST elevation is the upward shift of the ST segment between the end ofthe S wave and the start of the T wave.Indicates that a coronary artery has been blocked which cuts offoxygen to portion of the heart. Injured cells depolarise abnormally when the ST segment shouldusually be flat or depolarised. Corresponds with the middle of thesystolic phase of the cardiac cycle

-Cardiac biomarkers oCreatine kinase In heart and skeletal muscle Exists as a dimer BB,MM and MB(heart specific)Returns to normal within 48-72 hours oCardiac troponin (cTn)- gold standardcTn is a protein complex found in heart muscle cells release into the bloodstream indicate muscle damage Detected 4-10hr after AMI and peaks at 12-48hr , abnormal for 4-10days Aids in diagnosing delayed presentation AMI, because of itslong diagnostic window. Even if a patient presents several daysafter the onset of symptomstroponin can still be detected atelevated levelsSupersedes CK-MB due to its superiorsensitivity, specificity early detectioncapabilities, and prolonged diagnosticwindow. -AMI: size and location oMajor blockage can lead to cell death in a large part of the heart. Extent of damage caused is dependent of where the blockageoccurred oTissue repair is by re-organization (replacement by fibrous tissues) Potential for cardiac rupture due to weakened structure post MI o-Angina: Chest pain or discomfort that occurs when myocardium does not receieenough oxygen -rich bloodoSymptomatic of narrowing or partial blocking due to atherosclerosis -ACS: Acute coronary syndrome, umbrella term used to describe range of conditionsassociated with sudden, reduced blood flow to the heart

-NSTEMI: non-ST elevated Myocardial infarction partial blockage of a coronary arteryleading to reduction in blood flow. -STEMI: St elevated Myocardial infarction. Complete blockage -Angina pectoris--Nitro vasodilators are used to increase coronary perfusion and oxygen supply while reducing metabolic demand. both chronic and acute treatmentocan cause both venous and arterial dilation ovenous dilation reduces venous pressure and pre-load by reducing venous return to the heartreduces the volume of blood in the heart at the end of diastole, whichreduces stretching, thereby reducing the oxygen demand of the heart as it doesn’t have to work as hard to pump blood. oarteriolar dilation reduces peripheral resistance and after-load with consequent fall in cardiac oxygen consumption reduces the resistance the heart must overcome to eject blood into the systemic circulation ocoronary dilation: improves blood flow to the heart especially ischemic areas -Limited by tendency to cause tachycardia which increases cardiac oxygen consumption.--

-Angiotensin inhibition: o