Diabetes: Past, Present and Future Dr Shahjada Selim Assistant Professor Department of Endocrinology Bangabandhu Sheikh Mujib Medical University, Dhaka Email: [email protected] May 17, 2022 Shahjada Selim, MD, MACE.
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Diabetes: Past, Present and Future
Dr Shahjada Selim Assistant Professor
Department of EndocrinologyBangabandhu Sheikh Mujib Medical University, Dhaka
Email: [email protected]
May 3, 2023 Shahjada Selim, MD, MACE.
Shahjada Selim, MD, MACE.
In 1500 BCDiabetes First Described In Writing
Hindu healers wrote that flies and ants were attracted to urine of people with a mysterious disease that caused intense thirst, enormous urine output, and wasting away of the body.
May 3, 2023
Shahjada Selim, MD, MACE.
250 BCThe Word Diabetes First Used
• Apollonius of Memphis coined the name "diabetes” (διαβήτηςδιαβήτης) meaning "to go through" ‘‘to stand apart’’ or siphon. He understood that the disease drained more fluid than a person could consume.
May 3, 2023
Shahjada Selim, MD, MACE.
250 BCThe Word Diabetes First Used
• Gradually the Latin word for honey, "mellitus," was added to diabetes because it made the urine sweet.
• FirstFirst recordedrecorded inin EnglishEnglish inin aboutabout 14251425 as as ‘diabetes’‘diabetes’.
May 3, 2023
Shahjada Selim, MD, MACE.
Diabetes is a wonderful affection, not very frequent among men, being a melting down of the flesh and limbs into urine…The flow is incessant, as if from the opening of aqueducts…it takes a long period to form, but the patient is short-lived…for the melting is rapid, the death speedy.
150 BC Aretaeus the Cappadocian
May 3, 2023
Shahjada Selim, MD, MACE.
Moreover, life is disgusting and painful; thirst unquenchable; excessive drinking…and one cannot stop them either from drinking or making water... they are affected with nausea, restlessness, and a burning thirst; and at no distant term they expire.
150 BC Aretaeus the Cappadocian
May 3, 2023
TheThe sweetsweet tastetaste hadhad beenbeen noticednoticed inin urineurine byby thethe ancientancient Greeks,Greeks, Chinese,Chinese, Egyptians,Egyptians, andand IndiansIndians butbut itit waswas onlyonly inin 16751675 thatthat ThomasThomas WillisWillis addedadded thethe wordword ‘mellitus’.‘mellitus’.
May 3, 2023 Shahjada Selim, MD, MACE.
ItIt waswas inin 17761776 thatthat MatthewMatthew DobsonDobson confirmedconfirmed thatthat thethe sweetsweet tastetaste waswas becausebecause ofof anan excessexcess ofof sugarsugar inin thethe urineurine andand bloodblood ofof peoplepeople withwith diabetesdiabetes.
May 3, 2023 Shahjada Selim, MD, MACE.
Shahjada Selim, MD, MACE.
Early Diabetes Treatments• In 1000, Greek physicians recommended
horseback riding to reduce excess urination• In the 1800s, bleeding, blistering, and doping
were common• In 1915, Sir William Osler recommended
opium • Overfeeding was commonly used to
compensate for loss of fluids and weight• In the early 1900s a leading American
diabetologist, Dr. Frederick Allen, recommended a starvation diet.
May 3, 2023
Shahjada Selim, MD, MACE.
Early Research
• In 1798, John Rollo documented excess sugar in the blood and urine
• In 1813, Claude Bernard linked diabetes to glycogen metabolism
• In 1869, Paul Langerhans, a German medical student, discovered islet cells in the pancreas.
May 3, 2023
Shahjada Selim, MD, MACE.
Early Research
• In 1889, Joseph von Mehring and Oskar Minkowski created diabetes in dogs by removing the pancreas
• In 1910, Sharpey-Shafer of Edinburgh suggested a single chemical was missing from the pancreas. He proposed calling this chemical "insulin."
May 3, 2023
Shahjada Selim, MD, MACE.
Near Miss
• In 1908, a young internist in Berlin, Georg Ludwig Zuelzer created a pancreas extract named acomatrol.
• After injecting acomatrol into a dying diabetic patient, the patient improved at first, but died when the acomatrol was gone.
May 3, 2023
Shahjada Selim, MD, MACE.
Near Miss
• Zuelzer filed an American patent in 1911 for a "Pancreas Preparation Suitable for the Treatment of Diabetes”
• Disappointing results, however, caused his lab to be taken over by the German military during WWI
May 3, 2023
Shahjada Selim, MD, MACE.
Other “Pancreas Extractors”
• American scientist E. L. Scott was partially successful in extracting insulin with alcohol.
• A Romanian, R. C. Paulesco, made an extract from the pancreas that lowered the blood glucose of dogs.
• Some claim Paulesco may have been the first to discover insulin about 10 years before Banting and Best.
May 3, 2023
Shahjada Selim, MD, MACE.
Before Insulin
Before insulin was discovered in 1921, everyone with type 1 diabetes died within weeks to years of its onset.
JL on 12/15/22 and 2 mos later
May 3, 2023
Sir William Osler, in the year 1915, is said to
have even recommended opium! Early research
linked diabetes to glycogen metabolism, and the
islet cells of pancreas were discovered by Paul
Langerhans, a young German medical student.
May 3, 2023 Shahjada Selim, MD, MACE.
In 1916, Sharpey-Shafer of Edinburgh
suggested that a single chemical was missing
from the pancreas and proposed its name as
“insulin.” The term insulin originates from the
word Insel, which is German for an islet or
island.
May 3, 2023 Shahjada Selim, MD, MACE.
NothingNothing muchmuch happenedhappened forfor thethe nextnext fewfew centuries…centuries…
InIn thethe latelate 19th19th Century,Century, OskarOskar MinkowskiMinkowski andand othersothers discovereddiscovered thethe rolerole ofof thethe pancreaspancreas inin diabetesdiabetes byby takingtaking themthem outout ofof dogsdogs andand realizingrealizing thatthat theythey dieddied ofof the conditionthe condition.
May 3, 2023 Shahjada Selim, MD, MACE.
Researchers like E.L. Scott and Nikolae
Paulesco were successful in extracting insulin
from the pancreas of experimental dogs. The key
breakthrough, though, came from the Toronto
University with the discovery of insulin in 1921.
May 3, 2023 Shahjada Selim, MD, MACE.
ItIt waswas ‘ignorant’‘ignorant’ juniorjunior surgeonsurgeon FredFred BantingBanting whowho tooktook thethe germgerm ofof anan ideaidea toto JRRJRR McLeodMcLeod –– thethe renownedrenowned physiologistphysiologist McLeodMcLeod –– whowho knewknew ofof thethe unsuccessfulunsuccessful workwork ofof othersothers overover thethe precedingpreceding 3030 yearsyears –– gavegave BantingBanting aa tinytiny room,room, aa fewfew dogs,dogs, andand aa medicalmedical studentstudent –– CharlesCharles Best.Best.
May 3, 2023 Shahjada Selim, MD, MACE.
BantingBanting andand BestBest managedmanaged toto getget throughthrough dozensdozens ofof dogsdogs tryingtrying differentdifferent methodsmethods toto getget thethe pancreaspancreas toto failfail andand thenthen toto replacereplace it.it. DespiteDespite theirtheir poorpoor science,science, andand poorpoor records,records, theythey eventuallyeventually ‘stumbled’‘stumbled’ onon somethingsomething Promising.Promising.
May 3, 2023 Shahjada Selim, MD, MACE.
19211921 andand AllAll That……That……
Banting, Banting, Best,Best, Collip,Collip, andand McLeodMcLeod At theAt the UniversityUniversity ofof Toronto.Toronto.
May 3, 2023Shahjada Selim, MD, MACE.
FG Banting and JJR Macleod were awarded the
Nobel Prize for Physiology or Medicine in 1923.
They shared their prize money with CH Best and
JB Collip who were “left out” by the prize
committee.
May 3, 2023 Shahjada Selim, MD, MACE.
TheyThey hadhad lotslots ofof dogs –dogs – oftenoften obtainedobtained fromfrom dubiousdubious sources.sources.
Marjorie?Marjorie?
May 3, 2023 Shahjada Selim, MD, MACE.
Banting and Best injected the crude pancreatic
extract “thick brown muck” into a 14-year-old
boy named “Leonard” in January 1922. His
blood sugar levels dropped significantly, but an
abscess developed at the injection site making
him acutely ill.
May 3, 2023 Shahjada Selim, MD, MACE.
A refined extract was again administered after 6
weeks, causing drop in blood sugar levels from 520
mg/dl to 120 mg/dl within 24 h. Leonard lived for
13 years before dying of pneumonia (another
disease for which no cure was available in those
days)
May 3, 2023 Shahjada Selim, MD, MACE.
TheThe ProblemsProblemsTheirTheir pancreaticpancreatic extractextract waswas impureimpure andand lackedlacked consistency.consistency.
BantingBanting feltfelt thatthat McLeodMcLeod waswas tryingtrying toto stealsteal theirtheir thunderthunder byby takingtaking creditcredit forfor theirtheir work.work.
ApparentApparent lacklack ofof progress.progress.
May 3, 2023 Shahjada Selim, MD, MACE.
McLeod brought in a leading biochemist to help with purification – James Bertram Collip. Collip was working on calcium but agreed to work with McLeod during a 1 year sabbatical.
May 3, 2023 Shahjada Selim, MD, MACE.
The Solution
RegardedRegarded asas thethe firstfirst personperson toto everever receivereceive insulininsulin onon 11th11thJanuaryJanuary 19221922 agedaged 1414 HeHe livedlived forfor 1313 yearsyears beforebefore dyingdying inin aa carcar accidentaccident
May 3, 2023 Shahjada Selim, MD, MACE.
Leonard
Evolution of Insulin
May 3, 2023 Shahjada Selim, MD, MACE.
Recognition
InIn 1923,1923, BantingBanting andand McLeodMcLeod werewere awardedawarded the Nobelthe Nobel PrizePrize forfor MedicineMedicine
BantingBanting gavegave halfhalf hishis prizeprize immediatelyimmediately toto Best,Best, andand McLeodMcLeod gavegave halfhalf ofof hishis toto Collip.Collip.
May 3, 2023 Shahjada Selim, MD, MACE.
TheThe DiabeticDiabetic Association,Association, waswas setset upup inin 19341934 byby novelistnovelist HGHG WellsWells andand DrDr RDRD Lawrence “ToLawrence “To promotepromote
thethe study,study, thethe diffusiondiffusion ofof knowledge,knowledge, andand thethe properproper treatmenttreatment ofof diabetesdiabetes inin thisthis country.”country.”
1923 - “I’ve got some insulin. It works. Come back quick.”May 3, 2023 Shahjada Selim, MD, MACE.
On May 1922, Eli Lilly signed an agreement to pay royalties to the Toronto University to increase the production of insulin. In 1923, August Krogh and Hans Christian Hagedorn began the mass production of insulin extracted from porcine pancreas in Denmark.
May 3, 2023 Shahjada Selim, MD, MACE.
The Nordisk Insulin Laboratorium (now Novo Nordisk) was thus established. In 1955, Sir Frederick Sanger characterized the amino acid sequence of human insulin, making it the first protein to whose sequence was determined. He was awarded the 1958 Nobel Prize in Chemistry for this work.May 3, 2023 Shahjada Selim, MD, MACE.
Subsequently, Hans Christian Hagedorn
discovered the prolonged effect of insulin by
adding protamine to the insulin molecule. Various
intermediate acting preparations were formulated
to provide 24-h control of blood glucose.
May 3, 2023 Shahjada Selim, MD, MACE.
Purified versions of animal insulin were developed
in 1974 by chromatographic techniques (less than 1
pmol/l of protein impurities) known as
“monocomponent MC” “single peak” insulin in
order to reduce the allergic reactions and
lipodystrophy.
May 3, 2023 Shahjada Selim, MD, MACE.
In 1978, recombinant DNA technology was used
to produce synthetic human insulin in E. coli. In
early 1980s, mass production of rDNA human
insulin was commenced.
May 3, 2023 Shahjada Selim, MD, MACE.
By the mid of nineties, the structure of human
insulin was modified by altering the amino acid
sequence (addition, deletion, or exchange of
amino acids) to produce insulins with better
pharmacokinetic properties, which came to be
known as a “modern insulin” or “designer
May 3, 2023 Shahjada Selim, MD, MACE.
• 19221922 Banting,Banting, Best,Best, CollipCollip useuse bovinebovine insulininsulin extractextract inin humanhuman
• 19231923 EliEli LillyLilly producesproduces commercialcommercial quantitiesquantities ofof muchmuch purerpurer bovinebovine insulininsulin thanthan BantingBanting etet alal hadhad usedused
• 19231923 FarbwerkeFarbwerke Hoechst,Hoechst, oneone ofof thethe forerunner'sforerunner's ofof today'stoday's SanofiSanofi Aventis,Aventis, producesproduces commercialcommercial quantitiesquantities ofof bovinebovine insulininsulin inin GermanyGermany
• 19231923 HagedornHagedorn foundsfounds thethe NordiskNordisk• InsulinlaboratoriumInsulinlaboratorium inin DenmarkDenmark –– forerunnerforerunner ofof today'stoday's
NovoNovo NordiskNordiskMay 3, 2023 Shahjada Selim, MD, MACE.
AA BriefBrief HistoryHistory ofof InsulinInsulin
• 19261926 NordiskNordisk receivesreceives aa DanishDanish chartercharter toto produceproduce insulininsulin asas aa non-profitnon-profit
• 19361936 CanadiansCanadians D.M.D.M. Scott,Scott, A.M.A.M. FisherFisher formulateformulate aa zinczinc insulininsulin mixturemixture andand licenselicense itit toto NovoNovo
• 19361936 HagedornHagedorn discoversdiscovers thatthat addingadding protamineprotamine toto insulininsulin prolongsprolongs thethe durationduration ofof actionaction ofof insulininsulin..
• 19461946 NordiskNordisk formulatesformulates IsophaneIsophane porcineporcine insulininsulin akaaka NeutralNeutral ProtamineProtamine HagedornHagedorn oror NPHNPH insulininsulin
• 19461946 NordiskNordisk crystallizescrystallizes aa protamineprotamine andand insulininsulin mixturemixture • 19501950 NordiskNordisk marketsmarkets NPHNPH insulininsulin• 19531953 NovoNovo formulatesformulates LenteLente porcineporcine andand bovinebovine insulinsinsulins byby
addingadding zinczinc forfor longerlonger lastinglasting insulininsulin
May 3, 2023 Shahjada Selim, MD, MACE.
• 19551955 FrederickFrederick SangerSanger determinesdetermines thethe aminoamino acidacid sequencesequence ofof insulininsulin
• 19651965 SynthesizedSynthesized byby totaltotal synthesissynthesis byby andand coworkerscoworkers• 19691969 DorothyDorothy CrowfootCrowfoot HodgkinHodgkin solvessolves thethe crystalcrystal
structurestructure ofof insulininsulin byby x-rayx-ray crystallographycrystallography• 19731973 PurifiedPurified monocomponentmonocomponent (MC)(MC) insulininsulin isis introducedintroduced• 19781978 GenentechGenentech producesproduces syntheticsynthetic 'human''human' insulininsulin inin
EscheriaEscheria colicoli bacteriabacteria usingusing recombinantrecombinant DNADNA techniques,techniques, licenseslicenses toto EliEli LillyLilly
• 19811981 NovoNovo NordiskNordisk chemicallychemically andand enzymaticallyenzymatically convertsconverts porcineporcine toto humanhuman insulininsulin
• 19821982 GenentechGenentech syntheticsynthetic 'human''human' insulininsulin (above)(above) approvedapproved
May 3, 2023 Shahjada Selim, MD, MACE.
• 19831983 EliEli LillyLilly andand CompanyCompany producesproduces syntheticsynthetic 'human''human' insulininsulin withwith recombinantrecombinant DNADNA technology,technology, HumulinHumulin
• 19851985 AxelAxel UllrichUllrich sequencessequences aa humanhuman cellcell membranemembrane insulininsulin receptor.receptor.
• 19881988 NovoNovo NordiskNordisk producesproduces recombinantrecombinant humanhuman insulininsulin• 19961996 LillyLilly HumalogHumalog "lispro""lispro" insulininsulin analogueanalogue approved.approved.• 20002000 SanofiSanofi AventisAventis LantusLantus "glargine""glargine" insulininsulin analogueanalogue
approvedapproved forfor clinicalclinical useuse inin thethe USUS andand Europe.Europe.• 20042004 SanofiSanofi AventisAventis insulininsulin glulisineglulisine insulininsulin analogueanalogue
approvedapproved forfor clinicalclinical useuse inin thethe US.US.• 20062006 NovoNovo NordiskNordisk LevemirLevemir "detemir""detemir" insulininsulin analogueanalogue
approvedapproved forfor clinicalclinical useuse inin thethe US.US.
May 3, 2023 Shahjada Selim, MD, MACE.
TheThe firstfirst oraloral agentsagents werewere launchedlaunched inin 19421942 –– thethe SulphonylureasSulphonylureas
TheThe BritishBritish DiabeticDiabetic AssociationAssociation waswas formedformed inin 19541954 –– thethe NorwichNorwich branchbranch launchedlaunched inin 19581958
BiguanidesBiguanides werewere launchedlaunched inin thethe 1950’s1950’s –– withwith metforminmetformin beingbeing launchedlaunched inin 19791979
TheThe aminoamino acidacid sequencesequence ofof insulininsulin waswas reportedreported inin 19551955 byby FredFred SangerSanger (another(another NobelNobel Prize)Prize)
May 3, 2023 Shahjada Selim, MD, MACE.
InIn 19881988 GeraldGerald ReavenReaven describeddescribed thethe constellationconstellation ofof conditionsconditions makingmaking upup thethe MetabolicMetabolic SyndromeSyndrome
IInn thethe midmid 1990’s1990’s acarboseacarbose andand metaglinidesmetaglinides becamebecame availableavailable
TroglitazoneTroglitazone waswas launchedlaunched inin thethe UKUK inin MarchMarch 19971997 andand withdrawnwithdrawn inin MayMay 19971997
May 3, 2023 Shahjada Selim, MD, MACE.
InIn 2005 Incretin based therapy was Incretin based therapy was introduced.introduced.
May 3, 2023 Shahjada Selim, MD, MACE.
Shahjada Selim, MD, MACE.
Demands On Intelligent Devices
• Intuitive interface and language• Must be impartial and fair• Outcome driven – user feels better and
is more confident about control• Compatible with clinic workflow• Well funded• Able to rapidly evolve as errors appear• Must close the data loop between user
and MDMay 3, 2023
Shahjada Selim, MD, MACE.
Smart Phones And PDAs
• Fast internet & email communication• Convenient remote insulin delivery• Larger food and carb database• Better graphics for BG analysis,
display of patterns, etc• Larger event database for long-term
analysis
May 3, 2023
Shahjada Selim, MD, MACE.
Intelligent Devices
• 300 personal carb selections with accurate carb counts
• Carb factor (1:1 TO 1:100) • Correction factor (1:4 to 1:
400)
5 sec microdraw BG meter0.1 unit precision motorNon-volatile memory3,000 eventsBluetooth data transfer
May 3, 2023
Shahjada Selim, MD, MACE.
Thoughts And Developments For The Future
May 3, 2023
Shahjada Selim, MD, MACE.
New: Rapid Basal Reduction
A rapid basal reduction offsets excess BOB and eliminates the need to eat at bedtime.
May 3, 2023
Shahjada Selim, MD, MACE.
New: The Super Bolus
A Super Bolus helps cover high GI foods and prevent postmeal hyperglycemia. A 3 or 4 hour block of basal insulin is turned into a bolus to speed its effect.
A Super Bolus can be activated at a user-selected quantity, such as 40 or 50 grams
May 3, 2023
Shahjada Selim, MD, MACE.
New: The Super Bolus
• To ensure safety and success, the Super Bolus will require some clinical testing:– How long can basal delivery be stopped or reduced
without increasing the risk for clogging of the infusion line– How long (3, 4, 5 hours?) can the basal be lowered before
a rebound high will occur once the Super Bolus is gone?– Is a reduction of the basal delivery rather than complete
stoppage a better policy?– If a person sets their basal delivery too low or too high, will
this affect a Super Bolus?
May 3, 2023
Shahjada Selim, MD, MACE.
New: High BG Super Bolus
If a pumper misjudges the carb content of a meal, a super bolus enables a faster, safe correction.
May 3, 2023
Shahjada Selim, MD, MACE.
New: A Reminder Timer
• A simple timer alerts the user 25 minutes after a bolus that it is safe to begin eating a high GI meal.
May 3, 2023
Shahjada Selim, MD, MACE.
New: An Intelligent Reminder
An intelligent pump alerts the user when their BG is likely to cross a selected threshold value, such as 120 mg/dl. They can then eat without exposure to extremely high readings.
May 3, 2023
Shahjada Selim, MD, MACE.
New: Less Glucose Exposure
The lower the blood glucose is at the start of a meal, the less exposure to glucose there will be.
May 3, 2023
Shahjada Selim, MD, MACE.
New: An Intelligent Reminder
An intelligent pump alerts the user when their blood glucose is low enough to begin eating
May 3, 2023
Shahjada Selim, MD, MACE.
Future Intelligent Devices
• Useful remindersMay 3, 2023
Shahjada Selim, MD, MACE.
Future Pattern Management
• Finding problem patterns enables solutions• Set BG targets• Gather and record data• Analyze patterns in data• Assess factors that influence
patterns• Recommend action
May 3, 2023
Shahjada Selim, MD, MACE.
Only A Few Patterns
The relatively low number of BG patterns in diabetes makes them easy to identify:
• High most of the time• Frequent lows• High mornings (lunches, dinners, bedtime)• Low mornings (lunches, dinners, bedtime)• Postmeal spiking• High to low• Low to high• Poor control with little or no pattern
May 3, 2023
Shahjada Selim, MD, MACE.
Low High Pattern Alert
• Insulin dose suggestions and an alert about past overtreatment of lows.
May 3, 2023
Shahjada Selim, MD, MACE.
Low High Pattern Alert
• An intelligent device can provide a person’s precise carb requirement when the blood glucose is tested.
May 3, 2023
Shahjada Selim, MD, MACE.
Overnight Basal Patterns
bedtime 2 am breakfast
100
200
300 basal too low Dawn Phenomenon
just righttoo high
Goal for overnight BG change = +/- 30 mg/dl
just right
May 3, 2023
Shahjada Selim, MD, MACE.
User Interface – Critical Component
Despite 30 years of pump and meter development, device communication to the user is still in it’s infancy.
May 3, 2023
Shahjada Selim, MD, MACE.
Future Intelligent Devices
• Carb database for accurate carb counts.
May 3, 2023
Shahjada Selim, MD, MACE.
Future Intelligent Devices
• Suggestion for carb intake or to limit intake based on weight/calorie/carb goals
May 3, 2023
Shahjada Selim, MD, MACE.
Future Intelligent Devices
• A high glucose can be analyzed to determine the magnitude of the error
May 3, 2023
Shahjada Selim, MD, MACE.
Future Intelligent Devices
• Recommended carb intake (or insulin reduction) to balance activity.
May 3, 2023
Shahjada Selim, MD, MACE.
Future Intelligent Devices
• New dose recommendations based on A1c, % of TDD given as correction boluses, and frequency of hypoglycemia
May 3, 2023
Shahjada Selim, MD, MACE.
Future Intelligent Devices
• Pattern alerts and advice
May 3, 2023
Shahjada Selim, MD, MACE.
Future Intelligent Devices
• Fast lab results without calling. Messaging allows physician to make recommendations.
May 3, 2023
Shahjada Selim, MD, MACE.
Pump Plus Continuous Monitor
• Automatic basal and bolus testing• Trends allow exact short-term BG
predictions for rapid recognition of pending highs or lows
• Both user and device can relate problems to their source
Unfortunately, insulin delivery from an external pump is too slow to create an effective artificial pancreas with this combination
May 3, 2023
22 BIGBIG TrialsTrials I. I. TypeType 11 diabetesdiabetes -- DiabetesDiabetes ControlControl andand ComplicationsComplications StudyStudy (DCCT)(DCCT) NEJMNEJM 19931993 329(14):977-86329(14):977-86 II. TypeType 22 diabetesdiabetes -- UnitedUnited KingdomKingdom ProspectiveProspective DiabetesDiabetes StudyStudy (UKPDS)(UKPDS) LancetLancet 19981998 352:837-853352:837-853 && BMJBMJ 19981998 317:703-713317:703-713 BothBoth askingasking thethe samesame questionquestion –– doesdoes goodgood diabetesdiabetes controlcontrol makemake aa differencedifference inin diabetesdiabetes relatedrelated outcomesoutcomes
May 3, 2023 Shahjada Selim, MD, MACE.
Shahjada Selim, MD, MACE.
Questions???
May 3, 2023
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