"Risk and Prevention of Transfusion-associated GVHD and the Role of Pathogen Reduction and Blood Irradiation" and "E-cigarettes: Where do we go from here?"

January 14, 2021

Yale Cancer Center Grand Rounds | January 12, 2021

Edward Snyder, MD and Suchitra Krishnan-Sarin, PhD

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00:00Transfusion medicine, reduce morbidity,
00:02improve improve efficiency and
00:03really in some respects understand
00:05how we can always do better.
00:07And it's been a phenomenal service
00:09to our patients and to the mission of
00:12the Cancer Center and an Ed today is
00:15going to talk about GV HD and blood
00:18pathogens and the work he's done.
00:20So add, thank you.
00:23Thank you very much Charlie.
00:25It's a pleasure to be here and
00:28we can get this. Working right,
00:31I'll have to screen share, right?
00:34Yes. Sure there it is.
00:36OK, that looks like it's it works.
00:40Work yes, OK, well thank you very much.
00:44I'm going to talk today on prevention
00:48of transfusion, associated GVHD,
00:50and the role of a bladder
00:53radiation and pathogen reduction.
00:56If I can get the slides to move,
00:59there you go for conflict of interest I do.
01:03I am running three clinical trials
01:05on platelets and two on red cells
01:08for the serious Corporation,
01:10but I get no personal honor area.
01:13All the money goes to the University
01:16and support my salary for that effort,
01:19not for me.
01:20Personally,
01:21so I'm going to review the
01:23pathophysiology of transfusion,
01:26associated GVHD review,
01:27the rationale for using pathogen reduction,
01:30addressed the types of pathogen reduction,
01:33provide data on the toxicology study,
01:36talk a little bit about the clinical studies,
01:40and then compare the pathogen
01:42reduction versus gamma radiation
01:45for preventing PA GVHD so.
01:47Yale New Haven's got about 1600 beds.
01:50We have one transfuse,
01:52about 11,000 people a year.
01:54We transfuse about 54,000 products a year,
01:57broken down, as you see,
01:59below red cells, platelets, plasma,
02:01where first transfusion associated GVHD,
02:03therefore,
02:03is potential with many of these transfusions.
02:06And unfortunately,
02:07we don't see it for a variety of reasons.
02:10We will talk about TH GV HD occurs less
02:13than one per million transfusions.
02:16It's pretty rare.
02:17Clinical signs began about 8
02:19to 10 days after transfusion,
02:22with somewhere between 3 and 30 days.
02:25Usually is a rash associated
02:27with fever enterocolitis,
02:28watery diarrhea, and elevated LFTS.
02:30A key sign is pancytopenia with
02:33a higher risk being in men.
02:35The reason for the a plasia is that
02:38in regular graph versus host disease,
02:41if you will forward regular
02:44post bone marrow transplant,
02:45the bone marrow is that of the.
02:48Of the host of the recipient.
02:50I'm sorry, the head of the donor.
02:53So the donors bone marrow is
02:56basically replaced that of the
02:58of the recipient and the donors T
03:00cells therefore do not attack it
03:02because it's the donors own cells
03:04in transfusion associated GVHD,
03:06the host,
03:07or the recipients of bone marrow
03:09is there so that the donor cells
03:12attack the bone marrow as well
03:14as the liver and the skin.
03:17So that the a pleasure is due to GVHD
03:20involving the bone marrow of the recipient,
03:22and it is almost always fatal,
03:25and that's why it's that kind of
03:27fatality is not seen with affecting
03:29the bone marrow and graph versus
03:31host after a bone marrow transplant.
03:34The rash begins on the trunk
03:36and spreads to the extremities,
03:38diagnosis with usually a biopsy and death,
03:40occurs one to three weeks after the symptoms.
03:43The mechanism is that transfused lymphocytes.
03:46From an immuno competent donor,
03:49recognized the host HLA is being
03:51foreign and former response and
03:53then the host counterattacks with
03:56its own lymphocytes.
03:57However, in cases of TAA GV HD,
04:00there is no counter attack.
04:02If you will and you just get in
04:06continued growth and engraftment.
04:08If you will, of the donor T cells which
04:11caused the graft versus host problems,
04:15the lack of neutralization.
04:16And what does this do to? Well,
04:19it's do when the recipient several times,
04:22even if the recipient is immunocompetence.
04:26And you have an immuno competent
04:27donor from a blood transfusion.
04:30What happens is let's say
04:32the donor is homozygous?
04:34For HLA two or HLA B 44,
04:37the recipient does not see the donor cells
04:40as being foreign because the recipient
04:43has a two and in this case be 44.
04:47Whereas the donor cells are immuno competent,
04:50it does see the host as being foreign
04:53and it reacts against the host giving
04:57the graft versus host disease as opposed
05:00to like a rejection of a heart or a
05:04kidney would be host versus graft.
05:06So it's either can occur.
05:08Also an immunocompromised hosts
05:10due to congenital or acquired.
05:12Aziz, or, or medications,
05:14can do this, as we'll see in in.
05:17In a short while.
05:18So the whole concept here is that
05:20the host is incapable of eliminating
05:23the immunocompetent T cells.
05:25And they in graft.
05:26And they attacked the bone marrow
05:29and that causes the ATA associated
05:31graft versus host.
05:32So the requirements are to need to
05:35have a difference in donor recipient.
05:38HLA immuno competent competent donor
05:40cells need to be transfused and the
05:43host must be incapable of rejecting
05:45the immuno competent cells due to
05:48either disease or medication or
05:50congenital disease risk factors.
05:52The degree of recipient,
05:53cellular immunodeficiency plays a role.
05:55The number of viable T cells in
05:58the transfused product.
05:59The minimum number is not known.
06:01It is known some products like
06:03granulocytes are associated with
06:05GV HD more than other products.
06:07Also,
06:07the genetic diversity of the
06:09population is important.
06:10There was a fair amount of
06:12graft versus host disease.
06:13TAA GVHD in Japan and they thought
06:16was that it was more of a closed
06:18population because of the fact
06:20that it was an isolated island and
06:23therefore the genetic diversity
06:25was not as great as would be in.
06:27In a larger population.
06:29Also fresher cellular blood products
06:32like red cells stored list in a couple
06:35of weeks have a higher risk of GV HD.
06:37Also,
06:38for reasons that I'm not familiar with,
06:40I'm not sure if they're known
06:43the differential diagnosis.
06:44Once you start seeing things are ash you
06:46wonder about drug reaction or viral illness.
06:49So skin biopsy is done when it's done.
06:52It shows superficial
06:53perivascular infiltrates.
06:54Here's Grade 123 and then four
06:56in the lower right.
06:58You see bullae formation,
06:59and you can see bullae formation
07:02starting here with these white circles.
07:04And then you loss of reedy ridges,
07:07which are these intrusions into the dermis.
07:09Here's the epidermis on top,
07:11and then here's the dermis,
07:13the Rady Ridges,
07:14where the blood vessels go are lossed,
07:16and the dermis of the epidermis separate.
07:19Here you can see this set of little circles.
07:22They have a whole.
07:23This whole line shows the separation
07:25of the Germans to the epidermis of
07:28complete sloughing of that issue,
07:29and that of course leads to infection
07:32and causes problems as well.
07:34So that is what?
07:35The TA GV HD looks like on skin biopsy.
07:38This is a bone marrow showing
07:40a hypoplastic marrow.
07:41As you can see,
07:43this is patients back showing the rash.
07:46Here the rash on the extremities and
07:48this other one in the lower right
07:51before he seemed so the treatment
07:53there really is no treatment.
07:55It's a uniformly fatal condition,
07:57pretty much because of the marrow
07:59aplasia and in Allo transplants.
08:01You know when you give someone
08:03a unit of blood does this.
08:05This can cause problems because again
08:08the transplanted bone marrow is that
08:10of the of the marrow donor or not.
08:12If necessary,
08:13the transfusion donor.
08:14Which is usually not the same.
08:17Immuno suppression is rarely helpful.
08:19The radiation or whatever you're
08:21using to look to eliminate the T
08:24cells in this in the donor products
08:26does not apply to FFP cryoprecipitate
08:29derivatives and also frozen red cells.
08:32Interestingly,
08:32because they're washed multiple times,
08:34but it's not been reported with
08:37non cellular products or with
08:39frozen cells as far as I know it's
08:42you would need to irradiate the.
08:45Or in our case passage and reduce the
08:47product if it comes from a blood relative.
08:50If it's a directed donation which was more
08:53common in the age era than it is now,
08:55'cause people were donating for family
08:58members in the hope of preventing
09:00them from getting HIV at the time
09:02from unknown members of the blood supply.
09:05And that lets other problems
09:07as well because of the KGB HD.
09:09If it wasn't irradiated,
09:10and if the blood component is HLA match,
09:13that should be also treated as well.
09:16Look, our reduction is not protective.
09:18You're not removing enough.
09:19White cells are still four to five logs
09:22left after Leukoreduction standard
09:24blood washing doesn't remove it.
09:25You either need to gamma irradiate it
09:28with 2500 Centigrade or X radiation.
09:30The federal government wants to get
09:32rid of gamma radiation because of
09:34the potential to form dirty bombs.
09:37And we'll talk about that in a couple
09:39seconds and then pathogen reduction
09:41as you will see, is also protective.
09:43And what if you give a pathogen
09:46reduced product?
09:47You do not.
09:48We do not irradiate the product at all,
09:50so this is what a bloody radiator looks like.
09:54The blood red cells and or platelets,
09:56whatever is put into this canister.
09:58The canister is here where the rent
10:00is is rotating in a circle and then
10:03that whole thing rotates around to
10:05where the source of the cesium sources here.
10:08There are two pencils.
10:09As I said this,
10:11the great material is led.
10:12The person is standing over
10:14here watching the red cells
10:16swivel around like a lazy suzan.
10:18It's exposed for 456 minutes depending
10:19on the strength of the radiation source
10:22that last years and years and years,
10:24and then when the time is up,
10:26it automatically comes back to
10:28the opening and then it's removed.
10:30So that's what the gamma cell is.
10:32The concern is that that terrorists
10:34will break in and rip open several
10:36tons of lead and take out the.
10:39Pencil source can be done,
10:40but the government would like to get
10:43rid of this and move to X Ray devices.
10:46And if with gamma rate with pathogen
10:48reduction you won't need any
10:50kind of device at all actually.
10:52All the indications for radiated components,
10:55who are those that are immunosuppressed.
10:58Intrauterine transfusions, low birth weight.
11:01Exchange transfusions in newborns and you
11:03should've radiate the red cells for that.
11:06Patients with Digeorge syndrome,
11:08where does he sell immunodeficiency
11:10Hodgkin's lymphoma?
11:11Patients need to have irradiated
11:13blood products with for life not
11:15even after they've been cured.
11:17But for life, lors, auto transplants,
11:20not irradiating the transplant.
11:21Of course,
11:22just any red cells that they
11:24get outside of the transplant.
11:27If it's Rachel Emacs single donor platelets,
11:30or from relatives.
11:31Or someone's got various illnesses and are
11:34getting a purine analogue like fludarabine,
11:37cladribine, bendamustine,
11:38and other drugs as they come along patients.
11:42Getting Cam path anti CD.
11:4452 antithymocyte globulin granulocytes?
11:46If those products are used to treat
11:49illnesses they should get irradiated blood
11:52products not necessarily for aplastic anemia.
11:54MD S Hodgkin's lymphoma.
11:56I'm sorry,
11:57non Hodgkin's lymphoma and non
11:59Hodgkin's leukemia is solid organs.
12:02Unless they're being treated
12:03with one of these purine analogs
12:05or other types of therapies,
12:06so aplastic anemia getting ATG
12:08therapy would be a candidate.
12:09AA would.
12:10If you don't know what it is,
12:12I'm not going to give you a laundry
12:14list called The Blood Bank and ask the
12:17Blood Bank what their policy is right now.
12:19What happens if someone requests it?
12:21We've provided irradiated blood and
12:23then we review the indication and
12:25see if it needs to continue or not.
12:27So please call the Blood Bank for
12:29specific information on your patient.
12:31Interesting, Lee, when they.
12:32Reviewed the use of these products.
12:34They found that not all institutions
12:37follow the same criteria.
12:38Here are three institutions
12:40from Canada and one from Boston,
12:42and as you can see,
12:44not everybody irradiates for
12:45the same thing term.
12:47Infants MGH does not places in Canada.
12:50Don't do it for acute leukemias
12:52or chronic leukemias or stem
12:54cell donors during the harvest.
12:56Children with solid tumors,
12:57it varies,
12:58and it's an amazing amount of variability.
13:01Again,
13:01at Yale,
13:02give us a call and we'll be
13:04happy to talk about your patient
13:06if there's a new patient.
13:09And you have questions.
13:10So now that we know about TTA GVHD,
13:13what is the pathogen reduction?
13:14What is that about?
13:16Well,
13:16that is a technology that attempts
13:18to eliminate pathogens contained
13:20in units of blood.
13:21The only thing in it what it does,
13:23it does it by binding DNA or RNA,
13:26single or double stranded,
13:27whether it's viral or bacterial,
13:29and it prevents it from replicating.
13:31There's nothing in blood that
13:32should have DNA except a pathogen.
13:34Well, it shouldn't be in there,
13:36but there's nothing in blood
13:38that has DNA or RNA except.
13:40A pathogen there is.
13:41I know there's mitochondrial DNA,
13:43but that's not.
13:45What we're discussing in platelets here,
13:47and there's a little RNA left in
13:49red cells from the ridiculous site,
13:51but we're not discussing that.
13:53We're talking about pathogens,
13:54and that's where the material is attacked.
13:57Emerging pathogens just
13:58showed you as a concern.
14:00If COVID-19 was Bloodborne and
14:01was transmissible by blood,
14:03things would be even worse.
14:04If you can imagine that they are now
14:07and maybe covid 29 if it comes along.
14:10Hopefully not.
14:10Maybe Bloodborne,
14:11and we need to have pathogen reduction
14:13technology in place to mitigate that.
14:16So the therapies are two one for
14:18platelets and plasma and one for red
14:21cells with the service technology
14:23the active agent is called S 59.
14:26Is is a sorrel in call dammit oslin
14:28is added to the playlist at the time
14:31of collection by the Blood Center
14:34and the mcauslan goes through the
14:36cell membrane and binds to the DNA
14:39or RNA double or single stranded
14:41and then it's exposed to UV.
14:44A light in an illuminator.
14:46And it crosslinks preventing replication.
14:48That's how it inactivates pathogens S 303.
14:51It has to be used for red cells,
14:54because hemoglobin A will absorb
14:55the UV A and it will not provide
14:59an appropriate and effective.
15:01Mitigation technology so this material,
15:03which is a an alkylating agent,
15:06goes into the blood into the red cells
15:09and intercalates quickly and cross
15:11links without any any illumination at all,
15:14and then it degrades very rapidly
15:17into a non reactive material is 300
15:20so and this has been approved by the
15:23FDA since 2014 the the platelets
15:26or plasma and the red cell one is
15:29in phase three clinical trials.
15:31Which is what we're doing here at Yale,
15:33and I'll talk about that.
15:35So what types of pathogens is it and
15:39activate both the red cell and the
15:42platelet forms those two agents?
15:4559 and S 303 and activate the
15:48envelope viruses that we do.
15:50Blood tests for lots of other
15:52envelope viruses.
15:53Chikungunya dengue, influenza A gram.
15:55All the gram negatives.
15:56Most of the gram.
15:58Almost all the grammar negatives
16:00and positives, spirochetes,
16:01protozoa, and leukocytes.
16:02And this is where pathogen reduction
16:05eliminates the need for gamma radiation.
16:07Cousin and activates leukocytes by
16:09binding to the DNA of the T cells
16:13of the donor T cells and therefore.
16:15Does the same thing as radiation would.
16:18In fact it doesn't,
16:19as you'll see much more efficiently.
16:22There are some non envelope virus
16:24is that it also has affected as it
16:27doesn't affect parvovirus very well.
16:29Does it affect spores,
16:30hepatitis A or hepatitis E which
16:32are are not lipid envelope but
16:34don't cause a chronic problems
16:36generally in patients.
16:38So it is quite robust and all the
16:41other technologies to remove bacteria
16:43don't have any effect on removing.
16:45Viruses, which is why I felt that
16:48pathogen reduction was the way to go,
16:50rather than using other bacterial
16:52technologies to prevent bacterial
16:54contamination that did nothing for
16:55viruses and certainly didn't do
16:57anything for leukocytes either.
16:58There other technologies we don't
17:00have time to talk about riboflavin,
17:02which is also a photosensitizing agent
17:05intercalates into nucleic acids as well,
17:07and UV B light is used rather than UV
17:09A and that promotes oxygen radicals.
17:12UVC is another technology
17:13that's used in Europe.
17:15Make a pharma.
17:16There is no photoactive
17:18photosensitizing agent.
17:19The UVC itself acts to induce peering,
17:22permitting dimers,
17:23and that was discussed by Jake Owen Delaney,
17:26transfusion recently.
17:27This is a manuscript that we wrote for
17:31New England Journal of several years ago,
17:34but still accurate.
17:35I hope the sorlin works by
17:38forming DNA and RNA, adults,
17:40and cross linking the riboflavin.
17:42I mentioned cause direct DNA and RNA damage,
17:46guanine modification.
17:47And the UV C causes finding dimer formation.
17:49That's for the platelets.
17:51Similarly,
17:51and there are other types of
17:53pathogen reducing agents.
17:54We don't have time to discuss,
17:56but it's in this manuscript.
17:59If you give us Orland people,
18:02this was studied by serious .4
18:05micrograms per kig you wind up
18:08with 1100 picograms and after
18:10about 6 hours or so it's down to
18:14about 100 to 200 picograms per mil
18:17so it gets quite gets reduced to
18:20quite rapidly and studies on HPLC
18:23show as far as toxicology.
18:25This is before you VA.
18:28This is the HPLC.
18:30You see,
18:30after you via the photo
18:32products have formed over here.
18:34This is a standard and these
18:36sort of products are removed by a
18:38filtration technique that is used
18:40called compound or compound and sort
18:42of device which is really call us
18:44tyramine that absorbs the photo products.
18:46So the amount of of the S 59 that's
18:49goes into a recipient is minimal.
18:52It's in the in the picogram
18:54quantities the same thing with plasma.
18:56Here's plasma after you VA with
18:58multiple photo products and hear the
19:00photo products are pretty much gone after.
19:02Compound resource if device absorption.
19:06We've been using this product the platelet
19:08one at Yale since 2017 we started.
19:11We were among the first and we've been
19:13the leaders nationally for this product.
19:16This is the average.
19:17These are in the units of platelets.
19:19This is per year the average per year.
19:22Green is all the platelets.
19:24Red is pathogen reduced and blue is the
19:27play list that are not pathogen reduced.
19:29And as you can see there's
19:32been a steady decline.
19:33This is average for fiscal year 1718 and 19.
19:36Reminders going up and it has now them.
19:39Starting here, it's monthly,
19:41so this goes all the way
19:43out to fiscal year 2020.
19:44Now we're in fiscal year 2021.
19:47We are probably going to have
19:49about 100 non pathogen reduced a
19:51month and about 8 to 900 pathogen
19:53reduced non pathogen reduced about
19:55100 to 150 or so 900 or so pathogen
19:58reduced and that's the kind of the
20:01way it's been for a long long time.
20:04So we have a lot of data
20:06and a lot of patience.
20:08This is what the am Apostle.
20:10It looks like this is the regular shorland.
20:12This is the eight mop that's
20:14used for T cell lymphoma's and.
20:17Psoriasis this is the
20:18sort of content of food,
20:21not exactly the same sorlin,
20:23but in celery and celeriac
20:25which is celery root,
20:27milligram quantities and we're
20:28talking picogram so you have
20:31milligram and then you go to
20:33nanograms in micrograms that picogram.
20:35So it's quite a low amount
20:38that's infused as far as the
20:40toxicology is concerned on the FDA,
20:43therefore had no problem in allowing
20:46the psoralen treated platelets
20:48to be used for every patient.
20:50In the hospital,
20:51including neonates and preemies,
20:52including those receiving for
20:54the therapy which for reasons
20:56we don't have time to discuss,
20:58pregnancy, nursing mothers.
20:59It's been used in jail since 2017.
21:02We have a 3 1/2 year experience.
21:05We've transfused 10s of thousands
21:07of hundreds of thousands of
21:09patients of of units and we haven't
21:11had knock on pressboard,
21:12but any problems it's used for everyone.
21:15Jehovah's Witnesses,
21:16obviously because of their religious beliefs,
21:18it it's not acceptable to them generally.
21:21Before we brought it in,
21:22we went to all the C-Suite
21:24folks in the Department.
21:25Chairs have got their approval.
21:27Also the business office,
21:28'cause it is more expensive.
21:30We went all the clinical group Center,
21:32and.
21:32Train them on the new product
21:34'cause the bags look different.
21:36The plasma will look different color.
21:38We got all the service lines
21:39involved so it was it was a very
21:42large effort which we described
21:43in a manuscript that we wrote.
21:45This is what we're trying to prevent.
21:47This is what we call classical.
21:49EDS stands for egg drop soup if you
21:51will because that's what it looks like.
21:53It's a bacteria growing in this
21:55case staff orias in a unit
21:57of platelets in the pH drops,
21:59the acid causes the platelets to clump
22:01and you get this, which is obvious.
22:03What we're worried about,
22:04or those that are contaminated
22:05and look normal.
22:06That's the problem,
22:07and that's why we've had six
22:09near misses recently,
22:10and we've had two deaths at this
22:12institution from contaminated
22:13platelets or what actually one plate
22:15and one red cell over the years,
22:17and we've had a lot of near misses.
22:19Fortunately,
22:19our blood bank staff could pick
22:21up something if it looks strange.
22:23If there's a lack of platelets world,
22:25which is something we could
22:27talk about it another time.
22:28Probably never will talk about it,
22:31but I just say that,
22:33but this is what we're trying to prevent
22:36data from Europe because you say,
22:38well, three years of data.
22:40Why did you go on that?
22:42They've been using it in Europe
22:45for the past 15 years or 20 years,
22:482006 and earlier.
22:49They've used a total of 3.3 million
22:51trailer units of platelets.
22:53Transfused in these three countries
22:55between 2006 and 2017.
22:57There was 76 contaminated
22:58products in 12 deaths.
23:00There were 700 and 5000 intercept
23:01platelets transfused during that time.
23:03Admittedly, it's a fourth of it,
23:05but there were no deaths
23:06and no infections at all.
23:07And now that we have more data that
23:10Europe doesn't give the data out as as
23:12frequently as we would like to see it,
23:14but there's been no reports that I know
23:16of any problems with the exception of
23:18one or two cases of Acinetobacter,
23:21which is a separate a separate issue
23:23which we don't have time to talk about.
23:25Today we published our results in the
23:27British Journal of Hematology are Yale
23:29results with the weight Schultz and and.
23:31Others.
23:31And these were we had five
23:34near misses and Yale.
23:36There were septic reactions with
23:38conventional products about 9000 and
23:40they were about 12,000 pathogen.
23:42Reduced products had none.
23:44This was statistically significant.
23:45There were no other differences in
23:48any of the other types of reactions,
23:51basically.
23:51Then we did data who did studies which
23:54we don't have much time to talk about.
23:56Looking at the the number of subsequent
23:59platelet transfusions of platelets were
24:00damaged by the material and didn't work.
24:02Did they need to give another play
24:05live very quickly and with PR there
24:07was a slight amount of damage.
24:09We will list it 1/2 of 1/4 of a unit.
24:12More was needed.
24:13Cafe unit here.
24:1424 hours later maybe .6 of unit here
24:17was 1.2 of a unit versus 1 blue is
24:20the conventional non pathogen reduced?
24:22This is the pathogen reduced,
24:23and none of these were irradiated,
24:25obviously.
24:25Well, obvious to me anyway,
24:28and as you got out 96 hours there was,
24:31you know,
24:31a little more so the PR does a little damage,
24:35but the tradeoff is you've got
24:36a product that is not pathogen
24:39potentially pathogen contaminated.
24:40And this was the time between
24:42the next platelet transfusion.
24:44Again, if it didn't work,
24:45they would give play that sooner
24:47and there was no significant
24:49difference between the two.
24:51And as far as rental utilization
24:53actually 2448 up to 96 hours later,
24:55subsequent red cell transfusions.
24:57The platelets didn't work.
24:58They would probably transfuse more
25:00red cells that the patient would
25:02still be bleeding and there was a
25:04little more less again point units
25:06.2 more of a unit in the conventional
25:08group than all the way out that it
25:11wasn't the pathogen reduction group
25:13showing that the platelets worked.
25:14There may have been a little more
25:17platelets used port part of a unit,
25:19but nothing substantial and was
25:21in my approach.
25:22Expression of that of most,
25:23the reviewer says that it was
25:25worth the tradeoff.
25:26We also looked at our data for.
25:28Pediatric patients as well,
25:30'cause it's very little and we showed
25:32almost exactly the same results as
25:34far as the efficacy and the utilization.
25:37And there was really no difference
25:39between the conventional for neonates,
25:41infants,
25:42or pediatric up to 18 years for
25:44both conventional versus pathogen
25:46reduced in pediatric groups as well.
25:48So what we have is.
25:50A product that appears to be
25:53beneficial that it prevents
25:54the loss of removes pathogens,
25:57but it also allows platelets to function
25:59properly and be even statically effective.
26:02We finished a phase four trial
26:05called Piper with 3000 patients,
26:07comparing patients getting
26:08conventional versus intercept treated
26:10in the mock group and we trance.
26:13We contributed about 50.
26:15About 530 patients of the 3000.
26:17They would let us do more because
26:20they didn't want to overweight.
26:22This is being analyzed and will
26:24hopefully be in a New England Journal
26:27article near you at sometime in the
26:30future or another Journal, perhaps,
26:32but is the largest study looking at a
26:35group of patients getting conventional
26:37versus pathogen reduced platelets?
26:39The second part,
26:41just to close up,
26:42is with the red cell pathogens.
26:45Again, you want to have a pathogen material.
26:48Reduced by for red cells as well.
26:51This study is in phase three clinical trials,
26:53which we're doing now at Yale.
26:55We have two groups of patients
26:57were studying again,
26:58the benefit if you don't have a red cell
27:01product that you're not going to be able
27:03to get rid of the gamma irradiators,
27:06but you need to provide the radiation.
27:08Also eliminate not only the
27:10viruses and bacteria,
27:11but also beesia and also will
27:12eliminate the need to irradiate the
27:14the white cells for the same reason.
27:17This technology the S 303
27:18intercalates into the DNA.
27:20Or RNA the cross links by chemical reaction.
27:23It doesn't require light incurs
27:25faster than the linker degrades,
27:28allowing a blockage of replication
27:30so it does inactivate the pathogens.
27:32And then at the grades to Anon.
27:36A non toxic product it is
27:39a quitter in which is,
27:40uh those of you know there are some
27:43concerns but it inactivates quite rapidly
27:45and is washed and it's essentially
27:48removed and the data which I don't
27:50have time to share unfortunately
27:52shows that there is not a risk of
27:55toxicology associated with this and
27:57this is not used routinely in Europe.
27:59And is now being in phase three
28:02clinical trials here at Yale.
28:05It's again for up to 42 days of storage
28:08were studying two groups of patients,
28:11the which I'll talk about in a
28:14second of the log reduction.
28:16Dissimilar to what the psoralen is.
28:195 log reductions,
28:20and 99.9 is 3 log reduction,
28:23so these are 56 logs with
28:26various viruses and bacteria.
28:28The studies were doing the acute
28:29study in the cardiac surgery and
28:31we're doing one in chronically
28:33anemic patients getting simple
28:34transfusions called Redis,
28:36which is what we're going to be doing
28:38on the 7th floor and in the outpatient
28:40clinics where we patients who need a
28:43blood transfusion will get randomized
28:45after they signed written informed
28:46consent obviously went through the
28:48IRB to whether they get pathogen
28:50reduced or conventional red cells,
28:52and they're not transfused for this
28:54study if their doctor says they need
28:56a transfusion and they've agreed.
28:58We will give them one or the other,
29:00but we're not going to radiate the
29:03pathogen reduced product because that
29:05would cause a double damage to the
29:07platelet or the OR the red cell rather.
29:09So the purpose of this talk was
29:11also to reassure everyone that the
29:13data show clearly that pathogen
29:15reduction prevents graft versus host.
29:17So for those of your chemotherapy patients,
29:19that may need it.
29:21Pathogen reduction would be acceptable.
29:23And here's the major data showing the number
29:25of adduct formation with gamma radiation,
29:28one in every 37 thousand base pairs
29:30forms an adult which is enough
29:33to block references host 'cause
29:35that's the standard with S 59 plus
29:37UV A it's one in every 80 three
29:40base pairs shown in this cartoon.
29:42The data is in blood 1998 and for S 303
29:45the data is have been published yet,
29:48but you get an even more robust
29:51and up formation with whole blood.
29:53Or with red cells,
29:55it's an average of water every 38 to
29:57one in every 53 orders of magnitude
30:00more than the adult formation
30:02with gamma radiation.
30:04So there's no reason to believe
30:06that using pathogen reduced product
30:08in lieu of gamma radiated product
30:10will be as safe or not showing.
30:13It's obviously better,
30:14but as safe and then other studies
30:17coming out of Europe showed no reported
30:19PA GVHD with irradiated products.
30:21Conventional amat asselyn 186 thousand.
30:23Again, no reported cases.
30:25Again, orders of magnitude less,
30:27but in that Switzerland similarly
30:30no reports with the. With the.
30:33With the use of the Sourland
30:36TAA GV HD in summary is rare,
30:40but fatal treatment is unsuccessful.
30:42Prevention is best in attention.
30:43The only approach death due to marrow,
30:46a pleasure,
30:47gamma radiation or pathogen reduction are
30:49both acceptable to the FDA to the IRB.
30:52In Europe,
30:52the data are there PR playlist,
30:54usamma, TASSELL and UV.
30:56A red cells use a muscle in nucleic acid.
30:59After formation is more robust and
31:01there's no need to do both and this
31:04will produce unwanted cellular damage.
31:06And there are a couple of references here.
31:08An I will end there and thank
31:10you for your attention.
31:12Go
31:12ahead, thank you.
31:13It's a terrific work and really in
31:15advance and transfusion medicine that
31:18obviously addresses multiple complications
31:20just because we're running a little
31:22late I think will probably not will,
31:24will ask people to send you questions
31:27directly and turn to our next speaker
31:29so our next lecture is Doctor Suchitra
31:32Krishnan Sarin and Suchitra is is,
31:35you know, is a professor of
31:37psychiatry and the chair of the
31:39Human Investigations Committee.
31:40Yeah, and her work over the
31:43years has really been.
31:44As a leader in understanding tobacco
31:47treatment control and the interventions
31:49and risk factors associated with it,
31:52her work was instrumental in the
31:54Surgeon General's report of preventing
31:57tobacco use among young people.
31:59She served on the FDA's tobacco
32:02product Scientific Advisory Committee
32:04and currently serves serves on the
32:07CDC's Interagency Commission on
32:09Smoking and Health and her work on E
32:12cigarettes really has been critical,
32:14particularly as these.
32:15Have become far more trendy, sadly,
32:17particularly among young people,
32:19so Skeeter thank you for sharing
32:21your work with us.
32:26You run, I think your video
32:29and sound and audio is off.
32:37Let me fix this. Sorry about that, OK.
32:42Start again.
32:48Can you see the screen?
32:50OK yes, OK great wonderful again.
32:52Thank you for inviting me to
32:54speak to this group today,
32:56so I'm going to give you a tell
32:58you about something which is
33:00completely different than what
33:02you've heard about from Ed and.
33:04This relates to this public health
33:06problem of E cigarettes and I.
33:08I'm going to kind of give you an
33:10overview because I figured that many
33:12of you may not have really heard about
33:14this debate or about these products
33:16and what the concern is relating to these.
33:18So I'm just going to give you a little
33:21basic overview and give you an update
33:24of where we are as a field in this area.
33:27Oh OK, there we go.
33:34So I have no conflicts of disclosures
33:36to report as was mentioned,
33:39I have served as a member
33:41of FDA's tobacco products.
33:43Scientific Scientific Advisory Committee,
33:45which is a committee which reviews tobacco
33:48products and approves them for marketing
33:50and presentation in the US market.
33:52And I'm also a current member of CDC's
33:55Icy SH and I also called the Tobacco
33:59Center of Regulatory Science at Yale.
34:03So just a brief presentation
34:05of what the problem is.
34:07So this is something I'm going to be
34:10coming back to later in my talk to.
34:13With E cigarettes there are two parts
34:16to the public health problem in question
34:18that is being debated a lot today one
34:21is potentially they pose benefits.
34:23They could help reduce disease risk
34:26for current smokers if they switched
34:28to using these products they could
34:31reduce disease morbidity for smokers
34:32and I'm sure this is a huge concern for
34:35this community because of the known
34:38relationship between tobacco use,
34:39smoking and cancer risks.
34:41So this is very very beneficial if it.
34:44If it works out that way,
34:46on the other hand, you have the harms,
34:49which is in the right hand side panel an.
34:52Unfortunately, as we have seen in the US,
34:54increased rates of use of these
34:56products amongst youth.
34:57So there's an increased risk
34:59of exposure to nicotine,
35:00nicotine addiction, future disease risks,
35:02Anna hold real knee renormalization
35:04of tobacco use behaviors,
35:05and even amongst adults who
35:07switched to using this product,
35:08there is a great deal of
35:10concern of dual use behavior.
35:12So what a lot of adults are doing.
35:15Is not necessarily switching
35:17completely to use of these products,
35:19but are choosing to use both cigarettes
35:21and E cigarettes depending on
35:23convenience and where they can use these
35:25products and that is not good either.
35:27And of course,
35:28then there's a secondhand
35:30aerosol exposure issue,
35:31which again we know very little about,
35:33so these products are Sony on the market.
35:37So just to take a step back,
35:39as I said,
35:40this is the top public health
35:42concern which is cigarette smoking
35:44or tobacco smoking a cigar.
35:46Use all these combustible products that
35:48create havoc on multiple organ systems
35:51and also have contribute to cancer risks.
35:53So over the years in the US we've done
35:56multiple we put into place multiple
35:58public health policies to try and
36:01address cigarette use behaviors.
36:02As many of you know,
36:04and most recently the one that has.
36:07I've been quite influential.
36:08Is this FDA allowing FDA to
36:10regulate these tobacco products?
36:12If for those who know this area,
36:15you know the FDA had been trying
36:17for a long time to to get this role
36:20to have the ability to regulate
36:23these products and that only went
36:25into place when this family smoking
36:28prevention and Tobacco Control Act
36:30was signed in 2009 by President Obama.
36:32So since then,
36:33the FDA has been trying to put into place.
36:37Regulations on the manufacture,
36:39distribution,
36:39and marketing of these products
36:42to protect public health.
36:43And that's where the cigarettes
36:45kind of come into the picture
36:48they were actually invented by a
36:51Chinese pharmacist who wanted to
36:53develop a cleaner form of nicotine
36:55to help smokers quit smoking.
36:57It was created in 2003,
36:59started appearing in the US in about 2009,
37:02and two that today. There are over 400 E.
37:06Cigarette brands are basically cigarette
37:08is a very simple, really simple.
37:10I should say I don't know if you
37:13even college and equipment or a device.
37:16There is a. There's a power component
37:18here which charges the E cigarettes.
37:20Not all of them look like this.
37:23Obviously. I'll show you some pictures.
37:25There is a control element where
37:27the user can push a button to
37:30activate it and heat the juice,
37:32which is located in this compartment
37:34here and at the other end there
37:37is a there is a mouthpiece
37:39that the user can then use to.
37:41Get taken the papers that are created.
37:44Um be started.
37:45Address entering the US market in about
37:482009 and when they first entered the FDA,
37:50really tried to prevent them from
37:52entering the market by directing the
37:54Bottom Border Protection agencies to
37:56reject the entry of these products
37:58into the market because they were
38:00unapproved drug delivery devices.
38:01They wanted to classify them
38:03as a drug delivery device,
38:05but there was a lawsuit that was
38:07brought against the FDA by a E
38:10cigarette company at that time
38:11and they said that the FDA had
38:14no authority over E cigarettes
38:15because they were a tobacco product.
38:17And that they were not a drug delivery
38:20device or a drug device combination
38:22because they were not being sold for
38:25any therapeutic purpose in the US.
38:27One would think that that would
38:29have been turned down,
38:31but they actually were successful
38:32in the US District Court and US
38:35District Court basically prohibited
38:36the FDA from seizing the services,
38:38devices or drug devices,
38:40so they also ruled that the FDA
38:42could only regulate these signatures
38:44of tobacco product.
38:45Unless therapeutic claims are made.
38:47So any product you see on the market can
38:49only be regulated as tobacco products.
38:52They're not regulated yet,
38:53but they can only be regulated,
38:55and they cannot make any therapeutic claims.
38:58So the FDA is actually come
38:59up with the whole series.
39:01Of a whole another way that these
39:04products can be regulated and they
39:06give them marketing claims and
39:08they can make certain claims about
39:11what the product can be used for.
39:13But it cannot be a direct therapeutic
39:16claim because they are not.
39:18None of these companies are actually
39:21proceeding along the therapeutic
39:23side of FDA to get them approved
39:25as a cessation device.
39:26They're just getting them regulated
39:28or approved as a tobacco product.
39:31So essentially what I said here
39:33is that you know they can only be
39:36regulated as a tobacco product.
39:38They the FSB TC,
39:39it did not cover them till almost
39:412016 because the original law
39:43that President Obama signed did
39:46not cover E cigarettes,
39:47so they actually incorporated
39:48it into the law only in 2016.
39:51So therefore from 2010 to 2016 these
39:53products have been unregulated and
39:55they will probably remain unregulated
39:57through 2022 because as I said,
39:59the FDA has a different way
40:01of regulating them in.
40:02All these companies are now submitting
40:04their safety data to the FDA through
40:07this premarket tobacco product application,
40:09which were all due September 9th,
40:122020.
40:12So the FDA is just reviewing
40:14products from thousands
40:15and thousands of companies or products.
40:18As I understand.
40:19To really see if they should be
40:22allowed to have any marketing claims.
40:25In the meantime, there has just been
40:27an evolution of or an explosion
40:29I should say in the market in
40:31terms of the products available,
40:33you get product switch look like
40:35cigarettes on the left hand side,
40:37going all the way to these pens,
40:39which you can replace eliquids in.
40:41You have these box mods which
40:43look nothing like a cigarette,
40:44but which allow you to change,
40:46you know, produce huge vapor clouds
40:48and all these other kinds of behaviors.
40:50And then you have the most recent
40:53entrance which is the jewel which is
40:55that little black device you see.
40:57I'm a third from the right hand
40:59side and some other devices which
41:01are called pod devices,
41:02which essentially the way all
41:04these differs in terms of whether
41:06it is a closed system in the sense
41:08that the nicotine is contained in
41:10it and you and you vape it.
41:12Whether you can fill in new illiquid's
41:14like the weapons allow you to do,
41:16or these pod devices which are
41:18completely closed systems that
41:20come with these parts that are pre
41:22filled and you just slide them in.
41:24Now this is also left you a
41:26huge black market,
41:27so even with the pod devices now you can buy.
41:30Unfilled parts that you can then
41:32fill with whatever you want,
41:34and this has led to a huge increase
41:36in rates of marijuana use and use a
41:39variety of other products because
41:41people are filling pods with all kinds
41:44of different things and making them so.
41:46This is basically just to give
41:48you an idea of what exists,
41:51and this shows you the sales that has in
41:53Nielsen tracked retail channels by Brandon.
41:56You can see the amount of sales
41:58that go towards E cigarettes.
42:00And obviously a very,
42:01very profitable market,
42:02which is why a lot of people
42:04are investing in these products.
42:06So I bring you back now to
42:08what I started the talk with,
42:10which is let's not talk about
42:12the benefits of the harms.
42:14So let's proceed to talking
42:15about times or toxicity.
42:16First,
42:17I'm just going to show you snippets of data.
42:20There's a huge literature out there,
42:21but in the interest of time,
42:23let's ask the first question.
42:25When you look at E cigarettes,
42:27when you compare them to E
42:28cigarettes or combustible products,
42:30do they actually have reduced form?
42:31So if you do an apples to apples
42:34comparison and you look at things like
42:36like some of the nitrosamine's the NNN.
42:38And in case and some of these compounds,
42:41tobacco specific nitrosamine's
42:42that have been shown to be toxic
42:45enough significant cancer risk.
42:46When you look at the current content
42:49of these nitrosamine's in combustible
42:51products versus E cigarettes,
42:52you definitely see that E cigarette
42:54exposure results in less exposure
42:56to tobacco specific nitrosamine's
42:58does not completely eliminate them,
43:00but there's definitely lexical less exposure.
43:02But our concerns about this or not,
43:04just the nitrosamine's.
43:06There are a variety of other products that.
43:09Our existing E cigarettes,
43:10which by which combined with the
43:13way these products are being used,
43:15which is almost in many people almost
43:18constantly used throughout the day,
43:20raises a lot of concerns about what
43:22some of these contents could do.
43:25So an example of some of these are
43:27probably in glycol and vegetable
43:29glycerin which are used included
43:31as solvents or constituents.
43:33There are a lot of flavor
43:35chemicals which are all aldehydes,
43:38and I'll talk about them in a second.
43:41There are sweeteners that are present
43:43in these products and other solvents
43:46including alcohol and of course nicotine.
43:48Anna variety of metals and metals actually
43:51come from the coil when the coil is heated,
43:55it releases metals and so this is all
43:57part of what the individual is going
44:00to be inhaling when they inhale this
44:03particular product and the figure shows
44:06you some of the other ultrafine particles,
44:09and so on, which could be.
44:11Reduced Um,
44:13so I'll just briefly touch on
44:16Flavors because that is a huge.
44:18Focus of our tobacco center.
44:20Here at Yale,
44:21we're really interested in understanding
44:23the role of flavors and appeal,
44:25addiction and toxicity of these products,
44:27and I'm going to address toxicity
44:29here so the flavors as you know it
44:32are made up of flavor chemicals,
44:34so they're not just benign.
44:36You know flavor molecules.
44:38Some of these chemicals are
44:40identified and are listed out here.
44:42You'll see many of them are aldehydes
44:44and depending on the concentration,
44:46can have significant health effects.
44:48Not help to fix,
44:49I'm sorry.
44:50Let me back up significant toxicity.
44:52There was an argument made initially that
44:55these are flavor chemicals and they are
44:57gras or generally recognized as safe,
45:00but they are not generally recognized
45:02as safe for inhalational use.
45:04They are grass for edible use,
45:06not for any Hill inhalation.
45:08Using isn't very important distinction
45:10and what we're finding through a lot of
45:13the cellular toxicity work going on is
45:15that many of these flavor molecules are have.
45:18Are toxic to cells,
45:19some of them also have been
45:22known to have diseased risks.
45:24So an example of this is diacetyl,
45:26which is a chemical which is included
45:29to produce butter flavor and it has
45:32been known to be associated popcorn
45:34lung disease which is actually found in
45:37people who are working in popcorn factories,
45:40so this chemical is still used in many of
45:43these eliquids as a flavoring chemical,
45:45so there are concerns about
45:47toxicity of these flavors.
45:49And our tobacco center is also shown
45:51that his flavor aldehydes actually form
45:54what are called acetal addicts with
45:57the propylene glycol and glycerine in
46:00this illiquid and that these acetal
46:02out addicts that are formed when
46:05the salute are there just formed.
46:08When the illiquid just sitting on the
46:10shelf and these addicts we're showing
46:13are actually stronger airway irritants
46:15in the original aldehydes itself,
46:18so like vanillin.
46:19Adult will actually be is a stronger
46:21airway, urgent than vanillin itself,
46:23so this is an area which we need
46:26to need a lot more research on.
46:28The similar kind of work on all
46:30the other products that I listed
46:32earlier from E cigarettes from
46:33many other people in the country.
46:35And there was a National Academy of
46:38Science report which came out in 2018
46:40and the public health consequences
46:41of E cigarettes which basically I'm
46:43presenting you with an overview of findings,
46:46but you should feel free to check it out an.
46:49Be they concluded that E cigarettes
46:51were not risk free,
46:53while the current evidence suggests
46:54that they are far less harmful than
46:57combustible tobacco cigarettes and a
46:59smoker is exposed to lower levels of
47:02toxic substances other than nicotine.
47:03There may be some short term resulting
47:06in reduced short-term adverse health
47:08outcomes that there was very little data
47:10to assess the impact on cancer and health,
47:13heart disease risk.
47:14And there's a lot more evidence coming out
47:17on heart disease risk at this point, but.
47:20Not yet that much on cancer risk.
47:24I also thought you would be
47:26interested in seeing the specific
47:28cancer related section that they had
47:31in this public in this report.
47:33Essentially,
47:33what this says is there is no available
47:36evidence that E cigarette users associated
47:39with intermediate cancer endpoints,
47:40but that there is substantial evidence
47:43that some chemicals present present in E.
47:46Cigarette aerosol like formaldehyde
47:47and actually not capable of
47:49causing DNA damage in mutagenesis.
47:51But this has not panned out into
47:54a clinical outcome per say and.
47:56You know there's more to come and much more
47:59work that needs to be done on this issue.
48:01So let's move on to vivia concerned
48:04about this in the US and we're
48:06really concerned about it.
48:08We really started becoming very
48:10concerned about it because of
48:12the extensive use among youth.
48:13This show.
48:14This shows you the current tobacco
48:16product use amongst high school students
48:19in the US from the National Youth
48:21Tobacco data and you see here this,
48:24this red line is indicative of E cigarettes.
48:27Now their their rates were significantly
48:29increasing through 2019 and in 20.
48:3118 and 2019 we discovered a lot of
48:34these increasing rates was because of
48:36the presence of jewel in the market
48:38and they were certain regulations
48:40put on jewel in 2019.
48:42You do see a decrease in 2020,
48:44but I will tell you that we don't
48:47really know if this decreases
48:48because of the regulations that were
48:51put into place or whether it was
48:53covid related from 2 perspectives.
48:55First,
48:55this envy TS data collection of this data,
48:58which goes on pretty much through
49:00six months of the year.
49:01Had to be stopped because of Corbin's only,
49:04but they only got a partial sample.
49:07And Secondly,
49:07we are also seeing in Connecticut
49:10that rates in.
49:11Amongst you have gone down because
49:13of lack of access and lack of
49:15the same kind of cues that they
49:17experience in schools from seeing
49:19their peers use and so
49:21on and so forth so we don't
49:23know what this is related to,
49:25whether it's regulatory or related to kovid,
49:28but the rates have gone down at least in
49:31the early 2020 to what it was in 2018.
49:34That's still not low,
49:35but it's still, you know,
49:37did head in the right direction.
49:39Youth are using multiple kinds of devices,
49:42so this is the other concern BC youth using
49:45every device that's available on the market.
49:48There is a lot of concern about nicotine
49:51use in these devices because devices like
49:53the jewel contain very high levels of
49:56nicotine and the adolescent brain is more
49:59sensitive to nicotine than the adult Bremen.
50:02Israeli tobacco,
50:03nicotine exposure, primes,
50:04the adolescent brain for nicotine addiction,
50:06addiction to other substances that
50:08alters developmental maturing, and.
50:10It can also have effects on multiple organs.
50:12I'm sure you are all well aware of
50:14the of the acetyl choline or the
50:17cholinergic system and know that
50:19nicotine binds to cholinergic receptors
50:21and can therefore influence a variety
50:23of other organ systems shown here.
50:26You thought so use multiple flavors
50:28and I've already talked to you a little
50:30bit about the toxicity of flavors.
50:32Flavors are what draw youth to
50:33user these products,
50:34so this is a great deal
50:36of concern about this.
50:37You choose the cigarettes for
50:39many alternative purposes.
50:40You know they use them for vape tricks,
50:43which is a huge cloud competitions and
50:45vape clouds that you may have seen.
50:47They participate in cloud competitions.
50:49These are some of the clouds that
50:51you shapes that you can create
50:53using these products.
50:55They use it for something called dripping,
50:57which means opening up the device and
50:59putting the E liquid directly onto
51:01the open battery and inhaling it.
51:03They use it for vaping cannabis
51:05so this has in fact gone up.
51:08Significantly, as I said,
51:09a lot of these products can be manipulated.
51:11So Uther actually adding in
51:13other things into these devices.
51:14So if you see somebody vaping,
51:16there's no guarantee there,
51:17just vaping nicotine.
51:18They could be using something
51:20else in the product,
51:21and most likely that it's probably
51:23a cannabis related product.
51:25And as I said the there is
51:27multiple papers on this,
51:28but this is one of our papers
51:30which shows that E cigarette use,
51:32amongst Euclides to cigarette use.
51:34So let's now move on to talking
51:36about smoking cessation.
51:37So we've talked about all the bad things.
51:40Now let's see.
51:41Well, is it actually doing what it was?
51:44What it set out to do?
51:46Which is help smokers quit smoking.
51:48The evidence on that is still emerging.
51:50Unfortunately, we don't have clear cut.
51:52Answers yet because doing an RCT
51:54on this issue in the US is very,
51:57very difficult because of the
51:59way the products are regulated.
52:00Once the FDA maybe once the FDA gets
52:03more information on the toxicity and
52:05safety of some of these products,
52:07they would be willing to allow
52:09an RCT to proceed more easily
52:11for cessation purposes,
52:12but at this point that is very hard to do.
52:16There have been a few few.
52:18Weldon are our CTS and but the overall
52:20idea is based off based on some Cochrane
52:23reviews is there are small sample sizes.
52:25Um, and but they do seem to show
52:28some efficacy, but there are
52:29multiple observation ull studies.
52:30So if you go out and talk to
52:33smokers that are many smokers,
52:34who will tell you that these products have
52:37helped them reduce use of cigarettes?
52:38If not, completely quit,
52:40which of course then leads to the
52:42concern I had raised earlier about use
52:44of both products at the same time.
52:47This is a result of an RCT which
52:49came out in New England Journal
52:52of Medicine from the UK,
52:54which shows you that use of E
52:56cigarettes versus nicotine replacement.
52:58The outcomes at at the end of 52 weeks.
53:02After the initial start of the trial,
53:04the outcome is better for E cigarettes
53:07than it is for nicotine replacement,
53:09and also that those who use E cigarettes
53:12seem to have some benefits in terms of
53:15some of the respiratory outcomes that
53:18are associated with cigarette use.
53:20This is another trial that just
53:22came out from New Zealand,
53:25where they showed again that
53:27use E cigarettes do have some,
53:29albiet very small benefit over and above.
53:32Using patches alone in terms of produce,
53:34having an efficacy or helping
53:36smokers quit smoking so the jury is
53:39still out on this issue.
53:40Also and as the National Academy of
53:43Sciences report basically said there,
53:45there where they are very concerned
53:47about the use of the pump.
53:49When you consider the public health
53:52consequences of E cigarettes we have
53:54this huge divide of of a product that
53:57is really having an impact on youth.
53:59There is limited evidence that
54:01the product may help.
54:02Um people stop smoking cigarettes completely.
54:05There seems to be more evidence
54:07of dual use behaviors,
54:08so we really need more work to help
54:11people convert to E cigarettes.
54:14And they also said that if people
54:16are able to completely switch
54:18from cigarettes to E cigarettes,
54:20it will reduce exposure to numerous
54:23toxins that cops imagines.
54:25Now one might ask, well,
54:26is there some way of regulating
54:28these products to prevent use?
54:30You choose,
54:30but suppose smoking cessation and
54:32this is a debate that the field has
54:35been having for a very long time,
54:37and I will basically tell you
54:38that we haven't reached any big
54:40conclusions at this point,
54:42I've listed some ways we could go.
54:44We could regulate the nicotine levels.
54:46You for example only allows a nicotine
54:48level up to 20 milligrams per mil,
54:51in illiquid.
54:52To give you an example,
54:54jewel contains up to 60 milligrams per mil.
54:57The concern here is that smokers
54:58may actually need higher levels of
55:01nicotine to quit smoking and get
55:03satisfaction from their product,
55:04so this issue has really not been
55:06resolved and there doesn't seem to
55:08be that much movement in terms of
55:10regulating nicotine levels,
55:12we could regulate flavors.
55:13An example is Canada.
55:15They removed all flavors in Eliquids,
55:17but then there is a concern that smokers may
55:20actually need the flavors to quit smoking.
55:22We know this is something that
55:24will definitely be beneficial for
55:26youth because Uther really drawn
55:27to the flavors in the product.
55:29We could regulate the kind
55:31of devices available.
55:32You know, I talked about these
55:34open and close system products,
55:36open system products.
55:37You can add things in.
55:38It can sleep through a
55:40variety of other behaviors,
55:41but you know,
55:42there's a concern about that also.
55:44And you could just allow close
55:46system devices but close system
55:47devices were the ones which are
55:49very popular amongst youth,
55:51so we really not reached any.
55:53Consensus about this issue.
55:55So I just wanted to end with this
55:58about what you can do as clinicians.
56:01People working in this area,
56:03I would say continue to encourage
56:05your patients to quit smoking.
56:07I don't think there is.
56:08I think a combustible cigarette
56:10use is about the worst behavior,
56:12especially from a cancer risk,
56:14so that does need to continue.
56:16Use treatments that have been
56:17shown to work and that are approved
56:20like the existing behavioral
56:21interventions and gum and Chantix.
56:23And these are proven interventions
56:25have been shown to work.
56:27If nothing else works on your patients,
56:29want to use his cigarettes,
56:31then I think you could support them,
56:33but you need to warn them about
56:35not over using E cigarettes and
56:36getting in more nicotine than
56:38what they normally will do.
56:40They also need to have a plan for
56:42quitting cigarettes completely.
56:43No dual use behaviors,
56:44you know they shouldn't just use
56:46the product whenever convenient
56:47and they should have a plan
56:49to quit E cigarettes as well.
56:51We don't want to have a generation
56:53just dependent on nicotine either
56:54because we don't know what the long
56:56term consequences of this are.
56:58You can also educate your parents
57:00and help educate communities and
57:02local schools to really advise them
57:04of what these products could do.
57:07And finally I would say really help us
57:10collect scientific evidence on E cigarettes.
57:12I know that E cigarettes was on the
57:15grand challenge during the retreat and
57:17I hope that this push will continue
57:20and that you all will be involved
57:22in helping us collect more toxicity,
57:25safety and efficacy data on
57:27these product so we can.
57:28Regulate them appropriately.
57:29The point is they are out in the market.
57:32Everybody is using them and we are
57:35trying to develop all the signs.
57:37It's almost like backtracking on the
57:39development of science and that is
57:41where many of these concerns have risen.
57:44So I will stop there.
57:45Considering the time and happy
57:47to answer any questions.
57:49Mr Teacher, thank you.
57:51I know we're a little late,
57:53I just actually Melinda Irwin
57:55sent more comment than a question,
57:58but I think it's it's important she
58:00writes important talk an area focus.
58:03Given the 50% of reduction in
58:05cancer mortality from the peak.
58:07Do the tobacco control and obviously I guess,
58:11given your point, this sort of
58:13resurgence of exposure 3 cigarettes,
58:16do you perceive that that actually
58:19could reverse the trend, as it were?
58:23I'm hoping not. No, but we do.
58:27I think the question is
58:28can we get all these youth?
58:30Who are the new entrants
58:31into this area to stop?
58:33And that's what a lot of prevention work.
58:35And also our work at Yale.
58:37We're doing a lot of
58:38cessation related program,
58:39so we're doing a lot of education,
58:41prevention and cessation and high schools.
58:43So if you or any of you are aware of
58:45the need, please send me a note and
58:48we can certainly go out and talk to
58:50the group if we can prevent these entrance,
58:52I think we would be.
58:54We would really serve public
58:55health very well because we.
58:57One thing we don't want them to do,
58:59we don't want them to then
59:01convert to using the products.
59:03These are all all these kids are
59:05going to be nicotine addicted.
59:07If E cigarettes don't serve them well,
59:09they're going to want to move
59:11on to product switch.
59:12Serve them better.
59:13Which are cigarettes.
59:14Cigarette is one of the best nicotine
59:17delivery devices I have ever seen,
59:19so that's the biggest concern which
59:21is will there be a re emergence of
59:23combustible tobacco and nicotine
59:25use and will that then lead to?
59:27The problems we've seen earlier,
59:29so I can't answer that question.
59:31Melinda,
59:31it's a very good
59:32one though. Well, thank you.
59:34Excellent talk, you know it.
59:36It's 103 so I think will will break.
59:38But I wanted to say thank you
59:41teacher and Ed for two superb talks.
59:43Thank you all for attending
59:45and enjoy the rest of your day.
59:48Thank you bye bye.