"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?"

Transcript

• 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.