Good morning. My name is Dr. Monique Minema. I work as a hematologist in the UMSI Utrecht in the Netherlands. And today I will give the presentation about developments in AL amyloidosis, diagnostic centers of expertise, treatment pathway and stages of disease. And I would like to thank the myeloma patients Europe organizations for inviting me to give this lecture. This lecture will be has certain elements if we go to the next slides. I will talk a little bit about some disease specific information on AL amyloidosis about epidemiology, the current standards for diagnosis and which centers have expertise in Europe. I will explain a bit why it is so complex to diagnose and treat this disease. And I will also talk a little bit about treatment goals and treatment pathways. But I know that later on in the Congress you will hear more about it. So I will shorten that section a bit. So first of all the disease specific information on the next slide. Importantly is that AL amyloidosis is one of the plasma cell diseases that we have that we can diagnose. And many patients hear about that they have AL amyloidosis with amicus or with myeloma. But that's not correct. So it's a separate disease, a separate entity. And of course it's a quite rare disease and multiple myeloma is well more known to doctors and to patients. But also amicus monoclonal temopathy of unknown significance is a much more known disease. And I highlighted multiple myeloma and AL amyloidosis because during the presentation I will compare these two a bit so you can more clearly see the differences between those two diseases. And on the next slide you can see the basis of the disease AL amyloidosis. So like all plasma cell diseases it starts in the bone marrow where you have plasma cells that become malignant or pre malignant and we call them clonal. So clonal plasma cells that divide and divide and these plasma cells they maintain their normal function. So the function of a plasma cell is to produce antibodies. And plasma cells that form the disease AL amyloidosis especially form free light chain. So that's a little part of the antibody.  They are in the bloodstream and through the bloodstream they can enter or they pass every organ in your body. And what's so different about the free light chains of plasma cells in patients with AL amyloidosis is that they have a dysfunction in the way they are formed. They are shaped so in that three dimensional structure. And already in the bloodstream they have an intermediate stage. So they become a bit different in their shape. And when they reach the organs they shape differently a little bit more and they form fibrils. It's like deficits that are attached into the cells or next to the cells of several organs like the heart but also the liver and also your bowels can be can have deposit of amyloid fibrils. Also the kidneys is an organ that's much involved and also the neurological system that makes you sense or regulates your body. And if you go to the next slide I would like to stress out that not every systemic amyloidosis is a form of amyloid light chain amyloidosis. We have several precursor proteins in our bloodstream that can form amyloid fibrils and it is of the utmost importance to diagnose the right precursor protein so the right type of amyloidosis. Most amyloidosis are AL so that's the more frequent form but the more but the other amyloidosis are mostly inherited so you get them from your father or mother besides the ATTR wild type so that's also a form of amyloidosis that's more common but that's developing during your lifetime. So AL amyloidosis is something that you acquire during your life and the precursor protein is the amyloid light chain that is produced by your plasma cells and in the green the green bar you can see what happens when a precursor protein in AL it's the light chain dismantles and forms a misfolded protein and then it forms fibrils and those fibrils are the same in every type of amyloidosis and they are deposited in your organs. If you go to the next slides you can see the differences in complaints between multiple myeloma patients so they are in the blue bar on the right and the complaints that AL patients have and they are in the pink bar. So shortness of breath, fatigue, edema, foaming urine but problems swallowing or eating, diarrhea and weight loss, low blood pressure is very common in AL patients, property bleeding of the skin, having a large tongue, difficulty speaking or difficulty swallowing and carpal tunnel syndrome not in one hand but two hands are all typical complaints that you can have with AL amyloidosis. So you can see they are quite different than the complaints you can have with multiple myeloma, hypergalcemia, renal insufficiency, anemia or bone lesions and the problem is that with multiple myeloma you have four separate entities but in AL it's quite different and if we go to the next slide you can see that sometimes I hope that we can find an acronym so we can more easily detect AL amyloidosis because the acronym in multiple myeloma is CREP and that's easy to remember for many physicians if you think about multiple myeloma. In the next slide you can see why what are the problems with AL amyloidosis, it's a very rare disease so not common I think most physicians never heard about it and it's a very complex disease you have those more than 30 different subtypes, the subtyping of the amyloid fibres is important and you have complaints related to heart, kidney, nervous system, soft tissue with bleeding and they present with different combinations and different severity in each patient's individual and the problem with our healthcare system is that we are divided in organ systems you go to the cardiologist when you have problems with your heart and you go to the nephrologist if you have problems with your kidneys so for them it's very difficult to think about a systemic disease that can cause all your complaints of your heart for example and the other problem is that heart problems with AL amyloidosis are not typical in their presentation so your cardiologist normally thinks about other types of heart diseases and not of AL amyloidosis so that's also one of the difficulties in diagnosing this disease and sometimes it's like finding a needle in a haystack it's very difficult for an organ specialist to think about these systemic type of diseases if you go to the next slide I will talk a little bit more about the epidemiology and again you see AL in contrast with multiple myeloma and you can see that the median age but also the division between men and women are quite the same in both diseases but AL is a very rare disease six patients per million persons per year and multiple myeloma 70 patients per million per million persons per year the median time to first from your first consultation to diagnosis is already pretty long in multiple myeloma 163 days but in AL it's median in the Netherlands it's 441 days so that's extremely long before a doctor thinks about this diagnosis so we have to improve on that I think that's one of the most important tasks that we have and the median survival increased a lot in multiple myeloma it's now six to seven years median but in AL amyloidosis it's shorter the median survival is only a little four years after diagnosis so also there much improvement is needed and if you go to the next slide you can see that we do improve on overall survival so this is a study from the national national amyloid center in London and you could see different time periods with different lines so at diagnosis 100% of the patients are alive and on the vertical bar you see the time when they elapsed so you see that patients die during their disease course but you see improvements so the red line is the latest period of 2008 to 2012 and you see the improvement in survival is there but it's still not enough and what's also striking is that we have a curve in a different mode of way tempo that patients are deceased so in the beginning if you go to the next slide we have a very high mortality rate so in the first two years almost 50% of the patients die because of the problems with the heart and with the kidneys for example but if you go later on and if you go to the next slide you can see that in the end the curve is almost vertical again so it seems that if you survive for a very long time let's say after eight years your prognosis is much better because then perhaps some patients are cured from this disease so high amount of problems in the beginning but later on it seems to do a bit better than myeloma and on the next slide you can see how we stage AL patients so we don't stage them like myeloma patients but we stage them from the organ that is most important for their survival and that's the heart and the heart has some enzymes that they release into the blood stream we call them biomarkers and we can measure them when we take a blood sample and the two most important biomarkers are anti-pro-BMP and troponin so they are cardiac enzymes they are released from the heart and the higher they are the worse your heart is so if you have stage one disease both troponins and anti-pro-BMP are low but if they are elevated above 332 and also your troponins are elevated then your median survival is much worse and in this old scheme only four months later on an addition was made by the european amyloid working parties and they defined that patients with an anti-pro-BMP above 8500 picochroms per milliliter did even did even worse so now we have four stages of cardiac we have four cardiac stages and the staging system has to be used for every patient before you start treatment of AL patients because the patients who are the most fragile have the most severe heart disease so the stage 3B patients they cannot tolerate a lot of medication so they have to be treated differently than stage one patients and in the next slide you can see the survival in those in this cardiac staging system so on the left again AL amyloidosis patients and you can see the stage one patients who have little or no cardiac heart involvement do much better than the stage 3B patients in which death after diagnosis is very high in the first year already and you can also see that's very different from the multiple myeloma staging system that we call that the revised ESS and they use different parameters like better to microcobaline that are all parameters from the plasma cell dynamics and they have a different survival which is much better than for AL patients except for AL patients that don't have cardiac involvement and if you go to the next slide you can see in Europe where the centers of expertise are but we do have a problem there so in Europe we have organizations they're called European reference networks so they are the European organizations where expertise centers in every country in Europe can organize themselves together and try to enhance the knowledge and the treatment of patients with very rare diseases but for AL amyloidosis but for all amyloidosis they are divided again against different types of specialists so we have Euro blood net that's the ERN for hematologist but then we also have Rita and that's the ERN for immunologist and rheumatologist and they treat more ALAA amyloidosis so that's with inflammatory diseases we also have card heart they are specialized in heart diseases and euro and MD and they are specialized in neurological and muscle diseases so here you see the same problem as we have in diagnosing this disease is also that the centers of expertise are divided in four different European reference networks but if you look from a different perspective there are in many rest of European countries there are national amyloid centers so in London it's arranged very nicely but also in France Germany Italy Greece and in the Netherlands we have the UMC Groningen which is the national amyloid center but I'm from another hospital I'm from the UMC Utrecht in the Netherlands and we are more specialized in the more common forms of AL amyloid the more common forms of systemic amyloidosis like AL and ATTR amyloid doses so we have two centers in the Netherlands at the moment in the next slides you can see how we diagnose your disease so AL amyloidosis follows the rules of the IMWG diagnostic criteria and they were published in 2014 and all four criteria must be present so you must have organ damage caused by amyloidosis so you have to have heart failure or liver problems or complaints of your nervous system caused by those amyloid fibrils if you have just fibrils but all your organs function normal then you don't have amyloidosis to prove amyloidosis we have to have a biopsy so we have to have a biopsy that is positive for the conco-red staining for example you can do fat or bone marrow biopsy but the conco-red staining has to be positive if it's negative you don't have amyloidosis and after you prove amyloidosis you have to type the amyloidosis so it has to be tied by immuno-histochemistry but that's not very easy to use and most of the time it doesn't work that well but now we also have mass spectrometry also in Europe we have several centers that use mass spectrometry it was developed in the Mayo clinics and for example in Italy and we in Utrecht we have the immunoelectron microscopy so that's also a very nice way to type your amyloid and then when you type you know the precursor protein and then you will know how to treat it and for AL amyloidosis of course you have to have the precursor protein in your blood or your urine so you have to have measurements of your free light chains and you have to have a clonal plasma cells in your bone marrow and if you go to the next slide you can see where you can biopsy to see if you have amyloidosis so if you do a bone marrow puncture we always advise to do the biopsy and not only the aspirin because in the biopsy you can see the you can do the conchorette staining and on the right you see how conchorette looks through a microscope so this is a fat tissue and you can see the red lighting up and that's the conchorette dye that's that is attached to the fibrils and if the pathologist moves the microscope to another light bundle you can see it's lighting up in a green yellowish color that's very typical for amyloid fibrils they are the only ones that do that so we have a very secure instrument to diagnose amyloidosis what we do a lot of times when we see patients in our expertise center is that we ask for old biopsies to be taken because you remember most patients it takes around two years now not two years one and a half years before the diagnosis is made so sometimes they already had biopsies taken but nobody looked for conchorette for the for the amyloid so nobody did the conchorette staining I mean normally see when we ask for those old biopsies to be sent to us that we can't see already the conchorette the amyloid in in the stomach for example so that's a very important that always has to be done when you are seeing patients with AL and also if we if the bone marrow puncture of our old biopsies don't show amyloids we can do an abdominal fat tissue biopsy so it's important that you puncture the fat cells and not the skin so that's more a technical failure but that has a very high sensitivity for diagnosing amyloids in tissue and also salivary salivary glands biopsies also have a very high yield to diagnose amyloids so these are the most preferred organs to biopsy but if it doesn't work if you go to the next slide you can also biopsy the organ that has the problem so if you have a kidney involved with amyloidosis so we have an nephotic syndrome most of the times you can do a kidney biopsy you can do a heart biopsy you can do a liver biopsy but because there are a little bit more bleeding problems with those biopsies we only tend to do those when the other on the left side fail importantly we never biopsy the nervous system because they the biopsies very painful and they give a lot of complaints of pain afterwards so the nervous system biopsies can't be done if you go to the next slide you see some of the frequently observed problems after biopsy is taken and they are related to the underdiagnosis and we as an expertise center we see them a lot and we try to to warn our colleagues about it all the time so if a clinician has a patient with problems for example kidney problems and they do a biopsy but they don't ask for this specific concurrent staining or they don't mention the differential diagnosis amyloidosis in the remark to the pathologist the pathologist won't do this separate staining so therefore amyloid is not seen and it's not reported but it's there another more frequent problem if you type if you go one more next is that the concurrent staining is done but the pathologist think it's negative and that's something sometimes relates to the experience of the pathologist but also to the type of microscope the pathologist is using or sometimes the biopsy is too negative it's it's really not there and then the clinician thinks oh I can reject amyloidosis and no other biopsy is taken but you if you really think that amyloidosis is the problem then you should biopsy another organ for example the target organ or the pathologist should send this biopsy material to an expertise center like ours so the expertise pathologists can do the concurrent staining again and I think in a substantial amount of cases they do see the the amyloid present and another problem if you go to the next is that the concurrent staining is done it's positive but it's not subtyped so for example the fat biopsy is done they see amyloidosis the patient is an older patient also has some plasma cells or a free light chain in the in the in the bloodstream and they immediately think oh this will be AL amyloidosis but this can also be for example ATTR amyloidosis so subtyping is extremely important and this is I think one of the most important problems and this was published already in 2002 by the national amyloid center that in 10 percent of the patients with which they thought other centers thought they had AL really had ATTR amyloidosis so those patients received chemotherapy well they didn't do anything about that their amyloidosis because TTR amyloidosis is not treated with chemotherapy so subtyping is also extremely important if you go to the next slides you can see some my thinking about the problems and diagnosis so one of is one the first problem is that the clinician should think about it and the other problem if we move one more further is that after they think about it they should prove it and both think about it and prove it are very difficult in AL amyloidosis so what can we do about it if you move further on the slide you can see that we think about it by giving education education post-education training and repeat repeat repeat so that's my experience that we have to repeat ourselves every time again so we can reach as many clinicians as we want to as we need to we also have to give this education to several disciplines I can't only teach hematologist about this disease I also have to teach cardiologist neurologist neurologist about this disease because the patient doesn't enter the hematology clinic they enter the cardiac clinic or they enter the nephrology clinic with their problems so several disciplines has to be targeted and when we educate clinicians we talk about red flags so there are some typical things for example with cardiac disease that can help the cardiologists to think about AL amyloidosis we publish guidelines and we make publications and also for the diagnostic part we give education if you move on and the education is especially about the knowledge of the several techniques when to use it and how to subtype but also to offer our help so we have expertise centers in Europe and if you think about amyloidosis but your pathologist can't prove it send the material to us and we will help you with it and of course also national guidelines but also European guidelines are very important in this aspect if you go to the next slide I also think about this so prove it thinking about it again are we missing an acronym and I think perhaps with all the patients together now listening to this talk perhaps you can help us creating an acronym for this disease and I think it will help us a lot to educate our colleagues and our clinicians in diagnosing thinking about this disease and also proving amyloid in our patients next slide please some words about the treatment pathway if you go to the next slide so I talked about the precursor protein that's the the concept that we see and type our amyloidosis patients and in and the general principle is that we have to treat the precursor protein so in al it's done by lowering the free light chains in the blood and we can lower them by treating the plasma cells that are present in the bone marrow and we know how to do that because we have very effective anti plasma cell director therapies so if we treat a the plasma cells we stop the sink form from filling filling filling with amyloids and then the the body itself can try to break down some of the amyloid that's B so the total amyloid load will then lower a bit in the patients but the only thing that we can do as AL specialist is turn the tap closed so stop the amyloid growth stop the free light chains and stop the plasma cells from producing those free light chains so that's the general principle so how are we going to do that in the next slide you can see that there's no established anti amyloid treatment so I think we would prefer to have some type of treatment that we can remove the amyloids that in in the body of the patients like some kind of a dissolving mechanism or some other mechanism that we can stimulate your body to clean up the amyloid itself but we don't have it so that's a big area of research and we almost thought that we had it so this is also two publications from the amyloid center in London and they had developed an antibody that could really clear amyloid from your body and if you type one more if you go to the next slide you can see patients this is a sepscan and a sepscan that's only available in London and in Groningen so in the Netherlands in the complete world so that's a very special scan and that can visualize amyloid in the liver so in on the left side you see a liver full with amyloid and you see a patient in a trial that was given this antibody and they really cleared the amyloid in the liver because you see the intense black coloring diminishing but this drug proved to be also very dangerous to patients so they stopped the development of this drug and at the moment we don't have a clear anti-amyloid treatment besides if we go to the next slide perhaps an antibiotic so in patients with severe heart disease sometimes this antibiotic is given in addition to anti-plasmus cell treatment because there are some reports that it could work for patients but we are waiting the final there's a trial going on at the moment so we are waiting the final results of the trial another general principle is that patients with AL amyloidosis are frail they have problems with organs inside their body and they are much more sensitive to side effects and they can't tolerate treatment as myeloma patients do so my big message to all clinicians who are seeing patients mostly hematologists are don't treat them as if they were myeloma patients and also AL patients need additional care for their problems with their heart kidney and so on so for example in myeloma patients when you have a lot of cancer cells in your bone marrow sometimes the nurse will say to you drink a lot of fluid because when we start treatment all those plasma cells are going to die and you need to drink a lot to help your kidneys clear those plasma cells but in AL patients who have heart disease they can't tolerate a lot of treatment because they will have edema everywhere and they will have problems with the heart so they mostly have a limited fluid intake so the care for the organs is very different in myeloma patients and we really need experts on that field and we really need coordinating nurses or physicians that that can help the patients a way through all those difficult complaints they have when we are also starting chemotherapy anti plasma cell treatment so in the next slide you can see how we are going to do that but first the last general principle is that if we do it very well if we treat the plasma cell clone extremely well and if you go to the next slide you can see how that works so this is again a survival plot and you can see that patients who are reaching a cr that's the blue line so these are patients where the plasma cell clone and the free light chains in the bloodstream are completely gone so there's no plasma cells the free light chains are normal again we call that complete remission and if they are 90 degrees we call that a very good partial remission so feed gpr and if you can reach that with your chemotherapy treatment your outcome is much better than if you don't reach that so you can see the heart is very prognostic in al patients but secondly how we respond to treatment is also extremely prognostic if we can um treat the the plasma cell clone very effectively your prognosis will be much better than if we don't succeed with that so if you go to the next slide you can see why that is because if we stop the the the amyloid forming free light chains and we if we stop that completely then your body will have time to clear up the amyloid itself and there are cells in your body that can do that we call them macrophages so we can see that in patients who are having a cr or a feed gpr with years to follow that organs do improve we see that with the heart we see that also with the kidney and we don't see that as much with the nervous system for example and we also don't see it in all the patients but they can only reach that goal of organ improvement if we first stop the production of new amyloid forming free light chains and on the next slide you can see how we do it so this is a very nice overview that was published by the italians and you can see that we have the cardiac station in place because that will guide us through the treatment choices so low risk patients with some but are non-cardiac disease who are functioning well are aged below 70 their kidneys are still performing well and there are some other important things but mostly the heart they can have the most intensive treatment that we have and that's autologous stem cell transplantation but only 20 of the patients will have this treatment and that's different from myeloma where most of the patients below 70 can have this treatment so low risk patients can have an autologous stem cell transplantation the intermediate patients that's almost 60 of the whole AL group they will have chemotherapy and they will be treated with portesimib, dexamethasone and cyclophosphamide and that's a scheme we call it cyborg D that looks a lot like the scheme that's also used for myeloma patients but it's dosed differently so the doses of cyclophosphamide, portesimib and dexamethasone is much lower than in myeloma patients and also the frequency is lower than in myeloma patients because if you treat them like myeloma patients they won't complete this treatment and the very high risk patients so that's the patient with the cardiac stage 3b so where the heart is very much involved of the disease we are still struggling how to treat them well at the moment we have a european study for those patients with DeraTumorMap that's a monoclonal antibody treatment that you will hear more about later on in this day but we are still searching for that so sometimes we try just one of the cyborg D regimen for example only the portesimib and if it's tolerated we introduce another agent but we have to go very very slowly very well you don't have to go slowly but we have to go very careful with those patients because if you treat them with a harsh regime of chemotherapy patients won't tolerate it and they can die because of this very toxic regimen for them so I think we are moving to my last slide now this is again one of the differences that you can see with AL on the left and multiple myeloma on the right you can see the differences in autologous stem cell transplantation we still believe that it's an effective regimen but only 20 percent of the patients can tolerate it and you can see that the long-term survival is around 30 percent of the patients are still alive 20 years after they received their AL day autologous stem cell transplantation so that's very promising but it's a very selective treatment it's not for everybody and if you look at newly diagnosed multiple myeloma patients almost 80 percent of the patients can receive the autologous stem cell transplantation but their survival at 20 years is a bit lower than in AL patients because there the disease is more aggressive and will relapse more often than it does in AL if we go to the next slide you can see our general conclusions so if we treat AL we can only treat the plasma cells we can't treat the amyloid itself and the drugs used to treat those plasma cells are the same in AL as in multiple myeloma it can be well treated because it's mostly a small clone it's not that aggressive and remissions induced are longer than the myeloma but the dosing and schedules used are different side effects are different and also the co-medication is much different and if you go to the next slide you can see something of the future I think what you really need besides more early diagnosis more awareness of this disease is that we also need more treatments for the plasma cell clone that is less organ toxic and with the monoclonal antibodies like Darotumumap I think we have a very important tool in hands now and I know that later on in the day you will hear more about it from Professor Matteu's presentation but another development is targeted therapies and for example the fenetoclax that's sometimes used in multiple myeloma seems to be very effective in patients who have the 1114 translocation and the 1114 translocation in your plasma cells is the most frequent translocation in AL patients so almost 50 percent of the patients will have this translocation so we think that also fenetoclax can be a treatment option in the near future for our patients and you can see the results of a small trial in which many patients responded very well to fenetoclax treatments with combined with dexamethasone and only one patient in the gray bar did not respond but this patient also did not have this specific translocation so perhaps in the future the analysis of the mutations in the plasma cells can help us guide treatment for our patients and in the next slide I would like to thank you all for listening and I would like to think Mirjam Brink sees her research from the Dutch cancer registry and so she provided me with some data that I presented to you and I would like to thank the team in my hospital the UMC Utrecht and especially Dr. Rooslegheut sees our pathologist and you see her here on the picture with Dr. Laura Verca sees the pathologist from the amyloid center in Pavia Italy and they trained us to do the electro immunohistochemistry for typing the amyloid in biopsy material so we are very grateful to them as well thank you for your attention


check this out you're mentioning that you don't feel like it's things are breaking apart enough so are you just talking from my technical point of view right now that he is breaking apart in terms of his emotional state just checking touches you don't have any honor do you you all right I think what I would do is if you want to maximize intensity here and make it feel more organic that's a thing you mentioned one that's gonna kill anything that's human and especially at this point tense and you know stressed the way it is anything that's spliny with with too much of a nice arc overall so you don't even even that already is gonna kill it for you if you do this smooth sideways and this here like it's almost as if you want to just start I don't mind this like he's in a reflection but then I will make this a bit more you know he will go like this stop a bit I mean that was far right go a little bit hold a bit go over there go over there and even this will be more like one stop two stops it's almost I almost burred like in short bursts it's just a bit more abrupt but you could also just start from here if you're too concerned you don't have any honor and then this is what I mentioned before where if you track his nose it's it's doing basically this which is a bit too beautiful it's too nice you don't have any honor do you and in here too is when you go not too as in nice round the arcs but you're going up and you see how it's almost as if you want you attract his nose here any honor do you all right I'll take the sound off just look at the nose curls curls up and down it's almost like a bouncing ball curl curl whoop and down and that so there's a lot of stuff where it feels like you're doing that and that that kind of takes the organic part out of it because you don't quite believe his state of mind with arcs like that so what I would do is bring the audio back a bit you don't have any honor so it's what you don't have any honor so it's you don't have any honor you don't have any you can keep the the right to left I would just really really really minimize your your ups and downs here so it's not so much that and that but it's more that holds that you can almost do something more like that to give it a bit sharp sharpness to it you don't have any honor do you and then sushi through here so you want to stay down longer any honor do you right and then on honor it's really on all after he says honor honor that's when he sharpens up and goes up have any honor do you and then any honor do you do you even then you can go stay and stay stay stay like really minimize your ease into that and overshoot the honor do you and instead of doing one big movie do you will be a the nose will go down on do and then your head would do kind of a sideways twist to you down on do and you have a sideways thing but really your curves right now feel like they're like that and you want to get moments where it's almost like this right where it goes down ever so slide ease in and sharp down again you want to take those you know if you have your keys here you really want to take away those roundy tangents any honor do you and then do you and that would go like I mean you go like this you can counter rotate the head a bit so that the nose around here so he's already leaning which is fine but his kastai is staying kind of put looking at the guy but not too much you don't want to completely counter it but just so it's not so down my two here down and over so it's down hold of it and then over you careful here that is a weird see how that those go straight and then something to the right feels like if you do through your arc you know it's basically like this and you want to ease into that a bit more give us a bit more of a curve because at this point it's you're already having such a big move that you know by this point probably tilt the head a bit here and the rotated in wise that the nose around here ish they'll kind of soften that sudden turn you and that's great I love still that that's great you that's great and then on cow I would just do almost a linear key where the nose goes from here to here in a really sharp way you really want to feel that explosion and it could be that the nose spacing is this and yeah maybe one frame here and then next would be here so he's a tiny bit out of it but really bow like a really big explosion and then keep that and all the thing you need to do is watch this cheek bone boom look at that that's your wall right there or a mouse is boom so you have to take your roots your root goes screen left visually and then suddenly goes to the right and you really have to ease into that so somewhere you have a linear key so just blind that key to soften that and then you could have this point the nose a bit like you have a slight rotation in the while and a slight tilt over to also help with that direction change and then that's it you don't have any honor do you so this is your big offender right it's little twirl twirls here and then how smoothly this goes up and down because it doesn't feel like it's tied into the body moves and especially the audio I think that to me is where the organic part breaks down it just it feels like he's I see splines and I don't I don't feel how that head is motivated by the chest and the words and the energy that comes out of that right that gets better just that feel that little abrupt direction change and then your arms here feel a bit too even in timing and they're a bit I cash because it is not that much like that wrist would be going up like that fingers it's my awesome thing here right it's a bit more line with the forearm because it doesn't feel so I cash and your timing feels like the curve is doing kind of that as opposed to maybe yeah like here you want to be a bit more abrupt and chaotic because it is you know it is tied to the audio for watches here you so it's you and he goes up a bit and you could go up and then pause a tiny bit and then he goes round it gets a really exaggerated quick move that kind of anticipates almost this right you and not like as in like a huge way but it has a bit of a up and pause bit faster and then you want to stay in this position because he's really tense now so during all of this this softens that whole intensity so keep that a bit higher and then he goes coward and maybe two frames before two frames after you can kind of try it then his arms shoot down the way you have it you all right that is it thank you all right there's an email you can sign up you can start whenever you want you can submit whatever you want you get 16 submissions either way like and subscribe would be awesome all right thank you


Hello, this is Laptop Media, and today, we will show you how to open the Acer Swift 5 and what's inside of it. To access this laptop's internals, you need to undo 11 Torx head screws. Then, pry the bottom panel with a plastic tool, and lift it away from the chassis. Please remember, it would be of great help to us if you just hit the like button and subscribe to our channel. That would motivate us to make even more and better videos for you. This notebook is equipped with a 56Wh battery pack. It lasts for nearly 12 hours of web browsing, or about 10 hours of video playback. To remove it, unplug the battery connector from the motherboard, and undo the two Philips head screws. Memory-wise, you get 16GB of LPDDR5 RAM, working at 4,800 MHz. Unfortunately, it is soldered to the motherboard. On the other hand, you can upgrade the storage via 1M.2 PCE X4 slot, with the support of Gen4 SSDs. Here, we see two heat pipes, two heat sinks, and two very small fans. As you can see, the VRMs are left uncooled. If you'd like to see more disassembly videos of the latest notebooks we would highly appreciate if you hit the like button and subscribe to the channel.


volunteer because I was already at the meeting so staying extra day was fairly easy and kind of made it my travel arrangements work a little better. I was excited about the project because I've started out in photography conservation before I transitioned the objects and so I was kind of excited to look at some photographs again and it's really exciting sort of meeting the other people involved in the project. I really like the agency meeting just because you can meet other conservators and find out about their work and the Angels project is a good sort of casual opportunity to talk to people. I'm really excited I came mostly to try and network with people and find opportunities for internships it's a really great opportunity. I'm here at the Angels project I found out about this through the website it was listed as an option it sounded really fun and again it's just like a great it's a great way to meet people and talk to them and find out their stories. I've been thinking of doing AIC Angels for probably 15 years. This is the first opportunity I had to do it. I didn't know what they were going to be working on it's not exactly my area but glad to help out. The reason I'm here is because I found that being involved in ACPN events has really helped me network and meet people outside of the book and paper group. I feel a lot of times it's a very big group and we're kind of very insular but this year I've met tons of people and spent tons of time with especially the objects conservators. I came to Rochester to specialize in photograph conservation and this is my second Angels project. I think it's a great thing to do to like to give a service to the community we are having the meetings and all that. I learned so much just by working with the people from different cities. I got involved with the Angels projects to help with my expertise here but sort of at the end of the day ended up taking on the primary role of the beginning organization with some of the already fine conservators we have here so I sort of set up a workflow based on what Nancy Reinhold had done locally but she wasn't able to be here today so I think I worked together starting last night with two other conservators that I knew to set up the photography then the inventory spreadsheet that Michael the curator had had begun so that we could take down condition information and enter that in there and and then the basic workflow was to get some condition information based on conservators assessments and then put them into a new storage format after they've been photographed so now there's a document there's minimal condition notes really indicating primarily whether something is stable or unstable and then some quick notations of the kinds of issues so that there's a record for them photographing all the images are half of the images that we're coming through the Angels project in the last box of 340 basically 10 types and 60 daguerreotypes 62 amber types currently working here on the AIC Angels project and I am surveying amber types for its condition and noting whether or not it's stable or unstable and if it's unstable just listing some comments as to why to help the staff here the society better understand their collection and future preservation needs so this is an amber type it's in a thermoplastic frame and not actually case so I'm noting that the condition and it's very stable it's not falling out of its case and it doesn't have a significant corrosion problems either on the glass or the preserver or the math and the case does have some breaks or the frame does have some breaks at the corners but that's just a little area of loss and not actually structurally problematic in frame so it is still considered to be stable it's an inert plastic trying to balance not touching the way to affect any further it's already been tarnished and oxidized from exposure to the atmosphere for an extended period I don't want to get any other fingerprints or oils on it and it's trying to score the crease on the polyester here to the bottom part of the tray or to pull the tray and then place the stiffer mylar over the front and back of the package and seal the edges so that'll give us physical protection from any further scratches or abrasions and protect it from the atmosphere to keep it from tarnishing further it needs to be more safely housed it could be handled until such time as it can be treated by a conservator to reduce some of the tarnish or provide a little more stable housing for the longer term. It's a conservator at Illinois State University and we're working on rehousing these daguerreotypes we've gotten some archival boxes and lined them with some foam so to protect the objects and we're creating kind of separation so that when they're shelled they'll stay separated and protected. Housing up that these are tip-tips right and we are the sort of final temporary handling so of the crew so what we're doing is inserting them into mylar envelopes making sure that their temporary number goes with them so it matches up with all the data and the photography that's happened and imaging that's happened taking each step and they're being housed and appropriate archival materials in groups of 10 so the curator can find them more easily eventually it'll be much heavier tip-tips. There are three hundred and thirty three hundred and thirty four we're waiting for the last two to come in actually and so they're all organized 100 200 well this is up to 99 this is 100 up to 199 200 to 299 and then we begin with the 300 so and there's room for more to go in this is so satisfying look at them nicely everything tips in here just perfect preserve of text walkie walkie county history through our outreach programs through our exhibitions that educate that public not only native walking but tourists that come to walkie for dimensions like AIC or other dimensions to really get them integrated into a wide walkie history where a walkie has a very rich immigrant history has a rich industrial history so it's our mission and it's our duty so to convey why the past is important why how it relates to the present is important


now we will see how to debug our programs with ddd. So, what is ddd? ddd is basically for monitoring your program execution many times after writing the C program you have to debug it. So, may be it will be for C program C plus plus java ddd provides a common interface for all these debuggers.  So, we can use it for debugging executable binaries output of our gcc or g plus plus compiler. We can also use it for java white code output python pearl many support for many different languages is available. So, how to invoke ddd simple command ddd the other way is we can directly specify executable as a command line argument or you can attach some running program to ddd we will see that later. First let us start with a simple C program debugging we will switch to demo directly. So, that we can better understand it just start your browser mozilla browser and enter this path in your browser to get a sample C program once you enter it will ask you whether you want to save the file or not got the file just go to the save as file save as and save it in the current folder desktop folder the save file do not save it as a web page save it as a dot c file only after that just open the file from g edit open the terminal window if you do not have go to the terminal window and move to the desktop folder by default you will be here do cd desktop and vim sample dot c. So, this is a normal c file for bubble sort the simple bubble sort on array let us just walk through this code briefly go below this is the main starting point arguments, arguments passed are all elements in array and we want our program to sort this out here we are allocating an array for the elements this loop converts the text into the numbers using function a to i. So, it converts from string to integer the arguments that we have and this is main bubble sort function we are passing array to it and size size of array and this is simple printing let us just go to the bubble sort quickly. So, arguments are array a and size that is 0 to the number of element last element in the array and this is the simple implementation of bubble sort. So, now let us compile this program and we see how it works using ddd. So, just get out of vim and compile this program using gcc hyphen o sample dot o. So, that our output file will be sample dot o. Now let us run this program arguments are the elements we pass yeah. So, that is the bug we have to find using ddd. So, as you can see 4 elements we have passed our 10th, 20th, 10th, 30th, 25th and as a output we are getting 0. So, we will use now ddd to find this bug. So, use ddd sample dot o one step we imaged out whenever you want to debug any program using ddd you have to specify option g while compiling it. So, here specify gcc sample dot c and hyphen g hyphen o hyphen g enables the generation of debugging debug information in your executable. So, that ddd can debug it. So, do not miss this option otherwise ddd will not be able to debug your program. So, now we will do ddd sample dot o and now you can see the sample dot c is already open for you. So, this is your source window and this is debug window as you can see there is a prompt gdb. So, ddd internally uses the debugger known as gdb for debugging your program.  So, from the program menu go to the program menu and select run now program run. So, it will ask you for arguments here give any 4, 25 and say run. So, now in the gdb prompt you can type gdb prompt you will see the output it is same as what we had earlier. Now we will start debugging this. So, first thing that we want is a program should stop initially for us. So, we wanted to break on the main. So, click on main this is the arguments window it will immediately show you the text that you have selected and then go to the break and selected and you will see a break point has been inserted on the first instruction in your function. Now, again go to the program run arguments are already there last times arguments and choose run. So, now the program has stopped on the break point we have selected. Now from this point onwards we can go through stepping a program we can monitor data values and all. So, let us go step by step. So, here we are allocating array here the green arrow indicates that your execution has stopped on this line. So, let us go to the view menu and click on command tools. So, you will get this window that gives you all commands for executing this program view command tool. So, now the there is a next button in this that allows you to go to the next line. So, clicking on this your execution has moved forward the array a has been allocated using my lock and now this for loop is extracting the text from your command line into your array a. So, let us monitor contents of this array a for that click on a and in the window type in your arguments window type a of 0 a into square bracket 0 at the rate bracket arc c that was the first argument to main arc c minus 1. So, we are just saying it to display the contents of array a and its length is arc c minus 1 click on display and you will see array has been displayed here this is your data window it shows contents of the variables. So, I suppose everyone is now able to see this in data window contents of array a. So, now right click on this and select rotate. So, it will show your contents horizontally you can view it in one view it will just show it horizontally it was being displayed vertically it will show that horizontally. So, now as you can see contents are all 0s. Now, this for loop is going to convert 1 by 1 or element extract it into the array a make sure you have this command tool available you can display it using view command tool. Now, just click next. So, it will go to the first step and as you can see the element 20 has been extracted into array a. So, we go on extracting every element 10, 30, 25 and it has come out of loop. So, here we ensure that our the arguments that we have passed on the command line are getting extracted properly will go through this function directly will go over this function. So, click next and it goes to the for loop now just look have a look at array contents it is 0 10, 20, 25. So, this means this function bubble sort has some problem it is adding 0 to our program. So, we have to go we have to analyze it through. So, let us finish execution of this just click click on continue. So, program will run and finish. So, program exited normally and now run it again it has stopped there will go through this again now you can use until command. So, that the program will complete execution of loop and will stop on the next line as we have already monitored how the for loop works and we know it is running correctly we directly want to move to the next line will click on until. So, it has come out of that loop directly doing all iterations in that loop everyone has reached here bubble sort function. So, the array contents we have extracted arguments in array and now we want to step into this bubble sort remember that when we click next the control got to this for directly now we want to debug this function through for that we have to use step. So, step goes through the function. So, as you can see now the control is in this bubble function. So, it has stopped on the first line in bubble. Now, as you can see this array a has disappeared from data window this is because our stack frame has changed we have lost reference to the variable a that was allocated by earlier function we are on different stack frame now you can always view the stack frames using the status back trace click on status back trace and you will see two stack frames there this one and other one. So, one is the main command main function and this is the second call second stack frame you can just see the contents of other stack frame if you click on main the array a reappears. So, it is the array a is valid only in that function and in bubble sort it is not there. So, now we need to monitor a that is in bubble sorts context. So, let us add it again to data window similarly click on a into square bracket here in the argument window type a into square bracket 0 at the rate and specify size into the bracket and click on display you can also add size to the display like this you can add as many variables you want to the data window and you can monitor their execution then everyone getting this. So, now as you can see size is 5 and array already contains 0. So, there is a problem the arguments to the function the size argument to the function is probably missing we have to give 4 rather we have to give arc c minus 1, but we are passing arc c and it is taking the last element also let us debug through this for loop and verify this. So, command tool will use next for this. So, the first iteration and see it has swapped 10 and 20 as we know in bubble sort in every iteration it puts highest element to the end. So, again the second time. So, it has swapped 25 and 30 and now let us monitor this array closely and it has swapped 0 and 30. So, that means it is treating 0 as one of the elements in array. So, there is a problem this is because the size that we have passed is wrong. So, let us try to correct this and see if this works properly click on finish. So, it will come out of loop finish forces it to come out of the current stack frame that is the current function. So, after clicking finish it comes out of bubble sort directly and as you can see the output is 0, 10, 20, 25. So, there is the problem let us click on continue and now we will try to correct this problem. So, run it again with the same arguments will go to the bubble sort using step and now size is 5 and our prediction is size should be 1 less than what it is. So, let us try to set it here itself we will try to mutate it here and see if the program works fine. So, we will click on size it is there in the argument window and click on set it will ask you for a value the current value is 5 and we think that it should be actually 4. So, change it to 4 and click on ok. So, as you can see the size is 4 now we have changed it and now let us try to run this program normally we will click on finish. So, that the function will complete and now as you can see the array contents are fine. So, this means that the size that we are passing is 1 greater than what it should be there is the bug. So, we will now come out of this let us say continuous and let us close this ddd file exit open the sample dot c and go to the line calling bubble sort and change this arc c to arc c minus 1 just save and close this and now we will compile this again and now we will try to run this again with the same arguments and we are getting correct outputs. So, this is how we identified bug using ddd and we corrected it. So, we will just quickly go through these slides to see some additional things we can do with ddd. So, as we have seen invoking you can just give ddd and then open your file later the other way that we used is ddd executable and you can also attach ddd to the running program you just have to give process id and ddd will allow you to debug the running program. So, the syntax for this is the last one ddd program and pid you have to specify for quitting as we already know we are quite familiar with file and exit you can also enter gdb on the prompt quit on the gdb prompt I will just go to the ddd for better demonstration you have this gdb prompt here you can also type quit here to get out of ddd other way is pressing ctrl q. So, we have to use hyphen g for compiling then you can start ddd first and open your file later using file open. So, you can specify executable file there and you can debug it alternatively if you can also give source file dot c file and you can debug it. Now, this is one interesting thing looking up definition ddd allows you to look for the definitions of functions it allows you to browse through your code easily. So, I have seen the call for bubble sort here and I want to locate where definition of it is in source. So, just click on bubble sort and click on look up and it will automatically navigate you the definition of that function click on the function you want to search and click on look up now stopping execution as we have already seen we can set break points to stop execution. The other thing is watch points will not go through details of it but as we had set a break point on some instruction you can also set watch point on some variable so, that whenever value of that variable changes your program execution stops. So, maybe you can set the watch point on some array element and whenever its value gets modified your program execution stops and you can say where it is getting modified. So, that is watch points you can if you have some problems like infinite loops or something you will never get to the ddd terminal whenever you run it. So, you can use escape there to stop execution program how to run we have already seen the execution window is the other thing we have seen that the output appears here in gdb window the other way to view is program run in execution window and ddd will create a separate window for you and show output there it just to see how your output looks like when your program is executing. Examining data as we already seen there is something like value tips break on the main function again and I will run this I will run it several steps. Now you do not always have to create a data viewer something to watch the variables simplest way is just take your cursor to the variable you want to see and it will show the contents. So, arc c is 5 it is showing it will also show contents on the status line here as you can see arc c equal to 5. So, this is the simplest view to monitor way to monitor your variable values. The other way is print you can always print some variables on gdb prompt just type print and say arc c any variable you want to see value and it will print the value for you otherwise just click on it and there is a print tool available it will show the value in gdb window. We have already seen how to examine stack using back trace option then resuming execution the next we already seen it goes to the next execution line step also goes through the next execution line, but it allows you to debug through the functions next we will go over the functions it will directly execute function and go to the next line, but step will run through the function for you then until we already seen then continue continues execution normally from the current point and kill if you want to terminate your program abnormally you can use kill. So, I mean the running context and I am done with debugging I can directly say kill. So, the execution will stop there only now there is some interesting feature undoing program execution means just like you do undo in your other editors or something you can do undo in your debug it does not actually go backwards through your program, but what it does is it saves the execution status of every line and as you do undo it will show the previously saved execution status.  So, it is also useful sometime. So, that is all about gdb you can always refer to the ddd manual for more details everything is given there in detail that is it. Thanks.


I'm going to go pretty fast. One of the things I learned yesterday from Carl Dahl and that I only got 20 minutes. And so I've tried to shorten this down as much as I can. I'm not sure I've ever been asked to speak for only 20 minutes before in my life. But we're going to try. So I've called this weaning stewardship the art of weaning without stress. I'm not sure that's possible, but that's the title they gave me. So here we go. I want to talk about four things basically, but keep all these four points very brief. Why do we wean? Purpose of weaning. What's risk all about in terms of weaning stress and risk of respiratory disease? Talk a little bit about weaning strategies. In other words, different types of weaning.  Are these slides advancing quickly for you? You should be on stewardship purpose of weaning. All right. So why do we wean? What's the purpose of weaning?  There's a stewardship responsibility to the land resources we have, to the cattle that we have. And in this case, I got three bullet points. We reduce the demand on the available pasture and water resources by weaning. We want to maintain adequate gains in those calves. So there's a stewardship responsibility to those young calves. And finally, we want to maintain adequate body condition score in the cows for the winter and calving season. Which ultimately impacts reproductive rate in those cows as well. So that's the purpose. Specifically, how does that happen? Well, when we wean those calves, it reduces the demand on the land and on the cows. So dry cows consume 30% less forage than lactating cows. They also require only 60% of the energy and 50% of the protein. Dry cows require 60% less water than lactating cows. Makes sense. On the calf side, we want to maintain gains in those calves. And it's obviously more efficient to feed calves directly than to feed the cows to feed the calves. And the last point there, calf performance is not going to be compromised. And health need not be compromised either. We'll talk about that a little bit more later on. OK, this is kind of a famous picture that's circulated around the web for some time. I love this picture because I'm sure this bridge was used for years to cross over from one side to the other of this drainage canal. And I'm sure at that time that this bridge was built, people were perhaps even using horses and horse drawn cultivators and planters. And then they went with a little heavier tractors. Never thinking that when they reached the stage of this tractor that it might not hold up any longer. That's sometimes what happens to us in our cattle operations. As we increase the number of cattle, a whole lot of other things increases. And it tends to increase the risk to those cattle of getting sick as well. So I just want to spend just a minute here on this risk issue. The definition of the term risk is the possibility of loss or injury, or sometimes called peril. It's interesting to me, it actually comes from the French term called risqué, which most of us understand what that's all about. But I'm using it in this context. The purpose of utilizing the science and proper animal husbandry is to reduce the risk. Reduce the risk to those animals by stressors. It might be the stress of weaning. It might be the stress of comingly. It might be the environmental stress. It might be the stress of handling. Nutritional stress and people's stress. If we reduce those stressors, it ultimately enhances performance and reduces the risk of clinical disease. The reason I'm bringing this up is that we're going to talk about vaccination later on. Does vaccination reduce all of these stressors? No, it doesn't. It only reduces one of those. Sometimes we can get hung up on vaccination thinking, well, the calves got sick. I vaccinated them. Therefore, the vaccine didn't work. Well, we have to focus on perhaps other stressors that might have broke the bridge like that tractor did. OK. I'll maybe just skip over this one real briefly and maybe talk about it a little bit later in the different contexts. But a little bit of stress is OK. A lot of stress is not OK. I use the term piling on when I'm talking about too much stress. For those of you guys that have played football, you know what piling on is. And sometimes we do that to our livestock when we get too many stressors involved. A little bit of stress is OK. It's a little bit of stress is OK for people, too. Because I think we perform better than if we have no stress. Cattle probably perform a little bit better. And they're able to cope with it with just a little bit stress. When piling on occurs, then the bridge breaks. OK. Got a quick collage of pictures just here showing you a whole bunch of different stressors that can contribute to that calf right in the middle of becoming sick either early on or late. You have that image up in front of you? Yeah, you must. OK. All right. I'm going to leave that purpose of weaning. I'm going to leave the short little discussion of risk and talk about weaning strategies all by themselves.  We've probably not really thought a whole lot about different strategies regarding weaning. So what I've done here is listed four different strategies. First one is pasture, where we actually fence line wean. In other words, we're weaning those calves out on grass, out on pasture, the same pasture that the cows have been on. But we got a fence between the cows and calves.   And after seven to 10 days, then we separate the calves from the cows.  Third one is confinement weaning, which most of us do. And then you couple that with minimal separation. In other words, a cow might be right alongside the dry lot that we've confined that calf in.  I got a little bit information on each one of those. The first one I'm going to deal with is pasture weaning. There's not a whole lot of science or literature behind this one. You'll see down at the bottom there the anecdotal evidence there. But the definition is that calves remain on pasture while the cows are removed or pastured adjacent to the cows. The advantage is that there's less labor, typically. Less stress, typically. Lower feed costs, maybe. The disadvantages and the others can speak to this. Gains maybe less, depending on forage quality.  And finally, you're going to need more than just a couple of barbed wire fence structure. You're going to have a pretty solid fence to keep those calves separated from the cow. I've never done this one myself. I'd like to try it, but I've never done it. I think it's a good way to reduce the stress of weaning and leave those calves on a diet that they're used to already. I think that's the advantage. I've just got down there, maybe expect one to two to 1.5 pounds per day. But again, it's totally dependent on forage quality. And you may supplement those calves out on grass as well. The anecdotal evidence I have here is from Progressive Farmer 2001, where they reduced morbidity from 25% to less than 1%. You're not going to see that every year.  Talks about, in this case, using a three-strand electric fence. Just one slide that I have on anti-suckling devices. This is one I can't remember the trade name of this one. There's one that's made in New Zealand. There's others that are made in Canada. They actually work quite well in preventing that calf from nursing. Although there are a few calves in the population that will figure out how to nurse even with these on, they'll practically turn upside down just to be able to nurse. But there's a number of operations that I'm familiar with that have used this. I used to think that this technology was for people with 25 cows that didn't really have facilities. Yet I know very well a ranch in Nebraska with 11, 12 different ranches running about 5,000 cows where they actually use this technology quite successfully. This slide here just talks about potentially some of the advantages of reducing stress with these anti-suckling devices. In other words, what you do is you put this anti-suck device in this nose of this calf. And at that time, it presents a great opportunity for also pre-weaning vaccinations. And then somewhere around seven to 10 days later, you pull, you wean those calves and pull those devices out. You really don't want to leave them in any longer than that because then they start irritating the nasal passages, which you don't want to do. The only thing this slide here is telling us is that those calves exhibited less stressful behavior after weaning when they had these nose sock devices in them. So it allowed them to get over the temptation or the sense of needing to nurse cows and that you're able to wean them with a little bit less stress. This in some of these, I got some studies listed down below here and gains were similar by 50 days post weaning with those that had gone through normal weaning strategies compared with those that had these anti-suckling devices. Just want to switch gears a little bit to what may be more of what you and I would participate in and that's what we call confinement weaning. These next two slides just talk about confinement weaning with contact with the cows, with the mother cows versus complete separation. We'll tell you one little quick story. We actually made the mistake one time of moving the cows away from the calves. In other words, weaning calves in a confinement lot and then hauling the cows to a different pasture. We had cows all over the county. So that does not work very well. I'll just throw that out to you. But in this case, what they've done here is confined the calves and then at least move the cows away so that they couldn't have nose to nose contact in this dry lot situation. All I'm looking at here is the days after weaning. This is a two year study and the gain by days after weaning. You don't really see a whole lot of difference. There's some year to year variation here. In 1996, just look at that first column day zero to three, there was a significant advantage of those calves that had still had contact with the cows. It evened out, generally speaking, as they went farther along into the weaning phase. The next slide is 1997. You actually see in the first three days there that the gain actually improved for those where the cows were separated. What was interesting in this study is that 1997, there was a two times antibiotic treatment in those calves that where the cows were separated versus those that had maintained contact with the cows. I don't know if I have a good explanation for that, that sometimes the year to year variation you'll see with morbidity and mortality, okay? So all this trial did here was to compare dry lot separation, dry lot confinement, maintaining contact with the cows versus dry lot separation where the cows were completely away from the calves, okay? All right, another study comparing a little bit different, not different things, but kind of drawing a lot of these things together. What I've got here is four different, actually five different treatment groups. Not where they actually had a control where calves were maintained on the cow. In other words, they weren't weaned. And you had one treatment group where they had fence line contact but they were weaned and on pasture. Another group where they were separated, okay? Separated from their dams completely and still remained on pasture. And then the two final ones where they were separated but they had been preconditioned to hay and then separated not preconditioned to hay.  The only thing I wanna point out and this relates to what most of us feel like when we wean calves, if I can get them to eat, I've really, I've really complained victory because most of the time those calves are gonna perform better and have less illness. So I just want us to look at those five different treatment groups and look at their eating, the number of calves eating. Percentage of calves eating. When they stayed on pasture, not weaned obviously, during the observation time, a lot of them were eating. When you look at fence line contact, there wasn't a whole lot of difference. In fact, there wasn't any statistical difference between those in fence line contact with their cow, with their mothers remaining on pasture and those that were non weaned and stayed on pasture. So that was what was interesting to me is that those two groups statistically were the same in terms of their eating behavior. When you separated on them, separated the calves and they remained on pasture, separated from the cows. In other words, the cows were not in contact changed their eating behavior as did the rest of the treatment groups as well. So it kind of gives us an idea that staying on pasture is a good thing. If you can maintain fence line contact, you'll maintain some of that good behavior that the calves already had when they were still with their mothers, okay? All right, couple slides. Just talking about advantages and disadvantages of confinement weaning, which I'm imagining most of us do. Advantages that it allows us to feed a total mixed ration, which is Carl and John alluded to, you can usually predict gain better. You probably can shoot for higher gains when you've got those cattle confined. They're easier to spot when they have abnormal behavior. In other words, if we need to pull and treat them and then they're easier to pull and treat. The disadvantages are related to stress. In my mind, you got more commingling, more cattle closer together. You have to have a new pecking order, especially if you're bringing different cattle in, even from different pastures, there's closer contact between animals, greater chance for transmission of pathogens. And then sometimes the environmental challenges are greater when we confinement wean. Confinement with no separation. In other words, the cows are right outside the fence. There's less weaning separation stress, but all these other stressors are still there. The potential for commingling, the pecking order and the pathogen stress. When I compare confinement weaning without separation with confinement weaning and separation, I've got all the ones I just talked about, plus I now have the weaning separation stress. So in my mind, if I was gonna rank all those in terms of health, I would fence line wean on pasture, okay? And then I think I would confinement wean without separation, in other words, have the cows right on the outside of the fence. And lastly, and I know this doesn't fit everyone's management, lastly for me in terms of health would be confinements plus separation, okay? Mike, getting running out of time here. Okay, let me just jump. I wanna jump to weaning health and talk a little bit about vaccination. So this, the slide that you should have would be risk and vaccination, okay? So the purpose of vaccination is not to reduce all those other stressors, it's to reduce the stress from what I call bad bugs. To reduce the spread of bad bugs and decrease the risk of those calves becoming sick from what we call BRD, well, vine which is hard to disease or pneumonia, okay? Been just a little bit of time talking about vaccination because all of us practice it or most of us do, we need to know kind of what we're doing and why we're doing it. As a veterinarian, I try and have a philosophy of vaccination, okay? And there's three simple questions that I need to answer before I wanna stick a needle into an animal. Number one, is it actually necessary that I do this? Or do we just do it because we've always done it in the past? I don't think that's a good enough reason. I think we have to have a necessary answer for why we stick a needle into an animal. In other words, in the case of vaccination, is there a risk that these calves might get sick from this certain pathogen, okay? If that's true, then I need to answer the second question, is there a vaccine that's actually effective? And finally, if there's a vaccine that's effective, is it safe to use? Pretty simple philosophy, but I think it's an important one to ask ourselves. And actually most, I hope, most of our veterinarians that you deal with abide by this philosophy as well because it tends to keep vaccination protocols pretty short, okay? Which I think is a good thing. Use only what's necessary, use what's out on the market, demonstrate to be effective, and that it's safe to use, okay? All right, let's skip this. Am I out of time? I'm getting close. Okay. Let me go down here. Let me go to this slide, logic, management, and vaccination protocols. Remember that as a producer, and as I as a veterinarian, we've only got so many times in the life of those calves we can handle them. So I've called this handling events. Handle them early in life, we might handle them pre-weaning, weaning and post-weaning, okay? So that's my chance to put vaccines in those cattle or do something else to them, okay? In the context of vaccine, I've got two slides left, okay? In the context of vaccine, so I'm gonna base what I do to those calves based on what I think is necessary, what the risk is of those calves are developing disease, what my labor situation is and my philosophy of vaccination. I can choose to do nothing. I can do things at weaning alone. I might do things early in life and post-weaning, early in life and at weaning, early in life at pre-weaning, and on and on. You can see I have many different options depending on what the management is for that particular operation. What I've done here is rank these from the highest. If I have, if I do nothing, I expect there to be a considerable risk of developing BRD to all the way down at the bottom. So this is going from doing nothing at high risk and trying to reduce the risk in this last bullet point, okay? And finally, what do I think needs to be done? Early in life, modified live respiratory virus, seven-way claustridial, pre-weaning five-way modified live respiratory virus, claustridial, manhemiahemolytica, optional histophilus at weaning the five-way modified live and perhaps manhemiahemolytic histophilus, okay? That was a lot of stuff. I apologize. And I probably didn't maintain that 20-minute rule and it would be the first time anyway, so I didn't meet my goal. Sorry, Carl. Actually, Jerry, you're right at 20 minutes. So with that, are there any questions out there that there might have for Jerry? People are still wondering what I just said. Hey, Jerry, this is Carl and Fargo. Are you there? Yes. Yes, we're here. Can you comment about whether there's data out there that talks about the impact that creep feeding might have on weaning stress? Yeah, and in fact, I think I had a, I might have had a bullet point on one of them. And this, I don't know of any literature on that, Carl. What my bias is, is that when we creep feed calves prior to weaning, and I'm only talking about, my strategy is to do it only three to four weeks perhaps prior to weaning. Maybe longer, but that just depends on when we wean. Is that we get those calves to eat a lot quicker. They come into that weaning confinement wherever that is and they already know how to eat. And when they know how to eat, it seems to make my weaning strategy much smoother. What you may be referring to is if we allow those calves to get too fat and now you throw the stress of weaning and perhaps even another change in diet where they actually go into a short, little short-term weight loss, then health seems to be impacted negatively in that case. I don't know if that answers your question, but that's my bias anyway. Do we have a question here and a little more? Yes. I run a feed lot. And there's one other weaning method that you didn't address and that's called sales bar and weaning. Laugh all you want, but from September through first part of December, half the calves in there are all bawling. So the question becomes, do you trust the producer, the cow calf man's, say so that he's given them shots? The only way you can really know is if he's got a veterinarian sign certificate. Right. And buying these calves, and I know other feed lot operators, they have a seven day confinement pen and they get one of three things. These are nasal gen, micotill, or Draxon. Along with that, what I'm wondering is because I don't trust what the cow calf man is telling me. Should a guy be also incorporating a back double shots, even if the producer says he gave him fall shots because I'm giving them Draxon upon arrival at my place? If I'd have known you were gonna be here, I would have incorporated something in on buying bawling calves at the sale barn. That's kind of a topic all by itself.  But they may not just not know the answer as always. But in your case, if you're buying bawling calves at the totally different situation, you've got all these risk stressors that I just talked about all at one time, all in one place. And so you end up doing, your strategy is gonna be entirely different. In most cases, I would recommend, depending on where those calves came from, that you're also gonna include an antibiotic into your receiving protocol. On the other hand, if you are able to buy calves with documentation that they've received vaccines, you still may use antibiotic on arrival, but the risk of those calves is less, but you still may have to use antibiotics simply because of the co-mingling effect and the pecking order stress that those calves are going through. So I wish to have more time to develop that, but I don't, but that's a totally different discussion.