Hey, this is Brett, and this 2021 Chevy Silverado 2500 Crew Cab Short Box LT1 is stock number 13320Z. I am here at Summit Automotive in Fond du Lac, Wisconsin, near New and used heavy-duty truck headquarters. This 2021 Chevy Silverado 2500 has the 6.6-liter Duramax diesel engine. This is the L5P engine, puts out 445 horsepower, and it's paired up with the Allison 10-speed automatic transmission. This truck has been fully safety to and inspected by our service shop, has a fresh oil and filter change per the state of Wisconsin inspection process. All the fluids have been checked and topped off, and this truck is 100% ready to go. I'm going to go all the way around in this video. This side underneath started up and take a look under the hood to give you the most accurate representation of the vehicle as possible. Black clear coat is the color, and I shoot all my videos in 4K. So if you have HD capabilities, turn them on right now because it is your best way to check out the quality, condition, options, and of course, cleanliness of the vehicle before seeing it in person.  Very very nice. I'd give it an A rating on my grading scale. And if you like the video, you can subscribe to my YouTube channel, which is youtube.com slash summit auto. Click the bell notifications, you'll get updates on the videos I do each and every day here at Summit Automotive. You might just find your next truck here or there if this isn't the one for you. So this one comes with 22 inch hostile painted and polished aluminum rims, really nice condition on these rims. And it has Nitto Recon Grappler tires. These are 33 by 12 and a half R22LTs. They are brand new. We put those on in our safety inspection. You can still see the little wear knobs on there. So they have all the tread left on them. It comes with the Rancho shocks. Frame and underbody is extremely clean on this truck. Front fender is in excellent condition. You didn't see any dents or dings on there. Does come with the LED headlamps and the LED fog lamps. Front bumper is in great condition. Didn't see any dents or dings on there and it does have the front bumper parking sensors. You get the blacked out grill, Z71 grill there and you get the true cowl induction hood. No dents or dings on that and you do get the clearance lights up top. Other side front fender is in fantastic condition as well. No dents or dings on the passenger side rim. No major scuffs or scrapes on there. Really like those deep dish rims on this Chevy. Looks good and as you go down this side of this 2021 Silverado 2500 take note of how clean that body is, how reflective and mirror like the paint is. I take these HD videos so if you are far away or even if you're close by and you just cannot make the trip down but you're still interested in purchasing the truck, you can see the truck, hear the truck and of confidence in the vehicle that you're looking at before you even get here. So when you do get here, there's absolutely no surprises and you can make a smart and informed buying decision from wherever you're at. If this video helps you do that, let your salesmen know that you saw the video that it was helpful and that Brett sent you back rim excellent condition as well. No major scuffs or scrapes and the back tires are brand new too. Once again, frame and underbody, very nice and clean on this truck. It has all the remaining factory exhaust so it hasn't been altered in any way exhaust wise. Little rockers and cab corners look really good as well and you do get the side box steps on there. Once again, no dents or dings on that box coming around to the back. You get the rear bumper steps, the rear bumpers in great condition. Now I'm thinking this is probably a midnight addition just because it's got the painted bumpers, the painted handles and all that good stuff. Back of parking sensors, full towing package which includes the receiver hitch four pin and seven pin wiring and the tailgate is in excellent shape as well. You also get the gloss black grille. This has the power drop down tailgate. The tonneau cover keeps it from power dropping but either way it comes with a very nice spray and bed liner and this one does have the fifth wheel and gooseneck prep package. You do get LED lighting back here, four pin and seven pin wiring as well and very, very nice and clean back here. Spray and bed liner goes on to the tailgate which is nice as well and the tailgate shuts nice and solidly. Comes with a rough country soft tonneau cover. I didn't see any rips or tears on that. That's pretty good. And for full disclosure, this back rim is in excellent shape as well. Once again, down the rest of the side of the truck, the cabin doors all look very, very good. This one does have the telescopic tow mirrors. They have blind spot monitoring LED side lights, directional signals. They telescope out like so and they power fold in. I'll show you that in just a second.  It has the 40, 20, 40 split bench seating in here. No rips or tears on the seats. Very nice condition. Does have the power driver seat with lumbar and factory all-weather floor mats throughout. Auto headlamps, that's for your cargo lamps. That's also how you turn on your LED side lights, fog lights, push button four wheel drive. You get tilt telescopic steering wheel, power windows, power locks, power mirrors. Nice wood grain trim there and like I said, these mirrors do power fold in. And I always like showing both sides so you know that both sides are working properly. They're those LED side lights. And the back seats are just as clean as the front seats. No rips or tears back here. It does have the latch child safety system for any child car seats you may have. Fixed glass rear window with a built-in rear defrost. These headrests do fold down for better visibility if nobody's riding back there. The back seats are in great condition. You get an almost completely flat floor back here, all-weather floor mats. And you get two USBs and a 12 volt power point. These seats fold down like so. And the bottoms of the doors, you do get child safety locks. Bottoms of the doors, though, all look very good on this truck. We'll hop inside, check out the miles, the video, and everything that this truck has to offer on the interior. Let's go over here and see if we can see that a little bit better. 21,840 miles on this vehicle. Do get a compass display. Instrument cluster is very nice and clean. Leather-wrapped heated steering wheel. Bluetooth and information center controls on the right. Cruise controls and heated steering wheel controls on the left. 10-speed Allison transmission with the optional tap shift. And this one does have AM, FM, and Sirius XM radio capabilities. Your Apple CarPlay and Android Auto. So while this truck doesn't have the factory navigation system, you can project your cell phone to the screen with a nav system such as Waze or Google Maps. And it's like you have nav right in the screen, so that's a pretty sweet system to have there. See if it's going to let me check out the camera. I think the truck's got to be on, so we'll check that out in just a second.  You can turn those off and on. You can power drop down that tailgate, stability control, downhill assist control, factory brake controller. You get a USB, USB-C and a 12-volt power point there. Carpeting is very nice and clean. Smells very clean inside this truck. I don't think it's ever been smoked in. Pass under side seat is in excellent conditional rips or tears on there. And the headliner is in perfect condition as well. You do get map lights up here and on-star and SOS buttons up there as well. We'll start it up and take a look under the hood. We'll also check out all those LED lights in the front. Starts right up. No check engine lights or anything like that. And you can see the instrument cluster is very nice and clean. I did want to show you the tire and loading information sticker right there, as well as the trailering sticker. Sheddy's nice enough to give us that. And there is your gun sticker. No Canadian trucks here. I would personally like to thank you for checking out the video today. And hopefully from this HD video, you've been able to verify the quality condition options and cleanliness of this truck all the way around inside and out, all those LED running lights and headlights there looking really good under the hood. We have the 6.6 liter Duramax diesel engine. Engine bay is very clean, runs very smooth. Once again, this truck has been fully safety and inspected by our service shop, has a fresh oil and filter change. All the fluids have been checked and topped off. This truck is 100% ready to go. There is your emissions sticker. And that co-induction hood, air comes in there, comes down to this side, goes right into the air box. Very nice and clean truck. I would highly recommend this truck for make quality, condition, options, looks, standpoint. And to see more pictures of this truck or one of our other 550 new and used cars, trucks, SUVs, minivan, sprinklers, half tons, three-quarter tons, one tons, you name it. We got to go to that website right there, summitauto.com. Full pictures and descriptions of every single vehicle from two locations all at summitauto.com. And if you'd like to check out more HD videos, you can go to youtube.com slash summitauto. Remember to like, subscribe, and share on this video. And all the videos that you see there, click the bell notifications. You'll get updates on the videos I do each and every day here at Summit Automotive. In fact, in a second, you'll see a link to subscribe to my YouTube channel, the upper left. Link to more Chevy 2500 truck videos like this one, the upper right. And a link to this vehicle on our website in the lower left. And a link to one of our latest YouTube videos in the lower right. Quick post check us out. We're super excited to help you with this ultra clean 2021 Chevy Silverado 2500 Crew Cab Short Box LT1 Z71 Minite Edition in Black Crew Coat. Thanks again for checking out the video. Remember to like, subscribe, and share on the YouTube channel. I really appreciate it. Thanks again.


your hand over a second. This is called digit index ratio. Yeah, you both have high testosterone. How could you tell this on that? So digit index ratio in utero when you're in your mother's womb, a certain amount of testosterone is released. This is your testosterone finger. This is your estrogen. Do it on your dominant hand. I have a lot of tests. You guys have similar. You have pretty high tests. You have very high testosterone. People confuse testosterone. They think, oh, steroids, bodybuilder. Forget that. We're talking about in utero testosterone. It's not perfectly correlated, but it's pretty accurate. You can Google it. There's great science on this. It's not palm reading. It's not astrology.


Dr. Dr. Roberts is the Catherine Dexter McCormick and Stanley McCormick Professor and Chair of the Department of Psychiatry at Stanford University. Dr. Roberts is a graduate of the Pritzker School of Medicine and was a McLean fellow in 1988. Laura has written or edited more than 20 books and hundreds of articles on psychiatry, medical education, professionalism and clinical ethics. Recently at Laura's insistence, she and I co-edited a book collecting my own favorite papers over the course of my career. Laura was the 2015 recipient of the McLean Center Prize for her work in clinical medical ethics and today she will talk to us about ethics of assisted dying in the context of mental illness. Dr. Laura Roberts. I'm going to ask a quick question. Who thinks that kleptomania is sufficient medical cause for assisted death? Just putting it out there, the foreshadow, kleptomania. So I'm not really an expert on this topic. I did do some of the early studies about 20 years ago on assisted suicide in the context of psychiatry. But I have taken care of patients for more than 20 years and in that time I've had all of these patients who express suicidal impulses and ideation at different times and these are physically ill, mentally ill and actually otherwise healthy people and these suicidal impulses and suicidal thoughts typically resolve especially if people receive appropriate treatment and treatment for pain. So I come at this question of assisted suicide in euthanasia in the context of mental disorders with a bias of having seen hundreds of patients reverse the wish to commit suicide. And so today we're going to cover really four core ideas. One is really thinking about the nature of mental disorders. I want to share with you a little bit about the current understanding of influences and factors leading to the impulse or the wish to end your life. Third, a little bit about euthanasia and assisted suicide that is happening in real time in Europe and is a very compelling and interesting set of ethical questions there. And then also just to think and my colleague Debra Spitz alluded to this earlier about what's distinct about the therapeutic role of the psychiatrist and the patient. So first let's just think about mental disorders. They really affect fundamental aspects of the human person, their feelings, thoughts, perceptions, motivation, insight, judgment and self-governance. They cannot be diagnosed even in the presence of really perhaps almost bizarre to other people experiences thoughts. They cannot be diagnosed unless there is a diminished sense of well-being and deficits in the ability to live in a social role, to contribute and to love. And it's often very difficult to recognize, especially in the prodromal phase. And so little or late or no care are very common in the care of people living with mental disorders. One in four adults in the United States and one in eight children in the United States meet criteria for a diagnosable condition. It typically hits early and hits hard. So the average age of onset for psychiatric conditions is age 14 years. But it can occur at any point and have new onset even in advanced age. Very, very diverse phenomenology can be misdiagnosed or underdiagnosed and this is going to be relevant to what's happening now in Belgium and the Netherlands because, for example, I asked you about kleptomania, shoplifting. Now loneliness is loneliness a sufficient medical cause for euthanasia or assisted death. It's mental disorders are typically episodic but it may be a single experience or it may be chronic. And in general, there are outstanding treatments, evidence-based treatments that lead to improved health outcomes and complete remission for many conditions. So the issue of euthanasia or assisted suicide occurring pretty much ethically only in a very futile, boundary condition is really a question when it comes to mental disorders. From a public health point of view, mental disorders are the leading cause of premature death and disability in economically established countries like our own and second only to infectious diseases worldwide. So when you think about access to care, there really are insufficient resources, insufficient infrastructure throughout the country, very little understanding, tremendous stigma and all of these factors contribute overall to inadequate care, scientific neglect and grave health disparities for individuals, communities and populations living with mental disorders. And one only needs to look at our prisons and our streets to know this. And if you look at the world, this photograph on the bottom is a picture of a prison chained where in rural India where there are no resources for severe and persistent mental illness. People living with mental illnesses are really go through periods of being vulnerable but taken together as populations, people living with mental illnesses may be understood to be a vulnerable population. Now I have to admit that usually I make a different argument that people with mental illness should not be viewed as an exception, but in this particular case because there is so much in terms of health disparities that plays into the issue of assisted suicide in the context of mental disorders, I think it's important to look at the differences rather than some of the similarities with other physical conditions. And more than 36,000 people in the United States and more than 800,000 people in the world each year complete suicide. So this is a large contributor to premature death and disability in these conditions. So let's now pivot and think a little bit about suicide from a clinical perspective. You know the wish to end one's life can be a symptom of mental illness and its presence can be a clinical sign. It's related to other negative cognitions that accompany mental illness such as hopelessness or a sense of utility or a foreshortened future. In addition, authentic volunteerism and decisional capacity can be affected by these cognitions or threat to cognitive processing and threats to decisional capacity can be a signature feature of many mental disorders, but not all. And the urge to complete suicide is typically impulsive, transient and reversible. And I think most people in my field believe that in this context, it represents kind of a fluid, disordered, off problem solving of an ill and distressed brain. And I want to share this lovely poem by Emily Dickinson where I think she captures very much this kind of fluid quality of despair. As many of you know, Emily Dickinson suffered from very severe depression, episodes of very severe depression throughout her life. And she wrote, on the bleakness of my lot, bloom I strove to raise, late my acre of rock has yielded grapes and maize. I think it's a beautiful example. And actually all of the art that I'm presenting today are people who have lived with mental disorders. So the point is that mental disorders should really be thought of as having a fluid dynamic nature and often the impulse to end one's life as a clinical phenomenon associated with that. So what we've learned really quite tragically from the young veterans coming back and ending their lives and numbers much higher than our dying in conflict overseas is that we really are getting new insights into suicide. In the past, scholarship has really focused on what are relatively fixed characteristics such as gender or age, race, ethnicity, marital status, the presence of other physical conditions. And more recent work now has really looked at different elements that lead to the moment when a person has the impulse to end his life. And there are three elements that are thought to kind of contribute to this intense unbearable state of mind that leads a person to act on the impulse. The first is the existence of extreme distress due to some pre-existing mental illness or perhaps a situation. Second is access to and familiarity with the means of self-harm. And third is a feeling or sense of emotional rupture and experience of what we refer to as thwarted belongingness. So a loss of sense of place in the world, a loss of relationships and love, a loss of belonging. And this model is fabulous, I think, because it gives you intervention points, identify the source of distress, identify whether there's pre-existing mental illness, try to understand the situation, try to eliminate access to means of self-harm, try to create a sense of connection and to repair that rupture. So the model has tremendous value in terms of the interventions that it suggests. So just to bring it to the ethical argument then. So because people living with mental illness are marginalized in society have lessened healthcare resources and represent therefore a vulnerable population, and because mental disorders are not per se terminal conditions, and because intermittent and reversible negative cognitions including suicidal thoughts and impulses are part of the fundamental clinical phenomenology of many mental disorders, and further, because intermittent and reversible threats to volunteerism and decisional capacity are signature features of many mental disorders, it's my belief that assisted suicide in euthanasia in the context of mental illness requires far greater ethical scrutiny than in other contexts. So I don't know where I thought Belgium was and the Netherlands, it sounded sort of nether, it was like way up there, way nether, but if you actually look at the map, it's right there in Europe, wow, and it's right next to Germany, it's right next to France, it's like a short boat ride away from the United Kingdom, I mean this is not some extreme place that people don't have access to, this is the place where all of this tourism for assisted death is occurring, right there, highly accessible and a little geography lesson for everyone here, and if you look right now in Belgium and the Netherlands, assisted suicide in euthanasia is permissible for psychiatric conditions, and just again a little bit more information, Belgium is a population of about 11 million, in 2014 to 15 there were almost 4,000 euthanasia cases, euthanasia, and 124 of those were for people with a mental and behavioral disorder, so that's 3%, and it represents the 21% of the 600 non-terminal patients to whom Belgium doctors administered lethal injections in that period, so very overrepresented in the cases of non-terminal conditions. The Netherlands is a larger population, 16.8 million, euthanasia rose 75% in the last five years from 3,136 cases in 2010 to now 5,500 in 2015. The psychiatric cases rose from just 2, it was I think really not considered socially supported in 2010, but then 56 people were euthanized for psychiatric reasons in 2015, now 1% of the overall cases, and in particular dementia is going up, so it seems to be getting some traction, so let's go over the criteria by which termination of life may occur in the Netherlands. The attending physician must be satisfied that the patient's request is voluntary and well considered, so I just talked with you about threats to volunteerism, threats to decisional capacity, must be satisfied that the patient's suffering is unbearable with no prospect for improvement, so I've just told you about how mental disorders have extraordinary treatments, that there are almost always alternatives, I will acknowledge that many times the suffering is absolutely unbearable, but it does tend to be transient. The physician has to have informed the patient about a situation of prognosis, and they have come together, the physicians and the patients, that there's no reasonable alternative in the patient's situation, which I've argued is almost a priori impossible in mental disorders. In this process they have to have consulted with at least one other independent physician who must see the patient and give a written opinion about whether do-care criteria have been fulfilled, and then in the act of doing euthanasia or physician-assisted suicide they have to have shown do-care. So this was a study published in JAMA Psychiatry this past year conducted by my wonderful colleague Scott Kim at University of Michigan, who looked at 66 patients who had been euthanized or had received assistance in death for psychiatric conditions. And the pieces that I want to really emphasize are that of these 66 cases most are women, most are older, many have had psychiatric admissions, many have some degree of dependence or institutionalization, and social isolation and loneliness, which I think is a reversible condition, figures heavily into these cases. The conditions were depression, anxiety, PTSD, psychotic disorders, somatiform disorders, bipolar depression, substance abuse, eating disorders, neurocognitive impairment including mental retardation, prolonged grief, autism, and there it is, kleptomania is among the causes. Now what about the role of the psychiatrist? So in these 66 cases 41% had the involvement of a psychiatrist as the primary physician engaged in euthanasia. The psychiatrist was a consultant in or was the primary person in a larger proportion, however, in 11% of the cases no psychiatrist was engaged at all and often there were disagreements, so if you remember the Netherlands criteria, there was no requirement that the primary and the consulting physicians actually agreed on the decision. And in fact that's what they found in these cases was there was disagreement about whether it was well considered, competent, whether it was really a hopeless case or not. There was a follow up study done by Dr. Kim with others of the cases which the Dutch Regional Euthanasia Review Committee, so the oversight body that's looking at all of these cases and they found a subset of cases where they felt this oversight commission felt that due care criteria were not met. And Scott looked specifically at the psychiatric cases. 69% of these improperly conducted cases related to improper medication administration or consultation that was not sufficient. There were cases in which there were financial ties between the physicians that were rendering the opinion on the assisted suicide or euthanasia. 31% failed to meet substantive criteria related to no reasonable alternative, being tired of life was in one case the sufficient medical cause in the satisfied physician's view. Reversible psychiatric issues are patients without capacity. And the review committees don't say whether it was right or wrong, but just whether the procedures were followed and they found many that were not. So I just want to give you a few examples. Example one is an 80 to 90 year old woman who suffered from depression but was otherwise healthy. An end of life clinic physician saw the patient twice over three weeks. He did not interview the patient alone. The patient was with her family. They did not consult with a psychiatrist. And he told the commission that he had not a single doubt about the patient meeting criteria and therefore did not consult with a psychiatrist. The commission felt that the commission felt that the physician did not act with caution that would be appropriate in the psychiatric case. And this is a person's already dead. You got that part, right? Okay. The physician should have interviewed the patient not in the presence of her children and should have consulted with a psychiatrist. Second example, a 90 year old woman who was lonely but healthy. There was disagreement between the attending physician and the consultant. The commission concluded that her suffering cannot be primarily attributed to a medically classified disease or disorder. There was no sufficient medical cause or psychiatric cause. Therefore the physician could not have come to the conclusion that it was a matter of unbearable suffering and that there was no reasonable alternative solution. The third example is the most disturbing. A 70 to 80 year old woman who suffered from Alzheimer disease lacked capacity and had an advanced directive. In her advanced directive she said, when the time is right, I would like assistance in dying. Other people decided that the time was right and the patient was given a sedative covertly in her coffee to prevent her from resisting. During the insertion of the infusion line, the patient sat up, tried to fight them, tried to withdraw, was restrained and was then euthanized. The commission determined that the patient's advance directive suggested that the patient wanted to be able to choose when and the commission felt that the physician crossed a line with her actions. Kim and Miller concluded that evaluating patients' requests requires complicated judgments and implementing criteria that are intentionally open-ended, evolving and fraught with acknowledged interpretive difficulties. Our review suggests that the Dutch review system's primary mode of handling this difficulty is a trust-based system that focuses on procedural thoroughness and professionalism of physicians. So let's just spend a minute thinking about trust and professionalism and psychiatry. This is a poem I read to my residents at their graduation every year. It's called Crown. It's by Kay Ryan, who's a California poet laureate.  In the hills, giant oaks fall upon their knees. You can touch parts you have no right to. Places only birds should fly to. And I invite my young psychiatrist, who are gonna do amazing work and hard emotional work throughout the course of their careers, to think about this sacred relationship that actually I believe all physicians have with their patients, but especially psychiatrists where we enter into this intimate life of feelings, love and behavior, choices, motivations. There's something unique about what happens in this interpersonal healing with a psychiatrist, whether they use biological agents or just their soul and techniques. So I'd like to leave you with the thought that, as Helen Keller said, although the world's full of suffering, it's full also of the overcoming of it, systematically depriving people with mental disorders of the opportunity to overcome their life experience, gain the wisdom, share their art, share their poetry, share their perspective is our loss and really a devastating injustice. And I hope that this moves you to activism. As I had one patient tell me, she said, we wanna get rid of mental illness, we don't wanna get rid of the mentally ill. Thank you. I know it's lunch, I'm happy to answer any questions. Visit with people at lunch. I just assume a cray from the University of Toronto. Thank you so much for that stimulating presentation. Canada, as many of you know, has recently embarked upon this journey of medical assistance and dying. And at this very moment, a lot of negotiations are happening about how that's gonna be applied to children as well as the mentally ill. I personally work in one of the leading trauma therapy programs in Toronto at Women's College Hospital. And I was really happy to see, well, happy to see, I was happy to see it acknowledged that post-traumatic stress was on that list because I think that what a lot of people who don't work with people who have post-traumatic stress don't appreciate it and I know that you know this from your practice is chronic suicidality is so much a part of the work that I face every day. People, I would say 90% of the clients that I work with have chronic suicidality that's very significant in the room. But with proper strategies and understanding and therapeutic technique, those people often can identify that chronic suicidality as a last resort fight response that they may have had to build as a coping in their life. And it's very appropriate in that protective context. So I also really worry for people with chronic trauma, psychological trauma, that these kinds of things that we're seeing happen overseas could really impact a large number of people very significantly. So thank you for your advocacy. I really appreciate it. Yeah, thank you for the beautiful comment. I think understanding suicidality is a clinical sign and not getting confused in these rationalist arguments. I think our obligation is physicians first. I'll put it that way. Thank you so much. I don't know if you would have expected that there would be a Dutch person in the crowd. I'm Rene Eicholt. I work as a clinical ethicist and a bio ethicist at Michigan State University. And I actually stand by the legislative regime in the Netherlands now. It's very challenging to translate cultural context in these things. And so that is something that hurts me because the way that the Dutch system is portrayed is very inhumane. And I think it requires a very long talk on my end to explain some of the differences that why I stand behind our legislative scheme. I don't think it would be appropriate to translate it to the US the way we practice it. There's a very different mental health care system. There's a very different population, a very educated, rich population. And so it creates a very different context for these individuals. A couple of years ago, there was a physician who he was prosecuted. He actually committed suicide after he had been traced by one of the committees for not having fulfilled all the criteria. And the widow of the individual that he had assisted in dying, and I think there was euthanasia, actually was extremely upset with the committees.  And he did not fulfill all the criteria for undergoing this euthanasia. Instead of him committing suicide, in the Netherlands we do not have guns. Instead of him choosing a train, he chose to go to a professional and the professional work was bound to these sets of criteria to fulfill this. And he was not allowed to undergo it officially. So actually it was a very compassionate act from the physician that he overstepped the boundaries. Anyway, it's very challenging to translate the cultural context here, but I want to say that there's more to the story. I hear a lot of people go like, oh, outrageous. But there is a lot more to the story than the way how you've translated it. And I've actually, yeah, I feel uncomfortable with Kim's study or his conclusions. It just needs a little bit more social political context to make, you know, clear what's actually happening. Thank you for your comment. Yeah, thank you.


I thank the organizers for asking for an oral presentation of our abstract and I want to point out that this is the work of senior scientists at our institute, Dr. Christina Yau who was unable to attend. I do also want to point out that this afternoon you'll hear more from Josh Stewart who co-led the PENCAN analysis. It was the freezing of that data set on over 3,000 samples that enabled this kind of pathway analysis. So most people are familiar with the phosphatidinositol-3 kinases, a very large family, heterodimers between regulatory subunits, P85 alpha is most commonly known but there are other four others and the catalytic unit, the P110 alpha which is encoded by the PIC3CA gene which is very commonly mutated in human cancers as you heard. Modular domains of this PIC3CA gene are shown here. There's five of them. It's frequently mutated in multiple types of cancers I pointed out but there are hot spot mutations in both the kinase and helical domains that we'll talk about. These are thought to be early and possibly initiating events and malignancies like breast cancer. There's a notable absence of mutations in the RAS binding domain RBD and also within the core catalytic site of the kinase domain and that's seen across cancers. Now preclinical evidence which led to the rationale for doing this study indicates that PIC3CA mutations are activating and gain a function but domain-specific mutations may have different downstream effects in particular phosphorylation and activation of AKT and other downstream pathways including mTOR and also phenotypic consequences but these are preclinical studies in model systems. So the TCGA pan-cancer dataset is big enough to offer an opportunity to ask questions about possible pathway differences linked to domain-specific PIC3CA mutations in different tumor types. Are there common domain-specific pathway activities across the different tumors or are these cancer types specific? So in terms of pathways we're going to use an algorithm known as Paradigm that's been used in most of the marker papers of TCGA briefly. This integrates RNA gene expression data with DNA copy number data. Superimposes this on a super pathway to infer activities which refer to as inferred pathway links or IPLs and encompassing over 13,000 pathway features which can be displayed in a heat map or analyzed for differences between tumor subsets. Now the pan-can dataset characteristics that were used here and these were the frozen data sets employing the platforms including exon sequencing RNA expression and DNA copy number. We had over 3,500 samples that had the paradigm analysis in other words that we had IPL values. We had over 3,200 samples with exon sequencing data so we have an overlap set shown in the VEM diagram of 2637 with both IPL and PIC3CA mutation data. As you can see in the pan-can histograms here that the cancer type distribution among the valuable samples is very different. That's actually reflected a lot in in the overall TCGA cruel of these samples. So that's going to have to be taken into account. Now somatic PIC3CA mutations have an overall mutation frequency in this pan-can dataset of 22 percent that's 572 out of the 2637 cases but the frequency per tumor type is quite variable as you can see from 0 percent as seen in AMLs leukemia to greater than 50 percent as seen in uterine endometrial cancer with the intermediate values as shown there. Now in order to look at domain specific mutations we also filtered so that we would use only nonsense mutations because we're interested in coding gain of function abnormalities and also mutations that occurred in only one domain as you can see in nearly 100 of the cases there were multiple mutations across PIC3CA. So we ended up with a set of 447 cases that we could evaluate and you can see we eliminating the AML we have a very different again we have an uneven distribution across the tumor types that's going to have to be accounted for. The domain specific PIC3CA mutations are shown here as you can see there's a preference for the helical and kinase domains and you can see also the hotspots in particular specific mutations histidine to arginine at 1047 in the kinase domain glutamate to lysine at 545 and at 542 so the helical domain has two nearly adjacent hotspots and the kinase domain has a very common hotspot at one spot. So 83% of the cases had either helical or kinase domain mutations and 64% of these were at either of these three hotspots as shown. So the domain distribution of the mutations by cancer type was significantly different color coded here the helical domain is an orange and the kinase domain is in red and that's most common as shown and across the different tumor types and as an example again of this variation we see in breast cancer seems to prefer kinase domain mutations with 52% of those being in the kinase domain whereas in squamous cell of the head and neck and lung there's a preference for helical domain mutations 65% of those being in that domain and only about 20% in the kinase domain. So how did we look at pathway activation in cup N and control for or just for cancer type? Well we use the IPLs and identified significant IPLs for each domain versus all others by logistic regression and we adjusted for the cancer type with wall test P.05. The kinase domain ended up having 711 significantly different IPLs the helical domain over a thousand and amazingly these did not overlap much there were actually 1500 that were non-overlapping IPL features between the two kinase and helical domains. We then determined in pathway enrichment among the different IPLs with an FDR corrected e-score and we visualized by side escape. So as a kind of proof of consequence we first went through to the PI3 complex itself and here you see a color coding that indicates if it's very dark red this is a kinase domain positive association and a reciprocal helical domain negative relationship and if you have lighter shades of red increasing the pink this is again kinase domain positive blue is more helical domain positive or kinase domain negative for green but here what you see is in the PI3 kinase catalytic subunit itself in the center here where it's the red areas that the kinase domain mutations most strongly associate with the super pathway hub showing the PI3k catalytic subunit activation and this hub is negatively associated with the helical domain mutations and this is in fact consistent with the preclinical evidence which is why we looked look to that to begin with but then asking what was distinguishing the kinase domain mutations from the helical domain mutations in in other areas we first turned to cell cycle and proliferation activities and these were featured by the poli kinase 1 and FoxM1 hubs which were most strongly associated with kinase domain mutations you can see red and pink virtually everywhere and negatively associated with helical domain mutations using the same color coding as before and then if we go to helical domain mutations we see very different we see the ROGTPA's families and also gap junction degradation as hubs and pathway enrichments that were most strongly associated with the helical domain mutations and negatively associated with kinase domain mutations so although there's these are common across different cancer types in the TCGA pan cancer data set missense pic3ca mutations distribute very differently with respect to total mutation frequency and domain specificity examples being breast cancer with greater than 50 percent in the kinase mutants whereas squamous cell head and neck and lung less than 25 percent opposite sort of relationships with regard to the helical domain mutations the kinase domain mutations appear to be linked more strongly with pathway features like FoxM1 and poli kinase 1 that enable cell proliferation while the helical domain mutations appear to be linked more strongly with features enabling cell migration and dissemination such as the ROGTPA's now functional studies are clearly needed to confirm these findings including the suggestion that breast cancers preferentially mutate pic3ca to drive cell proliferation while lung and head and exquamous cancers prefer to helical domain mutations potentially to drive their malignant cell motility but additional comparisons are also needed here to identify potential tumor type specific or context dependent differences between the kinase and helical domain pathway preferences because as we've begun now to do the functional studies we then commit ourselves to a particular tumor type in fact working with the Hopkins group that has made isogenic lines in the mammary cell line MCF10A for these different mutants we need to know what context specific differences there are between the helical and kinase domain mutations as well as general differences across the entire pancan dataset as i've shown you today so i'd like to thank our UC Santa Cruz and Buck Institute GDAC team members again Christina Yao who did all this work our partners at 5.3 who've developed the paradigm and perform that for us and then also a point again to this afternoon session where i think you'll hear more about the pancancer 12 analysis working group and the subtype uh data that's uh in press thank you very much i'll take questions so we have time for a few questions yeah p85 alpha is that the regulatory uh i i guess i'm trying to understand it myself but i think the question is that do we did we see any mutations in the regulatory subunit which would be p85 alpha we did not look specifically for it but i do not believe many were reported if any at all maybe i think i could be corrected by that for someone in the audience that might know better so the uh the other interesting aspect okay that's the p85 that's a p85 we did not specifically look at that but that's an interesting aspect because these mutations that are outside the kinase domain are felt to alter the dependency on that regulatory subunit so when you look at the helico domain and kinase domain mutation and infer their functions for those low frequency mutations that could be bystanders or passenger mutation have you then go back to use those low frequency mutation in the kinase domain or in the helico domain and look at whether they still carry the same signature we didn't because most of the time it's highly the hotspot mutation you skew everything that you're seeing uh i mean the hotspot mutation of the kinase hotspot mutation of the helico domain they are so predominant and so the signature you're seeing could mainly from them i'm wondering in besides doing all the functional studies of the individual mutations can you take the individual mutation and go back to see whether they actually carry the same signature that can infer whether they actually have the functional uh we we could do that we didn't specifically do that no question so we usually see mutations some mutants are co-current pattern or mutually exclusive so have you checked that this co-current or mutually pattern for patient kinase different cross different cancer now we didn't we only looked for the no we didn't control for anything that was concurrent or mutually exclusive with regard to pic 3ca mutations we only looked at that question most broadly thank you so let us move on so now we move to the our last speaker um dr suyuan zheng from the university texas um md anderson cancer center he'll talk about comprehensive molecular profiling of um aderectal casemona um so this is the last talk hopefully serve as a appetizer for our lunch


Welcome to this overview of ear and facial safety for the machine shop. The head, face, and ears are continually exposed to potential dangers when working around machinery in an industrial setting. Personal safety equipment is the last line of defense against the hazards that exist in an industrial setting. Many manufacturing processes are very noisy and can result in permanent deafness if suitable precautions are not taken. For example, hand grinders and punch presses produce very high noise levels. Also, people using a pneumatic chisel or power saw are likely to be exposed to noise levels that can seriously damage their hearing. Remember, the danger is irreversible, a hearing aid will not replace lost hearing. There are several types of ear protectors. First, ear plugs, these fit inside the ear canal and can be reusable or disposable according to the manufacturer's instructions. They may sometimes be attached to a cord to prevent being lost. Ear plugs may not be suitable for people with a history of ear problems. Canal caps, these have soft rubber caps attached to a headband that presses them into the openings of the ear canals. Ear muffs, these are normally hard plastic cups with sound absorbent filling that fit over the ears and are sealed to the head by cushion seals. They need to be pressed to the head either by a headband or by special fittings attached to a safety helmet. To avoid any interference with other forms of PPE, it is important to note that most headbands can be worn over the head or the chin or around the back of the neck according to the manufacturer's instructions. There are three main things to consider when selecting hearing protectors. 1. Will they give sufficient protection? The frequency, content and volume of the noise must be considered. For construction plant noise, data should be obtained from the manufacturer or supplier. The data, plus any site measurement data obtained by employers, should be used along with performance data supplied by manufacturers. The information should be used to ensure that the equipment is suitable. 2. Are they right for the working conditions? If processes are dusty or dirty, soft plugs, which need to be molded by hand, could lead to your infections unless good personal hygiene is observed. 3. Are they right for the wearer? Long hair or thick spectacle frames may prevent the must from forming a close seal to the head, reducing the must effectiveness. Hearing protectors will only give proper protection if they fit, are worn properly, and are used whenever the wearer is exposed to high noise levels. The more comfortable they are, the more likely it is that workers will use them properly. Taking them off even for a short time when noise levels are high can quickly allow hearing damage to occur. Remember, hearing protectors that don't fit, don't protect. Many machining processes present a risk of injury to the eyes and face. For example, protection will be needed against flying chips or particles when using a disc cutter or cartridge operated tools, against archi and molten metal splash when using welding equipment or hot cutting metal, and against corrosive or irritant chemical splashes when working with epoxy resins and concrete. Remember, personal protective equipment is always the last line of defense, wherever possible, use face shields and machine guards. There are many types of eye and face protectors available, for example, spectacles, face shields, and goggles. Safety glasses, safety shields, and goggles provide important eye and face safety and should be used whenever the type of job requires eye or face protection. The table lists eye and face protection devices and gives examples of their use. You have completed this module, ear and facial safety for the machine shop.


What's going on everybody? Dato Doi here with some very exciting news for Dragon Ball fighters And that news is the first to officially announce DLC characters coming to the game and those two characters are Bardock and Broly Now we'll get to the specifics of each character listed here in a little bit But I do want to talk about how fantastic of a choice this was so I don't know how widely known this is But whenever they hold a popularity poll for characters in Japan Bardock usually comes out in number one and of course if you live in North America or literally anywhere else You've probably heard a bunch of people talk about how much they love Broly if you combine those two characters and release them as the first DLC characters you are setting yourself up for some of the best-selling DLC ever to be released in a fighting game now We got this information from the shonen jump magazine, which will officially come out a little later on But these scans usually get leaked around the 17th, which is how I'm giving you this information now Okay, and now let's get into the specifics of each character Broly's level three super is gigantic meteor which uses three bars of the energy gauge to fire off a cluster of energy and Bardock's level three is revenge or assault in which he transforms into a super Saiyan So yeah I'm actually really excited that they didn't make super Saiyan Bardock his base form because personally I like base Bardock a lot more than I like super Saiyan But I am glad that they gave super Saiyan Bardock some showtime for the fans that do like him in that form and with that That's really all I have for you today a super short video for sure But some amazing news for Dragon Ball fighters as I'll definitely be using Bardock on my team And I'll also be trying out Broly because who doesn't want to try out Broly So with these two characters out of the way the Fighters Pass is already paying off for me But I want to know from you guys down in the comments below Let me know what other six characters in this list would absolutely make the Fighters Pass worth it to you guys I know a lot of people want Janemba and stuff like that personally if I could choose one character It would probably be Raditz. I don't know why but he's the only one coming in my mind right now I know he's kind of a lame character But in all the past games I used to really like his moveset and how dumb they all were like double Sunday and triple Saturday Just based off the weekends for no rhyme or reason But yeah, let me know your thoughts on that guys I'll be down in the comments as always and while you're down there if you liked this video and enjoy this channel Make sure to leave a like and subscribe as I'll definitely be putting out more videos on these two characters and the rest of the characters When they get enough I'm Dothodoya, and I'll see you in the next one


Did you know that the command line is so powerful that you can actually create.NET Core projects within it? Learn more on this episode of Visual Studio Toolbox. Hey everyone, welcome to Visual Studio Toolbox. I'm your host Leslie Richardson coming to you from my very professional childhood bedroom studio. Today, I am joined by Syed Hashimi, who is a senior PM on the ASP.NET team. Welcome Syed. Hello. How's it going? Definitely happy to be here. Been on Visual Studio Toolbox a bunch of times in the past, then I always love coming out here to show the latest and greatest, so thanks very much for having me. Yeah, welcome back. Today, we're going to be talking about creating.NET Core projects in the command line, right? Yeah, that's right. What we're planning on doing is basically creating a series of videos, and the range of topics will be, we'll first start out with, how do you create projects using.NET new, and then we'll move on to using community created templates from both.NET new and Visual Studio, and then we'll move on to then start showing how to actually create templates and how to customize those for Visual Studio. This is really just the first video in that video series, and just like what you mentioned in this video, we'll be focusing on using.NET new and understanding the basics before we get started on creating our own templates here. Yeah. Exciting. Why the command line? What's the perk or why should I make a.NET Core project within the command line? Yeah, sure. I think that's a great question. If we were to rewind the clock five, six years back before there was.NET Core, there was.NET Framework, and in that world, everybody was creating and building and developing within Visual Studio itself, and I mean Visual Studio on Windows. But now with.NET Core, we live in a different world. So if you're creating a template, if you're creating a project template, and if you want to have the broad reach, you need to surface that in a way that can meet users where they're at, right? So today, users that will develop with Visual Studio 2019, or maybe with Visual Studio Code, or Visual Studio for Mac, and there's also third-party editors out there, like JetBrains Writer, and you can also customize any editors like Sublime and Nopad++ to also do development with.NET Core. So the way that we've architected this is, we have what's called the template engine, and you can think about that as being the foundation that everything would sit on. So we've got the template engine, and then sitting directly on top of that would be.NET new command line and also Visual Studio and Visual Studio for Mac. So the idea is we can create templates using the template engine, and then we can surface that in all the relevant locations, right? So if you create a template with template engine, you can get that to appear in the.NET new command line. It can also show up in Visual Studio 2019, Visual Studio for Mac, and also I believe Writer's got that extensibility as well to where it will show these kind of community created templates. So to answer the question is really, you just need to meet the users where they're at, and the people developing.NET Core applications, they're not only in Visual Studio anymore, they're in various different places. Then also, I think one kind of another benefit is creating a template with the template engine is very easy in comparison to the alternative technologies that are available out there. So that's why I would say that. Yeah. So you get the broadest reach, and then it's also easier to create and maintain your templates if you author them with the template engine. Great. Yeah. I personally enjoy using the command line, and I always forget that you can actually create a project in the command line to begin with. So can you show us how it works? That's right. Yeah. So let's go check out the terminal here. So let me get my terminal app opened up here, and I've got a helicopter flying in the background. I apologize about that. So first, I want to let's just explore .NET new, right? .NET new is delivered with the .NET SDK. So let's just go ahead and execute .NET new and see what we get out of this. So if you run .NET new, it'll go ahead and show you the various different templates that are available to be used. So here we can see I've got a mix of different things. I've got the, most of these are built-in templates, but we can also see I've got some community and custom templates installed here as well. So if I was to use this, sorry, at the bottom there's also some examples here. So let's take a look at that. So if I were to do .NET new, and then we would give it the name for the template that we want to create here, and that's what we see here in short name. So there's various different options here. Let's go ahead and explore the MVC option here. So if I was to do .NET new MVC, I could also get help that specifically, help that specific for this particular template here. So you can do .NET new, template name dash H to get the template specific help. And you can see we've got a bunch of different kind of parameters here as well. So the help will basically kind of spit out the different parameters that you've got here, and then we can kind of go from there. And there's also some common parameters here, where are we at? So those are here. So some of these that we'll be taking a look at is output, and then install we'll be looking at in the next video. And there's also a name value here. So we'll be using name and output here during this video. So this, let's go ahead and create a, let's go ahead and create a directory here. I'll say demo one, let's go ahead and go into that. If I would just wanted to create an MVC project, I can just do .NET new MVC. And then that'll go ahead and create a project right in this particular folder here. Yeah, so it creates the project and then it will call new get to restore them. Let's take a look at the contents here. So we can see I created an MVC project and it's named demo one.csproj. It got this name from the name of the folder here. So if you don't specify, if you don't specify a name, then the folder name will be used by default. So that's kind of the idea here. Let's also take a look at this demo project real quick. Or actually, sorry about that. Let's take a look at the program.cs. One thing that I want to point out to you. So the project name was demo one. So we can see that when I created this project, the namespace was customized for that project name. So now it's created demo one here. Nice. And yeah, so we'll talk a lot more about how these replacements work and all that sort of stuff and our kind of additional videos here. Yeah, so that's exactly what I'd expect if I were creating a template via Visual Studio. Yeah, that's right. That's right. And the mechanism that's used here is the same with .NET new as well as with Visual Studio. There's another way that I could do that as well. Let me pick a different template here. So we'll say web app. That's a name of another template that we have. Instead of just going into the directory itself, you can specify the directory that it should be created at. And then that will also be the name of the project. So I can say .NET new web app, My Cool Web. Gonna create that. So now that will create it into a folder that's called My Cool Web. And then if I was to go and look at the, let's just take a look at the startup.cs for this one, I guess. We'll see that the namespace for this one has also been kind of set to My Cool Web, right? And now we've got a project that builds and runs, right? So I can verify that by doing .NET build. And then we could also run this project with .NET run or we can go ahead and load this up into Visual Studio or whatever editor or IDE that users prefer here. So that was one kind of way of doing it. So we also mentioned that we would show the name option there. So let me go into this new folder, demo two. If I say .NET new, say web API. And then if I give it a name, I can say My Web API. Now that should create it in this folder, but with the name My Web API or in the folder called My Web API and then the name will be My Web API. And if I was to inspect the program or the startup or the weather forecast, we would see that that namespace has been declared appropriately as well. Let's take another look through the help real quick and see if there's any additional options here that we haven't talked about. So one was .NET new list. So let's go ahead and take a look at that real quick. .NET new dash L. So for .NET new dash L, this would just list out all the templates that have been installed here. And like I mentioned, I do have some kind of custom templates installed here. So if you see something different, then that means that I've just kind of installed something additional that you might not have on your box. Yeah, I don't recall seeing science tool on mine. Yeah, that's right. Let me kind of explain this output here. So here we've got the name of the template. This is just kind of a user friendly name. Here's the short name. So that was the name that I was using before, right? We saw MVC web app and web API and those are here. MVC web app and web API is right there. Here we can also see the language option. So let's say if I was an F sharp or a VB developer, I can take a look at this language column to tell me, you know what templates are available for that particular language as well. And then the tags are, they're just kind of categories, right? So if I was interested in a console app, I could do console. So let's do this..net new dash L dash H. So what help is available for list here? And we can see that I can filter by language and we can also filter by type here. So .net new dash L dash Lang F sharp. This should display only the F sharp templates and then similarly for VB, right? And then we can also do, I think we can also do something similar for the tags, I believe, or the type here basically. So if I was to say, Ash type console. Oh, sorry. Okay. So that one looks like it didn't. Oh, sorry about that. My bad. This is different. This is different. One thing that I forgot to mention here was, you know, in the list of templates that were kind of output here, there's a variety of different things. You know, the vast majority of these are project templates, but we do have a few item templates here, like get ignore global JSON and so on and so forth. So that's where the that's where the type filter comes in. So if I was to to list the project, I can do .net new dash L dash dash type project. And this would just show me all the project templates. If I wanted to see only the item templates or to replace the type with item there, you go back and see how can we filter on the the tag? I'm not sure if that's that might not actually be possible here to actually filter on the tags here. But but in Visual Studio, these tags will appear and you can actually filter in Visual Studio there. That is pretty sweet. I had no idea you could get all the same functionality that you normally would if you were to open Visual Studio for the first time, just in the command line. Yeah, yeah, that's right. And then, you know, one thing that I kind of forgot to mention here was, you know, everything that I showed here was was with built in templates. But you would get the same exact functionality with with custom templates as well. So forward to do .net new site web dash age. I would get the the template specific help. For that custom template that I've created here. So so you get the exact same experience, whether it's a built in template created by Microsoft or if it's a template that you created yourself or if a third party company created it, you know, you get the same exact experience here. It's not like we're special casing the Microsoft templates here. You know, we got the same exact experience all across the board. That's really cool. Makes you feel more official with the templates that you create. Yeah, definitely. And that was that was some feedback that we have received, you know, a lot over the course of the last several years was, you know, people, the template authors, they want their templates to appear in a first class way. So when we when we created .net new, we made sure to to kind of, you know, fulfill that promise. And we're also trying to do the same thing in Visual Studio and Visual Studio for Mac as well. That is exciting stuff. Yeah. So I think that's that's really about it here. You know, we kind of talked about how can we use .net new and how can we use the help system to kind of explore, you know, how to learn more about the command and also some kind of basics here. So I think that's really the that's really it for this video. And then the the next videos that follow, we'll we'll start seeing how can we install community templates and then use those in .net new as well as Visual Studio. That is some good stuff. I can't wait. And just to close out, you mentioned that you need the .net SDK for the command line functionality. So where can users go to make sure they have that installed? Oh, yeah, right. So so they can go to usually, I just go to to GitHub actually to get that. But, you know, I think the easiest way is to just do .net core download. And that'll take that'll take them to the right place here. So just .net.microsoft.com to get the the latest download of .net core. All right. Can't wait. Yeah, and yeah. Yeah. And everything that I'm showing here applies to both .net core 3.1 as well as .net core 5. Yeah. Sweet. That is very exciting. So yeah, thank you. And tune in next time when we talk more about the awesomeness you can do with .net templates and projects. So to Lynn, happy coding.