Sharing Ventilators, More on Sleep, Immunity, & COVID-19 Prevention (Lecture 45)
Welcome to another MedCram covid-19 update. Now for the first time, the US tops the charts at 85653 infections that are confirmed, staggering 24,000 total deaths. Daily new cases in the United States are continuing to rise, and if we look at total cases in the United States, the state of New York tops that list by a large amount.
It is the epicenter of the new cases at this point because supplies are running scarce. There’s an article in the New York Times talking about the scarcity of mechanical ventilators. New York starts sharing ventilators, and this was approved by the governor. To keep coronavirus patient’s breathing, hospitals pioneer a little tested method. You can see there a portable ventilator that ambulances use to transport patients who are on ventilators.
They mention here that this is not the first time that this has happened. Before they did this in Las Vegas when there was a mass shooting. In previous updates here on MedCram, we showed you Dr. Babcock, the ER physician, demonstrating that in a video on YouTube.
Also in the news and updated about six hours ago was a story on Fox by Prisma Health that says that their new innovative ventilator adaptor can actually treat up to four patients on a ventilator at a time. It was another ER physician named Sarah Ferris and her husband who is a software engineer developed this device called Vesper as it turns out this is a 3D-printed device and they are making it available so that it can be printed in your local hospital.
另外在新闻中，大约六个小时前进行了更新，Prisma Health在Fox上发表了一篇报道，说他们改进的新型创新呼吸机实际上一次可以治疗多达四名患者。这是另一位名为Sarah Ferris的急诊医师和她的软件工程师丈夫，开发了这种称为Vesper的设备，是一种3D打印设备，他们正在推广使用该设备，以便可以在您当地的医院打印。
In addition to this, the US Food and Drug Administration has granted emergency use authorization for this type of ventilator, and down here you can see a link other hospitals that want to begin using Vsepr can receive the free source code and printing specifications for the device today by registering on Prisma Health website and you can see it there.
除此之外，美国食品药品监督管理局（US Food and Drug Administration）已授予此类呼吸机的紧急使用授权，在这里您可以看到其他想要开始使用Vsepr的医院的链接，可以获取该设备的免费源代码和打印规范。今天通过在Prisma Health网站上注册，您可以在那里看到它。
Okay, so not so fast because there is a joint statement that was put out by the American Association for Respiratory Care in conjunction with a number of other societies, which are pretty heavy-hitting like the society for Critical Care Medicine issued a joint statement basically saying no, we don’t think that this is a good idea. The reasons they include here are quite numerous, including the fact that volumes could go to the most compliant lung segments that it would be impossible to manage the positive end-expiratory pressure among other things. And you can read some of the others and they give references as well in this joint statement.
So it’s going to be interesting to see what happens because as the New York Times pointed out ‘The Other Option Is Death. The AARC, however, is saying that it could jeopardize both patients on the ventilator. I think, regardless of which way you take it, it’ll be clear that there’ll be people taking care of people on ventilators that aren’t used to taking care of people on ventilators.
If you or if you know somebody that’s going to be taking care of somebody on the ventilator, we wanted to offer this course as a refresher on mechanical ventilation.
Okay, I wanted to continue our discussion with improving immunity. We talked before about the beneficial effects of an elevated body temperature with respect to killing infections in the virus, and we are going to move on to other things, but I wanted to restate and reunderline the importance of rest and sleep in terms of the activation of the immune system, especially at a time like now where people are very concerned they may not be getting enough sleep. It’s important for us to not underestimate the benefits of sleep.
Now, we’re just going to review a little bit. But if you want to know more in detail, go back to update 17 on the coronavirus that we’ve done. But real briefly, this was a study that looked at the effects of sleep deprivation on response to immunization.
The participants were sleep-deprived and given a vaccine to the influenza virus. And those that were not sleep-deprived had a much better immune response in terms of antibodies to the vaccine, and the conclusions that the authors drew were these results indicate that the response to the influenza vaccination is likely to be impaired in individuals who suffer from chronic partial sleep restriction because adults who show poor responses to vaccines and other antigenic challenges also experience higher rates of clinical illness. Our findings support the concept that adequate amounts of sleep are needed to maintain resistance to an infectious challenge such as COVID-19.
This is the other study that we looked at in update 17 and it looked at the sleep habits: how long they slept and what was the efficiency of their sleep in terms of 14-day baseline, and then they went ahead and dropped rhinovirus-filled drops into the nasopharynx of these subjects and they waited to see how many of them would develop the common cold symptoms, and what they found was quite astounding.
They found that those with an average sleep duration of fewer than seven hours were not 10% more or 50% more or even a hundred percent more likely to develop the cold, but actually almost three times more likely to develop a cold. And when they look for confounders, these things could not be explained in terms of differences in pre-challenge virus, specific antibody, demographics, season of the year, body mass, socioeconomic status, psychological variables or health practices.
And so here we have at least for rhinovirus evidence that poor sleep efficiency and shorter sleep duration in the weeks preceding and exposure were associated with lower resistance to the viral illness. But there’s even more research that just came out last year and this is the focus of sleep that I want to look at today.
So the first thing you have to understand is that there is a cell, which is infected with a virus. And in this case, it was a CMV infected cell. CMV stands for cytomegalovirus. It’s a common virus that can cause a chronic infection. Here we have the nucleus and because this cell is infected with cytomegalovirus, it makes its normal proteins on the cell surface so that the cells of the immune system would recognize it, but it also puts a little portion of that cytomegalovirus protein out on the surface to let the immune cells know that it’s an infected cell.
And so these regular proteins that are made in the cell are known as ICAM. That’s not that important to understand, but that’s the name of the protein. This here is a portion of the virus that lets the immune system know that it is in fact an infected cell. There are other proteins that are also on the cell and these proteins help immune cells dock with them so that they can make the appropriate determination of whether or not this cell should be destroyed or should survive, and this protein is known as ICAM-I C A M.
So far so good. Now let’s bring in our immune cell. It’s our cytotoxic T-cell. It’s responsible for going around and making sure that cells are not infected and taking care of cells that are infected and this would be the cells that would be going around and getting rid of coronavirus infected cells, so they don’t produce more virus to infect more cells. And in fact, if this can be done early in the course, you would have a limited disease and it wouldn’t lead to many many cells being infected, causing many T cells to have to try to fight and causing that cytokine storm.
Well, there’s a couple of proteins on these T cells. So this is a T-cell and it’s a cytotoxic T-cell, not toxic to you but cytotoxic to the cell that’s infected. These are actually your friends. So there is a receptor on the T cell that sees that little particle of the virus and understands that this cell needs to be destroyed and that is called the T Cell receptor or the TCR.
The TCR also activates right next to it and I’ll show this here in green that it’s activating the beta integrin. This interaction between beta integrins and the ICAMs allows for a very strong docking that allows these cells to bind very very strongly to these infected cells and that allows these T cells to secrete cytokines that will shut down and kill the cell before it produces more viruses.
So it’s very important that the beta integrins and the ICAMs are able to bind together. Normally, the beta integrins are not activated and they will not bind these ICAMs. Otherwise, your immune system would start to destroy your own body. So they’re shut down, but there are certain situations where they need to be turned on and, if they are not turned on, your immune system is not going to work very well.
Well, in this case, it is the TCR that activates these beta integrins and allows this to occur. The purpose of this article was to see whether or not things can affect this turning on of the beta integrins and sure enough, they discovered that there is a receptor called the G alpha S receptor, and this receptor is coupled to what is known as a g-protein. And it’s coupled to an enzyme known as adenylate cyclase.
在这种情况下，正是TCR激活了这些β整合素并使其发生。本文的目的是了解β整合素的这种开启是否会受到影响，他们确实发现了一种叫做G alpha S的受体，该受体与所谓的ag蛋白结合，它与腺苷酸环化酶结合。
There’s a lot of moving parts to this receptor, but I’m going to simplify it and show you that essentially it takes ATP, which is abundant in the cell, and it converts it into something called cyclic AMP and as it turns out cyclic AMP shuts down the ability of the TCR to activate the beta integrase. So the question is what is actually stimulating this G alpha S receptor.
该受体有很多运动部件，但我将对其进行简化，并向大家展示，它实际上吸收了细胞中丰富的ATP，并将其转换为称为循环AMP的物质，结果证明是循环AMP关闭了TCR激活β整合酶的能力。因此，问题是什么实际上在刺激该G alpha S受体。
There are a number of things that can activate this. One of them is epinephrine, typically dopamine, histamine, serotonin. And the thing about all of these things that can actually stimulate this receptor here. They’re all quite elevated when you are awake, and so you can see it’s possible that epinephrine, dopamine, histamine, and serotonin could stimulate this receptor, which would eventually convert ATP into cyclic AMP, which would then inhibit TCR‘s ability to have the beta integrin bind with ICAM and to have this T-cell destroy with cytokines this infected cell.
So it is possible that sleep could stop epinephrine, dopamine, histamine and serotonin from binding this receptor and allow the beta integrin and the ICAM to bind tightly so that the immune response would be more robust.
And so now the title becomes a little bit more understandable—Gas coupled receptor signaling and sleep regulate integrand activation of human antigen-specific T-cells—and this was published last year in the Journal of Experimental Medicine. They infected these with the Epstein-Barr virus as well. And so we’ve got data for both of those.
So here we can see the data for CMV-specific CD8 cytotoxic T cells. They looked at isoproterenol, which does hit that receptor epinephrine, which does hit the receptor, and norepinephrine as well. Here on the x-axis, as we increase the concentration, you can see that the binding of ICAM one as a percentage of the control starts to drop off precipitously. And you can see that here with prostaglandins, as well as adenosine in the EBV, or the Epstein-Barr virus-cell cultures that were infected as the increased concentration of the same substances that we talked about. You can see that the ICAM does drop.
So it’s one thing to say that these specific substances make it drop, but the question is whether or not sleep is actually beneficial in making sure that the cells can bind to their targets and take them out, and that’s what they attempted to show here in human patients.
What we see here again is the same thing on the y-axis. We’re looking at ICAM binding, but we have two types of patients in this scenario. We have the ones that are filled in with black circles. And these were the ones that were sleeping at night and awake during the day as opposed to these Open Circles, which are white in the middle where they’re awake during the night and also awake during the day. And so you can see the effects here in the CMV-infected cells on the left and the EBV infected cells on the right.
In the night time, which is shaded here and over here as well, at least at two o’clock in the morning and here at six o’clock in the morning, there was a statistically significant increase in ICAM binding in these patients that were sleeping at two o’clock in the morning as opposed to being awake at 2 o’clock in the morning. And I just wanted to point out for those of you who are doing shift work that, so long as you are working at night and going home and sleeping with your lights off and no light coming in through the windows and you do this every single day throughout the weekend, you can also get the same benefit from getting sleep even though it’s when the sun is up.
And then they decided to look at that over the different types of differentiation of these cytotoxic T cells. They looked at ones that were early in their life, intermediate in the cell life, and late in the cell life. And what they found was these effects seem to be the strongest in the early phase of the cell’s life despite the fact that it didn’t have a lot of these G receptors that we talked about. That might suggest that it’s the early cells that are being amplified against the infection at hand that is more influenced by the effect of sleep versus wake.
So the conclusions of the authors are this. We show here that several Gas–coupled receptor ligands potently inhibit TCR-mediated integrin activation on antigen-specific CD8+ T cells, (These are the ones that are doing the killing here), whereas sleep-up regulates integrin activation by suppressing Gas–coupled receptor signaling. Given the importance of integrin activation for the formation of immunological synapses, our data suggest a critical role of conditions like sleep that are characterized by low levels of Gas–coupled receptor ligands, in boosting the T-cell responses. And I’ll tell you it’s those T Cell responses that are very important in your immune system getting rid of coronavirus infected cells.
因此，作者的结论是这样的。我们在这里表明，几种Gas结合的受体配基有效抑制TCR介导的整合素在抗原特定的CD8 + T细胞上激活（这些是细胞杀手），而睡眠则通过抑制Gas结合的受体发送信号来调节整合素激活。考虑到整合素激活对于形成免疫突触的重要性，我们的数据表明，像以低水平的Gas结合的受体配基为特征的睡眠条件在增强T细胞反应中起着至关重要的作用。我告诉你们，正是这些T细胞反应对于你的免疫系统摆脱被冠状病毒感染的细胞非常重要。
So you can imagine the current scenario and it doesn’t take a lot of drawing on here to modify this picture for the current Covid-19 situation. Sleep is important and you don’t have to go to the store to buy it and you don’t have to wait for pharmacists to dispense it. It’s something that we can do. Put down your iPads, put down your phones and go to sleep and wake up with a better immune system.
For those of you who have difficulty sleeping if you have insomnia, we have a free course on how to deal with insomnia. Thanks for joining us.
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