Family of large biological molecules
On today's ID the Future distinguished nanoscientist James Tour explains to host Eric Metaxas why the origin-of-life community is further than ever from solving the mystery of life's origin, and how the public has gotten the false impression that scientists can synthesize life in the lab. Tour explains that origin-of-life scientists aren't even close to intelligently synthesizing life from non-life in the lab. The problem, Tour says, is that some leading origin-of-life researchers give the impression they are right on the cusp of solving the problem. Not so, Tour says. He offers the analogy of someone claiming, in the year 1500, that he has the know-how to build a ship to travel to the moon, when no one yet knows Read More › Source
Please join author Subodh Verma and Guest Editor Christopher Granger as they discuss the article "Empagliflozin and Left Ventricular Remodeling in People Without Diabetes: Primary Results of the EMPA-HEART 2 CardioLink-7 Randomized Clinical Trial." Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-host. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Dr. Peder Myhre: And I'm Dr. Peder Myhre, social media editor and doctor at Akershus University Hospital at University of Oslo in Norway. Dr. Carolyn Lam: Peder, I am so excited to be discussing this issue. So many great articles and a feature discussion coming up on the SGLT2 inhibitor, empagliflozin. And do you think it's got effects on left ventricular remodeling in people without diabetes? Very interesting question. Dr. Peder Myhre: That is so interesting, Carolyn. I can't wait to hear this discussion. Dr. Carolyn Lam: Yep, I agree, but we got to wait till we discuss the other papers in today's issue. I want to go first. So we know that non-vitamin K oral anticoagulants, or NOACs, they've become the standard therapy for preventing stroke and ischemic thromboembolism in most patients with atrial fibrillation. But, what is the effectiveness and safety of NOACs in patients on dialysis? That is hemodialysis. The AXADIA-AFNET 8 study sought to test the hypothesis that apixaban would be non-inferior to vitamin K antagonists in these very patients undergoing hemodialysis. Dr. Peder Myhre: Oh wow. This is really a gap of knowledge that we've been waiting to hear more about. NOACs in patients with hemodialysis. Tell us about this trial, Carolyn. Dr. Carolyn Lam: Sure. So this is from corresponding author, Dr. Reinecke, and colleagues, from University of Munster in Germany. And it's an investigator initiated prospective randomized open-blinded outcome assessment of 97 patients with atrial fibrillation on chronic hemodialysis randomized to either apixaban 2.5 mg BID, or a vitamin K antagonist, aiming for an INR between 2 and 3. Over a median follow-up time of 429 days for apixaban, and 506 days for the vitamin K antagonist, the composite primary safety outcome of first, major bleeding, clinically relevant, non-major bleeding, or all cause death, occurred in 46% of patients on apixaban, and 51% of patients on the vitamin K antagonist. That would be a hazard ratio of 0.91, with a p for non-inferiority being 0.157. How about the primary efficacy outcome? While this was a composite of ischemic stroke, all cause death, myocardial infarction, or deep vein thrombosis, and/or pulmonary embolism, and that occurred in 21% of patients on apixaban and 31% of patients on the vitamin K antagonists. Again, no difference when there was testing. So, in summary, Peder, there were no differences in the safety or efficacy observed between apixaban and vitamin K antagonists in patients with atrial fibrillation on chronic hemodialysis. Of note, however, even receiving oral anticoagulations, these patients remain at very high risk of cardiovascular events. So these data really support the consideration of apixaban for prevention of cardiovascular complications in patients with atrial fibrillation on chronic hemodialysis, but larger studies are definitely needed. Dr. Peder Myhre: Oh wow, Carolyn, that is so clinically relevant. And the next paper is also a clinically relevant paper. And it comes to us from the SPRINT authors. And to remind you, the SPRINT study was a study of intensive systolic blood pressure lowering compared to standard blood pressure lowering. And the results demonstrated that there was a robust reduction in both heart failure endpoints and all cause mortality. And in this sub-study that comes to us from corresponding author Jarett Berry from University of Texas Tyler School of Medicine, these authors look at the mechanisms through which intensive blood pressure lowering reduces the risk of these endpoints. And given the important role of cardiac injury and neurohormonal activation in the pathways leading from hypertension to heart failure, and strong association that has been observed between hypertension and levels of cardiac troponin and NT-proBNP, the authors hypothesized that intensive systolic blood pressure lowering would decrease levels of high sensitivity cardiac troponin T and NT-proBNP. Dr. Carolyn Lam: Cool. That's interesting. So how did they do this, and what did they find? Dr. Peder Myhre: So, as expected, Carolyn, the authors found that increases in troponin and NT-proBNP from baseline to 1 year were associated with a higher risk of heart failure and death. And there were really no significant interaction by treatment assignment. But let's look at the changes in troponin. And these results showed that randomization to intensive blood pressure lowering versus standard blood pressure lowering resulted in a significant 3% increase in cardiac troponin T level over 1 year follow up, and a higher proportion of participants with more than 50% increase, and that's with an odds ratio of 1.47. And Carolyn, in contrast, NT-proBNP decreased by 10% in intensive blood pressure arm. And these patients had substantially lower probability of increasing more than 50% in NT-proBNP, with an odds ratio of 0.57 compared to the standard arm. And now, to the most interesting part of this analysis, Carolyn, the association of randomized treatment assignment on changes in troponin was completely attenuated after accounting for changes in eGFR during the follow up, whereas the association of treatment with NT-proBNP changes were completely attenuated after adjusting for changes in systolic blood pressure. So Carolyn, the authors highlight in their discussion the importance of non-cardiac factors influencing variation in cardiac biomarkers, and raise questions about the potential role of cardiac troponin T as a surrogate marker for heart failure or death in blood pressure lowering studies. Dr. Carolyn Lam: Wow, very interesting. Thanks, Peder. Can I tell you now about a preclinical study? Very interesting, because it shows that cardiac inflammation and hypertrophy are regulated by a heart-brain interaction. Dr. Peder Myhre: Wow, Carolyn, a heart-brain interaction. I'm excited to hear more about this. Please explain. Dr. Carolyn Lam: I'd love to, but first some background. Interleukin-1 beta, now that is a pro-inflammatory cytokine that causes cardiac hypertrophy and heart failure. I need to familiarize you with this, the nucleotide-binding domain leucine-rich containing family, pyrin domain-containing-3, NLRP3 for short, which is an inflammasome, which is a cytosolic multiprotein complex that mediates active interleukin-1 beta production. Okay? So you know these terms, and now I want to tell you about the study. This is an elegant series of experiments performed by co-corresponding authors, Dr. Higashikuni, from University of Tokyo, and Dr. Sata, from Tokushima University Graduate School of Medicine, and their colleagues. They first showed that genetic disruption of the NLRP3 inflammasome resulted in significant loss of interleukin-1 beta production, cardiac hypertrophy, and contractile function during pressure overload. Next, a bone marrow transplantation experiment revealed an essential role of NLRP3 inflammasome in cardiac non-immune cells in myocardial interleukin-1 beta production and the cardiac phenotype. It was extracellular ATP released from sympathetic nerve terminals that induced the hypertrophic changes of cardiac cells in an NLRP3 and interleukin-1 beta dependent manner in vitro. And finally, depletion of ATP release from sympathetic efferent nerves, or ablation of cardiac afferent nerves, or a lipophilic beta-blocker, all reduced cardiac extracellular ATP, and inhibited the NLRP3 inflammasome activation, the interleukin-1 beta production, and the adaptive cardiac hypertrophy during pressure overload. So all of this suggests that controlling the neuronal brain signals might have therapeutic potential for the treatment of hypertensive heart disease. Neat, huh? Dr. Peder Myhre: Oh, that is so interesting. The heart and brain interaction. And, Carolyn, we're going to stay in the field of preclinical science. And now we're going to talk about another field that is really interesting, and that is regeneration of cardiomyocytes. Because, Carolyn, developmental cardiac tissue holds remarkable capacity to regenerate after injury, and consists of regenerative mononuclear and deployed cardiomyocytes. Whether reprogramming metabolism promotes persistence of these regenerative mononuclear and deployed cardiomyocytes that enhance cardiac function in repair after injury is unknown. Therefore, these researcher, led by corresponding author, Mohsin Khan, from Temple University School of Medicine, investigated whether the RNA binding protein, LIN28a, which is a master regulator of cellular metabolism, plays a role in cardiac repair following injury. Dr. Carolyn Lam: Wow. That is always, always interesting, regeneration and repair following injury. So what did the authors find? Dr. Peder Myhre: Well, Carolyn, through a number of elegant experiments, the authors made the following key findings. For the first time, they documented a role for RNA binding protein LIN28A in regulating cardiomyocyte turnover in the postnatal and adult heart. And LIN28a overexpression promotes cardiomyocyte cell cycle activity during postnatal development and extends cardiac regenerative ability of the mammalian heart to postnatal day 7. And in the adult heart, the authors could demonstrate that LIN28a drives new myocyte formation, augmenting cardiac structure and function after myocardial injury. And Carolyn, I'm sure you're going to ask the clinical implications of this study. Dr. Carolyn Lam: Indeed. Dr. Peder Myhre: And that is that these results may suggest a novel translational role for LIN28a based strategy to replenish cardiomyocytes in the adult heart after injury. Dr. Carolyn Lam: Very nice, Peder. Thank you. Also in the issue is a Research Letter by Dr. Bick on interleukin-6 receptor polymorphism attenuates clonal hematopoiesis mediated coronary artery disease risk among many individuals in the UK Biobank. There's also Cardiology News by Tracy Hampton, where she highlights few really interesting things, like aging cardiomyocytes accumulate new genetic mutations that was published in Nature Aging, cytokines promote tissue repair after a heart attack in mice, and that was published in Science, and scientists identifying molecular alterations in a failing heart at a single cell resolution, which was published in Nature. Dr. Peder Myhre: And there are a couple of other papers also in this issue, Carolyn. And there's first, an exchange of letters by Drs. Halushka, Lu, and Mayr, regarding the article "Circulating MicroRNA-122-5p is Associated with a Lack of Improvement in Left Ventricular Function after TAVR and Regulates Viability of Cardiomyocytes Through Extracellular Vesicles." And finally, we have an "On My Mind" piece by doctors Monda and Limongelli entitled "An Integrated Sudden Cardiac Risk Prediction Model for Patients with Hypertrophic Cardiomyopathy." Dr. Carolyn Lam: Oh, nice. Nice full issue. Thank you, Peder. Let's go to our feature discussion now. Shall we? Dr. Peder Myhre: Let's go. Dr. Greg Hundley: Welcome listeners to this feature discussion on January 24th. And we have with us Dr. Subodh Verma, from St. Michael's University in Toronto, Canada. And a guest editor, Dr. Christopher Granger, from Duke University in Durham, North Carolina. Welcome gentlemen. Well, Subodh, we will start with you. Can you describe for us some of the background information that went into the preparation of your study, and what was the hypothesis that you wanted to address? Dr. Subodh Verma: First, my great pleasure to be here, and thank you very much for the opportunity to discuss this paper with your viewers. As you know, SGLT2 inhibitors have been truly transformative therapies. From a heart failure perspective, we know that they prevent incident heart failure in people with diabetes who have vascular disease or risk factors. They also have been shown to treat prevalent heart failure in people with heart failure and either a reduced, mildly reduced, or preserved ejection fraction independent of glycemic status. And really, these have been the basis of very strong recommendations to use these agents in the prevention of heart failure in people with diabetes, and also in the treatment of prevalent heart failure in people with and without diabetes. Now, the fact that these drugs have such broad effects in people with heart failure has led to a theory that maybe these drugs could be introduced earlier on in the natural history of heart failure in people who neither have diabetes nor have significant heart failure, the so-called sort of stage A or stage B patient. But there really have been no clinical trials evaluating this question. There've been a lot of translational randomized trials that have provided some mechanistic insights about LV remodeling in people with diabetes or in people with prevalent heart failure. And we hypothesized that maybe the first step to evaluate whether SGLT2 inhibitors may have favorable effects on cardiac remodeling in people without diabetes or without heart failure would be to conduct a randomized double-blind control trial looking at indices of left ventricular remodeling in a population that I've just described. Dr. Greg Hundley: Very nice, Subodh. So you've started us into your study design. Maybe describe that a little more fully, and then who was included in your study population? Dr. Subodh Verma: So EMPA-HEART 2 CardioLink was a multi-center double-blind placebo control randomized trial in which we studied the effects of empagliflozin, an SGLT2 inhibitor, at a dose of 10 mg per day versus placebo in people who did not have type 2 diabetes or significant heart failure. We included people who were adults between the age of 40 and 80 who met 1 of 2 entry criteria. Either they had to have one major criteria, which was an increase in left ventricular mass index by specific echo criteria or MRI criteria, or they could have increased LVH as identified by ECG or by intraventricular septal or posterior wall thickness. They could also get in if they had resistant hypertension, hypertension despite being on 3 antihypertensive agents, or the second strata was entry through 2 minor criteria, which included a history of myocardial infarction, a GFR between 30 or 60, or evidence of overweight or obesity. Dr. Greg Hundley: And how many subjects did you randomize? Dr. Subodh Verma: So we randomized, of the 318 that we screened, 169 were randomized to receive empagliflozin 10 mg or a placebo. Patients had a baseline cardiac MRI done, and then the exposure was 6 months. They had a follow-up MRI at the end of 6 months. And the primary outcome measure was a 6-month change in left ventricular mass index from baseline to 6 months between the two groups. Dr. Greg Hundley: Very nice. And so , Subodh, can you describe for us now, what did you find? What were your study results? Dr. Subodh Verma: So, first and foremost, what we found in terms of baseline characteristics was that we enrolled a population of people with a mean age of around 60 with a BMI of around 30 kg/m2, predominantly men, about 80% or so were men. These were patients who did not have significant heart failure. The NT-proBNP at baseline was around 50 pg/mL. The eGFR was around 80 mL/minute, and the vast majority of these patients actually had a history of hypertension. Of course, none of them had diabetes by definition. The hemoglobin A1C was around 5.8%. Now what we found was, despite the fact that we went after patients who we thought would be enriched for a baseline increase in LV mass indices, the baseline LV mass index was mildly elevated, was around 63 g/m2. And over the course of 6 months, we did not find any significant difference in terms of LV mass regression between the placebo and empagliflozin groups. In fact, the adjusted treatment effect was minus 0.30 g/m2, which was not statistically significant. No other differences were found in terms of other indices of a remodeling, including left ventricular and diastolic or end systolic volume indices or in terms of left ventricular ejection fraction. There was a 2% increase in ejection fraction, and the p-value for that was 0.07, but really was not statistically significant. Dr. Greg Hundley: And very nice. And realizing that women may have smaller LV masses, any stratified analysis that evaluated effects on men versus women? And then what about, perhaps in the higher quartile versus lower quartile, of age? Dr. Subodh Verma: Right. So, Greg, we actually did look at various subgroups and covariates, including gender, including age. And age or gender did not really influence the overall result that we obtained. There was really a neutral result in empagliflozin, irrespective of these 2 covariates. We also looked at baseline blood pressure, baseline NT-proBNP, LV mass indices, the presence or absence of heart failure, chronic kidney disease. So for the covariates that we have evaluated over a short term of 6 months in this relatively low risk population, we did not find any heterogeneity the result, per se. Dr. Greg Hundley: Very good. Well, Subodh, thank you so much for that beautiful presentation. And listeners, now we're going to turn to our guest editor, Dr. Chris Granger. And Chris is an expert in the field of heart failure. Also, a lot of familiarity with HFpEF, which sounds a little bit, we're looking at precursors. We don't have HFpEF yet, but maybe trying to inhibit this from happening using empagliflozin. How do you put these results in the context with other studies that have emphasized utilizing SGLT2 inhibitors in patients with sort of a preserved ejection fraction and absence of diabetes? Dr. Christopher Granger: Yeah. Well thanks, Greg. And again, congratulations, Subodh, to your study. And I think you framed some of the context here as these drugs, the SGLT2 inhibitors, as being transformative, which I think is exactly right. And it's such a fascinating story. Right? These drugs, which we thought originally, with their cause of glucose spilling in the urine, and a modest decrease in blood glucose, might have a role for modestly improving glucose control in diabetes. And low and behold, they've turned out to be one of the great stories I think in recent, across all of medicine, in terms of their consistent and substantial improving clinical outcomes for patients with heart failure, with diabetes and cardiovascular disease, and now even kidney protection, and much broader implications. And their well tolerated, and they don't have dose titration. So there's some practical appeal to this class of drugs in terms of their benefits, in terms of clinical outcomes. But we're left with having this amazing evidence-based generated without really understanding why are these drugs so effective? And what are they doing? And you've provided, I think, an important piece to the puzzle. We did have the data from patients with diabetes and heart failure, with diabetes and left ventricular hypertrophy, that there is a modest reduce in LV mass with SGLT2 inhibitors. And what you've shown is that for patients that with mild LVH, with risk for LVH, that we simply don't see a substantial reduction in LV mass with the use of these drugs. So I think that provides this evidence that that's not a major cause of benefit, at least in this earlier phase of development of heart failure. And I think it really underscores the fact that there's a lot of work to do still to understand. We know that the renal effects are obvious place that these drugs have such an important benefit. And then the linkage of renal disease and cardiac performance is one of the areas, I think, that's a very exciting aspect of a probable contribution of the mechanism of these drugs. But I think in the end, we're left with still not really understanding why these drugs are so beneficial. But understanding that, I think, will be important, both for opening new avenues of targeting pathways, as well as being able to tell the clinical community, okay, you have these important benefits, but people do want to also know why are we seeing these benefits. Dr. Greg Hundley: Very nice. Well, listeners, we're going to turn back to Dr. Verma here. Subodh, what do you see is the next study to be performed in this sphere of research? Dr. Subodh Verma: Well, first, my thanks to Professor Granger, Chris, for handling this paper and for his very thoughtful comments. And he's absolutely right. We have such wonderful clinical data, and these results, of course, should not in any way take away from the importance of using empagliflozin or other SGLT2 inhibitors in the prevention of heart failure in people with diabetes, or in the treatment of HFpEF or HFrEF. But we're struggling with trying to understand what is the dominant mechanism of action here. And, in the previous precursor to EMPA-HEART 2, we did EMPA-HEART 1 in people with diabetes, and we saw a modest effect that was statistically significant of reduction in LV mass index. And we did not see this, of course, in a lower risk population without diabetes. And that tells me that remodeling may be occurring to a modest effect, it may require a longer time to actually show its benefits, but that this is unlikely a dominant sort of mechanism through which these drugs are working. And I do share Chris's thoughts that one of the key mechanisms of benefit that needs to be further explored is looking at the renal cardiac axes. We know that these drugs are profoundly renal protective, and that the benefits may actually be secondary to improvements in renal hemodynamics, improvements in renal function. And I think that is a population that needs to be, that's a mechanism that needs to be studied further. So I think the next generation of translational mechanistic studies need to really tease out the renal cardiac axes, maybe tease out populations that are at risk but have more significant left ventricular hypertrophy, maybe evaluate patients for a longer duration of treatment, or select people who truly have significant hypertension at baseline. I think those are groups and questions that need further exploration. And, of course, the translational science needs to be also studied in the context of larger completed clinical trials, where biomarkers are currently available and they can be linked, of course, to the outcomes in those trials. So those are some of my thoughts as to where the field could move towards. Dr. Greg Hundley: Very nice. And Chris, do you have anything to add? Dr. Christopher Granger: Subodh, I think that was a great summary. And I might just make a comment on the other end of the spectrum. That is, we have these drugs and the evidence of their benefit, and yet they're grossly underused in the populations that have proven to have benefit. Now it takes some time to educate, to get people familiar with, and get them to integrate these treatments into practice, but there's an enormous opportunity, and I think there is a linkage here. I think when people understand the mechanism, and when they're thoughtful about how these drugs may be working, that that really helps to make the case that the drug should be used, and that people are on board with using them. So I think there's this linkage here, there's the need to both better understand mechanism, and there's the need to have systems of care where these treatments are integrated to provide the benefit that's been so clearly shown in the randomized trials. Dr. Greg Hundley: Very nice. Well, listeners, we want to thank Dr. Subodh Verma, from St. Michael's University in Toronto, and our guest editor, Dr. Chris Granger, from Duke University in Durham, North Carolina, for bringing this paper highlighting that among people with neither diabetes nor significant heart failure but with risk factors for adverse cardiac remodeling, that SGLT2 inhibition with empagliflozin did not, did not, result in a meaningful reduction in LV mass index after 6 months. Well, on behalf of Carolyn, Peder, and myself, we want to wish you a great week, and we will catch you next week on the run. This program is copyright of the American Heart Association 2023. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.
Dr. Paul Alexander Liberty Hour – A Swedish study by Alden et al. (and Zhang et al. showed that SARS-CoV-2 RNA could be reverse-transcribed and integrated into the genome of human cells) showed us that, indeed, mRNA, e.g., mRNA in Pfizer's vaccine, can be reverse transcribed back into DNA. This has dramatic implications for our...
This month on Episode 44 of Discover CircRes, host Cynthia St. Hilaire highlights four original research articles featured in the January 6th and January 20th issue of Circulation Research. This episode also features an interview with Dr Timothy McKinsey and Dr Marcello Rubino about their study, Inhibition of Eicosanoid Degradation Mitigates Fibrosis of the Heart. Article highlights: Prasad, et al. ACE2 in Gut Integrity and Diabetic Retinopathy Cui, et al. Epsins Regulate Lipid Metabolism and Transport Li, et al. Endothelial H2S modulates EndoMT in HF Luo, et al. F. plautii Attenuates Arterial Stiffness Cindy St. Hilaire: Hi, and welcome to Discover CircRes, the podcast of the American Heart Association's Journal Circulation Research. I'm your host, Dr Cindy St. Hilaire from the Vascular Medicine Institute at the University of Pittsburgh. And today I'm going to be highlighting articles from our January 6th and January 20th issues of Circulation Research. I'm also going to have a chat with Dr Timothy McKinsey and Dr Marcello Rubino about their study, Inhibition of Eicosanoid Degradation Mitigates Fibrosis of the Heart. But before the interview, I want to get to a few articles to highlight. Cindy St. Hilaire: The first article is titled, Maintenance of Enteral ACE2 Prevents Diabetic Retinopathy in Type 1 Diabetes. The first authors are Ram Prasad and Jason Floyd, and the corresponding author is Maria Grant, and they are from the University of Alabama. Type 1 Diabetes has a complex etiology and pathology that are not entirely understood. In addition to the destruction of insulin-producing cells, a recently discovered feature of the disease in both humans and in rodent models is that the levels of angiotensin converting enzyme 2 or ACE2 can be unusually low in certain tissues. ACE2 is a component of the renin angiotensin system controlling hemodynamics and interestingly, genetic deficiency of ACE2 in rodents exacerbates aspects of diabetes such as gut permeability, systemic inflammation and diabetic retinopathy, while boosting ACE2 has been shown to ameliorate diabetic retinopathy in mice. This study shows that ACE2 treatment also improves gut integrity and systemic inflammation as well as retinopathy. Six months after the onset of diabetes in a mouse model, oral doses of a bacteria engineered to express humanized ACE2 led to a reversal of the animal's gut barrier dysfunction and its retinopathy. Humans with diabetic retinopathy also displayed evidence of increased gut permeability in low levels of ACE2. This study suggests they may benefit from a similar probiotic treatment. Cindy St. Hilaire: The next article I want to highlight is titled, Epsin Nanotherapy Regulates Cholesterol Transport to Fortify Atheroma Regression. The first authors are Kui Cui, Xinlei Gao and Beibei Wang, and the corresponding authors are Hong Chen and Kaifu Chen and they're from Boston Children's Hospital. Epsins are a family of plasma membrane proteins that drive endocytosis. They're expressed at varying levels throughout the tissues of the body, and recent research shows that they are unusually abundant on macrophages within atherosclerotic lesions. In mice, macrophage specific Epsin loss results in a reduction in foam cell formation and atherosclerotic plaque development. This study now shows that this effect on foam cells is because Epsins normally promote the internalization of lipids into macrophages through their endosytic activity. But that's not all. The proteins also impede cholesterol efflux from macrophages to further exacerbate lipid retention. It turns out out Epsins regulate the endocytosis and the degradation of a cholesterol efflux factor called ABCG1. Importantly, these pro atrogenic activities of Epsins can be stopped. Using macrophage targeted nanoparticles carrying Epson specific silencing RNA, the team could suppress reduction of the protein in cultured macrophages and could reduce the size and number of plaques in atherosclerosis prone mice. Together these results suggest blocking Epsins via nanotherapy or other means could be a therapeutic approach to stopping or slowing atherosclerotic plaque progression. Cindy St. Hilaire: The third article I want to highlight is coming from our January 20th issue of Circ Res and is titled, Hydrogen Sulfide Modulates Endothelial-Mesenchymal Transition in Heart Failure. The first author is Zhen Li, and the corresponding author is David Lefer and they're from Cedars-Sinai. Hydrogen sulfide is a critical endogenous signaling molecule that exerts protective effects in the setting of heart failure. Cystathionine γ-lyase, or CSE, is one of the three hydrogen sulfide producing enzymes, and it's predominantly localized in the vascular endothelium. Genetic deletion of CSE, specifically in the endothelium, leads to reduced nitric oxide bioavailability, impaired vascular relaxation and impaired exercise capacity, while genetic over-expression of PSE in endothelial cells improves endothelial cell dysfunction, and attenuates myocardial infarction following myocardial ischemia-reperfusion injury. In this study, endothelial cell specific CSE knockout mice and endothelial cell specific CSE overexpressing transgenic mice were subjected to transverse aortic constriction to induce heart failure with reduced ejection fraction. And the goal was to investigate the contribution of the CSE hydrogen sulfide access in heart failure. Endothelial specific CSE knockout mice exhibited increased endothelial to mesenchymal transition and reduced nitric oxide bioavailability in the myocardium. And this was associated with increased cardiac fibrosis, impaired cardiac and vascular function, and it worsened the vascular performance of these animals. In contrast, genetic overexpression of CSE in endothelial cells led to increased myocardial nitric oxide, decreased EndoMT and decreased cardiac fibrosis. It also improved exercise capacity. These data demonstrate that endothelial CSE modulates endothelial mesenchymal transition and ameliorated the severity of pressure overload induced heart failure , in part through nitric oxide related mechanisms. This data further suggests that endothelium derived hydrogen sulfide is a potential therapeutic for the treatment of heart failure with reduced ejection fraction. Cindy St. Hilaire The last article I want to highlight is titled, Flavonifractor plautii Protects Against Elevated Arterial Stiffness. The first authors are Shiyun Luo and Yawen Zhao, and the corresponding author is Min Xia, and they are at Sun Yat-sen University. Dysbiosis of gut microbiota contributes to vascular dysfunction and gut microbial diversity has been reported to be inversely correlated with arterial stiffness. However, the causal role of gut microbiota in the progression of arterial stiffness and the specific species along with the molecular mechanisms underlying this change remain largely unknown. In this study, the microbial composition in metabolic capacities were compared in participants with elevated arterial stiffness and in normal controls free of medication. And these groups were age and sex match. Human fecal metagenomic sequencing identified a significant presence of Flavonifractor plautii or F. plautii in normal controls, which was absent in the subjects with elevated arterial stiffness. The microbiome of normal controls exhibited an enhanced capacity for glycolysis and polysaccharide degradation, whereas individuals with increased arterial stiffness exhibited increased biosynthesis of fatty acids and aromatic amino acids. Additionally, experiments in the angiotensin II induced and humanized mouse model show that replenishment with F. plautii or its main effector cis-aconitic acid or CCA improved elastic fiber network and reversed increased pulse wave velocity through the suppression of matrix metalloproteinase-2 and through the inhibition of monocyte chemoattractant protein-1. And this was seen in both the angiotensin II induced and humanized models of arterial stiffness. This study now identifies a novel link between F. plautii and arterial function and raises the possibility of sustaining vascular health by targeting the gut microbiota. Cindy St. Hilaire: Today with me I have Dr Tim McKinsey and Dr Marcello Rubino from the University of Colorado Anschutz Medical Campus, and we're here to talk about their paper Inhibition of Eicosanoid Degradati`on Mitigates Fibrosis of the Heart. And this article is in our January 6th issue of Circulation Research, so thank you both so much for joining me today. Timothy McKinsey: Thank you for inviting us. Marcello Rubino: Yeah, thank you for the opportunity. Cindy St. Hilaire: And so Dr McKinsey, you're a professor at the University of Colorado. How long have you been investigating cardiac fibrosis? Timothy McKinsey: Oh, a long time. Before I started the lab here in 2010, I was in industry working in biotech with Myogenic Gilead, and we were very interested in cardiac fibrosis all the way back then. Cindy St. Hilaire: Oh wow, so you actually made an industry to academia transfer. Timothy McKinsey: Yes. Cindy St. Hilaire: Good topic for another podcast. That is really great. Timothy McKinsey: Yeah, it's of interest to a lot of people, including trainees. Cindy St. Hilaire: Yeah, I bet. Dr Rubino, you were or are a postdoc in the McKinsey lab? Marcello Rubino: Yeah, I was a postdoc in Timothy McKinsey lab. I spent four years in Tim's lab. It was my first time studying cardio fibrosis, so it was a little bit difficult at the end, but I think I was right choosing Tim, so I'm really happy now. Cindy St. Hilaire: Nice and are you sticking with fibrosis or are you moving on? Marcello Rubino: Yeah, so now I'm back in Milan where I did my PhD student and postdoc. I am like an independent researcher, but it's still not a principal investigator, so I want to become one of the that, studying cardiac fibrosis. Yeah. And inflammation and epigenetics, so yeah, I'm going try to go to my way, thanks to Tim, I think that I find my own way. Cindy St. Hilaire: I'm sure you will. I mean, based on the great work in this study, right. Building upon that, I'm sure you'll be a success. Timothy McKinsey: No doubt about it. Cindy St. Hilaire: So your manuscript, this study, it's investigating whether eicosanoid availability can attenuate fibrosis in the heart. But before we kind of jump into this study, why is fibrosis in the heart a bad thing? Is it always detrimental? Is there some level of fibrosis that's necessary or even helpful? Timothy McKinsey: I mean, a certain level of extracellular matrix is deposited in your heart and that maintains the structure of the heart. Fibrosis can also be good after you have a myocardial infarction and a big piece of the muscle of your heart has died, it needs to be replaced with a fibrotic scar, essentially to prevent rupture of the ventricle. So fibrosis isn't always bad, but chronic fibrosis can be really deleterious to the heart and contribute to stiffening of the heart and cause diastolic dysfunction. It can create substrates for arrhythmias and sudden cardiac death. So we're really trying to block the maladaptive fibrosis that occurs in response to chronic stress. Cindy St. Hilaire: Yeah, yeah. And what about eicosanoids? What are they and what role do they play in cardiac fibrosis or what was known about their role in this process before your study? Timothy McKinsey: Eicosanoids are lipids, they're basically fatty acids, 20 carbon in length and a lot is known about them. It's a very complex system. There are many different eicosanoids, but they're produced from arachidonic acid through the action of cyclooxygenase enzymes like COX-2. And so you're probably familiar with the literature showing that non-steroidal anti-inflammatory drugs that target the COX enzymes can actually increase the risk of cardiac disease, so there was a lot known about what produces eicosanoids in the heart, but our study is really the first to address how they're degraded and how that controls cardiac fibrosis. Cindy St. Hilaire: What I thought you did really well in the introduction and what I guess I didn't really fully appreciate until I had read your study, was that your goal was to identify compounds that could attenuate fibrosis. And you spent some time emphasizing the differences between a targeted small molecule screen and a phenotype based screen. And I was wondering if you could just expand on this difference for the audience and maybe just explain why in your case you went with the latter. Timothy McKinsey: Well, we wanted to use an unbiased approach and some people call this a chemical biology approach where we took a targeted library, meaning we took compounds with known activities, meaning compounds that with known targets and we screened that library using a phenotypic assays that we developed in the lab. And the phenotypic assay is an unbiased assay, right? We're just screening for compounds that have the ability to block the activation of fibroblasts. And we monitor activation by looking at markers of fibroblast activation such as alpha smooth muscle Actin. And we can do this in a very quantitative and high throughput manner using this imaging system, high content imaging system that we have in the lab. It was an unbiased screen looking for inhibitors of fibroblasts activation across organ systems. We not only studied cardiac fibroblasts, but we also studied lung and renal fibroblasts looking for compounds with a common ability to block the activation state of each of those cell types. One of the things that I get asked frequently is how do we maintain the cardiac fibroblasts in a quiescent state? Because you may know this, but when fibroblasts are plated on cell culture plastic, which has a very high 10 cell strength, they tend to spontaneously activate, so we actually spent a couple of years working out the conditions to maintain the cells in quiescent state, and I think that will also be of great interest to the field. Cindy St. Hilaire: Probably even the smooth muscle cell biology field where I hang out and even valve interstitial cells that we study. All of those, I guess basic things related to cell culture, we have taken for granted that plastic is not physiological. Timothy McKinsey: Right. Cindy St. Hilaire: And so I think with this really nice phenotypic or chemical screen that you conducted, you first identified nine compounds, but what made you zero in on this one, SW033291? Timothy McKinsey: When we got the hits, we were intrigued by the SW compound SW033291 because there was only one paper describing its action and there was a paper published in Science showing that SW or inhibition of this enzyme 15-PGDH could enhance organ regeneration. Cindy St. Hilaire: Oh, okay. Timothy McKinsey: And there's a very interesting interplay between fibrosis and organ regeneration where fibrosis inhibits regeneration and if you can stimulate regenerative pathways, they can actually block fibrosis, so there's this back and forth. And so that's really the main reason we were interested in pursuing SW just because of the novelty and the potential. And also it was a compound that behaved beautifully in our cell culture models with beautiful dose-dependent inhibition of each of the fibroblast types. Cindy St. Hilaire: It's kind of like the cleanest thing to start with. Also, if there's nothing known, it's ripe for investigation, so that's great. You just said this SW compound acts on 15-PGDH, so what is the role of that protein in fibroblasts and what if any known effects are there on this protein's inhibition in other cell types or disease states? Marcello Rubino: In fibroblasts team, I would like to say that this was really the first article that was published. Maybe there was just one published in Pulmonary Fibrosis, but like last year, but I didn't really talk about 15-PGDH, so you need to consider that 15-PGDH is an inhibitor, an enzyme that degrades prostaglandin, so if you inhibit the inhibitor, the release increase production, a lot of prostaglandin. And so a lot of paper were talking about this effect, so they will see we are just using SW in order to increase Prostaglandin E2 level and that was why we had this like anti-inflammatory or whatever effect. I would like to say that until now, maybe this can be the first really paper talking about no more than not just prostaglandin but 15-PGDH. Its action total level, a global level at particularly on fibroblasts. To answer your question, I would like to say that this was also our question first and we checked by level other browser to try to find the answer to your question. We figured out that it was known that 15-PGDH was increasing a pathology condition in different organ, not just related by fibroblasts, not just related to cardiac disease, about the function with discover a function in macrophage that interested us because it can regulate maybe the polarization macrophage, so still involving the prostaglandin production inflammation, so that's why also we decide to take a look because it was still novel in fibrolbasts and we still know that it was doing something important and we were trying not to put the piece together and find something new in that we were lucky for this. Timothy McKinsey: 15-PGDH is actually expressed at very low levels in fibroblasts. It's much more highly expressed in macrophage, just as Marcello pointed out, so in the future we're very interested in knocking out or inhibiting 15-PGDH in different cell types to see how that contributes to inhibition of cardiac fibrosis. Cindy St. Hilaire: Really interesting. Related to that, you used a couple different animal models for fibrosis. They're all different or special in their own way. How well did these recapitulate what we observe in humans. Are there any limitations of benefits? Timothy McKinsey: They're always limitations to animal models. We started out with a very robust commonly used model of cardiac fibrosis, which relies on Angiotensin II infusion in mice. We like that model because it's robust and quick so we can get answers quickly. And then we transitioned into a model of diastolic dysfunction that we've been working with in a lab where we remove a kidney from a mouse and we implant something called DOCA, which is an aldosterone memetic. And so the animals develop hypertension that leads to a mild but significant diastolic dysfunction with preserved ejection fraction. And that's a model that we like a lot. It has something that we call hidden fibrosis, so if you just do standard histochemical staining of the hearts from the DOCA unit, nephrectomy model, that diastolic dysfunction model, you really can't see robust fibrosis. It's only when you dive more deeply with more sensitive assays like mass spectrometry or atomic force microscopy that you can detect this fibrosis and stiffening of the heart, so we usually lead with a robust model of fibrosis, cardiac fibrosis, and then transition into a slightly more complex model but more physiologically relevant model or disease relevant model. Cindy St. Hilaire: Obviously you showed some really nice robust results with this SW compound. So in the continuum of heart failure in human, what do you think or what would you speculate would be the ideal timeframe for administration of this compound? Timothy McKinsey: Wouldn't want to give it immediately after someone's had a heart attack. As we discussed earlier, you need that reparative scar to form so you don't want to block that fibrotic remodeling. We believe that there's kind of smoldering fibroblast activation in the heart, even in someone who's had heart disease for many, many years. And if we can dampen that, we can either prevent further progression of heart failure or perhaps reverse it. We don't really know if we can reverse really established fibrosis in the heart yet. But I would want to try to catch fibrosis fairly early on in the disease process in someone who has chronic hypertension or obesity or a variety of different comorbidities and then start delivering an antifibrotic therapy at that point. Marcello Rubino: I would like to add that, so it is really tricky when we talk about clinical trials because a lot of molecules that maybe they can work hopefully in a preclinical model don't work at the end in the clinical model. That's because can be some off target also like you just asked what is really important is when you do the administration of the molecule and talk about this in SW, like things say we don't want to prevent the fibrosis because there is something like called a kneeling at the beginning, so it is the good fibrosis we like to say, but the good thing of SW compound is that is affecting in a good way the proliferation of fibroblast that is different for all the other. I would like to say all the other inhibitor that we saw so far, because I remember the first time that I presented this work, there was an expert told me that he didn't believe that all my data because the compound was inhibiting fibrosis, it was inhibiting proliferation. And I show him, no, this is contrary, so oh okay, I like it. We need to consider this that the action seems to be not like the retire for the cell, so because the cells continue to proliferate, they can proliferate more. But the good thing and we need to investigate more is that SW action seems to increase when the cell are more fibrotic, because we show just few human fibroblasts isolating from a human patient and we saw a higher positive effect of SW compound when the cell were more fibrotic. That can be interesting. I think that it's worth to try to test in the future like in different preclinical models and maybe in patients at the end because if we really can find something like maybe SW that can be specific for the state of pathology, that will be wonderful. I don't really know if we can really do it, but we need some therapy like this, so that's why we were really excited about what we discovered for this compound. Timothy McKinsey: We have a lot more to learn about this pathway and about fibrosis in general. Cindy St. Hilaire: Yeah. Timothy McKinsey: It's a very exciting time to be doing science because of the amazing technologies that we have at our disposal to address detailed mechanisms of disease. Cindy St. Hilaire: What was the most challenging aspect of the study? Timothy McKinsey: This was an incredibly difficult study. I can't even stress to you how much work went into this. Spearheaded by Marcello's awesome leadership. There was huge input from a big team. Keith Cook and I worked together in industry and we were able to recruit him over here for a few years as part of our fibrosis center called the CFReT. It's an advertisement. And Keith was able to implement some of the drug discovery approaches that we used in biotech and create this imaging system that we initially employed for the screens. That was challenging. Maintaining the cells in a quiescent state was very challenging as I mentioned. That took a couple of years and then just following up on SW and trying to figure out its mechanism of action was really challenging as well because as Marcello mentioned, most people have attributed SW's effects to an increase in PGE2 levels, so PGE2 is an eicosanoid that is degraded by 15-PGDH. And definitely when you inhibit 15-PGDH with SW, you see increased PGE2. But surprisingly we couldn't find that PGE2 was doing anything in our cell culture systems, meaning when we added it exogenously it was not blocking fibroblast activation, so then Marcello set out to identify which eicosanoid that is regulated by 15-PGDH is actually the antifibrotic eicosanoid. And that led him to something called 12(S)-HETE. That was challenging. And then just determining at the molecular level what was going on was also challenging. And that led Marcello to this kind of paradoxical discovery that it activating ERK signaling was actually blocking fibroblast activation. Cindy St. Hilaire: And of course ERK does everything right? Marcello Rubino: It does. Everything. Timothy McKinsey: And sort of the dogma is that ERK is promoting fibrosis in the heart, but Marcello's data suggests otherwise. Timothy McKinsey: And then other shout outs, Josh Travers, who's the second author of the paper provided huge input, especially after Marcello left. Josh helped get this across the finish line. We have an amazing in vivo team conducting the animal model studies. Maria Cavasin and Elizabeth Hardy. I could go on and on. There are a lot of authors and if I didn't mention one of them, it doesn't mean that they weren't key contributors. I just wanted to throw that out there. We also had great collaborators. I think another component of this paper that is of great interest to us, and initially I was against doing any of this, is that Marcello and Josh created this biobank of human cardiac fibroblasts that we obtained from explanted hearts from individuals undergoing heart transplantation. And initially I thought it was going to be a waste of time and money for Marcello and Josh to do that, but they were persistent and they started isolating these cells. And the cells are really fascinating because even after you take them out of that failed human heart and culture them, they maintain this constituently active state, which is different than the cells we were using for screening where we kept them quiescent and then we stimulated them with TGF-β to activate them. These human cardiac fibroblasts from the failed human hearts are just on all the time. Cindy St. Hilaire: Wow. Timothy McKinsey: And SW does a really amazing job of reversing that activated state. Cindy St. Hilaire: Very cool and excellent resource I'm sure for future studies. So my last question is what's next? You know, you discovered a lot in this paper. What's the next thing you want to tackle? Timothy McKinsey: Cell type specific roles for 15-PGDH in the heart, in the control of cardiac homeostasis and disease. Basically we want to knock it out in fibroblasts. We want to knock it out in our macrophages and see what the consequences are. That's one thing. We want to really pursue the whole GPR31 12(S)-HETE pathway in the heart. That's something that has never been studied. And so GPR31 is a G protein coupled receptor that is bound by this eicosanoid called 12(S)-HETE. And that seems to be blocking fibroblast activation, so we're going to further pursue that pathway. And then we think that this paradoxical finding related to ERK signaling in the heart is also worthy of pursuit. Why is it that stimulating ERK in a cardiac fibroblast is actually blocking the activation state of that cell? Marcello Rubino: I'm interested in this like Tim says, but also interested in the role of the interaction of the cell because it's important to study like a specific gene inhibitor, whatever role in a specific cell, but what happened to the other cell, the interaction the other cell when you do knocking in some specific cell, so that's what I'm trying to do in general. Now I move back in Italy, like I told you, I'm like a kind of independent research and I'm studying a lot single cell sequencing right now. Try to do also try to see what happened to interaction, understand during pathology. The idea is to study like inhibitor treatment and to see what really happened because gene expression is important, but we need to consider also of course the protein shape, the protein interaction, the cell interaction, so I try to grow in this field and see what really happened because the problem of the cell, they're just cell in vitro. They can mimic what happened, but it's not what really happened in vivo, so can we use this novel technology to improve our knowledge, that's what I want to try to do. Cindy St. Hilaire: Well that's great. Dr McKinsey, Dr Rubino, thank you so much for taking the time to speak with me today. Title of their article was Inhibition of Eicosanoid Degradation Mitigates Fibrosis of the Heart. It's in our January 6th issue of Circ Res. And thank you both so much for joining me today and thank you to you and all of your colleagues who worked so hard on this for this amazing study. Timothy McKinsey: Thank you. We really enjoyed this visit and we're grateful to have our work published in Circulation Research. Cindy St. Hilaire: That's it for highlights from the January 6th and 20th issues of Circulation Research. Thank you for listening. Please check out the CircRes Facebook page and follow us on Twitter and Instagram with the handle @CircRes or #DiscoverCircRes. Thank you to our guests, Dr Tim McKinsey and Dr Marcello Rubino. This podcast is produced by Ishara Rantayaka, edited by Melissa Stoner and supported by the editorial team of Circulation Research. Some of the copy text for highlighted articles is provided by Ruth Williams. I'm your host, Dr Cindy St. Hilaire, and this is Discover CircRes, your on-the-go source for the most exciting discoveries in basic cardiovascular research. This program is copyright of the American Heart Association 2022. The opinions expressed by the speakers of this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more information, please visit ahajournals.org.
Join Dr. Jeffrey Gladden and Ian White in this episode of the Gladden Longevity Podcast. Dr. White is considered a leading expert in the field of aging and regenerative medicine, with 20 years of experience working with stem cells, regenerative cells, and tissue regeneration. Dr. White currently sits as the CEO and CSO of Neobiosis, LLC, a perinatal regenerative tissue research and manufacturing CDMO facility, and serves as the vice president and member of the board of directors of the American College of Regenerative Medicine. Dr. White is the co-founder of the Space-Aging Research Institute. In this episode, they talk about how aging in nature is optional, how many species are able to uncouple biological aging from chronological aging, and the need for the public to change their perception of longevity research if they want to see scientific advancements in their lifetime Listen to this episode to learn about making a hundred, the new thirty, and living beyond 120! Dr. Gladden introduces Dr. Ian White and notes that Dr. White is the co-founder of the Space Aging Research Institute. (1:15) Ian gives an example of putting a young mouse and an old mouse together, the old mouse becomes younger, and the young mouse becomes older based on different markers of aging. (2:16) Ian talks about the progress of the work they are doing and how they have been able to identify over four hundred bioactive proteins that are secreted into the amniotic fluid. (5:42) Ian explains that there are many different types of RNA. (7:00) Ian mentions that DNA can last for millions of years. (9:00) Dr. Gladden asks Ian to run through how the process works. (11:25) Dr. Gladden wants to know how the fluids collected are being used. (13:10) Ian describes how sports people, celebrities, and people from all walks of life use the products to regain what they have lost due to injury or concussion. (14:55) Ian says that the biological structure of a human is very complex, and there can't be one cure-all. (16:25) Ian speaks about how space is unexplored and how our physiology in relation to space is largely unexplored as well. (19:00) Ian emphasizes that since space travel is becoming more popular, they hope to have more short-term excursions to space. (21:45) Dr. Gladden shares that he expects senescence to accelerate up there on some level. (24:30) Dr. Gladden asks Ian to share which metrics are most impacted by the product use. (26:20) Ian reveals that a patient using the product got huge benefits, and her wounds got healed in six days instead of three months, as the doctors said. (28:04) Ian points out that the body does not seem to heal the heart when it's wounded, as that may cause it to rupture. (30:50) Dr. Gladden questions Ian about his experience in areas related to using regenerative medicine for the heart and brain. (33:40) Ian details how to attract new nerve tissues using intramuscular injections. (37:45) Dr. Gladden wants to know what is next for Ian. (39:03) Ian states that in his book, he unifies physics, chemistry, and biology to find out what aging really is. (41:55) Ian clarifies that the reason we age is that we lose the ability to process entropy. (44:11) Ian thinks there is a connection between exiting the growth phase and entering the degenerative phase. (46:18) Ian highlights the importance of asking the right questions about aging. (48:12) Ian notes that eating a lot of sugar when you are young may make it more difficult to stay healthy as you get older. (50:08) Ian advises that we start fighting aging early. (52:22) Dr. Gladden says this is a really fascinating conversation and that he really enjoyed it. (54:32) Visit our website, www.gladdenlongevitypodcast.com, for more information on this episode and other episodes as well. Click on the link to let us know what you'd like us to talk about on the podcast too! Follow us on social media! Instagram: @gladdenlongevity Twitter: @gladdenlongevit Facebook: @GladdenLongevity LinkedIn: @GladdenLongevity For more information on our practice or how to become a client, visit: www.gladdenlongevity.com Call us: 972-310-8916 Or email us: email@example.com To learn more about Dr. White and Neobiosis, check out the following: Kathy Hebert (Director of Strategic Development): firstname.lastname@example.org, 864-353-5781. Dr. Ian White's LinkedIn: (17) Ian White, Ph.D. | LinkedIn Neobiosis' LinkedIn: https://www.linkedin.com/company/neobiosis/ Neobiosis' Website: https://neobiosis.com Get more info about longevity: https://tacrm.org/
What is CRISPR?DNA contains the fundamental information about an organism, and is used as an instruction manual to guide organism structure and function. Until CRISPR (short for Clustered Regularly Interspaced Short Palindromic Repeats) technology was developed by Jennifer Doudna and Emmanuelle Charpentier, editing DNA sequences was very difficult. Here's the short version of the CRISPR process. First, a CRISPR enzyme is guided by an RNA strand to a DNA strand researchers want to edit. The RNA strand guides the enzyme to a specific point, and the enzyme cuts the DNA molecule. This CRISPR process can be used to eliminate DNA strands, as well as to replace DNA strands using other “repair” enzymes. It is a direct way for human beings to alter the planet's biological blueprint, and, accordingly, its impact can be a strong force for change, positive or negative. How can CRISPR be used to fight climate change?CRISPR can be used to edit the genetic sequences of plants so that they capture more carbon during photosynthesis, and store it in the ground long-term. Since around a third of the Earth's land is cropland, CRISPR-modified agriculture could potentially sequester billions of tons of carbon each year. Professor Kris Niyogi at UC Berkeley studies how CRISPR can be used to increase the efficiency of sunlight utilization in plants during photosynthesis. Photosynthesis captures carbon dioxide, and requires sunlight to do so. By not letting any sunlight go to waste, the plant can capture more carbon dioxide from the atmosphere. CRISPR can also be used to create plants with deeper roots, enabling carbon to be stored deeper in the ground. UC Berkeley Professor Peggy Lamaux studies sorghum plants, searching for the genes responsible for sorghum's deep roots. Related genes in rice and wheat could be altered to have deeper roots, like the sorghum plant. And UC Berkeley Professor Jill Banfield studies how plant-microbe interactions can be altered by CRISPR to store more carbon in soil. Soil microbes secrete sticky biopolymers, which can take soil humic substances and lock them with minerals to create long-lasting associations (potentially up to 100 years) that hold carbon. The Banfield lab aims to CRISPR-modify plants so that they chemically “talk” to microbes, emitting chemicals that encourage the microbes to create more “sticky” carbon, rather than carbon that would be emitted into the atmosphere. Who is Kris Niyogi?Kris Niyogi is a Howard Hughes Medical Institute Investigator, a professor in the Department of Plant and Microbial Biology at the University of California, Berkeley, and a faculty scientist in the Molecular Biophysics and Integrated Bioimaging Division at Lawrence Berkeley National Laboratory. The Niyogi Lab studies photosynthetic energy conversion and its regulation in algae and plants. The lab's long-term research goals are to understand how photosynthesis operates, how it is regulated, and how it might be improved to help meet the world's needs for food and fuel. Dr. Niyogi earned his biology PhD from MIT. Further ReadingIn 10 years, CRISPR transformed medicine. Can it now help us deal with climate change? | University of CaliforniaThis scientist thinks she has the key to curb climate change: super plantsSupercharging Plants and Soils to Remove Carbon from the AtmosphereCRISPR-Cas Can Help Reduce Climate ChangeCan we hack DNA in plants to help fight climate change?
World economic touts having “write level” permission to edit your genes and how the COVID vaccine was an “engineered code” with messenger RNA. On average, 1,600 tech workers have been laid off every single day in 2023 according to a recent report. The ongoing Silicon Valley slump has caused the Masters of the Universe including Facebook, Amazon, and Salesforce to lead the way in cutting high-paid tech employees. The majority of likely U.S. voters would prefer that President Joe Biden do “more of what Congress wants,” while a plurality thinks the new Congress will do better than the past two years, and more on today's episode.
Episode SummaryIn this livecast episode, we welcome back Dr. Zain Chagla, Dr. Stefan Baral, and Dr. Sumon Chakrabarti to address some of the issues we've seen throughout the pandemic, new variants and what to expect with future variants, discussing what we've done well over the past few years, misinformation, the effect of social media and the messaging on Twitter, the role media plays and the influence of experts on policy, public health agencies, booster shots to combat new variants and who actually needs them, where we are at with public trust, and much more!SHOW SPONSORBETTERHELPBetterHelp is the largest online counselling platform worldwide. They change the way people get help with facing life's challenges by providing convenient, discreet and affordable access to a licensed therapist. BetterHelp makes professional counselling available anytime, anywhere, through a computer, tablet or smartphone.Sign up today: http://betterhelp.com/solvinghealthcare and use Discount code “solvinghealthcare"Thanks for reading Solving Healthcare with Dr. Kwadwo Kyeremanteng! Subscribe for free to receive new posts and support my work.Thank you for reading Solving Healthcare with Dr. Kwadwo Kyeremanteng. This post is public so feel free to share it.Transcript:KK: Welcome to ‘Solving Healthcare' I'm Kwadwo Kyeremanteng. I'm an ICU and palliative care physicianhere in Ottawa and the founder of ‘Resource Optimization Network' we are on a mission to transformhealthcare in Canada. I'm going to talk with physicians, nurses, administrators, patients and theirfamilies because inefficiencies, overwork and overcrowding affects us all. I believe it's time for a betterhealth care system that's more cost effective, dignified, and just for everyone involved.KK: All right, folks, listen. This is the first live cast that we have done in a very long time, probably a year.Regarding COVID, we're gonna call it a swan song, folks, because I think this is it. I'm gonna be bold andsay, this is it, my friends. I think what motivated us to get together today was, we want to learn, wewant to make sure we learned from what's gone on in the last almost three years, we want to learn that,in a sense that moving forward the next pandemic, we don't repeat mistakes. We once again, kind ofelevate the voices of reason and balance, and so on. So, before we get started, I do want to give acouple of instructions for those that are online. If you press NL into the chat box, you will be able to getthis. This recording video and audio sent to you via email. It'll be part of our newsletter. It's ballin, you'll,you'll get the last one the last hurrah or the last dance, you know I'm saying second, secondly, I want togive a quick plug to our new initiative. Our new newsletters now on Substack. Everything is on therenow our podcasts our newsletter. So, all the updates you'll be able to get through there. I'm just goingto put a link in the chat box. Once I find it. Bam, bam, bam. Okay, there we go. There we go. That's itright there, folks. So, I feel like the crew here needs no introduction. We're gonna do it. Anyway, we gotDr. Zain Chagla, we got Dr. Stef Baral, we got Dr. Sumon Chakrabarti back in full effect. Once again, like Isaid, we were we chat a lot. We were on a on a chat group together. We were saying how like, we justneed to close this out, we need to address some of the issues that we've seen during the pandemic. Talkabout how we need to learn and deal with some of the more topical issues du jour. So, I think what we'llstart with, well get Sumon to enter the building. If you're on Twitter, you're gonna get a lot of mixedmessages on why you should be fearful of it or why not you should be fearful of it. So, from an IDperspective, Sumon what's your what's your viewpoint on? B 115?SC: Yeah, so, first of all, great to be with you guys. I agree, I love doing this as a as a swan song to kind ofmove to the next stage that doesn't involve us talking about COVID all the time. But so yeah, I think thatwe've had a bit of an alphabet soup in the last year with all these variants. And you know, the most oneof the newest ones that we're hearing about recently are BQ 1, xBB. I think that what I talked aboutwhen I was messaging on the news was taking a step back and looking at what's happened in the last 14months. What that is showing us is that we've had Omicron For this entire time, which suggests a levelof genomic stability in the virus, if you remember, variants at the very beginning, you know, that wassynonymous with oh, man, we're going to have an explosion of cases. Especially with alpha for the GTAdelta for the rest of, of Ontario, and I'm just talking about my local area. We saw massive increases inhospitalizations, health care resources, of patients having been sent all over the province. So, it was itwas awful, right. But you know, I think that was a bit of PTSD because now after anybody heard theword variant, that's what you remember. As time has gone on, you can see that the number ofhospitalizations has reduced, the number of deaths has reduced. Now when omicron came yeah, therewas an explosion of cases. But you know, when you look at the actual rate of people getting extremely illfrom it, it's much, much, much less. That was something that, you know, many of us were secretlythinking, Man, this is great when this happened. So now where we are is we're in January 2023, we'vehad nothing but Omicron, since what was in late November 2020, or 21? Maybe a bit later than that.And x BB, if you remember, be a 2x BB is an offshoot of BH two. Okay. Yeah, if you're noticing all thesenew variants are their immune evasive, they tend to be not as they're not as visually as, I see this in myown practice, like all of us do here. You know, they are, well, I'm kind of piecemeal evolution of thevirus. Now, there's not one variant that's gonna blow all the other ones out of the water, like Oh, microndid or delta. Right. I think this is a good thing. This is showing that we're reaching a different stage of thepandemic, which we've been in for almost a year now. I think that every time we hear a new one, itdoesn't mean that we're back to square one. I think that this is what viruses naturally do. And I thinkputting that into perspective, was very important.KK: Absolutely. Zain just to pick your brain to like, I got this question the other day about, like, what toexpect what future variants like, obviously, is there's no crystal ball, but someone alluded to the ideathat this is what we're to expect. You feel the same?ZC: Yeah, absolutely. It's interesting, because we have not studied a Coronavirus this much, you know, inhistory, right. Even though we've lived with coronaviruses, there probably was a plague ofcoronaviruses. What was the Russian flu is probably the emergence of one of our coronaviruses areseasonal coronaviruses. You know, I think we had some assumptions that Coronavirus is when mutate,but then as we look to SARS, cov two and then we look back to see some of the other Coronavirus has,they've also mutated quite a bit too, we just haven't, you know, put names or other expressions tothem. This is part of RNA replication of the virus is going to incorporate some mutations and survival ofthe fittest, the difference between 2020, 2021, 2022, and now 2023 is the only pathway for this virus tokeep circulating is to become more immune evasive. This is what we're seeing is more immune evasion,we're seeing a variant with a couple more mutations where antibodies may bind a little bit less. But Ithink that the big difference here is that that protection, that severe disease, right, like the COVID, thatwe saw in 2020/2021, you know, that terrible ICU itis, from the COVID, you know, for the level ofantibody T cell function, non-neutralizing antibody functioning mate cell function, all of that that's builtinto, you know, humanity now through infection, vaccine are both really, you know, the virus can evolveto evade some of the immunity to cause repeat infections and, you know, get into your mucosa andreplicate a bit, the ability for the virus to kind of, you know, cause deep tissue infection lead to ARDSlead to all of these complications is getting harder and harder and harder. That's us evolving with thevirus and that's, you know, how many of these viruses as they emerge in the population really have kindof led to stability more than anything else? So, yes, we're going to see more variants. Yes, you know, thisis probably what what the future is, there will be some more cases and there may be a slight tick inhospitalizations associated with them. But again, you know, the difference between 2020/2021/2022/2023 is a syrup prevalence of nearly 100%. One way or another, and that really does define how thisdisease goes moving forward.KK: Yeah, absolutely. Maybe Stef we could pipe it a bit on, the idea that, first of all, I just want toreinforce like as an ICU doc in Ottawa with a population of over a million we really have seen very littleCOVID pneumonia since February 2022. Very minimal and it just goes to show know exactly whatSumon and Zain were alluding to less virulent with the immunity that we've established in thecommunity, all reassuring science. One question I want to throw towards Stef, before getting into it. Youdid an interview with Mike Hart. As you were doing this interview, I was going beast mode. I was hearingStef throw down. I don't know if you were, a bit testy that day, or whatever. There was the raw motionof reflecting on the pandemic, and how we responded and far we've gone away from public healthprinciples, was just like this motivator to say, we cannot have this happen again. I gotta tell you, boys,like after hearing that episode, I was like ‘Yeah, let's do this'. Let's get on. Let's go on another, doanother show. I'm gonna leave this fairly open Stef. What has been some of the keyways we'veapproached this pandemic that has really triggered you?SB: Yeah, I mean, so I guess what I'd say is, in some ways, I wish there was nobody listening to this rightnow. I wish there was like, I don't know what the audience is. I don't know if it's 10 people or underpeople, but I think it's like, I wish nobody cared anymore. I want Public Health to care. I want doctors tocare, we're going to keep talking because you know, Kwadwo, you've had folks in the ICU we we'vewe've seen cases in the shelters, we have outbreaks, like public health is always going to care aboutCOVID, as it cares about influenza cares about RSV, and other viruses, because it needs to respond tooutbreaks among vulnerable folks. That will never stop COVID, it was just clear very early, that COVID isgoing to be with us forever. So that means tragically, people will die of COVID people. I think that, youknow, there's that that's a reality, it's sometimes it's very close to home for those of us who areproviders, as it has for me in the last week. So COVID never ends. I think the issue is that like when doesCOVID And as a matter of worthy of discussion for like the average person? The answer is a long timeago. I mean, I think for the folks that I've spoken to, and the way that we've lived our lives as a family isto focus on the things that like bring folks joy, and to kind of continue moving along, while also ensuringthat the right services are in place for folks who are experiencing who are at risk for COVID and seriousconsequences of COVID. Also just thinking about sort of broader systems issues that I think continue toput folks at risk. So, one: I think it's amazing, like how little of the systematic issues we've changed,we've not improved healthcare capacity at all. Amazingly, we've not really changed any of the structuresthat put our leg limitations on the on the pressures on the health system, none of that has changed. Allof it has been sort of offset and downloaded and just like talking about masks and endless boosterswhen we've never really gotten to any of the meaty stuff. As you said three years into it, andeverybody's like, well, it's an emergency. I'm like, it was an emergency and fine. We did whatever wasneeded, even if I didn't agree with it at the time. But irrespective of that, whatever that was done wasdone. But now it's amazing that like the federal money expires for COVID In next few months, and allwell have shown for this switch health guys got became millionaires like a bunch of people, I don't mindnaming and I don't care anymore. These folks, these Grifters went out and grabbed endless amounts ofmoney. These cash grabs that arrival, the ArriveCan app with, like these mystery contractors that theycan't track down millions of dollars. So it's like all these folks like grabbed, you know, huge amounts ofmoney. And I think there's a real question at the end of it of like, what are we as a country? Or youknow, across countries? What do you have to show for it? How are you going to better respond? Andthe answer right now is like very little, like we have very little to show for all this all these resources thathave been invested, all this work that has been done. That I think should be the conversation. That tome needs to be this next phase of it is like billions and billions and billions of dollars trillion or whatever,like 10s of billions of dollars were spent on what? and what was achieved? And what do we want to donext time? And what do we have to show for it? that, to me feels like the meat of the conversationrather than like silly names for these new variants that do nothing but scare people in a way that isn'thelpful. It does not advance health. It doesn't you know, make the response any more helpful. It justscares people in a way that I think only detracts them from seeking the care that we want them to beseeking.KK: Yeah, I think you brought up a point to about or alluded to how some of this was the distraction.That was one of the points that really stuck home is that we, we didn't really dive into the core s**t, thecore issues. This is why at the end of it all, are we that much more ready for the next pandemic that wellsee, you know, and so like maybe Sumon, what do you think in terms of another tough one, are weready for the next pandemic? Do you think we've done enough? do we think are in terms of what we'veinvested in, how we've communicated to the public. The messaging to the public. Are we learning? Is myquestion, I guess.SC: I'm a clinician and I don't work with the public health and the policy aspect as closely as Stefan does.But I will say that, obviously, I've been in this realm for quite a long time, since in ID, I think that, youknow, what that's important to remember is that for SARS 1 we actually had this document thatoutlined all of this, you know, masking, social distancing, what to do with funding and all that kind ofstuff. Basically, I was actually interviewed about this, I remember back way back in 2020, and half of itwas basically just thrown out the window. I think that a lot of what happened is that fear came indecisions were made from emotion, which is, by the way, understandable, especially in April 2020. I'veshared with you guys before that, in February 2020, I was waking up at night, like nervous, that I wasgonna die. I that that's where I was thinking I it was, it was terrible. I completely understand makingthose decisions. I think as time went on, I wish that, you know, there's a bit more of public healthprinciples. You know, making sure that we're dealing with things without, you know, stepping onpeople's bodily autonomy, for example, you know, doing things in an equitable way, where you, youknow, we all know that every intervention that you do is squeezing a balloon, you must remember theunintended consequences, I think that we did. So, kind of putting that all together. I think, right now, aswe stand in Canada if we do have another pandemic. I fear that a lot of these same mistakes are goingto be made again, I should say, a disruptive pandemic of this because it's not forgotten H1N1, thepandemic it that was a pandemic, right. It wasn't nearly as disruptive as COVID was, but I do think thatinquiry and like you mentioned at the beginning, Kwadwo was talking about what we did, well, we didn'tdo well, and making sure the good stuff happens, and the bad stuff doesn't happen again, because this islikely not the last pandemic, in the information age in our lifetimes.KK: Zain, was there anything that stuck out for you? In terms of what you'd really want to see usimprove? Or whether it is messaging, whether it is public health principles, does any of those stick out inyour mind?ZC: Yeah, I mean, I think the one unique thing about this pandemic that is a lesson moving forward andfor us to kind of deal with I think we talked about messaging. This was the first major pandemic thatoccurred with social media and the social media era, right, and where, information, misinformation,disinformation, all the things that were all over the place, you know, we're flying, right, and there doesneed to be some reconciliation of what's been we have to have some reconciliation of some of thebenefits of the social media era in pandemic management, but also the significant harms the people,you know, we're scared that people got messaging that may not have been completely accurate, thatpeople had their biases as they were out there. I will say even that social media component penetratedinto the media. This is also the first time that I think we saw experts you know, including myself andSuman and all of us you know, that you know, could be at home and do a news interview on NationalNews in five minutes and be able to deliver their opinion to a large audience very quickly. So, you know,I think all of that does need a bit of a reconciliation in terms of what worked, what doesn't how youvalidate you know, good medical knowledge versus knowledge that comes from biases how we evaluatepsi comm and people you know, using it as a platform for good but may in fact be using it you know,when or incorporating their own biases to use it for more, more disinformation and misinformationeven if they feel like they have good intentions with it. I you know, I think this is a, you know, for thesociologists and the communications professionals out there, you know, really interesting case exampleand unfortunately, I don't think we came out the other side. Social media being a positive tool, it mayhave been a positive tool, I think in the beginnings, but, you know, I think I'm finding, it's nice tocommunicate with folks, but I'm finding more harm and more dichotomy and division from social mediathese days is compared to the beginnings of the pandemics where, you know, I think, again, there's justbeen so much bias, so much misinformation so much people's clouds and careers that have been, youknow, staked on social media that it's really become much, much harder to figure out what's real andwhat's not real in that sense.KK: Absolutely, I fully agree Zain. At the beginning, in some ways, I'll tell you, ICU management, thatwhole movement for us to delay intubation, as opposed to intubation early, I really think it was pushedby in social media. So, I think it saved lives, right. But then, as we got through more and more thepandemic, wow, like it, like the amount of just straight up medieval gangster s**t that was going on thatin that circle, in that avenue was crazy. Then just like, I mean, this might be controversial to say, I don'tknow, but news agencies got lazy, they would use Twitter quotes in their articles as, evidence, or asproof of an argument. It's like, what is happening? It? Honestly, when you think about it, it was it wascrazy. It still is crazy.ZC: Yeah. And I think expertise was another issue. Right. And, you know, unfortunately, we know of, youknow, certain experts that were not experts that weren't certified that weren't frontlines and a varietyof opinions and various standpoints and epidemiology, public health, intensive care, infectious diseases,whatever is important. But, you know, there were individuals out there that had zero experience thatwere reading papers and interpreting them from a lens of someone that really didn't have medicalexperience or epidemiologic experience, that chased their clout that made money and, we know someexamples that people that eventually had the downfall from it, but you know, at the end of the day,those people were on social media, and it penetrated into real media, and then that is a real lesson forus is that validation of expertise is going to be important. You know, as much as we allow for anyone tohave an opinion, you know, as they get into kind of real media, they really have to be validated that thatopinion comes from a place that's evidence based and scientific and based on a significant amount oftraining rather than just regurgitating or applying one small skill set and being an expert in many otherthings.KK: SumonSC: So we're just gonna add really quickly is that, in addition to what Zain saying. When this stuff bledover from social media to media, the thing that I mean, at least what it seemed like is he was actuallyinfluencing policy. That's, I think that's the important thing is, so you can have 10 people 20 peopleyelling, it doesn't matter if they're extreme minority, if it's influencing policy that affects all of us, right.So, I think that's important.KK: I'll be honest with you, like, I got to the point where I really hated Twitter, I still kind of hate Twitter.Okay. It was conversation. I remember Sumon that you and I had I don't remember it was we weretexting. I think we talked about this. But the fact that policy could be impacted by what we're throwingdown the facts or the messages that we were doing on media that this can impact policy, you had tolike, especially when there was some badness happening, we had to step up. We had to be a voice oflogic, whether it was mandates, whether it was you know, lockdown school closures, whatever it mighthave been like, the politicians, we heard about this politicians looking at this, the mainstream medialooking at this, and for us not to say anything at this point, like we had, we had to do something Sorry,Stef, you're gonna jump in?SB: Yeah, I think I think what was interesting to me to see and I think a clear difference between H1N1was that in a lot of places, and including in Ontario, across the US, where this sort of emergence of theselike the science tables, these task forces, these whatever you want to call them, it was like a new bodyof people often whom had never spent a day in a public health agency. Often academics that you know,are probably good with numbers, but really don't have a lot of experience delivering services, you know,all of a sudden making decisions. So I think there's a real interesting dynamic that when you compare,for example, Ontario and British Columbia, one has this science table one does not, and just howdifferent things played out, I mean, given it's a, you know, an end of have to, or no one in each camp,but I think what you see is like, there's a place there where like public health or you know, let's say,Sweden, you know, as a public health agency that didn't strike up its own taskforce that used itstraditional public health agency. I think was in a place to make more like reasoned and measureddecisions, and just was better connected, like the relationships exist between the local healthauthorities and the provincial health authorities and the national ones. I think when you set up these,the one thing that I hope we never do, again, is that something like the science table never happensagain. That's not to sort of disparage most of the people. Actually, most of the folks on the science tableI like, and I respect, say many of them, maybe not most, but many of them, I like and respect, but it isthe case that there was it was they weren't the right group of people. They weren't representativeOntarians he was like, ten guys and two women, I think, I don't know many of them white, they weren'trepresentative socio economically, racially diverse, anything. They didn't have the right expertise onthere. I would have liked to see some like frontline nurses on there to say ‘listen, this stuff is silly' orsome frontline, whoever just some frontline folks to be say ‘listen, none of the stuff that you're sayingmakes any sense whatsoever'. And luckily, there was some reason, voices on there, but they were theminority. But luckily, they prevailed, or we would have had outdoor masking and even tougherlockdowns. I don't know how folks really; it was really close. I think we fortunately had thatrepresentation, but that should have never even happened, we should have had public health Ontario,being its agency and making recommendations to the ministry and to the government. There shouldhave never been a science table. Then second thing, I just want to say I've we've talked about thisforever and I do think we should talk about this more, not in the context of like this, this podcast, but isalso just absolutely the role of the media. I do want to say that, like historically, media had to do a lot ofwork, they had to go to universities or hospitals and ask for the right expert, and then the media orcomms team, ‘you should really talk to Zain Chagla' Because he has good example, you know, it givesgood expertise on this or you start to like, I don't know, like Dr. so and so for this or that, and they puttogether the right person, they organize the time and then they talk. Now you know that it was reallylike the story I think was more organically developed on based on what the experts had to say. Nowyou've got reporters, for people who are not from Ontario, there's a sports reporter in the city ofToronto that I looked historically, I can't see that they've ever done anything in public health suddenlybecame like the COVID reporter in the city of Toronto, for a major newspaper. It's like this person hasnot a clue of what they're talking about, just like has no clue they've never trained in. I don't disparagetheir sports reporter like why should they? but they became the voice of like public health for like theaverage person. It just it set us up where that person just had a story and then just found whateverpeople on Twitter that they could to like back up their story irrespective to drive controversy, to driveanger towards the government based on sort of political leanings. Even if maybe my political leaningsare aligned with that person, it's a relevant because it's not about politics, it's about public health. So Ithink the media, we have to think about, like, how do we manage the media's need for clicks and profit,you know, during this time, in with, like, their role as like, the responsible are an important part of like,you know, social functioning, in terms of the free press. So, I, there's no easy answers to that. But I'll justsay, I think there was a fundamentally important role that the media played here. And I have to say, itdidn't play out positively, in most places.KK: I gotta say, like, this is gonna be naive talk. But we're in a pandemic, there had to be so many of ushad a sense of duty, like, I was surprised at the lack of sense of duty, to be honest with you. Even if youare about your cliques, ask yourself, is this is this about the greater good here? Is this really gonna get usfurther ahead? I've said this a few times on my platform, I would have a balance of a mess. The balancedmessage on was usually one specific network that would bail on the interview. They would literally bailon the interview because my message might not be as fearful. What the actual f you know what I mean?Like it's crazy.(?) I will say there were some good reporters. I don't want to say that that you know, there were someincredible folks. I was talking to someone the other day, I won't mention who but I think the mark of thegood reporter was, you know, they have a story, they want to talk about it. They contacted us. And theysaid, what time can we talk this week, right? They didn't say I need to get this filed in three hours. If yousay you need to get this filed in three hours, the expert you're gonna go to is the one that's available inthe next three hours, right? They wanted to hear an opinion, they wanted to get multiple opinions onthe table, but they would carve out the time so that everyone could give their story or, what theiropinion was or what evidence they presented. They made sure it rotated around the experts rather thanthe story rotating around being filed. I think it's important and, you know, you can get a sense of certainthings that are on the need to be filed this day, or even on the 24/7 news cycle, where they may not beas well researched, they're they're a single opinion. They're quoting a Twitter tweet. Now, I think insome of these media platforms, you can just embed that Twitter tweet, you don't even have to, youknow, quote it in that sense, you just basically take a screenshot of it basically. Versus again, thosearticles where I think there was there more thought, and I think there were some great reporters inCanada, that really did go above and beyond. Health reporters, particularly that really did try to presenta picture that was well researched, and evidence based, you know, with what's available, but therecertainly are these issues and it's not a COVID specific issue, but with media ad reporting, in that sense.Yeah, it's and it's important to say like, it's not actually just the reporter, it's the editors, its editorialteams, like I had said, OTR discussions with reporters very early on, I've tried to stay away from themedia, because I think the folks who have done it, I've done it well. But it was interesting, because BobSargent, who sadly passed away, an internal medicine physician, and an amazing mentor to manyclinicians in Toronto. Put me in touch with a couple of reporters. He's like, you know, you're a publichealth person, you should really talk to these reports. We had this; can we talk to you privately? It wasso weird. This was summer of 2020. So, we had a very private discussion where I said ‘Listen, I haveconcerns about lockdowns for like, these reasons' I think it's reasoned, because it's not it, I've got noconspiracy to drive, like, I've got no, there's no angle in any of it. So, but it was just fascinating. So, theywere like we might be able to come back to you, and maybe we'll try to do a story around it. Then theycame back and said, we're not going to be able to pursue it. I said that's fine. It's no problem. It just sortof showed that I think, similar as academics, and clinicians, and all of us have been under pressure basedon everything from like CPSO complaints, the complaints to our employers, to whatever to just saw, youknow, the standard attacks on Twitter. I think there was also a lot of pressure on reporters based on thiswhole structure, and of it. So I think, I don't mean to disparage anybody, but I do think the point thatyou made is really important one is. I'll just say, in our own house, you know, my wife and I both werelike talking at the beginning of this and being like, what do we want to know that we did during thistime? So, my wife worked in person, as a clinician alter her practice all throughout her pregnancy? Shenever didn't go, you know, she did call she did all of that, obviously, I have done the work I've done interms of both clinically and vaccine related testing. But this just idea of like, what do you want toremember about the time that you would like what you did when s**t hit the fan? And, you know,because first, it'll happen again, but just also, I think it's important to sort of, to be able to reflect andthink positively about what you did. Anyways,KK: I hear you both, part of it, too, for me, I'll just straight up honesty. In some ways, I'm just pissed, I'mpissed that a lot of the efforts that were that a lot of people put into to try and get a good message outthere. The backlash. Now people reflecting saying, ‘Oh, I guess you did, you know, many of you do tohad a good point about lockdowns not working out'. I know it may be childish in some way, but it's just,you know, a lot of us have gone through a lot to just try and create a balanced approach. I think therewas a little bit of edge in this voice, but I think it comes with a bit of a bit of reason to have a bit of edge.I think in terms of the next couple questions here are areas to focus on. A lot of people in terms of like,decisions regarding mandates, boosters, and so forth, like we talk a lot about it on public health, it's thedata that helps drive decisions, right. That's really what you would think it should be all about. So, one ofthe many questions that were thrown to us, when we announced that this was happening was, the needfor like, almost like universal boosters, and Sumon, I'll put you on the spot there, at this stage in thepandemic, where I'm gonna timestamp this for people on audio, we're on January 10th, 2023. There aresome questions that we get, who really needs to push through to we all need boosters? What's yourthoughts on that?SC: So, I think that one of the things that I said this, as Zain makes fun of me throughout the pandemic, Icame up with catchphrases, and my one for immunity is the way that we've conceptualized immunity inNorth America. I think a lot of this has to do with an actual graphic from the CDC, which likens immunityto an iPhone or a battery, iPhone battery. So, iPhone immunity, where you have to constantly berecharging and updating. I think that has kind of bled into the messaging. That's what we think of it. Iremember back in I think it was October of 2021, where they were also starting to talk about the thirddose. The third dose, I think that at that time, we knew that for the higher risk people, it was probablythe people who would benefit the most from it. We had Ontario data from it was I think, was ISIS.There's vaccine efficacy against hospitalization, over 96% in Ontario in health care workers 99%, if you'reless than seventy-seven years of age, yet this went out, and everybody felt like they had to get thebooster. So, I think that the first thing that bothered me about that is that there wasn't a kind ofstratified look at the risk level and who needs it? So now we're in 2023. I think that one of the big thingsapart from what I said, you know, who's at higher risk, there's still this problem where people think thatevery six months, I need to recharge my immunity, which certainly isn't true. There wasn't a recognitionthat being exposed to COVID itself is providing you a very robust immunity against severe disease, whichis kind of it's coming out now. We've been we've all been talking about it for a long time. And you know,the other thing is that the disease itself has changed. I think that I heard this awesome expression, thefirst pass effect. So, when the COVID first came through a completely immune naive population, ofcourse, we saw death and morbidity, we saw all the other bad stuff, the rare stuff that COVIDencephalitis COVID GB GBS tons of ECMO, like 40-year old's dying. With each subsequent wave asimmunity started to accrue in the population, that didn't happen. Now we're at a different variant. Andthe thing is, do we even need to be doing widespread vaccination when you're with current variant, andyou can't be thinking about what we saw in 2021. So, putting that now, all together, we have as Zanementioned, seroprevalence, about almost 100%, you have people that are well protected against severedisease, most of the population, you have a variant that absolutely can make people sick. And yes, it cankill people. But for those of us who work on the front line, that looks very different on the on the frontlines. So, I really think that we should take a step back and say, number one: I don't think that thebooster is needed for everybody. I think number two: there are under a certain age, probably 55 andhealthy, who probably don't need any further vaccination, or at least until we have more data. Numberthree: before we make a widespread recommendation for the population. We have time now we're notin the emergency phase anymore. I really hope that we get more RCT data over the long term to seewho is it that needs the vaccine, if at all. And you know, who benefits from it. And let's continue toaccrue this data with time.KK: Thanks Sumon. Zain, are you on the along the same lines assume on in terms of who needs boostersand who doesn't?ZC: Yeah, I mean, I think number one: is the recognition that prior infection and hybrid immunityprobably are incredibly adequate. Again, people like Paul Offit, and we're not just talking about youknow, experts like us. These are people that are sitting on the FDA Advisory Committee, a man thatactually made vaccines in the United States, you know, that talks about the limitations of boosters andprobably three doses being you know, The peak of the series for most people, and even then, you know,two plus infection probably is enough is three or even one plus infection, the data may suggest maybe isas high as three. Yeah, I think, again, this is one of these things that gets diluted as it starts going downthe chain, if you actually look at the Nazi guidance for, you know, bi-Vaillant vaccines, it's actuallyincorporates a ‘should' and a ‘can consider' in all of this, so they talked about vulnerable individuals,elderly individuals should get a booster where there may be some benefits in that population, the restof the population can consider a booster in that sense, right. And I think as the boosters came out, andagain, you know, people started jumping on them, it came to everyone needs their booster. Andunfortunately, the messaging in the United States is perpetuated that quite a bit with this iPhonecharging thing, Biden tweeting that everyone over the age of six months needs a booster. Again, wereally do have to reflect on the population that we're going at. Ultimately, again, if you start pressing theissue too much in the wrong populations, you know, the uptake is, is showing itself, right, the peoplewho wanted their bi-Vaillant vaccine got it. Thankfully the right populations are being incentivized,especially in the elderly, and the very elderly, and the high risk. Uptake in most other populations hasbeen relatively low. So, people are making their decisions based on based on what they know. Again,they feel that that hesitation and what is this going to benefit me? and I think as Sumon said, theconfidence is going to be restored when we have better data. We're in a phase now where we can docluster randomized RCTs in low-risk populations and show it If you want the vaccine, you enter into acluster randomized RCT, if you're in a low-risk population, match you one to one with placebo. You wecan tell you if you got, you know, what your prognosis was at the end of the day, and that information isgoing to be important for us. I don't think that policy of boosting twice a year, or once a year is gonnaget people on the bus, every booster seems like people are getting off the bus more and more. So, wereally do have to have compelling information. Now, as we're bringing these out to start saying, youknow, is this a necessity? especially in low-risk populations? How much of a necessity is that? How muchdo you quantify it in that sense? And again, recognizing that, that people are being infected? Now, thatadds another twist in that sense.KK: Yeah, and we'll talk a little bit about public trust in a bit here. But Stef, you were among someauthors that did an essay on the booster mandates for university students. As we've both alluded toZain, and Sumon there's this need to be stratified. From an RCT booster point of view that we're not wellestablished here. When Stef's group looked at university mandates and potential harm, when we'redoing an actual cost benefit ratio there, their conclusion was that there's more room for harm thanbenefits. So, Stef I want you to speak to that paper a bit.SB: Sure. So, I will say this, I don't actually have much to add other than what Zain and Sumon said. Runa vaccine program we are offering, you know, doses as it makes sense for folks who are particularlyimmunocompromised, multiple comorbidities and remain at risk for serious consequences related toCOVID-19. We'll continue doing that. And that will, you know, get integrated, by the way into like, sortof a vaccine preventable disease program, so offering, shingles, Pneumovax, influenza COVID. And alsowe want to do a broader in terms of other hepatitis vaccines, etc. That aside, so this, this isn't about, youknow, that it was really interesting being called antivax by folks who have never gotten close to avaccine, other than being pricked by one. Having delivered literally 1000s of doses of vaccine, so it'salmost it's a joke, right? but it's an effective thing of like shutting down conversation. That aside, I thinkthere's a few things at play one as it related to that paper. I find it really interesting, particularly foryoung people, when people are like, listen, yes, they had a little bit of like, inflammation of their heart,but it's self-resolving and self-limiting, and they're gonna be fine. You don't know that. Maybe sure we'llsee what happens with these folks twenty years later. The reality is for younger men, particularly, thishappens to be a very gender dynamic. For younger men, particularly, there seems to be a dynamicwhere they are at risk of myocarditis. I don't know whether that's a controversy in any other era for anyother disease, this would not be a controversy would just be more of a factual statement, the data wereclearer in I'd say, probably April, May 2021. I think there's lots of things we could have done, we couldhave done one dose series for people who had been previously infected, we could have stopped at two.There are a million different versions of what we could have done, none of which we actually did. In thecontext of mandating boosters now for young people, including at my institution, you were mandated toget a booster, or you would no longer be working. So obviously, I got one. There's a real dynamic ofwhat is it your goal at that point? because probably about 1011 months into the vaccine programbecame increasingly clear. You can still get COVID. Nobody's surprised by that. That was clear even fromthe data. By the way, wasn't even studied. I mean, Pfizer, the way if you just look at the Pfizer, Moderna,trials, none and look to see whether you got COVID or not, they were just looking at symptomaticdisease. That aside, I think that it just became this clear thing where for younger men, one or two doseswas plenty and it seems to be that as you accumulate doses for those folks, particularly, it's alsoimportant, if somebody had a bad myocarditis, they're not even getting a third dose. So, you're alreadyselecting out, you know, some of these folks, but you are starting to see increased levels of harm, as itrelated to hospitalization. That what we basically did, there was a very simple analysis of looking ataverted hospitalization, either way, many people say that's the wrong metric. You can pick whatevermetric you want. That's the metric we picked when terms of hospitalization related to side effects of thevaccine versus benefits. What it just showed was that for people under the age of 30, you just don't seea benefit at that point, as compared to harm that's totally in fundamentally different. We weren't talkingabout the primary series, and we weren't talking about older folks. So indeed, I think, you know, thatwas that was I don't know why it was it was particularly controversial. We it was a follow up piece tomandates in general. I'll just say like, I've been running this vaccine program, I don't think mandateshave made my life easier at all. I know, there's like this common narrative of like mandates, you know,mandates work mandates work. I think at some point, and I'll just say our own study of this is like we'rereally going to have to ask two questions. One: what it mandates really get us in terms of a burdenCOVID-19, morbidity, mortality? and two: this is an important one for me. What if we caught ourselvesin terms of how much pressure we put on people, as it relates to vaccines right now, in general? Thevery common narrative that I'm getting is they're like, oh, the anti Vax is the anti Vax folks are winning.And people don't want their standard vaccines, and we're getting less uptake of like, MMR andstandard, you know, kind of childhood vaccines, I have a different opinion. I really do at least I believesome proportion of this, I don't know what proportion, it's some proportion, it's just like people beingpushed so hard, about COVID-19 vaccines that they literally don't want to be approached about anyvaccine in general. So, I just think that with in public health, there's always a cost. Part of the decisionmaking in public health as it relates to clinical medicine too. It's like you give a medication, theadvantage and then you know, the disadvantages, side effects of that medication. In public health, thereare side effects of our decisions that are sometimes anticipated and sometimes avoidable, sometimescan't be anticipated and sometimes can't be avoided. You have to kind of really give thought to each ofthem before you enact this policy or you might cost more health outcomes, then then you're actuallygaining by implementing it.KK: Yeah, number one: What was spooky to me is like even mentioning, I was afraid even to use a termmyocarditis at times. The worst part is, as you said, stuff, it's young folk that were alluding to, and for usto not be able to say, let's look at the harm and benefit in a group that's low risk was baffling. It reallywas baffling that and I'm glad we're at least more open to that now. Certainly, that's why I thought thatthe paper that you guys put together was so important because it's in the medical literature that we'reshowing, objectively what the cost benefit of some of these approaches are. Sumon: when you think ofmandates and public trust, that Stef was kind of alluding to like, every decision that we madethroughout this thing. Also has a downside, also has a cost, as Stef was mentioning. Where do you thinkwe are? In terms of the public trust? Talking about how the childhood vaccines are lower. I don't knowwhat influenza vaccine rates are like now, I wouldn't be surprised if they're the same standard, but whoknows them where they're at, currently. Based on your perspective, what do you think the public trust isright now?SC: Yeah, as physicians, we obviously still do have a lot of trust in the people we take care of. People arestill coming to see us. I wish they didn't have to because everyone was healthy but that's not the case. Ido think that over the last two and a half, we're coming up on three years, I guess right now, that peoplethat we have burned a lot of trust, I think that mandates were part of it. I do think that some of it wasunavoidable. It's just that there's a lot of uncertainty. There was back and forth. I think that one thingthat were that concern me on social media was that a lot of professionals are airing their dirty laundry tothe public. You could see these in fights, that doesn't, that's not really a good thing. We saw peoplebeing very derisive towards people who were not listening to the public health rules. You know what Imean? There's a lot of that kind of talk of othering. Yeah, I think that that certainly overtime, erodedpublic trust, that will take a long time to get back, if we do get it back. I think that the bottom line is that,I get that there are times that we have to do certain things, when you have a unknown pathogen comingat you, when you don't really know much about it. I do think that you want to do the greatest good forthe, for the population or again, you always must remember as Stefan alludes to the cost of what you'redoing. I do think that we could have done that much early on. For example, Ontario, we were lockeddown in some areas, Ontario, GTA, we were locked down in some regard for almost a year and a half. Ifyou guys remember, there was that debate on opening bars and restaurants before schools. It's just like,I remember shaking my head is, look, I get it, I know you guys are talking about people are going to beeating a burger before kids can go to school, that might ruin everything. But the problem is, is that youmust remember that restaurant is owned by someone that small gym is someone's livelihood, you'remoralizing over what this is, but in the end, it's the way somebody puts food on the table. For a yearand a half, we didn't let especially small businesses do that. I'm no economist, but I had many familymembers and friends who are impacted by this. Two of my friends unfortunately, committed suicideover this. So, you know, we had a lot of impact outside of the of the things that we did that hurt people,and certainly the trust will have to be regained over the long term.KK: It's gonna take work. I think, for me, honestly, it's, it's just about being transparent. I honestly, I putmyself in some in the shoes of the public and I just want to hear the truth. If we're not sure aboutsomething, that's okay. We're gonna weigh the evidence and this is our suggestion. This is why we'resaying this, could we be wrong? Yes, we could be wrong but this is what we think is the best pathforward, and people could get behind that. I honestly feel like people could get behind that showing alittle bit of vulnerability and saying ‘you know, we're not know it alls here' but this is what our beststrategy is based on our viewpoint on the best strategy based on the data that we have in front of usand just be open. Allowing for open dialogue and not squash it not have that dichotomous thinking ofyou're on one side, you're on the other. You're anti vax, you're pro vax, stop with the labels. You know,it's just it got crazy, and just was not a safe environment for dialogue. And how are you supposed to he'ssupposed to advance.SB: Yeah, I do want to say something given this this is this idea of our swan song. I think there was thissort of feeling like, you know, people were like ‘you gotta act hard, you gotta move fast' So I thinkeverybody on this, you guys all know I travel a lot. I like to think of myself as a traveler. In the early2020's I did like a COVID tour, I was in Japan in February, then I was in Thailand, and everywhere Ilanded, there were like, COVID here, COVID here, COVID here. Then finally, I like got home at the end ofFebruary, and I was supposed to be home for like four days, and then take off. Obviously things got shutdown. It was like obvious like COVID was the whole world had COVID by, February, there may have beena time to shut down this pandemic in September 2019. Do you know what I mean? by November 2019,we had cases. They've already seen some and Canadian Blood Services done some showing someserological evidence already at that time. There was no shutting it down. This thing's gonna suck. Thereality is promising that you can eliminate this thing by like, enacting these really like arbitrary that canonly be described as arbitrary. Shutting the border to voluntary travel, but not to truckers. Everythingfelt so arbitrary. So, when you talk about trust, if you can't explain it, if you're a good person do it. If youdon't do it, your white supremacist. Kwadwo you were part of a group that was called ‘Urgency ofNormal' you are a white supremacist. It's so ridiculous. You know what I mean? It creates this dynamicwhere you can't have any meaningful conversation. So, I really worry, unless we can start having somereally meaningful conversations, not just with folks that we agree with. Obviously, I deeply respect whateach of you have done throughout this pandemic, not just actually about what you say, but really whatyou've done. Put yourselves out there with your families in front of this thing. That aside, if we can't dothat, we will be no better off. We will go right back. People will be like ‘Oh, next pandemic, well, let'sjust get ready to lock down' but did we accomplish anything in our lock downs? I actually don't think wedid. I really don't think we got anything positive out our lock downs, and I might be alone in that. I mightbe wrong, butut that said it needs to be investigated and in a really meaningful way to answer that,before it becomes assume that acting hard and acting fast and all these b******t slogans are the truthand they'd become the truth and they become fact. All without any really meaningful evidencesupporting them.KK: I gotta say, I'll get you Sumon next here, but I gotta say the idea of abandoning logic, I think that'sthat's a key point there. Think about what we're doing in restaurants, folks. Okay, you would literallywear your mask to sit down, take off that bloody thing. Eat, chat, smooch even, I mean, and then put itback on and go in the bathroom and think this is meaningful. Where's the logic there? You're on a plane,you're gonna drink something, you're on a six hour flight, you know what I'm saying.(?) During the lockdown, by the way, you're sending like 20 Uber drivers to stand point. If you ever wentand picked up food, you would see these folks. It'd be like crowding the busy restaurants all like standingin there, like arguing which orders theirs, you know what I mean? then like people waiting for the foodto show up.KK: I mean, that's the other point. The part that people forget with the lockdowns, tons of people willwork. I'm in Ottawa, where 70% are, could stay home, right? That's a unique city. That's why we werevery sheltered from this bad boy.(?) Aren't they still fighting going back to the office?KK: Oh, my God. Folks, I'm sorry. Yeah, it's like 70% could stay home, but you're in GTA your area. That'sa lot of essential workers. You don't have that option. So, how's this lockdown? Really looking at the bigpicture? Anyway, sorry. Sumon you're gonna hit it up.SC: We just wanted to add one anecdote. I just think it kind of talks about all this is that, you know therewas a time when this thing started going to 2020. Stefan, I think you and I met online around that time.You put a couple of seeds after I was reading stuff, like you know about the idea of, you know, risktransfer risk being downloaded to other people. That's sort of kind of think of a you know, what, like,you know, a people that are working in the manufacturing industry, you're not going to receive them alot unless you live in a place like Brampton or northwest Toronto, where the manufacturing hub of, ofOntario and in many cases, central eastern Canada is right. So, I remember in, I was already starting touse this doing anything. And when I was in, I guess it would have been the second wave when it was itwas pretty bad one, I just kept seeing factory worker after factory worker, but then the thing that stuckout was tons of Amazon workers. So, I asked one of them, tell me something like, why are there so manyAmazon workers? Like are you guys? Is there a lot of sick people working that kind of thing? Inretrospect, it was very naive question. What that one woman told me that her face is burned into mymemory, she told me she goes, ‘Look, you know, every time a lockdown is called, or something happenslike that, what ends up happening is that the orders triple. So, then we end up working double and tripleshifts, and we all get COVID' That was just a light went off. I was like, excuse my language, guys, but holys**t, we're basically taking all this risk for people that can like what was it called a ‘laptop class' that canstay home and order all this stuff. Meanwhile, all that risk was going down to all these people, and I wasseeing it one, after another, after another, after another. I'm not sure if you guys saw that much, but Iwas in Mississauga, that's the hardest, Peele where the manufacturing industry is every single peanutfactory, the sheet metal, I just saw all of them. That I think was the kind of thing that turned me andrealize that we what we'll be doing. I'll shut up.ZC: Yeah, I would say I mean, I think Stefan and Sumon make great points. You know, I think that thatwas very apparent at the beginning. The other thing I would say is 2021 to 2022. Things like vaccinationand public health measures fell along political lines. That was a huge mistake. It was devastating. Iremember back to the first snap election in 2021. Initially great video of all the political partiesencouraging vaccination and putting their differences aside. Then all of a sudden, it became mudslingingabout how much public health measure you're willing to do, how much you're willing to invest in, andit's not a Canadian phenomenon. We saw this in the United States with the Biden and Trump campaignsand the contrast between the two, and then really aligning public health views to political views, andthen, you know, really making it very uncomfortable for certain people to then express counter viewswithout being considered an alternative party. It's something we need to reflect on I think we havepublic health and public health messengers and people that are agnostic to political views but are reallythere to support the health of their populations, from a health from a societal from an emotional fromthe aspects of good health in that sense. You really can't involve politics into that, because all of asudden, then you start getting counter current messaging, and you start getting people being pushed,and you start new aligning values to views and you start saying, right and left based on what peopleconsider, where again, the science doesn't necessarily follow political direction. It was a really bigmistake, and it still is pervasive. We saw every election that happened between 2021 to 2022 is publichealth and public health messaging was embedded in each one of those and it caused more harm thangood. I think it's a big lesson from this, this is that you can be proactive for effective public healthinterventions as an individual in that society that has a role, but you can't stick it on campaigns. It reallymakes it hard to deescalate measures at that point when your campaign and your identity is tied tocertain public health measures in that sense.KK: Amen. I am cognizant of the time and so I'm gonna try to rapid fire a little bit? I think, there's only acouple points that people hit up on that we haven't touched on. There was a push for mass mandates inthe last couple months because of of RSV and influenza that was happening. It still is happening in,especially in our extreme ages, really young and really old. Any viewpoint on that, I'll leave it open toalmost to throw down.(?) I think mass mandates have been useless. I don't expect to ever folks to agree with me, it's like it's aninteresting dynamic, right? When you go and you saw folks who were on the buses, I take the bus to theairport. Our subway in Toronto just for folks only starts at like, 5:50am. So, before that, you gotta jumpon buses. So the construction workers on the bus who were wearing masks during the when the maskmandates were on taking this what's called, it's like the construction line, because it goes down Bloorare basically and takes all the construction workers from Scarborough, before the subway line, get todowntown to do all the construction and build all the stuff that you know, is being built right now.Everyone is wearing this useless cloth mask. It's like probably the one thing that the anti-maskers who Ithink I probably am one at this point. The pro-maskers and all maskers can agree on is that cloth masksare useless. That's what 100% of these folks are wearing. They're wearing these reusable cloth masksthat are like barely on their face often blow their nose. So, to me, it's not so much about like, what couldthis intervention achieve, if done perfectly like saying the study you were involved with the help lead,it's like everybody's like, but all of them got COVID outside of the health care system, they didn't get itwhen they're wearing their N95. That's like, but that's the point, like public health interventions live ordie or succeed or fail in the real world. I was seeing the real world, I would love to take a photo but Idon't think these folks have been friendly to me taking a photo of them, but it was 100%, cloth masks ofall these folks in the morning all crowded, like we're literally like person to person on this bus. It's like aperfect, you know, vehicle for massive transmission. I just I just sort of put that forward of like, that'swhat a mask mandate does to me. I think to the person sitting at home calling for them, they are justimagining, they're like ‘Oh but the government should do this'. But they didn't. The government shouldbe handing out in N95's. How are you going to police them wearing a N95's and how are you gettingthem? It would be so hard to make a massive program work. I would say it's like if you gave me millionsand millions and millions of dollars, for me to design a mass program, I don't know, maybe I could pull itoff you really with an endless budget. But for what? So, I just think that like as these programs went outin the real world, I think they did nothing but burn people's energy. You know because some people itjust turns out don't like wearing a mask. Shocking to other folks. They just don't like wearing a mask.Last thing I'll say is that just as they play it out in the real world, I think we're functionally useless, otherthan burning people's energy. I'm a fervent anti masker at this point because it's just an insult to publichealth. To me everything I've trained in and everything I've worked towards, just saying these two wordsmask mandate, as the fix. That is an insult to the very thing that I want to spend my life doing .ZC: Yeah, I mean, three points, one: you know, masks are still important in clinical settings. I think we allunderstand that. We've been doing them before we've been continuing to do them. So I you know,that's one piece. Second: I mean, to go with the point that was raised here, you know, the best study wehave is Bangladesh, right? 10% relative risk reduction. It's interesting when you read the Bangladeshstudy, because with community kind of people that pump up masking that are really trying to educateand probably are also there to mask compliance. Mask's compliance people, you get to 54% compliance,when those people leave compliance drops significantly. Right. You know, I think you have to just lookaround and see what happened in this last few months, regardless of the messaging. Maybe it's thecommunities I'm in, but I didn't see mass compliance change significantly, maybe about 5%. In thecontext of the last couple of months. You must understand the value of this public health intervention,Bangladesh has actually a nice insight, not only into what we think the community based optimalmasking efficacy is, but also the fact that you really have to continue to enforce, enforce, enforce,enforce, in order to get to that even 10%. Without that enforcement, you're not getting anywhere inthat sense. That probably spells that it's probably a very poor long term public health intervention in thecontext that you really must pump it week by week by week by week in order to actually get compliancethat may actually then give you the effects that you see in a cluster randomized control trial. Again, youknow, the world we live in is showing that people don't want to mask normally. Some people can, i
Today, I am blessed to have here with me Damon Sununtnasuk. He is the founder and CEO of the Sunt Group and Palmara Health which is previously named Nature Cure Labs. He has received numerous awards and recognitions in 2020. These awards include but are not limited to Company of the Year - Health Products & Services, Health & Wellness Nutrition Manufacturer of the Year, 10 Most Influential CEOs in 2022, and many more. Damon is also part of the board of directors of the University of Florida Alumni Association. Damon was born and raised in Florida where he graduated Magna Cum Laude from the University of Florida with the degree of Bachelor of Science in Business Administration. He had an opportunity to live overseas which is why he was able to take his Master of Business Administration at the University of Cambridge. After living overseas, Damon came back to the United States in the year 2015. During this time, he experienced various serendipity. One of them is not having a way of looking after his health. At the time, he was also surrounded by the technological industry, entrepreneurial spirit, and startups. Aside from that, his group of friends was also into MCTs for health purposes which triggered his curiosity. There was even a time when he discovered "oil pulling" which is the process of putting coconut oil in the mouth for 10 minutes before spitting it out to help remove dirt and help maintain the health of your teeth and gums. After these events, he began to research MCTs where he was able to discover the different therapeutic benefits of Medium-Chain Triglycerides. Together with his desire to improve his health and the will to help others, he was able to establish his company in 2015. Currently, they have 3 manufacturing facilities and 35 warehouses in the United States. In this episode, Damon discusses Medium-Chain Triglycerides, specifically Monolaurin, and their role and benefits to the body. He talks about different studies about it and briefly discusses how these supplements are collected and made. He also mentions the Monolaurin product that his company offers. Get your monolaurin supplements with a discount here: Visit https://www.naturalcurelabs.com/products/?ref=KetoKamp Use the coupon code ketokamp for 10% off Take my FREE toxicity quiz to determine your level of toxicity. Visit www.toxicmiami.com for the free quiz. / / E P I S O D E S P ON S O R S Paleo Valley beef sticks, apple cider vinegar complex, organ meat complex & more. Use the coupon code KETOKAMP15 over at https://paleovalley.com/ to receive 15% off your entire order. Upgraded Formulas Upgraded Magnesium & Charge Electrolyte Supplements: http://www.upgradedformulas.com Use KK15 at checkout for 15% off your order. Text me the words "Podcast" +1 (786) 364-5002 to be added to my contacts list. [03:36] Medium Chain Triglycerides and its Benefits in the Body Plant fats contain medium chain triglycerides, coconut oil is a common example. 90% of the fats in coconut oil are saturated fats in which 50% of these saturated fats are MCTs. The health benefits of MCTs have been studied over the years. Some people put it on their coffee, protein shakes, food and etc. When MCTs have been converted in the body, it becomes monolaurin. The three main types of MCTs are Capric, Caprylic, and Lauric Acid. They bring benefits to the body by giving immune support and regulation as well as an aid in ketosis. Damon is focusing on Lauric Acid as based on their research, it helps in immune, digestive, and inflammatory support. [11:33] Everything About Monolaurin: Role and Benefits in the Body Damon read a study about the use of Monolaurin to fight off Giardia Lamblia, one of the most common causes of malnutrition. One of the studies Damon has read used Monolaurin to try cure Giardia Lamblia on animal subjects in which the cure rates reached over 90%. On the other hand, Damon has also read another study wherein Monolaurin was used on the animal subjects first before giving Giardia Lamblia. 60% of the test subjects didn't get sick. Research shows that Monolaurin helps in breaking down the protective envelope of the DNA and RNA viruses. Breast milk contains 6.5% of Monolaurin. Monolaurin can be found on coconut oil and palm oil. However, palm oil can only be harvested on sensitive environments which can affect natural habitats which is why coconut oil is more preferred. [20:21] The Different Ways You Can Take Monolaurin Before taking any supplements, you must contact a health professional in order to determine the right dosage for you to take. Introductory dose - Taking Monolaurin once a day, once every other day, and slowly increasing that up into the therapeutic dosage you're looking to get as an individual. Maintenance - In this way, monolaurin is taken daily to help maintain and regulate the healthy immune response. Some people also take Monolaurin when they feel sick or immunocompromised. [25:30] How Safe is Monolaurin for the Body? Monolaurin, under its chemical name 'Glycerol Monolaurin', is included on the 'Generally Recognized as Safe' list of the FDA. Different studies have not indicated a limit on the use of Monolaurin. Monolaurin impacts gut health. Research suggests that the continuous use of Monolaurin does not creates resistance in the body. [27:38] What Should You Do Before Buying a Product? Check out product testimonials posted on the website or marketplaces. Some product reviews are incentivized and not true so you should try and search about it first. Research through trusted websites like PubMed, familiarized yourself on different products, the science, the background, then the mechanics of it all and sort of trust the science and not necessarily someone's opinion. AND MUCH MORE! Resources from this episode: Website Get your monolaurin supplements with a discount here: Visit https://www.naturalcurelabs.com/products/?ref=KetoKamp Use the coupon code ketokamp for 10% off Check out Nature Cure Labs on social meida Facebook: https://www.facebook.com/NaturalCureLabs Instagram: https://www.instagram.com/naturalcurelabs/ Check out Damon Sununtnasuk LinkedIn: https://www.linkedin.com/in/damonsun/ Academic Resources: PubMed: https://pubmed.ncbi.nlm.nih.gov/ Monolaurin and More: https://www.monolaurinandmore.com/articles/monolaurin-keto-diet Studies referenced: Using monolaurin pre- and post- infection: Fahmy ZH, Aly E, Shalsh I, Mohamed AH. The effect of medium chain saturated fatty acid (monolaurin) on levels of the cytokines on experimental animal in Entamoeba histolytica and Giardia lamblia infection. African Journal of Pharmacy and Pharmacology. January 2014. https://academicjournals.org/journal/AJPP/article-abstract/0C0410F43049 Monolaurin and Ketosis: Avgerinos, Konstantinos I, et al. “Medium Chain Triglycerides induce mild ketosis and may improve cognition in Alzheimer's disease. A systematic review and meta-analysis of human studies.” Ageing Research Reviews, 2020. https://pubmed.ncbi.nlm.nih.gov/31870908/ Customer Reviews: (you can choose to read a couple testimonials in the intro / outro) 600mg Premium Monolaurin: https://www.amazon.com/Natural-Cure-Labs-Premium-Monolaurin/dp/B017RHHEVG?ref_=ast_sto_dp&th=1#customerReviews 800mg Extra Strength: https://www.amazon.com/Natural-Cure-Labs-Strength-Monolaurin/dp/B07GQ1RQHW?ref_=ast_sto_dp&th=1#customerReviews 1:1 L-Lysine + Monolaurin: https://www.amazon.com/Natural-Cure-Labs-L-Lysine-Monolaurin/dp/B07VNV2ZKP?ref_=ast_sto_dp#customerReviews Monolaurin mechanisms in the body: Research on monolaurin's impact on cell mechanisms or organs (ie: liver) is limited, but here is some research. Please don't attribute this to me, as it could be seen as a disease claim. “When monolaurin is consumed, it circulates in the bloodstream & is metabolized in a delayed fashion over 8-12 hours. Monolaurin is not excreted or detoxified out of the body. Instead, it is turned into energy in the form of ketones, [which in turn can] support ketone levels in the body.” - https://dralexrinehart.com/articles/monolaurin-a-secret-coconut-oil-compound-with-powerful-immune-benefits/ “When coconut oil is consumed, the medium-chain triglycerides (MCTs) are broken down into individual medium chain fatty acids and monoglycerides, which can kill or inactivate pathogenic microorganisms inside the body. The antiviral action, attributed to monolaurin (the monoglyceride of lauric acid), is that of solubilizing the lipids and phospholipids in the envelope of the pathogenic organisms causing the disintegration of their outer membrane. There is also evidence that MCFA interfere with the organism's signal transduction and the antimicrobial effect in viruses is due to interference with virus assembly and viral maturation.” - Arora, Rajesh, et al. “Potential of Complementary and Alternative Medicine in Preventive Management of Novel H1N1 Flu (Swine Flu) Pandemic: Thwarting Potential Disasters in the Bud.” Evidence-Based Complementary and Alternative Medicine, 13 Oct. 2010. “[Monolaurin] removes the M protein from the virus envelope resulted in loss of envelope integrity, which is essential for virus infectivity… the loss of envelope integrity results in loss of infectious virus titer” - Hierholzer, John C, and Jon J Kabara. “In Vitro Effects of Monolaurin Compounds on Enveloped DNA and RNA Viruses.” Journal of Food Safety, vol. 4, no. 1, Mar. 1982, pp. 1–12. “Medium-chain saturated and long-chain unsaturated fatty acids, on the other hand, were all highly active against the enveloped viruses... Antiviral fatty acids were found to affect the viral envelope, causing leakage and at higher concentrations, a complete disintegration of the envelope and the viral particles. They also caused disintegration of the plasma membranes of tissue culture cells resulting in cell lysis and death.” - Thormar, H, and et al. “Inactivation of Enveloped Viruses and Killing of Cells by Fatty Acids and Monoglycerides.” Antimicrobial Agents and Chemotherapy, doi:10.1128/AAC.31.1.27. Watch Keto Kamp on YouTube: https://www.youtube.com/channel/UCUh_MOM621MvpW_HLtfkLyQ Take my FREE toxicity quiz to determine your level of toxicity. Visit www.toxicmiami.com for the free quiz. / / E P I S O D E S P ON S O R S Paleo Valley beef sticks, apple cider vinegar complex, organ meat complex & more. Use the coupon code KETOKAMP15 over at https://paleovalley.com/ to receive 15% off your entire order. Upgraded Formulas Upgraded Magnesium & Charge Electrolyte Supplements: http://www.upgradedformulas.com Use KK15 at checkout for 15% off your order. Text me the words "Podcast" +1 (786) 364-5002 to be added to my contacts list. *Some Links Are Affiliates* // F O L L O W ▸ instagram | @thebenazadi | http://bit.ly/2B1NXKW ▸ facebook | /thebenazadi | http://bit.ly/2BVvvW6 ▸ twitter | @thebenazadi http://bit.ly/2USE0so ▸ tiktok | @thebenazadi https://www.tiktok.com/@thebenazadi Disclaimer: This podcast is for information purposes only. Statements and views expressed on this podcast are not medical advice. This podcast including Ben Azadi disclaim responsibility from any possible adverse effects from the use of information contained herein. Opinions of guests are their own, and this podcast does not accept responsibility of statements made by guests. This podcast does not make any representations or warranties about guests qualifications or credibility. 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Welcome to the NeurologyLive® Mind Moments® podcast. Tune in to hear leaders in neurology sound off on topics that impact your clinical practice. In this episode, we spoke with Sarah Boyce, president and CEO of Avidity Biosciences, who shared insight into the company's ongoing work with its antibody oligonucleotide conjugates (AOC) platform and the focus on myotonic dystrophy type 1 (DM1), Duchenne muscular dystrophy (DMD), and facioscapulohumeral muscular dystrophy (FSHD) treatments, as well as the challenges with developing successful RNA therapies, and more. Looking for more neuromuscular disorder discussion? Check out the NeurologyLive® neuromuscular clinical focus page: neurologylive.com/clinical/neuromuscular Episode Breakdown: 1:20 – Current limitations with RNA therapies 4:50 – The decision to focus on rare genetic muscle diseases 7:45 – The patient needs in DM1, FSHD, and DMD 9:05 – Neurology News Minute 12:25 – Other clinical areas of focus and collaboration for Avidity 14:10 – Upcoming data presentations planned for 2023 in DMD and myotonic dystrophy 16:15 – The benefits of collaboration in the rare disease community 18:15 – Looking ahead to the future of therapies in rare muscular disease This episode is brought to you by the Giants of Multiple Sclerosis®. This premier neuroscience award program celebrates pioneers, innovators, and future generations of leaders for their remarkable achievements in Multiple Sclerosis. Nominations close January 31, 2023! Nominate: neurologylive.com/Giants-of-MS The stories featured in this week's Neurology News Minute, which will give you quick updates on the following developments in neurology, are further detailed here: Anti-CD20 Therapy Ublituximab Gains FDA Approval for Relapsing Multiple Sclerosis FDA Clears First Stroke-Specific Radial Access Platform for Mechanical Thrombectomy FDA Designates Myasthenia Gravis Agent Rozanolixizumab Application for Priority Review FDA Approves Eisai's Lecanemab for the Treatment for Alzheimer Disease FDA Accepts sBLA for Revance's Cervical Dystonia Treatment DaxibotulinumtoxinA Thanks for listening to the NeurologyLive® Mind Moments® podcast. To support the show, be sure to rate, review, and subscribe wherever you listen to podcasts. For more neurology news and expert-driven content, visit neurologylive.com.
Join Hugh Ross and James Patterson, MD, as they discuss new discoveries taking place at the frontiers of science that have theological and philosophical implications, including the reality of God's existence. Viruses Fuel the Carbon Cycle (Hugh Ross) A recent study shows that DNA and RNA viruses in the oceans play a crucial role in the ocean carbon flux cycle. Additionally, they play significant roles in the sulfur, nitrogen, and deep ocean cycles. Viruses deposit huge amounts of carbon, sulfur, nitrogen, and oxygen on an ongoing basis onto the ocean floors. Once there, subducting plates move these elements into Earth's mantle. Without this process, advanced life wouldn't be possible. These huge deposits require that ocean viruses be extremely abundant and diverse and that they be specifically designed in a variety of ways so that advanced life can thrive. References: Diversity and Ecological Footprint of Global Ocean RNA Viruses Digital Health (James Patterson) In a world that is now more connected than ever in a digital sense, it seems that humans are becoming more and more disconnected. We've all seen it—a room full of people, all staring at their smartphones. Why is that? Why are more people depressed and suicidal now than ever before? What can we do to promote healthy living in a digitally connected society? References: Glenn Geher, “The Dark Side of Civilization,” https://www.psychologytoday.com/us/blog/darwins-subterranean-world/202209/the-dark-side-civilization
Experiência dos EUA mostra que desenvolver um ecossistema para fomentar projetos na área reduz custos e atrai investidores. Há três décadas, pesquisadores estudam soluções mais simples para ativar as defesas imunológicas do corpo humano. Uma das hipóteses testadas foi a de orientar a própria célula a produzir anticorpos sem que fosse preciso receber um pedaço do organismo ou vírus vivo. Em vez disso, o RNA mensageiro (mRNA) serviu para levar uma parte do código genético do vírus, dando “instruções” para combatê-lo em caso de infecção. O processo da criação das vacinas de mRNA ilustra a magnitude e o impacto do investimento em inovação na saúde. Em 2020, na fase mais crítica da crise sanitária mundial, empresas que atuam na área de biotecnologia dispararam nas bolsas de valores. No episódio desta semana, Laura Murta, Camila Pepe e Jonas Sertório conversam com o fundador e CEO da GRIDS Capital, Guy Perelmuter, sobre o que o cenário internacional de investimentos em biotechs vem ensinando para a gente que pode nos ajudar a atrair investidores e até reduzir custos.
Jakob Uszkoreit and Vijay Pande discuss all things AI — from Jakob's time at Google Brain, to how humans (and computers) process language, to Inceptive's belief in the promise of RNA, and how Jakob believes we're entering inflection point territory. You can also find a full transcript of this episode on our website.Additional reading:Attention is All You NeedA Decomposable Attention Model for Natural Language Inference
Synopsis: This special episode features a panel discussion with three biotech leaders about drug development for rare diseases. James Mackay, Ph.D., is the Founder, President and CEO of Aristea Therapeutics, an immunology-focused clinical stage biotech that is focused on inflammatory diseases. Arthur T. Suckow, Ph.D., is the Co-Founder and CEO of DTx Pharma, which is focused on developing novel technology for delivery of RNA medicines. Eslie Dennis is the SVP and CMO of Kyowa Kirin North America, a Japan-based global specialty pharmaceutical company. Our guests discuss the patient journey for those living with rare diseases, the importance of driving awareness for this patient population, important points to consider when partnering with big pharma, clinical trial design for patients with rare diseases, and best practices for driving awareness and inclusion of people of color in rare disease trials. Biography: James Mackay, Ph.D., Founder, President and Chief Executive Officer, has over 25 years of development and commercialization expertise in the pharmaceutical industry, including 6 drug product approvals across multiple therapeutic areas. Prior to founding Aristea, he was President and Chief Executive Officer of Ardea Biosciences, Inc., following the company's acquisition by AstraZeneca in 2012. James was instrumental to setting up an innovative model for Ardea Biosciences that retained the biotech's independence and accountability for the development of the gout franchise while also developing a synergistic and collaborative relationship with the parent company, AstraZeneca. Prior to Ardea, James held senior executive positions at AstraZeneca where he led the development and commercialization of drugs across a range of therapy areas. and managed significant global functional departments. James plays a pivotal role in the San Diego Ecosystem and currently sits on the Board and Executive Committee of CONNECT and sits on the Board of BIOCOM. He is a former Board member of the San Diego Economic Development Corporation (EDC). James holds a BS in Genetics and Ph.D. in Medical Genetics from Aberdeen University, Scotland. Dr. Arthur Suckow founded DTx Pharma in 2017. An innovative leader in drug discovery, he previously worked on the ophthalmology, diabetes, and NASH programs at Regulus Therapeutics, at the MedImmune arm of AstraZeneca, and in the Diabetes Drug Discovery program at Johnson & Johnson. Dr. Suckow received his BS from the University of Delaware and his PhD from University of California, San Diego. He has received numerous awards including a Beckman Fellowship, a NSF graduate research fellowship, and a BIOCOM catalyst award. Dr. Eslie Dennis joined Kyowa Kirin in May 2021 as SVP, Chief Medical Officer for Kyowa Kirin North America. Prior to joining this organization, she was Vice President and Head Global Medical Affairs at Ventana/Roche Tissue Diagnostics. She is a physician with 10 years experience in clinical practice (internal medicine and hematology/oncology) and research, and over 20 years international biopharma experience holding positions of increasing responsibility in pharmaceutical and diagnostic organizations at MSD, Novartis and Roche, including leadership of public-private consortia at the Critical Path Institute. Throughout her career, Dr. Dennis has championed innovative science and solutions to address unmet needs for patients and society, particularly addressing healthcare disparities. Dr. Dennis received her MBChB from the Godfrey Huggins School of Medicine in Harare, Zimbabwe, and was the recipient of the Winston Churchill, Margaret Low, and Prankard-Jones Scholarships, as well as the Guy Elliot Bursary. She is a Fellow of the College of Physicians of South Africa and received her internal medicine and hematology/oncology training at Groote Schuur Hospital in Cape Town, South Africa.
Please join authors Loren Field and Sean Reuter, as well as Associate Editor Thomas Eschenhagen as they discuss the article "Cardiac Troponin I-Interacting Kinase Affects Cardiomyocyte S-Phase Activity But Not Cardiomyocyte Proliferation." Dr. Greg Hundley: Welcome listeners, to this January 10th issue of Circulation on the Run, and I am Dr. Greg Hundley, associate editor, director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Dr. Peder Myhre: I am Dr. Peder Myhre from Akershus University Hospital and University of Oslo in Norway. Dr. Greg Hundley: Well, listeners, this week's feature discussion delves into the world of preclinical science and evaluates cardiac troponin I and its impact on S phase activity in cardiomyocytes, and does that relate to cardiomyocyte proliferation. But before we get to that, how about we grab a cup of coffee and Peder and I will work through some of the other articles in the issue. Peder, how about this week I go first? Dr. Peder Myhre: Go ahead, Greg. Dr. Greg Hundley: Right. So Peder, this first study evaluated whether the burden of positive coronary artery calcification on cardiovascular disease differed by multidimensional individual characteristics, and so the investigators led by Dr. Kosuke Inoue from Kyoto University sought to investigate the heterogeneity in the association between positive coronary artery calcium and incident cardiovascular disease. And so Peder, to examine this question, the authors implemented a cohort study design that included adults aged greater than 45 years, free of cardiovascular disease, from the Multi-Ethnic Study of Atherosclerosis, or MESA, and after propensity score matching in a one-to-one ratio, they applied a machine learning causal forest model to, first, evaluate the heterogeneity in the association between positive coronary artery calcium and incident cardiovascular disease and then, second, to predict the increase in cardiovascular disease risk at 10 years when the coronary artery calcium score was greater than zero, so versus is it zero at all at the individual level? Dr. Peder Myhre: Oh, Greg, that is so cool, so using machine learning for coronary artery calcium and risk prediction, I'm very excited. What did they find? Dr. Greg Hundley: Right, Peder, so the expected increases in cardiovascular disease risk when the coronary artery calcium score was greater than zero were heterogeneous across individuals. Moreover, nearly 70% of people with low atherosclerotic cardiovascular disease risk showed a large increase in cardiovascular disease risk when the coronary calcium score was greater than zero, highlighting the need for coronary artery calcium screening among such low-risk individuals. And Peder, future studies are really needed to assess whether targeting individuals for coronary artery calcium measurements based on not only the absolute ASCVD risk, but also the expected increase in CVD risk when a CAC score is greater than zero and whether that improves overall assessment of cardiovascular outcomes. Dr. Peder Myhre: Wow, that is so clinically relevant and very interesting. And we're actually going to stay clinically relevant with the next paper which is about anti-platelet therapy after PCI. And this paper describes the long-term results of the HOST-EXAM trial. To remind you, Greg, the HOST-EXAM trial was an investigator-initiated prospective, randomized, open label, multicenter trial done at 37 sites in Korea. They enrolled patients who had undergone PCI with DES and maintained dual anti-platelet therapy without any clinical event for a mean 12 months and then they were randomized one to-one to either clopidogrel, 75 milligrams once daily, or aspirin, 100 milligram once daily. The primary results of this trial was published in Lancet in 2021 and showed superiority of clopidogrel over aspirin in prevention of the composite of MACE and major bleeding during 24 months of followup. And then, through the current paper, this describes the results of the post trial extended followup of about five years. Dr. Greg Hundley: Very nice, Peder, so aspirin versus clopidogrel and looking at the maintenance of that monotherapy and cardiovascular outcomes. Wow, so what did they find? Dr. Peder Myhre: Yeah, Greg. They, in this extended followup study, had a total of 5.8 years median followup, and the primary endpoint occurred in 12.8% in the clopidogrel group versus 16.9% in the aspirin group, and that has a range of 0.74 with a 95% conference interval ranging from 0.63 to 0.86. So also the clopidogrel group had lower risk of the secondary thrombotic endpoint and the secondary bleeding endpoint while there was no significant difference in the incident on all caused death. So Greg, to conclude, these very interesting results from the primary analysis of the HOST-EXAM trial was consistent through the longer followup, and this support the use of clopidogrel over aspirin monotherapy from 12 months onwards after PCI. Dr. Greg Hundley: Very nice Peder, beautiful description and sounds like long-term clopidogrel use over aspirin was quite beneficial. Well, the next study comes to us from the world of preclinical science, and it is from the investigative group led by Dr. Yunzeng Zou from Shanghai Institute of Cardiovascular Diseases and the Zhongshan Hospital and Fudan University. Peder, the study pertains to diabetes. So diabetic heart dysfunction is a common complication of diabetes mellitus and cell death is a core event that leads to diabetic heart dysfunction. However, the time sequence of cell death pathways and the precise intervening time of particular cell death type remained largely unknown in diabetic hearts. And so, Peder, this study aimed to identify the particular cell death type that is responsible for diabetic heart dysfunction and propose a promising therapeutic strategy by intervening in this cell death pathway. Dr. Peder Myhre: Wow, Greg, that is really interesting. Heart dysfunction in diabetes is something that we really have to learn more about and I'm so excited to hear what these authors found, Greg. Dr. Greg Hundley: Right. So first, Peder, the authors identified necroptosis as the predominant cell death type at later stages in the diabetic heart. And then second, Peder, the CB2 receptor, and we'll call that CB2-R, recruits transcription factor Bach2 to repress necroptosis and protects against diabetic heart injury while hyperglycemia and MLKL in turn phosphorylates CB2-R to promote ubiquitous dependent degradation of CB2-R, thus forming a CB2-R centric feedback loop of necroptosis. And finally, Peder, cardiac CB2-R or Bach2 expression negatively correlates with both MLKL 10 expression and the extent of diabetic heart injuries in humans. And so the clinical implications of these findings, Peder, are that the CB2-R centric necrotic loop represents a promising target for the clinical treatment of diabetic heart injuries. Dr. Peder Myhre: So Greg, this paper that comes to us from corresponding author Amanda Paluch from University of Massachusetts Amherst, is a meta-analysis of eight prospective studies with device measured steps including more than 20,000 adults who were followed for CVD events. And the mean age of participants in this study was 63 years and 52% were women. And the participants were followed for a median of 6.2 years and 1,523 cardiovascular events occurred. So first, Greg, there was a significant difference in the association of steps per day in cardiovascular disease between older, that is greater or equal to 60 years, and younger, that is less than 60 years adults. So for older adults that has the ratio for cardiovascular disease using Q1 as reference was 0.80 for Q2, 0.62 for Q3, and 0.51 for Q4. And for younger adults that has ratio for cardiovascular disease using Q1 as reference was 0.79 for Q2, 0.90 for Q3, and 0.95 for Q4. And in the paper, Greg, there are some beautiful, restricted cubic lines that really illustrate the association between daily steps and the risk of cardiovascular disease among older adults and in younger adults. So the authors conclude that for older adults taking more daily steps is associated with a progressively lower risk of cardiovascular disease. And monitoring and promoting steps per day is a simple metric for clinician patient communication and population health to reduce the risk of cardiovascular disease. Dr. Greg Hundley: Well, Peder, we've got some other very interesting articles in this issue and how about we dive into that mail bag and discuss a few of those. So I'll go first. The first is a Perspective piece by Professor Powell-Wiley entitled “Centering Patient Voices through Community Engagement in Cardiovascular Research.” A very important topic where can those in the community actually help us design meaningful outcomes for our research initiatives? And next Peder, there is a Research Letter from Professor Evans entitled “Increasing Mononuclear deployed Cardiomyocytes by Loss of E2F7/8, and does that fail to improve cardiac regeneration post myocardial infarction?” Dr. Peder Myhre: Thanks, Greg. We also have an ECG Challenge by Dr. Li entitled, “What Is The Truth Behind Abnormal ECG Changes?” And this is describing a very rare and interesting cause of ST segment elevation. I recommend everyone to read that case. We also have our own Nick Murphy who gives us the Highlights from the Circulation Family of Journals where he summarizes five papers from the Circulation subspecialty journals. First, the experience with a novel visually assisted ablation catheter is reported in circulation A and E. The impact of various exercise training approaches on skeletal muscle in heart failure with preserved the F is presented in circulation heart failure. Gaps in heart failure treatment over a decade are reported in circulation cardiovascular quality and outcomes, and the associations of machine learning approaches to plaque morphology from coronary CTA with ischemia are reported in circulation cardiovascular imaging. And finally, Greg, an observational study of left main PCI at sites with and without surgical backup is reported in circulation cardiovascular interventions. Let's go on to the feature paper today describing the cardiac troponin I interacting kinase and the impact on cardiomyocyte S phase activity. Dr. Greg Hundley: Great, let's go. Welcome listeners to this January 10th feature discussion. Very interesting today as we are going to delve into the world of preclinical science. And we have with us today Dr. Loren Field and Dr. Sean Reuter from University of Indiana in Indianapolis, Indiana. And our own associate editor, Dr. Thomas Eschenhagen from University Medical Center of Hamburg in Hamburg, Germany. Welcome gentlemen. Well, Loren, we're going to start with you. Can you describe for us some of the background information that went into the preparation of your study, and what was the hypothesis that you wanted to address? Dr. Loren Field: Sure. This study actually came about in a rather roundabout fashion. We were doing a study with Kai Wollert in Hanover, Germany, where we were looking at the impact of a CXCR4 antagonist, which is used to mobilize stem cells from the bone marrow. And we had sent our mice over to Kai's lab and we have a mouse model that allows us to track S phase activity in cardiac myocytes, so these are cells are starting to replicate. And Kai crossed them into a different genetic background. And when he sent the mice back to us to analyze the hearts, we observed that we saw things that we never saw before in our experiments here. His injury model was different than ours and now the mouse also had a genetic background, so we had to spend about a year to figure out if it was the injury model or the background. It turned out to be the genetic background, and the phenotype was these mice had about a 15-fold elevated level of cell cycle reentry. So then it became a relatively simple genetics game where we took the progenitor mice, made F1 animals, looked for the phenotype, did backcross animals, and basically identified the gene responsible for the phenotype. Dr. Greg Hundley: Very nice. And so in this study moving forward, what hypothesis did you want to address? Dr. Loren Field: Well, the main hypothesis was to figure out what the gene was and then secondarily to figure out the degree of cell cycle progression. When the cell is proliferating, the first task is to replicate its genome, which is S phase activity that's followed by the nuclei dividing and then finally by the cell itself becoming two cells. So our task was to identify, first, the gene and secondly, how far through the cell cycles the cells progressed. Dr. Greg Hundley: Very nice. And how did you construct your experiment? Dr. Loren Field: It was, again, very straightforward. It was simply setting up the appropriate genetic crosses to produce the animals. For the past 10, 15 years, we've been developing a computer assisted assay that allows us to identify the anatomical position of S phase positive cardiac myocytes in sections of the heart. And basically, we apply that program to the different genetic backgrounds and after that it's a ball of mapping studies, QTL mapping. Dr. Greg Hundley: So really mechanistic understanding. Well listeners, we're next going to turn to Sean, and Sean, can you describe for us your study results? Dr. Sean Reuter: Yes, as Loren stated, we saw a 15-fold increase in the S phase activity within the remote zone. Now we partition the heart in three different zones after injury, so the scar, the border zone, and then the remote zone or injury. And as Loren stated, we saw a 15-fold increase in the S phase activity, cell cycle activity, in the remote zone. And it's only because we have this system in hand that we can anatomically map the S phase activity within the heart that we were able to detect and also quantify this. And I think that's the reason we discovered this particular phenotype. But in addition to that, we performed RNA-seq or Exome sequencing and discovered that TNNI3K was the responsible gene for elevated S phase activity within the remote zone and border zone, but interestingly not in the scar. Dr. Greg Hundley: Very interesting, Sean, and so describe for us the importance of the TNNI3K and its relationship to this S phase. Dr. Sean Reuter: Sure. This particular gene was first discovered around 2000, and it's been studied for a while now, but the targets of this kinase specifically expressed in the heart, and it does get elevated after injury, but the actual targets are not well described or well known. It's believed that it phosphorylates some mild filament fibers and structural proteins, but the actual mechanism and the consequence of this is not known. So when we saw this in the remote zone, the elevated S phase, our current theory is that we believe that it's probably increasing oxidative stress that would basically further out from the at-risk zone or the border zone and then it now is in the remote zone. So we think it's just causing the heart, a pathological area of the heart, basically to expand. And so that's our current theory. Other groups have published on the oxidative stress in over expression of TNNI3K as well. Dr. Greg Hundley: Very nice. Well listeners, next we are going to turn to our associate editor, Thomas many articles come your way and come across your desk. What attracted you to this particular article, and how do we put its results really in the context of cardiac regeneration? Dr. Thomas Eschenhagen: Indeed, there were several arguments. It's a cool paper and the whole field is still very important. As probably most of you know, the field have a rough ride over the last 20 years, went up and down, lots of bad findings. And in the end it turns out that we are there where we have been 20 years ago, the mammalian heart essentially doesn't regenerate. So anything which would improve that would be of very major importance. Why is it a good paper? Because it starts from a very clear finding, one mouse, which looks like strongly regenerating after MI, another mouse line, which doesn't. And so by applying, let's say, classical genetic, very stringent methodology, Loren Field and his group identified this troponin I kinase to be the culprit. And they also proved it, because putting it back in the strain with a low, so-called, regeneration brought it back to the other level. So it's a very clear, nice methodology. And finally, it's also a bit provocative because others in a very prominent paper, actually, have shown that this kinase... Or they concluded more or less just the opposite. The reason for the discrepancy is not quite clear and I was very happy to learn that the two groups actually discussed about it. So it's not just a bad controversy, but something which brings forward science. And finally, I think something we didn't talk about yet today, what I particularly liked, maybe the most, on this paper is that this group didn't stop at the point of DNA synthesis. Everybody else would've probably said, "Okay, here we are, one regenerate the other doesn't." But in the very important extra finding of this paper is that this is just increased DNA synthesis and not more myocytes. And this distinction is so critical to the field because people forget that adult mammalian cardiomyocytes often have several nuclei and individual nuclei have more than one set of chromosomes, so this polyploid. And so if you see DNA synthesis like in this paper, it doesn't necessarily mean more myocytes. And actually here it was shown that it is not more myocytes but more polyploidization and making this difference so clear, I think it's a very important contribution to the field. Dr. Greg Hundley: Very nice. Well, listeners, we're going to turn back to each of our guests today and we'll start with you Loren. Based on your results, what do you see as the next study moving forward in this sphere of research? Dr. Loren Field: I think these results made me appreciate for the first time that the intrinsic level of cell cycle reentry, that's just the S phase, not the cell division, is actually much higher than I had thought previously. And this was because we just fortuitously, or I guess anti-fortuitously, we're using a strain that had low levels of S phase induction. If you calculate the turnover, if every nucleus that it synthesized DNA actually went on to have that cell divide, you could replace a 50% loss of myocytes over the course of about 550 days, give or take. And to me, that's actually telling me that if we could push those cells from just being polypoid, as Thomas was saying, to actually go through cytokinesis, there would be enough intrinsic activity to go forward. So this really tells me that what we should be focusing on is now not trying to induce cell cycle, but to allow the cells that are entering the cell cycle to actually progress through it. Dr. Greg Hundley: Very nice. And Sean? Dr. Sean Reuter: Yes, well, echoing Loren's point there, it's really not necessarily cell cycle induction, it's cell cycle completion to the cytokinetic fate. And that's the key. If we can get to that point, if we can figure out the mechanism to get to that point, then we have a wonderful discovery. However, we're not quite there yet, but we hope to be. Dr. Greg Hundley: And Thomas. Dr. Thomas Eschenhagen: Well, nothing to add really from my side, except that I would like to know what this Troponin I kinase does, because that is somehow still a missing link. How does this kinase lead to more DNA synthesis or the initiation of cell cycling? That would be an important finding and I'm sure there will be more research going on. Particularly also, to solve this discrepancy, I mean, there must be something in it and we don't quite yet know how, but I think we are in a good way. I'm sure there will be papers showing that soon. So I think that's, again, a very good start for this discussion. Dr. Greg Hundley: Well, listeners, we want to thank Dr. Loren Field, Dr. Sean Reuter and Dr. Thomas Eschenhagen for bringing us this really informative study in mammalian myocellular regeneration, highlighting that the level of cardiomyocyte cell cycle reentry in hearts expressing TNNI3 kinase would lead to significant regenerative growth if each cardiomyocyte exhibiting S phase activity was able to progress through cytokinesis. And this in turn suggests that identification of factors which facilitate cardiomyocyte cell cycle progression beyond S phase will be key to unlocking the intrinsic regenerative capacity of the heart. Well, on behalf of Carolyn, Peder and myself, we want to wish you a great week and we will catch you next week on the run. This program is copyright of the American Heart Association 2023. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.
Download the cheat: https://bit.ly/50-meds View the lesson: Generic Name rifampin Trade Name Rimactane Indication tuberculosis Action inhibits RNA synthesis Therapeutic Class Antitubercular Pharmacologic Class rifamycins Nursing Considerations • can turn body fluids red • may cause diarrhea, nausea, vomiting, confusion • assess lung sounds and sputum characteristics • evaluate renal and liver function tests • instruct patient not to skip or double dose • must complete entire dose (6-12 month therapy)
Synopsis: Geoff Nosrati is the Chief Business Officer of Nutcracker Therapeutics, an early-stage company that is pioneering a revolutionary therapeutic development and manufacturing platform designed to enable the advancement of RNA-based treatments for as many diseases as possible. Early in his career, Geoff joined McKinsey & Co. as a consultant, working with biotech and pharma companies. He then worked with several small oncology-focused biotech companies, including Aduro Biotech and ImmunoScape before joining Nutcracker. In this episode he provides his perspective on the RNA space as it stands right now and the diversity of applications that exist, some of the opportunities and challenges of working on an RNA therapeutic, how he thinks about indication selection, Nutcracker's complete RNA platform and the work they're doing to develop therapeutics, and where the company is now from a building and R&D perspective. Biography: As Chief Business Officer, Geoff oversees Nutcracker's business development and corporate strategy functions. Prior to Nutcracker, Geoff served as Chief Business Officer at ImmunoScape and as SVP of Strategy and Corporate Development at Aduro Biotech. Earlier in his career, Geoff was a consultant with McKinsey & Co., where he primarily served clients across the pharmaceutical and biotechnology industries. Geoff was awarded a B.S. in Chemistry from Duke University and received his Ph.D. in Biochemistry and Molecular Biology from the University of California, Los Angeles.
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.01.06.522870v1?rss=1 Authors: Riggins, T. E., Whitsitt, Q. A., Saxena, A., Hunter, E., Hunt, B., Thompson, C. H., Moore, M. G., Purcell, E. K. Abstract: Implanted microelectrode arrays hold immense therapeutic potential for many neurodegenerative diseases. However, a foreign body response limits long-term device performance. Recent literature supports the role of astrocytes in the response to damage to the central nervous system (CNS) and suggests that reactive astrocytes exist on a spectrum of phenotypes, from beneficial to neurotoxic. The goal of our study was to gain insight into the subtypes of reactive astrocytes responding to electrodes implanted in the brain. In this study, we tested the transcriptomic profile of two reactive astrocyte culture models (cytokine cocktail or lipopolysaccharide, LPS) utilizing RNA sequencing, which we then compared to differential gene expression surrounding devices inserted into rat motor cortex via spatial transcriptomics. We interpreted changes in the genetic expression of the culture models to that of 24 hour, 1 week and 6 week rat tissue samples at multiple distances radiating from the injury site. We found overlapping expression of up to ~250 genes between in vitro models and in vivo effects, depending on duration of implantation. Cytokine-induced cells shared more genes in common with chronically implanted tissue ( greater than or equal to 1 week) in comparison to LPS-exposed cells. We revealed localized expression of a subset of these intersecting genes (e.g., Serping1, Chi3l1, and Cyp7b1) in regions of device-encapsulating, glial fibrillary acidic protein (GFAP)-expressing astrocytes identified with immunohistochemistry. We applied a factorization approach to assess the strength of the relationship between reactivity markers and the spatial distribution of GFAP-expressing astrocytes in vivo. We also provide lists of hundreds of differentially expressed genes between reactive culture models and untreated controls, and we observed 311 shared genes between the cytokine induced model and the LPS-reaction induced control model. Our results show that comparisons of reactive astrocyte culture models with spatial transcriptomics data can reveal new biomarkers of the foreign body response to implantable neurotechnology. These comparisons also provide a strategy to assess the development of in vitro models of the tissue response to implanted electrodes. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC
Canary Cry News Talk #578 - 01.06.2023 - Recorded Live to Tape A EYE | Psychonauts, Nano Goons, TikTok College, P. Antarctica A Podcast that Deconstructs Mainstream Media News from a Biblical Worldview Harvard: Index of MSM Ownership (Harvard.edu) Logos Bible: Aliens Demons Doc (feat. Dr. Heiser, Unseen Realm) A Podcast that Deconstructs Mainstream Media News from a Biblical Worldview Harvard: Index of MSM Ownership (Harvard.edu) Logos Bible: Aliens Demons Doc (feat. Dr. Mike Heiser, Unseen Realm) This Episode was Produced By: Executive Producers Dame Sarah of the Shadows** Sir Martin K Night Of The Wrong Timeline** Producers Marty K, Lady Knight Little Wing, Tami C, Sir Morv Knight of the Burning Chariots, Dame Gail Canary Whisperer and Lady of X's and O's, Runksmash, Sir Darrin Knight of the Hungry Panda's, Veronica D, Sir Scott Knight of Truth, Sir LX Protocol V2 Knight of the Berrean Protocol Audio Production JonathanF LittleOwen Visual Art Sir Dove Knight of Rusbeltia Microfiction Runksmash - With a mighty pull the two old men rend the villain in two, the shower of sparks from the ancient lizard robot blinds the crowd for a moment. When they finally recover there is no longer anyone on the hill. Stephen S - Chief meets with celebrity handler Sosumi Gonzales in a small cat cafe in Chicagoland. “Great work on last your assignment. Now we need a female pop star, but more. More Christian, More Nationalistic.” Gonzales wonders, “How can I top loving Hitler?” CLIP PRODUCER Emsworth, FaeLivrin TIMESTAPERS Jade Bouncerson, Christine C SOCIAL MEDIA DOERS Dame MissG of the OV and Deep Rivers LINKS HELP JAM REMINDERS Clankoniphius SHOW NOTES Podcast = T - 2:41 from D-Live HELLO, RUN DOWN 4:48 V / 2:07 P AI 7:23 V / 4:42 P ChatGPT Creator OpenAI Discussing Offer Valuing Company At $29 Billion (Forbes) → OpenAI would be top 6 unicorns → List of AI tools to get things done ‘Robot lawyer' powered by AI will help fight speeding ticket as it takes first case in court (NY Post) → AI legal assistant will help defendant fight a speeding case in court (New Scientist) → China has had this for a while (SCMP, July 2022) DAY JINGLE/PERSONAL/EXEC. 22:08 V / 19:27 P FLIPPY 31:28 V / 28:47 P ‘Consciousness' in Robots Was Once Taboo. Now It's the Last Word (NY Times) → The study in Science Robotics → Canary Cry Radio Personhood episode 2012 NEW WORLD ORDER/MIND CONTROL 45:06 V / 42:25 P Banning TikTok Hurts Higher Education (Wired) → Danger of TikTok: Study Shows Social Media Use Changes Brains of Teens (Breitbart) PHARMAKEIA 59:00 V / 56:16 P Psychonauts Training to Explore Another Dimension (New Republic) PARTY TIME: http://CANARYCRY.PARTY 1:20:59 V / 1:18:18 P BREAK 1: TREASURE: https://CanaryCryRadio.com/Support 1:21:47 V / 1:19:06 P COVID/WACCINE 1:33:34 disclaimer, 1:34:05 V / 1:31:21 P Spike Protein Detected in Post–COVID-19 mRNA Vaccine Myocarditis (American Heart Ass.) → Reuters report 2021 cytotoxicity → Politifact 2022 spike protein Fact Check → Salk Edu study WACCINE 1:50:12 V / 1:47:28 P (Featuring Basil's “Vaccinate the Bees” Jingle) US government approves use of world's first vaccine for honeybees (Guardian) CRISPR/DAYS OF NOAH 1:57:35 V / 1:54:51 P 2.6 billion-year-old ancestors of the CRISPR gene-editing tool are resurrected (Phys.org) → RNA targeting unleashes indiscriminate nuclease activity of CRISPR–Cas12a2 (Nature) BREAK 3: TALENT 2:08:24 V / 2:05:40 P ANTARCTICA/RABBIT HOLE 2:21:11 V / 2:18:27 P Efforts to save the planet must start with the Antarctic (WEF, 2019) BREAK 4: TIME 2:32:06 V / 2:29:22 P END
Die Themen in den Wissensnachrichten: +++ Archäologie-Team interpretiert Linien und Pünktchen in Höhlenmalereien als eine Art Jäger-Kalender +++ Neue Variante der CRISPR-Cas-Genschere könnte gegen Krebszellen helfen +++ Kartoffelförmige Steine flitschen höher +++ **********Weiterführende Quellen zu dieser Folge:An Upper Palaeolithic Proto-writing System and Phenological Calendar, Cambridge Archaeological Journal, 05.01.2023Cas12a2 elicits abortive infection via RNA-triggered destruction of dsDNA. Nature, 04.1.2023The role of body shape and mass in skimming on water, Proceedings of the Royal Society A, 04.01.2023Decoupling the skull and skeleton in a Cretaceous bird with unique appendicular morphologies, Nature Eology and Evolution, 02.01.2023I Love It, I'll Never Use It: Exploring Factors of Product Attachment and Their Effects on Sustainable Product Usage Behaviors, International Journal of Design, Dezember 2022**********Ihr könnt uns auch auf diesen Kanälen folgen: Tiktok und Instagram.**********Weitere Wissensnachrichten zum Nachlesen: https://www.deutschlandfunknova.de/nachrichten
Everyone knows that we are not all the same, there is wonderful diversity in our bodies, our genetics, our lifestyles, and our preferences. And yet, when it comes to nutrition, the most successful public health messages are the broad guidelines, which suggests one size can fit all. Think five-a-day, taking Vitamin D through the autumn and winter, and so on. At the same time, the science behind nutrition, the understanding of our metabolism and of our gut microbiome, has been increasing at a fantastic rate. The question is: how do you bring these two worlds together? How do you bring the best of intricate nutritional science to a broader population? Could the answer lay in precision nutrition? It is an emerging and exciting field which helps tailor dietary recommendations and nutritional guidelines, and there is some evidence it can have remarkable health impacts. It is an area which seems to offer huge potential, but exactly how much is yet to be discovered. Karen Vousden, Principal Group Leader, Francis Crick Institute Karen received her PhD from the University of London and following postdoctoral fellowships at the ICR and NCI, she returned to London to establish a research group at the Ludwig Institute. Returning to the US, she was Chief of the Regulation of Cell Growth Laboratory at the NCI before coming back to the UK to take on the role of Director of the CRUK Beatson Institute in Glasgow. In 2017, she moved her research group to the Francis Crick Institute in London and served as Chief Scientist for Cancer Research UK from 2016-2022. Karen's research has made contributions to our understanding of how the tumour suppressor protein p53 is regulated and the functions of p53 that contribute to its ability to control cancer progression. During these studies, her group revealed an unexpected ability of p53 to help cells adapt and survive under transient periods of nutrient starvation. This work led to a more general investigation of cancer cell metabolism, focused on exploring the role of oxidative stress and serine metabolism in cancer development and metastatic progression. Greg Hannon, Director of Cancer Research UK Cambridge Institute Greg Hannon FRS FMedSci is a professor of molecular cancer biology and director of the Cancer Research UK Cambridge Research Institute at the University of Cambridge. Professor Hannon is internationally recognised for his contributions to small RNA biology, cancer biology, and mammalian genomics. He has a long history in the discovery of cancer genes, beginning with work at CSHL that led to the identification of CDK inhibitors and their links to cancer. More recently, his work has focused on small RNA biology, which led to an understanding of the biochemical mechanisms and biological functions of RNAi. Building upon this foundation, he has developed widely-used tools and strategies for manipulation of gene expression in mammalian cells and animals and has generated genome-wide shRNA libraries that are available to the cancer community. He was among the first to uncover roles for microRNAs in cancer, including the discovery of the miR-17-92 cluster as an oncogene, the placement of miR-34 within the p53 pathways, and the understanding that let-7 and miR-93 are critical regulators of both normal stem cells and tumour initiating cells in several tissues. His laboratory also discovered the piRNA pathway and linked this to transposon repression and the protection of germ cell genomes.
In the first epitope of 2023, TWiV reviews our coverage of virology in 2022, including favorite story arcs, episodes, show titles, and much more. Hosts: Vincent Racaniello, Dickson Despommier, Rich Condit, Kathy Spindler, and Brianne Barker Subscribe (free): Apple Podcasts, Google Podcasts, RSS, email Become a patron of TWiV! Links for this episode Our favorite 2022 virology stories: •Vincent: Paul Offit on bivalent boosters (TWiV 917, 942, Special) •Dickson: Interviews with Paul Offit and Andy Slavitt •Rich: TWiV 948: Breathless with David Quammen •Kathy: TWiV 915: Mouse mouth to mouse mom •Brianne: Spillovers (TWiV 923 and 876) •Vincent: Giant viruses (TWiV 873, 906, 968) •Dickson: TWiV 960 – Getting Funky with Dan Wilson •Rich: TWiV 927: Merchlinsky vs monkeypox •Kathy: TWiV 958: Pass the RNA and have some venison pi •Brianne: TWiV 869: Epstein-Barr virus and MS, a perfect storm •Twiverse •Letters read on TWiV 968 •Timestamps by Jolene. Thanks! Weekly Picks Dickson – Jazz Project: Tenor saxophone: John Coltrane/Dexter Gordon/Stan Getz: John Coltrane: Signature album: Giant Steps: Signature song: Blue Train; Dexter Gordon: Signature album: The Other Side Of Round Midnight. Signature song: Round Midnight; Stan Getz (with Charlie Byrd on guitar): Signature Album: Jazz Samba; Signature song: Desafinado Brianne – A Full Circle Rainbow over Norway Kathy – Frozen soap bubbles Rich – It's Turtles All the Way Down in the Fossil Record by Asher Elbein Vincent – Vincent's Top Ten Music Listener Picks Charles – Wayne Bergeron and Vince DiMartino MacArthur Park Intro music is by Ronald Jenkees Send your virology questions and comments to email@example.com
Listen to a blog summary of an editorial perspective published in Volume 13, entitled, "The future of bioorthogonal-chemistry for targeting of exosomes in precision medicine." ____________________________________________________________ Extracellular vesicles are membrane-bound vehicles released by cells into the extracellular environment. There are three known types of extracellular vesicles: microvesicles, apoptotic bodies and exosomes. Discovered in 1983, exosomes can be defined as packets of bio-nanoparticles released by cells containing bioactive molecules such as proteins, lipids and nucleic acids. Exosomes can deliver their payload to other cells and are now also recognized for their role in cell-to-cell communication. This makes exosomes attractive targets for precision medicine tactics. However, targeting exosomes is challenging due to their nano-size and reactive contents. Bioorthogonal-chemistry may provide a new approach for targeting exosomes in precision medicine. “Bioorthogonal is the name of a chemical reaction that can occur inside of living cells without interfering the naïve biological process [1, 2].” Bioorthogonal-chemistry allows for the attachment of bioactive molecules to the surface of exosomes without disturbing the native environment. Developed in the early 2000s, this strategy could potentially be used to deliver therapeutic drugs or bioactive molecules directly to the target site with high precision. Bioorthogonal-chemistry is still at an early stage of development, but it holds promise in precision medicine for the treatment of cancer and other illnesses. By providing a way to target exosomes with bioactive molecules, bioorthogonal-chemistry could help to significantly improve the efficacy of medical treatments. It could also reduce the side effects of current treatments and increase safety for patients. “The concept of bioorthogonal chemistry has inspired a generation of biologists to think about RNA editing and bioengineering of exosomes [3, 4].” Full blog - https://www.oncotarget.org/2022/12/20/a-new-method-of-targeting-exosomes-in-precision-medicine/ DOI - https://doi.org/10.18632/oncotarget.28323 Correspondence to - Mujib Ullah - firstname.lastname@example.org About Oncotarget Oncotarget is a primarily oncology-focused, peer-reviewed, open access journal. Papers are published continuously within yearly volumes in their final and complete form, and then quickly released to Pubmed. On September 15, 2022, Oncotarget was accepted again for indexing by MEDLINE. Oncotarget is now indexed by Medline/PubMed and PMC/PubMed. To learn more about Oncotarget, please visit https://www.oncotarget.com and connect with us: SoundCloud - https://soundcloud.com/oncotarget Facebook - https://www.facebook.com/Oncotarget/ Twitter - https://twitter.com/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/OncotargetYouTube LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ For media inquiries, please contact: email@example.com
Videos : The Covid Redemption with Tim Robbins – #048 – Stay Free with Russell Brand MP calls for complete suspension of mRNA jab in extraordinary British Parliamentary speech Turmeric studied for its ability to seek out and destroy cancer stem cells, the source of all tumors Montclair State University, December 13, 202 Turmeric has gained immense popularity over the years not just for the unique flavor it adds to dishes like curries, but also for its various health benefits. One of its most promising therapeutic applications is as a natural remedy for cancer. Although the anticancer potential of turmeric isn't new, a recent study published in Cancer Letters further proved the importance of this golden spice in understanding and treating cancer. The team of American researchers evaluated the ability of curcumin, which is a polyphenol in turmeric, to target cancer stem cells that are assumed to be the primary cause of cancer tumor formation and malignancy. Unlike conventional cancer models used in previous studies, the cancer stem cell model suggests that only a small population of cancer cells drive the initiation, maintenance, and growth of tumors. These stem cells regularly undergo renewal and differentiation into other cancer cells, which no longer have the ability to regenerate themselves. Therefore, in this model, cancer stem cells that are not killed by treatments lead to the formation of more invasive and treatment-resistant tumors. In this study, the researchers found that curcumin is more effective in eradicating cancer since unlike conventional treatments, this polyphenol also targets cancer stem cells. It can do so through various mechanisms of action, which include the following. Regulation of cancer stem cell self-renewal pathway — There are different pathways involved in the self-renewal of cancer stem cells. These include the Wnt/beta-catenin, sonic hedgehog 89 (SHH), and Notch pathways. The researchers found that curcumin can directly or indirectly interfere with these pathways in 12 different cancer cell lines Modulation of microRNA — The body contains microRNAs, which are short RNA sequences that don't encode for anything. These microRNAs regulate more than 33 percent of protein-coding genes by targeting and binding to their corresponding messenger RNAs so that these won't be expressed. In this study, the authors observed that curcumin altered microRNA expression in cancer stem cells so that they can't produce everything that they need for tumor formation and growth. Direct anti-cancer activity — Curcumin selectively targets cancer cells and programs their death. When used in conjunction with conventional anticancer agents, this effect becomes more evident and the damage typically caused by chemotherapy is no longer observed. Overall, the results of this study show that for cancer treatments to be effective, they have to target and kill cancer stem cells just like turmeric does. Otherwise, these cancer stem cells will pave the way for the formation of more invasive and treatment-resistant tumors. (NEXT) Chiropractic spinal manipulation associated with reduction in low back surgery University Hospitals Cleveland Medical Center, December 19, 2022 A recent study from University Hospitals (UH) Connor Whole Health has found that adults who initially visit a chiropractor to receive spinal manipulation for low back pain caused by disc herniation or radiculopathy (i.e., sciatica) are less likely to undergo discectomy (i.e., disc surgery) over the subsequent two years. This study was recently published in the journal BMJ Open. In this retrospective cohort study, the authors selected adult patients, age 18 to 49, from a 101 million patient United States health records network (TriNetX, Cambridge, MA, U.S.). Patients with serious pathology or urgent indications for surgery were excluded from the study. Ultimately, the authors identified 5,785 patients who initially received chiropractic spinal manipulative therapy, and the same number of patients who received other forms of medical care for their low back pain. The authors used a statistical technique called propensity score matching to control for variables that could influence the likelihood that patients would undergo discectomy. In this process, they matched patients in both cohorts according to several such as age, sex, obesity, smoking, previous injections, and medications. The authors found that patients who initially received chiropractic spinal manipulation for their low back pain were significantly less likely to undergo lumbar discectomy through two years' follow-up. At one year follow-up, 1.5% of the patients in the chiropractic cohort had undergone discectomy, compared to 2.2% of patients in the cohort receiving other care At two years' follow-up, 1.9% of the patients in the chiropractic cohort had undergone discectomy, compared to 2.4% of patients in the cohort receiving other care This study represents the first study to examine whether chiropractic care is associated with a reduction in likelihood of discectomy. (NEXT) High-intensity exercise delays Parkinson's progression Northwestern Medicine and University of Denver, December 11, 2022 High-intensity exercise three times a week is safe for individuals with early-stage Parkinson's disease and decreases worsening of motor symptoms, according to a new phase 2, multi-site trial led by Northwestern Medicine and University of Denver scientists. This is the first time scientists have tested the effects of high-intensity exercise on patients with Parkinson's disease, the second most common neurodegenerative disorder and the most common movement disorder, affecting more than a million people in the United States. It previously had been thought high-intensity exercise was too physically stressful for individuals with Parkinson's disease. “If you have Parkinson's disease and you want to delay the progression of your symptoms, you should exercise three times a week with your heart rate between 80 to 85 percent maximum. Because medications for Parkinson's have adverse side effects and reduced effectiveness over time, new treatments are needed. The randomized clinical trial included 128 participants ages 40 to 80 years old from Northwestern University, Rush University Medical Center, the University of Colorado and the University of Pittsburgh. Participants enrolled in the Study in Parkinson Disease of Exercise (SPARX) were at an early stage of the disease and not taking Parkinson's medication, ensuring the results of the study were related to the exercise and not affected by medication. “The earlier in the disease you intervene, the more likely it is you can prevent the progression of the disease,” Corcos said. “We delayed worsening of symptoms for six months; whether we can prevent progression any longer than six months will require further study.” Scientists examined the safety and effects of exercise three times weekly for six months at high intensity, 80 to 85 percent of maximum heart rate, and moderate intensity, 60 to 65 percent of maximum heart rate. They compared the results to a control group who did not exercise. After six months, participants were rated by clinicians on a Parkinson's disease scale ranging from 0 to 108. The higher the number, the more severe the symptoms. Participants in the study had a score of about 20 before exercise. Those in the high intensity group stayed at 20. The group with moderate exercise got worse by 1.5 points. The group that did not exercise worsened by three points. Three points out of a score of 20 points is a 15 percent change in the primary signs of the disease and considered clinically important to patients. It makes a difference in their quality of life. (NEXT) Meditation adapts the brain to respond better to feedback University of Surrey UK, December 11, 2022 In a study in the Journal of Cognitive, Affective & Behavioral Neuroscience researchers from the University of Surrey have discovered a link between meditation and how individuals respond to feedback. Participants in the study, a mixture of experienced, novice and non-meditators, were trained to select images associated with a reward. Each pair of images had varying probabilities of a reward e.g. images that result in a reward 80 per cent of the time versus those that result in a reward 20 per cent of the time. Participants eventually learnt to select the pairing with the higher outcome. Researchers found that participants who meditated were more successful in selecting high-probability pairings indicating a tendency to learn from positive outcomes, compared to non – meditators who learned the pattern via low-probability pairings suggesting a tendency to learn from negative outcomes. During the study participants were connected to an EEG, a non-invasive method that records electrical patterns in the brain. Results from the EEG found that while all three groups responded similarly to positive feedback, the neurological response to negative feedback was highest in the non-meditation group, followed by the novice group and then by the experienced meditation group. These results indicate that the brains of meditators are less affected by negative feedback, and that this may be a result of altered dopamine levels caused by meditation. Paul Knytl, lead author and PhD candidate in psychology at the University of Surrey, said: “Humans have been meditating for over 2000 years, but the neural mechanisms of this practice are still relatively unknown. These findings demonstrate that, on a deep level, meditators respond to feedback in a more even-handed way than non-meditators, which may help to explain some of the psychological benefits they experience from the practice.” (NEXT) Caution to pregnant women on red meat diabetes link University of Adelaide (Australia) December 12, 2022 Pregnant women and women planning to become pregnant can make use of the holiday season to adjust their diets and reduce the risk of gestational diabetes, according to researchers at the University of Adelaide's Robinson Institute. The recommendation comes at a time when there is increasing evidence to suggest that red meat is linked with a higher rate of gestational diabetes in pregnant women, which poses risks to the health of both the mother and the baby. In a commentary published in the jjournal Evidence-Based Nursing, author Philippa Middleton says the latest international research shows that women who eat a lot of red and processed meats even before they become pregnant have a significant risk of developing gestational diabetes. “There have been several reports linking red meat with increased risk of type 2 diabetes, and now the work of a number of research teams worldwide is showing this link for diabetes during pregnancy,” says Ms Middleton, who is one of the Robinson Institute's research leaders. “While this news is alarming, there are also some positives. The latest research from the United States has shown that eating fish and poultry does not increase the risk of gestational diabetes, and consuming more vegetable and non-meat protein is associated with a reduction in risk. “For example, just over half a serving of nuts per day can reduce the risk of gestational diabetes by 40%.” “Based on current evidence, pregnant women or women planning to become pregnant should consider eating more vegetable protein, and nuts, and replacing some red meat with fish and poultry. (NEXT) Treatment for lupus may depend on restoring proteins in patients' blood Singapore General Hospital, December 19, 2022 Restoring protein balance in the blood may be key to developing an effective treatment for lupus. The incurable autoimmune disease reportedly affects about 100 in every 100,000 people worldwide, and disproportionally affects women between 15 and 45 years-old and Asians. Lupus causes the body's immune system to attack itself, which can inflame several vital organs like the kidneys, brain, heart, and lungs. The aggressive nature of the disease is what makes it life-threatening for many who have it, especially since current treatments don't help that much. “We are excited about the possibility of a new treatment option for lupus as 30 to 60 percent of patients do not respond to conventional medications despite aggressive regimens. In the past 65 years, only three drugs for lupus have been approved by the United States Food and Drug Administration but these drugs have modest efficacy. There is therefore a real and urgent need for better therapies, particularly for the more severe spectrum of lupus that we see in Asia,” says senior author Andrea Low, the Head and Senior Consultant in the Department of Rheumatology & Immunology at Singapore General Hospital (SGH), in a media release. To reach their findings, Low and her team studied CXCL5, a protein that helps to regulate the immune system through neutrophils, which are a type of white blood cell. They revealed that lupus patients had considerably lower levels of the protein in their blood compared to healthy people, thus suggesting that it may have a connection to the disease. They also discovered that mice with severe lupus injected weekly with CXCL5 displayed restored protein balance. Moreover, their survival outcomes increased from 25 percent to over 75 percent after 10 weeks. Not only did the injections reduce mortality risk, but they didn't cause any adverse side-effects, study authors report. “Our study has shown CXCL5 to be safe. There was no liver or kidney toxicity or cancer inducing effects. Major components of the immune system were also not compromised,” reports principal investigator Dr Fan Xiubo, Senior Research Fellow, Department of Clinical Translational Research, SGH. The entire team is hopeful that they can continue to build on their research to better the lives of patient's suffering from this debilitating disease. “To be in the forefront of medicine means we have to constantly further our understanding of diseases and offer patients better treatment options through rigorous scientific research. I'm heartened that the team has shed new light on lupus and the possibility of a more efficacious therapy for patients some years down the road,” says Professor Fong Kok Yong, Deputy Group CEO (Medical and Clinical Services), SingHealth, and Senior Consultant, Department Rheumatology & Immunology, SGH
This episode of Have You Herd? is sponsored by Allflex. Producers all over are going all in on Allflex monitoring solutions and they want to tell you why. Allflex empowers producers to get the most from their operations. Allflex monitoring solutions increase labor efficiency, improve herd health and boost reproduction rates. Ongoing training and support keeps things running smoothly from install and beyond. For more details, visit this website. AABP Executive Director Dr. Fred Gingrich is joined by Dr. Russ Daly, extension veterinarian from South Dakota State University. Today we discuss bovine virus diarrhea (BVD), an RNA envelope virus that can have devastating effects in beef and dairy herds. BVD can have many effects in cattle and Daly discusses the impacts of the virus on reproduction and immunosuppression. The primary focus of a control program should be in preventing persistently infected (PI) calves. Daly discusses that 2/10-4/10% of animals that arrive in the feedlot are PI animals, but the incidence can vary between and within cow calf herds. Data from the SDSU laboratory shows that of submissions, about 1.5 to 3% of calf samples are PI for BVD. When determining which diagnostic test to run, Daly states that we want to detect viral antigen and this is typically done using antigen capture ELISA testing. He discusses pooling ear notch samples to decrease cost but recommends veterinarians contact their laboratory diagnostician for advice on submitting samples. It is also important to not forget purchased heifers, cows and bulls. When testing purchases, it is critical to not forget the gestating fetus to screen for PI and therefore all fetuses born to purchased animals should be tested at birth. Ensuring that PI animals do not enter the breeding pasture is important to mitigate the risk of PI animals being born into the herd. Veterinarians should work with producers to make sure they have a good BVD control program implemented. Outbreaks tend to be much more costly and devastating than preventing the introduction of BVD into the herd. A sound reproduction protocol, biosecurity measures, vaccination and strategic diagnostic testing are ways that veterinarians can implement control programs to prevent BVD in herds.
Breaking news! Measles outbreak in Ohio has prompted us to talk a little bit about this.Measles is highly contagious and requires 95% of eligible human beings in the community to be vaccinated. 25% in this Ohio community are unvaccinated. It is an RNA virus, the only host is human.Clinically, viral syndrome like fever, malaise, cough, runny nose, conjunctivitis, so called "koplik" spots which we try to describe. The scary stuff, is encephalitis (we explain), pneumonia, and other brain complications, and death.The freshly coughed pocket of air is not the only way it is transmitted! And you can infect others before you have symptoms!Folks with measles have weakened immune systems!Mina MJ, Kula T, Leng Y, et al. Measles virus infection diminishes preexisting antibodies that offer protection from other pathogens. Science 2019 November 01; 366(6465):599-606Petrova VN, Sawatsky B, Han AX, et al. Incomplete genetic reconstitution of B cell pools contributes to prolonged immunosuppression after measles. Science Immunology 2019 November 01; 4:1-14Vaccine is incredibly effective! No known transmission among vaccinated folks. Send us your questions and comments at firstname.lastname@example.orgThanks to Jeff Jeudy for providing the music!Part 2 is about Voldemort!