Podcasts about ccl4

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.07.29.551032v1?rss=1 Authors: Sun, C., Zhou, C., Daneshvar, K., Kratkiewicz, A. J., Ben Saad, A., Hess, A., Chen, J. Y., Pondick, J. V., York, S. R., Li, W., Moran, S. P., Gentile, S., Ur Rahman, R., Li, Z., Sparks, R., Habboub, T., Kim, B.-M., Choi, M., Affo, S., Schwabe, R. F., Popov, Y. V., Mullen, A. C. Abstract: Background & Aims: Fibrosis is the common endpoint for all forms of chronic liver injury, and progression of fibrosis leads to the development of end-stage liver disease. Activation of hepatic stellate cells (HSCs) and their transdifferentiation to myofibroblasts results in the accumulation of the extracellular matrix (ECM) proteins that form the fibrotic scar. Long noncoding (lnc) RNAs regulate the activity of HSCs and may provide targets for fibrotic therapies. Methods: We identified lncRNA TILAM as expressed near COL1A1 in human HSCs and performed loss-of-function studies in human HSCs and liver organoids. Transcriptomic analysis of HSCs isolated from mice defined the murine ortholog of TILAM. We then generated Tilam-deficient GFP reporter mice and quantified fibrotic responses to carbon tetrachloride (CCl4) and choline-deficient L-amino acid defined high fat diet (CDA-HFD). Co-precipitation studies, mass spectrometry, and gene expression analyses identified protein partners of TILAM. Results: TILAM is conserved between human and mouse HSCs and regulates expression of ECM proteins, including collagen. Tilam is selectively induced in murine HSCs during the development of fibrosis in vivo. In both male and female mice, loss of Tilam results in reduced fibrosis in the setting of CCl4 and CDA-HFD injury models. TILAM interacts with promyelocytic leukemia protein (PML) to stabilize PML protein levels and promote the fibrotic activity of HSCs. Conclusion: TILAM is activated in HSCs and interacts with PML to drive the development of liver fibrosis. Depletion of TILAM may serve as a therapeutic approach to combat the development of end stage liver disease. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

This week, please join authors Mikhail Kosiborod and Christian Schulze and Editorialist Stefan Anker as they discuss the original articles "Effects of Empagliflozin on Symptoms, Physical Limitations and Quality of Life in Patients Hospitalized for Acute Heart Failure: Results From the EMPULSE Trial" and "Effects of Early Empagliflozin Initiation on Diuresis and Kidney Function in Patients With Acute Decompensated Heart Failure (EMPAG-HF)" and the editorial "SGLT2 Inhibitors: From Antihyperglycemic Agents to All-Around Heart Failure Therapy." 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-hosts. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore. Dr. Greg Hundley:           And I'm Dr. Greg Hundley, associate editor, director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Dr. Carolyn Lam:             I'm so excited about the feature discussion this week. It is a paired feature along with their editorial and it's all focused on SGLT2 inhibitors. The first, results from the EMPULSE trial, Effects of Empagliflozin on Symptoms, Physical Limitations and Quality of Life in Patients Hospitalized for Acute Heart Failure; and the second, the EMPAG-heart failure trial, The Effects of Early Empagliflozin Initiation on Diuresis and Kidney Function in Patients with Acute Heart Failure. Incredibly important topics, incredibly important discussion. Wait up for it. We're just going to tell you a little bit more about two other original papers in today's issue, and I'm going to go first, Greg. Is that okay? Dr. Greg Hundley:           You bet. Dr. Carolyn Lam:             Now, really interesting topic here. We have strong evidence supporting the effective blood pressure and cardiovascular disease risk lowering properties of healthy diet such as the DASH diet, Mediterranean diet, and so on and so on. But what about the diet consumed by a fifth of the entire world's population? The Chinese cuisine. Interestingly, today's paper addresses just that. This is from authors, Dr. Wu, from Peking University Clinical Research Institute and colleagues who performed a multicenter patient and outcome assessor blind randomized feeding trial among 265 participants with baseline systolic blood pressure of 130 to 159 in four major Chinese cuisines. And these are the Shandong, Huaiyang, Cantonese, and Szechuan cuisines, and here's how they did it. After a seven day run in period on a control diet matching the usual local diets, participants were randomized to continue with the control diet or the cuisine based Chinese heart healthy diet for another 28 days. The primary outcome was systolic blood pressure. The study developed the first heart healthy Chinese diet that fits Chinese food culture and emphasizes its palatability by involving master shifts in developing the recipes. Dr. Greg Hundley:           Oh wow. Carolyn, this is really interesting, especially one fifth of the world's population in studying a heart healthy diet. So did it work? I can't wait to hear the results. Dr. Carolyn Lam:             Well, the change in systolic and diastolic blood pressure from baseline to the end of the study in the control group was five millimeters mercury and 2.8 millimeters mercury reduction, respectively. The net difference of change between the two groups in systolic and diastolic blood pressure were a reduction of 10 and almost four millimeters mercury, respectively. The effect size did not differ among cuisines, and so in summary, with a patient and assessor blind randomized feeding trial, this study really demonstrated that the blood pressure lowering effect of the Chinese heart health diet could indeed be substantial, and importantly, be compatible with medications while palatable and affordable in Chinese adults with high blood pressure, and so these results support the idea that food is medicine and will give many patients with high blood pressure the confidence to adopt heart healthy diets in their lifestyle treatment. Dr. Greg Hundley:           Wow, Carolyn, that is really an interesting article. So many of these articles today could all be features in and of themselves. That was just outstanding. Well, my next paper comes to us from the world of preclinical science, and it's from Dr. Sean Wu from Stanford University School of Medicine. So Carolyn, immune checkpoint inhibitors are monoclonal antibodies that are used to activate the immune system against tumor cells. Now, despite their therapeutic benefits, immune checkpoint inhibitors have the potential to cause immune mediated adverse events such as myocarditis, a rare but serious side effect with up to 50% mortality in affected patients. Now histologically, patients with immune checkpoint inhibitor of myocarditis have lymphocytic infiltrates in the heart implicating T-cell mediated mechanisms. However, the precise pathologic immune subsets and molecular changes in immune checkpoint inhibitor myocarditis are unknown. Dr. Carolyn Lam:             Wow. So insights into the etiology of these immune checkpoint associated myocarditis cases must be very important. So what did they find? Dr. Greg Hundley:           Right, Carolyn? So clonal cytotoxic, TEMRA CD8+ cells were found to be significantly increased in the blood of patients with immune checkpoint inhibitor myocarditis corresponding with an analogous increase in effector cytotoxic CD8+ cells in the blood and hearts of PD-1 deficient mice with myocarditis. These expanded effector CD8+ cells had unique transcriptional changes, including upregulation of the chemokines CCL5, CCL4, and CCL4L2, and they may serve as attractive diagnostic therapeutic targets for reducing life threatening cardiac immune related adverse events in immune checkpoint inhibitor treated cancer patients, and Carolyn, just like so many of our articles, there's a very nice accompanying editorial by Professor Gianluigi Condorelli that also offers an update on current research pertaining to non-systemic steroid therapy to treat immune mediated myocarditis. Well, Carolyn, how about we jump to some of the other articles in the issue? Dr. Carolyn Lam:             Oh, you bet, Greg. There's an exchange of letters between Drs. Madias and Knops regarding the article “Efficacy and Safety of Appropriate Shocks and Antitachycardia Pacing in Transvenous and Subcutaneous Implantable Defibrillators: The Analysis of All Appropriate Therapy in the PRAETORIAN Trial.” Dr. Greg Hundley:           And also in the mail bag, Professor Mark has a Research Letter entitled “Effect of Empagliflozin on Kidney Biochemical and Imaging Outcomes in Patients with Type 2 Diabetes, or Prediabetes, and Heart Failure with Reduced Ejection Fraction, The SUGAR-DM-HF Study,” and our own Tracy Hampton has several synopses from articles published elsewhere in our piece on cardiovascular news. Well, how about we get onto that feature forum discussion, two papers, two editorialists. I can't wait. Dr. Carolyn Lam:             Me too. Let's go, Greg. Dr. Greg Hundley:           Welcome, listeners to this July 26th feature forum discussion. So remember, listeners, for forum discussions, we have several manuscripts that focus on a singular topic and we bring together the authors, our associate editors, and also an editorialist, and today, I want to introduce, we have with us Dr. Mikhail Kosiborod from Mid America Heart Institute in Kansas City, Missouri, Dr. Christian Shults from University Hospital Jena in Germany, Stefan Anker from Charité in Berlin, Germany, and our Associate Editors, Brendan Everett from Brigham and Women's Hospital in Boston, Massachusetts, and Justin Grodin from University of Texas Southwestern Medical Center in Dallas, Texas. Welcome, gentleman, and we'll start with you, Mikhail. Could you describe for us the background information that went into the preparation of your study and what was the hypothesis that you wanted to address? Dr. Mikhail Kosiborod:   Well, thanks very much, Greg. The background for the study, which was the secondary analysis of the EMPULSE trial was patients that are hospitalized with acute decompensated heart failure represent a very high risk group. We know that they have high risk of death and hospitalizations, and we also know that they have very poor health status that's very high burden of symptoms, physical limitations, and poor quality of life, and so addressing those treatment goals, trying to reduce the risk of clinical events like death and hospitalizations and improve the symptoms and physical limitations in this patient population are very important treatment goals. Now we previously demonstrated in the main results of the EMPULSE trials that using empagliflozin initiating empagliflozin SGLT2 inhibitor in this patient population as compared with placebo provided a significant total clinical benefit, which was a composite of total death, repeat hospitalizations for heart failure, or a change in a Kansas City cardiomyopathy questionnaire, which is a kind of a gold standard measure of patient's health status. What we tried to do in a much more granular fashion in this study is to understand the effects of empagliflozin as compared with placebo on this very important outcome, the Kansas City cardiomyopathy questionnaire, and we actually evaluate all of the key domains and composite symptoms, physical limitations, as well as quality of life. Dr. Greg Hundley:           Very nice, and Mikhail, can you describe for us what study population specifically, and then what was your study design? Dr. Mikhail Kosiborod:   Well, this was a population of patients that were hospitalized with heart failure and that EMPULSE was unique in its design because first of all, previous SGLT2 inhibitor trials mostly focused on patients with chronic heart failures that were in an outpatient setting, including prior trials of empagliflozin, and EMPULSE really focused on acutely hospitalized patient population, but it included patients regardless of ejection fraction. So as they were hospitalized with decompensated heart failure and reduced or preserved ejection fraction. They were enrolled regardless of if they had type 2 diabetes, they were enrolled essentially, regardless of kidney function, only patients with EGFR of less than 20 were excluded, and also importantly, was this study and a unique feature of the study in particular was that we enrolled patients whether they had acute de novo heart failure. That means that was a new diagnosis of heart failure that was bad enough for them to be hospitalized or worsening chronic heart failure requiring hospitalization. So it was really an all-comer trial for patients acutely hospitalized for heart failure. So we had just over 500 patients and they were randomized in the hospital. After a brief period of stabilization, we use empagliflozin, 10 milligrams daily or placebo and treated for 90 days, and the primary outcome at 90 days was a total clinical benefit that I described that was a composite, hierarchical composite of total death hospitalizations, repeat hospitalizations for heart failure and changing KCCQ. In this study, again, we focused predominantly on KCCQ, trying to understand the effects on health status, again, symptoms, physical limitations, and quality of life. Dr. Greg Hundley:           Excellent. And Mikhail, what were your study results? Dr. Mikhail Kosiborod:   Well, what we observed, a couple of things. One is we first examined the effects of empagliflozin on the primary endpoint across the range of KCCQ and baseline, and what we found was that regardless of the degree of symptomatic impairment and baseline, empagliflozin was consistent in providing them total clinical benefits that I described previously, and then kind of shifting to what I think is the most interesting findings, the effects of empagliflozin versus placebo on KCCQ, what we found was that as you would imagine in this population of patients that were acutely hospitalized with heart failures, that had very poor health status, very low KCCQ at baseline, and within the first 90 days, which was observation period, both groups of patients had substantial improvements in KCCQs. As one would expect after acutely decompensated episode of heart failure and treatment in a hospital, everyone got better. But patients treated with empagliflozin had significantly greater improvement in KCCQs than those that were treated with placebo, and that was first of all, a very substantial difference between the two groups. It was more than five points in favor of empagliflozin already at 15 days and was highly statistically significant, and it was maintained throughout the 90 day treatment period. So the fact that we saw both a clinical meaningful and statistically significant improvement in just 15 days, I think is a very important clinical message, and then finally, I guess what I will mention is these benefits of empagliflozin while main outcome we looked at was KCCQ total symptoms, we're focusing on the symptoms, but it was consistent when we looked at physical limitations as well as quality of life. So really, all key domains of KCCQ were impacted in a similar way. Dr. Greg Hundley:           Very nice. So in acute heart failure, marked symptomatic improvement after the administration of the SGLT2 inhibitor empagliflozin at 10 milligrams per day. Well, now listeners, we're going to turn to our associate editor, Dr. Brendan Everett, and Brendan, again, you have many papers come across your desk. What attracted you to this particular manuscript? Dr. Brendan Everett:      Well, thanks, Greg, and I think this manuscript caught my eye because of the importance of the clinical question, and Mikhail outlined why I think that was really relevant. So we understand that this class of medications or SGLT2 inhibitors have important effects on outcomes like re-hospitalization in patients with heart failure, and what was particularly striking about this paper is that it took patients rather than those with chronic heart failure, but as Mikhail mentioned, enrolled a patient population that was actually in the hospital, and I think this was an important frontier for this particular question about when to start the SGLT2 inhibitor and what kind of benefits there might be. Furthermore, I think the fact that they did not select the population based on ejection fraction was particularly striking, and of course, I think is remarkable, but now old news, they did not select on the presence or absence of diabetes as well. And so those three components really attracted me to the paper. I also think the outcome is one that really is valuable and worth exploring, and specifically, I'm talking about how patients feel on the medication after a hospitalization for heart failure. Appropriately, we focused on re-hospitalization for heart failure and cardiovascular death in prior trials in this space, and I think we need to embellish those findings or further deepen those findings with a perspective on how patients actually feel when they get the medication, and of course, it goes without saying that what's particularly important here also is that it was a randomized placebo controlled trial, and so the results have some element of internal validity that I think is really important. So those were the things, Greg, that really attracted my attention as I read the paper for the first time. Dr. Greg Hundley:           Thank you so much, Brendan. Well, listeners, we've got a second paper today and we're next going to hear from Dr. Christian Shults, and he also is focusing on really another aspect of the administration of empagliflozin in patients with acute heart failure and that pertains to the renal function of the patients. So Christian, could you describe for us the background pertaining to your study and what was the hypothesis that you were intending to address? Dr. Christian Schulze:     Thanks, Greg. Well, it's great to introduce all study here in this running. So our study impacted those in acute decompensated heart failure. The impact HF trial was a study based on the hypothesis that we wanted to test, whether empagliflozin has effects in acute decompensated heart failure, and we focused on the patient population that was not addressed in EMPULSE, patients that came to the ER and needed to be treated right away, and we wanted to know and this was our main hypothesis, but are the diuretic and [inaudible 00:17:11] effects of the SGLT2 inhibitor on this case, empagliflozin, actually had an impact on diuretic regimens and kidney functions since this is one of the main end points that limits treatment, and also is one of the outcomes of patients with acute decompensated heart failure in the hospital. Dr. Greg Hundley:           Very nice. And so Christian, what study design did you implement and who was included in your study population? Dr. Christian Schulze:     So we also used the randomized two arm study design. We included patients with acute decompensated heart failure independent of left ventricular ejection fraction. Patients needed to have an NT-proBNP of more than 500. The average NT-proBNP in fact was 4,300 in our entire patient population, and we included patients within 12 hours of presentation. So many of these patients have been recruited in the ER, they presented two hour cardiology heart failure service, and then were immediately randomized to the trial in the two arms, and we tested not 10 milligrams of empagliflozin. We actually tested 25 milligrams of empagliflozin based on in-house data that 25 milligrams potentially had a stronger diuretic effect compared to 10 milligrams. Dr. Greg Hundley:           And what did you find? Dr. Christian Schulze:     So we followed patients for five days. It was a relatively short period of time. It was designed to address the in-house phase of patients with acute decompensated heart failure. The mean duration of stay was 6.3 days in the hospital so this was exactly the time that we wanted to test. We had a 30 day endpoint for safety issues, and what we could see is that patients on 25 milligrams on empagliflozin on top of standard diuretic regimens and medical care had 25% higher diuretic outputs compared to patients in the placebo group. We also found no differences in markers of renal injury dysfunction, and could in fact confirm that after 30 days, patients in the empagliflozin group had a better EGFR compared to patients in the placebo group. On top, we saw a more rapid decrease in body weight and also a more profound decrease in NT-proBNT values. Dr. Greg Hundley:           And Christian, just for our listeners to put a little bit of this in perspective, what was the range of serum creatinine for the patients that were enrolled in your study? Dr. Christian Schulze:     So the main EGFR in the entire population was around 60 and the creatinine values were around 107 on average in the entire cohort. So this is a very typical population. We had around 30% of the population with de Novo heart failure, around 20 to 30% of the population was pre-treated for preexisting heart failure. So very typical population of patients with heart failure presenting to the emergency room. Dr. Greg Hundley:           And did you have any kind of lower level EGFR cutoff, I mean, for enrollment into this study? Dr. Christian Schulze:     So when we designed the trial, we actually still had the sub classification of diabetes or impaired glucose or homeostasis as an inclusion criteria. We dropped it before we started the trial because the data came out that this is actually, in fact, not a critical issue for patients with heart failure. So diabetes was not a subgroup in our trial and the lower limit of EGFR was actually a thoroughly defined protocol. Dr. Greg Hundley:           Very nice. Well, listeners, now we're going to turn to our second associate editor, Dr. Justin Grodin from University of Texas Southwestern Medical Center in Dallas, Texas, and Justin, similar to Brendan, and you see many papers come across your desk and so what attracted you to this particular paper by Christian and his colleagues? Dr. Justin Grodin:            Well, Greg, I think first and foremost, and I think very similar to Brendan, but I think what's always striking is if I may just take a step back, decompensated heart failure in the United States is the number one cause for hospitalization among Medicare beneficiaries. So I think really, the brunt and really the truly public health message of the disease is very important in the applicability, and even though that decompensated heart failures is one of the most common things that we ever encounter when we practice, internists, cardiologists, et cetera, we have very, very little clinical trial guidance that tells us how to decongest individuals when they're hospitalized with swelling and heart failure and a lot of these individuals can be quite ill, and we have some clinical trial data, but largely, we have a lot of negative studies or inconclusive studies in this space. So certainly, what drew me to this trial was definitely that context, and obviously, based on the mechanistic data with SGLT2 inhibitors, I think one of the natural questions, which Christian addresses, is that we know that up front, they do augment natriuresis. So I think it's very compelling to marry those two together because this is what many of us that use these medications regularly have been asking is whether or not they would have some efficacy in that regard, and then another thing that caught my eye and me as a cardiorenal investigator was, just as Christian highlighted, was we have a clinical trial that randomly assigned individuals, really that were ill and many of whom were not stabilized within 12 hours of presentation, and we're talking about patients that are coming into the hospital at all times during the day in and I think that's very remarkable that we have something with standard... We have a study with standardized assessments where we're really trying to ask a very practical, pragmatic question, which is do these therapies lower the sodium balance in individuals with decompensated heart failure, and I think what's important is largely, we've got a lot of medications that supplement loop diuretics, which are the class of drugs that the majority of us use, and we have a lot of other therapies that we use that really have very little data or poor data that guide us such as thiazide diuretics, carbonic and hydrase inhibitors, mineralocorticoid receptor antagonists, and so here, we have a clinical trial that asks a question that's on many people's minds. And then we do have very compelling, at least short term pragmatic and mechanistic data that does tell us that these individuals do have a greater natriuretic effect when empagliflozin is used as an adjunct to standardized loop diuretic therapy. So it's a very practical clinical question, and I think what's very important, and we could debate probably all day about the implications of GFR change and kidney function change while we're decongesting somebody with diuretics, but I think what's reassuring to all the clinicians is we really didn't see an effect on kidney function despite a greater natriuretic effect or enhanced diuretic effect, if you will, with the use of empagliflozin. Dr. Greg Hundley:           Very nice. Well, thank you, Justin. Listeners, now we have an editorialist and as you know, editorialists really help us put the scientific presentation of an original manuscript into the perspective of really the global theme of a topic, and we have Stefan Anker from Berlin, and Stefan, can you describe for us how do we put these two manuscripts and results that we've heard about really in the context now of moving forward with the use of SGLT2 inhibitors in the management of patients with acute decompensated heart failure? Dr. Stefan Anker:            Thank you so much. Really, I think these two papers, on the one hand, enhance our certainty about early use, and on the other hand, possibly show us that there might be even more to achieve by, on the one hand, moving even earlier with the application of SGLT2 inhibitors or possibly consider the higher dose. Now let's take one step back. These drugs were developed in type two diabetes and the first successful trial was the [inaudible 00:25:42] outcome trial. Many people have forgotten that this trial tested two doses and not only one, the 10 and the 25 milligram dose, and of course, with the success for improving kidney outcomes and heart failure hospitalization outcomes, we move forward into these two specialist areas, on the one hand, broadening it to the non-diabetic communities, but on the other end, narrowing it by focusing on the 10 milligram dose regardless of whether there is [inaudible 00:26:12]. And we basically now learn A, to use these drugs even earlier than we did in the big trials and we can now be sure to start their use in the hospital, and if you take the average change in quality of life results seen, you actually get a better result for the patient on quality of life when you start earlier than when you start late in the ambulatory studies where basically, in the chronic setting, maybe you have one and a half to two points difference. Here, you now have four and a half points in the study shown by Mikhail, and of course, it's also good to know that you can start this in any type of patient, regardless of their quality of life. The impact study from Christian, they basically moved it now even earlier, moving into the hospital space is possible based on EMPULSE. Moving it into the acute admission space is at least a consideration now based on what Christian here has shown. And he is actually addressing the one question I hear very often in my presentations about SGLT2 inhibitors, what about this 25 milligram dose? Is there a place for this in cardiology as well, and a possible place is shown here, not only that this is a safe thing to do, but also you get urinary output. Of course, we may in the future, want to see this compared, directly compared to the 10 milligram dose, but of course, the world is not created in one day, but needs more than one and so really, I think these two studies, on the one hand, address an important issue, when to start using them. On the other hand, show us a little bit of a glimpse to the future. Dr. Greg Hundley:           Very nice, Stefan, and listeners, we get to take advantage of having these authors, editors, and editorialists together and ask them what they see as the next study to be performed in this sort of sphere of research. So Mikhail, we'll start with you. In 30 seconds or less, what do you see as the next study to be performed in this arena of research? Dr. Mikhail Kosiborod:   I think, Greg, what we've learned recently, including from the EMPULSE trial, we have this population of patients in a hospital with heart failure's a huge issue as Justin mentioned, and until recently, we had very little [inaudible 00:28:31] for them beyond the usual kind of decongestion with loop diuretics and trying to make them feel better, but you look at outcome data. It really was a dearth of effective therapies that have meaningful impact on important outcomes. Now that's changing, SGLT2 inhibitors is one example. There are some other recent examples in this patient population, like a firm HF and iron deficient patients with heart failure. But the bottom line is it's no longer kind of a desert, if you will, of positive trials. We now have something we can do and I think what this proves is that we need to actually invest more, both in terms of resources and time to really do what we we're being able to do in other areas of heart failure and those patients with chronic, half and half where we can start developing pillars of therapy that can actually truly improve outcomes with this patient population and there is a lot going on that makes me optimistic that's going to be the case in the coming years. Dr. Greg Hundley:           Very nice. And Brendan? Dr. Brendan Everett:      Well, I think both trials mentioned today really pushed our understanding of this population forward. I think the biggest clinical question that I face when I'm caring for these patients is that we have four, at least, guideline directed therapies, right? We have beta blockers, we have ARBs, ACE inhibitors and ARNIs. We have mineral receptor antagonists and we have SGLT2 inhibitors. So which do we use in what order and how do we start them, and what kind of parameters do we use to guide us if we're limited either by renal function or by blood pressure or by some other factor. And we often, if not always, have one of those constraints that we're dealing with and so I would say the next step for me is trying to sort out which of these therapies and what order ought to be our highest priority for patients with acute decompensated heart failure as we move quickly from the acute decongestion stage towards discharge and a chronic therapy that will then be followed as an outpatient over the ensuing days and months. Dr. Greg Hundley:           Very nice. And Christian. Dr. Christian Schulze:     Thank you again, and Brandon pointed out very nicely. I mean, we have good evidence now for chronic heart failure treatment. We have the four columns of heart failure medical therapy. Questions that remain open is what do we do with all these patients that are now guideline medicated, come to the hospital with an acute decompensation? Should we carry on with the medication? Should we terminate and in particular, should be carry on with full dose, 50% dose of SGLT2 inhibitors, and the next question is, what dose should we use, in fact, for SGLT2 inhibitors? Is it in group effects or is sotagliflozin comparable to empagliflozin, and then is there a role for a step by scheme that we initially have in high dose therapy that we then downgrade to 10 milligrams on the chronic heart failure treatments, and then of course, quality of life is very important. We should ask this question also in this patient population that is early on treated, do we see benefits that carry on in the outpatient setting and do we see an effect of early treatment on long term benefits? Dr. Greg Hundley:           Justin? Dr. Justin Grodin:            Well, I would have to agree with all of my colleagues here on this call. I think all have raised really good points, but I think one very simple, and I'll echo some of Brendan's statements, but one very simple question is we know that when we decongest people and initiate a negative salt balance in the hospital for decompensated heart failure, we cause neurohormonal activation and there are a lot of downstream untoward effects from chronic decongestive therapies, and I think one of the more compelling things is we still yet have defined what is the best way to decongest individuals with swelling or volume overload in the hospital. Here, we have compelling studies with SGLT2 inhibitors for quality of life and really, the way patients feel. And this is really what's important to them, and then something very pragmatic to clinicians and let's make people pee more, but I think one of the compelling questions, and I don't know if it will be answered, is we have a lot of choices for supplemental therapies and different diuretic strategies when patients come in the hospital for decompensated heart failure, and I do think that these studies do move the needle with SGLT2 inhibitors. I think that's abundantly clear, but we still don't know what is the best way to dry out my patient or make my patient pee so that they feel better, but I do think that these studies do at least set the stage that there's some compelling advantages to SGLT2 inhibitors. Dr. Greg Hundley:           And then lastly, Stefan. Dr. Stefan Anker:            Thank you. Besides the detailed points mentioned by many, and Christian, totally support 25 versus 10 milligram, how long 25 milligram, if at all in the future. Besides this, I'm interested in the big picture question. So what about the post myocardial infarct congestion/heart failure situation, and there will be two trials in the next 18 to 24 months that report on this, and my pet kind of area is actually to treat heart failure where nobody thinks it is heart failure, and what I mean is for instance, advanced cancer patients, cardiac wasting cardiomyopathy. So the heart failure in sick cancer patients, and indeed, we are planning to do exactly that now in a study focusing on hospice care patients to really improve the quality of life, the very thing focus here on the EMPULSE trial. Dr. Greg Hundley:           Well, listeners, we want to thank our authors, Dr. Mikhail Kosiborod from Mid America Heart Institute in University of Missouri, and Christian Shults from the University Hospital in Jena, Germany. Also, our associate editors, Dr. Brendan Everett from Brigham and Women's Hospital in Boston, and Dr. Justin Grodin from University of Texas Southwestern in Dallas, Texas, and also, our editorialist, Dr. Stefan Anker from Charité in Berlin, Germany for bringing us these two manuscripts pertaining to two randomized clinical trials regarding the administration of the SGLT2 inhibitor, empagliflozin in acute heart failure, demonstrating first, marked improvement in heart failure symptoms and health related quality of life. And second, in those with estimated GFRs greater than 30 mls per minute, an augmentation of natriuresis in the setting of the co-administration of diuretics without deterioration in renal function. Well, on behalf of Carolyn 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, 2022. 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.

Mushrooms boost immunity, suggests research   University of Florida Institute of Food and Agricultural Sciences, April 16, 2022   A new University of Florida study shows increased immunity in people who ate a cooked shiitake mushroom every day for four weeks. In a study led by UF Food Science and Human Nutrition , 52 healthy adults, age 21 to 41, came to the Gainesville campus, where researchers gave them a four-week supply of dry shiitake mushrooms. Participants took the mushrooms home, cleaned and cooked them. Then they ate one, 4-ounce serving of mushrooms each day during the experiment. Through blood tests before and after the experiment, researchers saw better-functioning gamma delta T-cells and reductions in inflammatory proteins. If you eat a shiitake mushroom every day, you could see changes in their immune system that are beneficial. "We're enhancing the immune system, but we're also reducing the inflammation that the immune system produces."   (NEXT)   Oral milk thistle extract stops colorectal cancer stem cells from growing tumors   University of Colorado, April 22, 2022   In results presented at the American Association for Cancer Research, a University of Colorado Cancer Center study shows that orally administering the chemical silibinin, purified from milk thistle, slows the ability of colorectal cancer stem cells to grow the disease. When stem cells from tumors grown in silibinin-fed conditions were re-injected into new models, the cells failed to develop equally aggressive tumors even in the absence of silibinin. "It's very simple: tumors from mice that were initially fed silibinin had fewer cancer stem cells, were smaller, had lower metabolisms and showed decreased growth of new blood vessels. Importantly, when these cancer stem cells from tumors in mice fed silibinin were re-injected into new mice, we found these stem cells had lost their potential to repopulate even in the absence of silibinin exposure. Silibinin is a non-toxic, potentially chemopreventive agent derived from milk thistle seeds.   (NEXT)   Chilli peppers hold promise of preventing liver damage and progression   European Association for the Study of the Liver (Austria), 23 April 2015    Results revealed  that the daily consumption of capsaicin, the active compound of chilli peppers, was found to have beneficial effects on liver damage. In the study, capsaicin was found to reduce the activation of hepatic stellate cells (HSCs) in mice models. HSCs are the major cell type involved in liver fibrosis, which is the formation of scar tissue in response to liver damage. The study demonstrates that capsaicin partially improved liver damage in the BDL mice and inhibited further progression of the injury. In the second group of CCl4-treated mice, capsaicin prevented livers from injury development but did not reduce the fibrosis when it was already established.   (NEXT)   Compassion meditation reduces 'mind-wandering,' research shows    Stanford University, April 23, 2022    The practice of compassion meditation may be a powerful antidote to a drifting mind, new Stanford research shows.   Compassion meditation focuses on benevolent thoughts toward oneself and others, as the researchers noted. It is different in this aspect than most forms of meditation in the sense that participants are "guided" toward compassionate thoughts. This is the first report that demonstrates that formal compassion training decreases the tendency for the mind to wander, while increasing caring behavior not only towards others but towards oneself. "Mind-wandering" is the experience of having your thoughts not remain on a single topic for long. Prior research suggests that people spend as much as 50 percent of their waking hours in mind-wandering, often without realizing it. Doty said that mindfulness is extremely useful in today's world with its myriad of distractions, as humans are often overwhelmed and can find it difficult to attend to necessary tasks. "By closing one's eyes and engaging in attention training through a mindfulness practice, not only does it diminish the negative physiologic effects of distraction, which can result in anxiety and fear, but it can increase one's ability to attend to important tasks and not have an emotional response to the often negative dialogue which is frequent in many individuals," he said. As the researchers noted, compassion is defined by an awareness of suffering, sympathetic concern and a wish to see the relief of that suffering, and a responsiveness or readiness to help relieve that suffering. The study examined 51 adults during a compassion meditation program, measuring their various states of mind-wandering (neutral, pleasant, and unpleasant topics) and caring behaviors for themselves and others.  They were encouraged to meditate at least 15 minutes daily and, if possible, 30 minutes. The results indicated that compassion meditation decreased mind-wandering to neutral topics and increased caring behaviors toward oneself.   Videos: Tucker: You are seeing a full-scale attack on free speech How is everything getting coordinated globally on the scale that it is. “Ministry of Truth.”

In this very Special Christmas episode David returns, Ali get annoyed, and Squinkles sings as well a gives his very... special... version of the Classic Ghost story "Smee" by A. M. Burrage. "Angels We Have Heard" & "March of the Spoons" by Kevin MacLeod Licensed under CCL4.0. Artist: http://incompetech.com/ Unspoken, Winds Wreck, & Reversion By MYUU Licensed under CCL4.0. https://thedarkpiano.com/ Merry Christmas - covered by Mr. Squinkles. Originally by Wesley Willis.

Gary takes on the real issues that the mainstream media is afraid to tackle. Tune in to find out the latest about health news, healing, politics, and the economy. Meta-analysis finds dietary supplements improve sleep quality Hong Kong Polytechnic University, January 27 2021.    A systematic review and meta-analysis published on January 13, 2021 in Postgraduate Medical Journal found benefits for supplemental vitamin D, melatonin and amino acids in improving the quality of sleep among men and women.  The meta-analysis included 15 randomized, controlled trials that examined the association between subjective sleep quality as assessed by the Pittsburgh Sleep Quality Index (PSQI) and supplementation with amino acids, the hormone melatonin, omega 3 fatty acids and vitamin D. Pooled data for the two studies involving amino acid supplements, seven studies involving melatonin, and four studies involving vitamin D each showed significant differences between supplemented and control groups, with more favorable PSQI scores occurring among those who received the supplements. The two studies that evaluated omega 3 did not reveal significant differences between the treatment and control groups. Two reviewed trials that were not eligible for inclusion in the meta-analysis added evidence to the benefit of melatonin in sleep quality. Other non-included trials found a benefit for nitrate-containing beetroot juice, resveratrol and zinc supplements. Co-supplementation with melatonin, magnesium and zinc was also associated with a significant benefit in comparison with a placebo.  “Although we found a significant improvement in sleep quality by dietary supplementation, randomized, controlled trials with longer duration and larger sample size should be conducted to verify our findings,” noted authors Vicky Chan and Kenneth Lo of The Hong Kong Polytechnic University. “Furthermore, dose–response effect of different supplements on sleep quality has not yet been evaluated.” “Amino acids, vitamin D and melatonin supplements were significantly beneficial to improve sleep quality,” they concluded. “Further research on the effect of magnesium, zinc, resveratrol and nitrate supplementation on improving sleep quality is required.”     Green coffee extract and silymarin protect against carbon tetrachloride-induced liver toxicity University of Tabuk (Saudi Arabia), January 26, 2021   According to news originating from the University of Tabuk research stated, “During the last few decades, patients worldwide have been interested in using alternative medicine in treating diseases to avoid the increased side effects of chemical medications. Green coffee is unroasted coffee seeds that have higher amounts of chlorogenic acid compared to roasted coffee.” Our news journalists obtained a quote from the research from University of Tabuk: “Green coffee was successfully used to protect against obesity, Alzheimer disease, high blood pressure and bacterial infection. This study aimed to investigate the probable protective activity of the green coffee methanolic extract, silymarin and their combination on CCl4-induced liver toxicity in male rats. Thirty Sprague - Dawley male albino rats were divided into 5 groups; control negative (G1) just got the vehicle (olive oil) and the other four groups received CCl4 dissolved in olive oil through an intraperitoneal injection and were divided into untreated control positive group (G2), the third group (G3) was treated with green coffee methanolic extract, the fourth group (G4) was treated with silymarin, and the fifth group (G5) was treated with a combination of green coffee methanolic extract and silymarin. In the positive control group treated with CCl4 (G2), the CCl4-induced toxicity increased lipid peroxidation, IL-6, kidney function parameters, liver function enzymes, total cholesterol, triglycerides and low-density lipoproteins, and decreased irisin, antioxidants, CYP450 and high-density lipoprotein levels. Hepatic tissues were also injured. However, treating the injured rats in G3, G4 and G5 significantly improved the altered parameters and hepatic tissues.” According to the news reporters, the research concluded: “Green coffee methanolic extract, silymarin, and their combination succeeded in protecting the male rats against CCl4 hepatotoxicity due to their antioxidant activity. Effect of green coffee methanolic extract mixed with silymarin in G5 was more efficient than that of green coffee methanolic extract in G3 or silymarin in G4.”     Vitamin D status and outcomes for hospitalised older patients with COVID-19 NHS Foundation Trust and University of Cyprus, January 21, 2021   Purpose Older adults are more likely to be vitamin D deficient. The aim of the study was to determine whether these patients have worse outcomes with COVID-19. Methods We conducted a prospective cohort study between 1 March and 30 April 2020 to assess the importance of vitamin D deficiency in older patients with COVID-19. The cohort consisted of patients aged ≥65 years presenting with symptoms consistent with COVID-19 (n=105). All patients were tested for serum 25-hydroxyvitamin D (25(OH)D) levels during acute illness. Diagnosis of COVID-19 was confirmed via viral reverse transcriptase PCR swab or supporting radiological evidence. COVID-19-positive arm (n=70) was sub-divided into vitamin D-deficient (≤30 nmol/L) (n=39) and -replete groups (n=35). Subgroups were assessed for disease severity using biochemical, radiological and clinical markers. Primary outcome was in-hospital mortality. Secondary outcomes were laboratory features of cytokine storm, thoracic imaging changes and requirement of non-invasive ventilation (NIV). Results COVID-19-positive arm demonstrated lower median serum 25(OH)D level of 27 nmol/L (IQR=20–47 nmol/L) compared with COVID-19-negative arm, with median level of 52 nmol/L (IQR=31.5–71.5 nmol/L) (p value=0.0008). Among patients with vitamin D deficiency, there was higher peak D-dimer level (1914.00 μgFEU/L vs 1268.00 μgFEU/L) (p=0.034) and higher incidence of NIV support and high dependency unit admission (30.77% vs 9.68%) (p=0.042). No increased mortality was observed between groups. Conclusion Older adults with vitamin D deficiency and COVID-19 may demonstrate worse morbidity outcomes. Vitamin D status may be a useful prognosticator.   Mental Disorders Forecast Chronic Physical Diseases, Premature Death University of Michigan, January 22, 2021 Poor early-life mental health may jeopardize later-life physical health, according to a new study led by a University of Michigan researcher. The study, published in the journal JAMA Network Open, indicates that people who experience psychiatric conditions when they are young are likely to experience excess age-related physical diseases when they are older. Leah Richmond-Rakerd, U-M assistant professor of psychology, and colleagues found that this association cannot be explained by preexisting physical illness; they ruled out the possibility of reverse causation in which having a physical illness precipitates mental health problems. Prior studies had not taken this into account. This association is present across different mental disorders and different physical diseases, she said. The researchers conducted a nationwide hospital-register study of 2.3 million New Zealanders—aged 10-60 years at baseline—followed across three decades (1988 to 2018). They tested whether individuals with mental disorders are at increased risk for subsequent chronic physical diseases and premature mortality. Richmond-Rakerd and colleagues collected information about hospital admissions for different mental disorders, such as substance use disorders, psychotic disorders, mood disorders, anxiety disorders and self-harm behavior. In addition, researchers collected information about hospital admissions for different chronic physical diseases, ranging from coronary heart disease to cancer. Across the 30-year period, individuals with mental disorders were more likely to develop subsequent physical diseases and they also died earlier than people without mental disorders, the study showed. They also experienced more medical hospitalizations, spent more time in hospitals for physical-disease treatment and accumulated more associated health care costs. These associations were present across all age groups and in both men and women. The findings indicate that addressing mental health problems in early life might be a window of opportunity for preventing future physical diseases, Richmond-Rakerd said. They also suggest the importance of joined-up services, or integrated care. “Our health care system often divides treatment between the brain and the body,” she said. “Integrating the two could benefit population health.” Richmond-Rakerd said they chose New Zealand because there it is possible to link hospital registers and other administrative databases for the entire population of the country. The study’s co-authors are Stephanie D’Souza and Barry Milne of the University of Auckland, Avshalom Caspi and Terrie Moffitt of Duke University and King’s College London.   'Aging well' greatly affected by hopes and fears for later life, study finds Oregon State University, January 21, 2021   If you believe you are capable of becoming the healthy, engaged person you want to be in old age, you are much more likely to experience that outcome, a recent Oregon State University study shows. "How we think about who we're going to be in old age is very predictive of exactly how we will be," said Shelbie Turner, a doctoral student in OSU's College of Public Health and Human Sciences and co-author on the study. Previous studies on aging have found that how people thought about themselves at age 50 predicted a wide range of future health outcomes up to 40 years later -- cardiovascular events, memory, balance, will to live, hospitalizations; even mortality.  "Previous research has shown that people who have positive views of aging at 50 live 7.5 years longer, on average, than people who don't," said Karen Hooker, co-author of the study and the Jo Anne Leonard Petersen Endowed Chair in Gerontology and Family Studies at OSU.  Because self-perceptions of aging are linked to so many major health outcomes, Hooker and Turner wanted to understand what influences those perceptions. Their study looked specifically at the influence of two factors: self-efficacy associated with possible selves, meaning a person's perceived ability to become the person they want to be in the future; and optimism as a general personality trait.  The researchers measured self-perception of aging by having respondents say how strongly they agreed or disagreed with statements such as, "Things keep getting worse as I get older," "I have as much pep as I had last year," "As you get older, you are less useful." They measured optimism in a similar way, with respondents ranking their agreement with statements like "In uncertain times I usually expect the best."  To measure self-efficacy, the study used a dataset that compiled survey responses from older adults where they listed two "hoped-for" future selves and two "feared" future selves, and ranked how capable they felt of becoming the person they hoped to be and avoiding becoming the person they feared to be.  Among the "hoped for" selves were things like "A social person with a strong network of friends" and "A healthy, active person." Examples of "feared" selves were "Chronically sick and in pain," "Being dependent on others for my day-to-day needs" and "A cranky, angry old woman."  Results showed that, as predicted, higher optimism was associated with more positive self-perception of aging. Both "hoped-for" self-efficacy and "feared" self-efficacy were also significantly associated with self-perception of aging, above and beyond optimism as a trait.  A major factor in how people see their own aging selves is internalizing ageist stereotypes, the researchers said. Examples of such stereotypes include assumptions that older adults are bad drivers, or suffer memory problems, or are unable to engage in physical activity anymore.  "Kids as young as 4 years old already have negative stereotypes about old people," Hooker said. "Then, of course, if you're lucky enough to live to old age, they eventually apply to you."  Those stereotypes get reinforced every time an older adult forgets something and jokes, "Another senior moment!" But the researchers say these thought patterns can do real harm. "People need to realize that some of the negative health consequences in later life might not be biologically driven. The mind and the body are all interwoven," Hooker said. "If you believe these bad things are going to happen, over time that can erode people's willingness or maybe even eventually their ability to engage in those health behaviors that are going to keep them as healthy as they can be."  A way to mitigate those negative stereotypes about aging is to promote intergenerational relationships, so younger people can see older adults enjoying happy, healthy lives.  "The more you're around older people, the more you realize that it's not all bad," Turner said. "Older people can do some things better than young people do. Increasing opportunities for intergenerational relationships is one way we can make people more optimistic about aging."   Over half of cannabis users with Parkinson's disease report clinical benefits University Medical Center Hamburg-Eppendorf (Germany), January 26, 2021   With medicinal cannabis now legalized in many parts of the world, there is growing interest in its use to alleviate symptoms of many illnesses including Parkinson's disease (PD). According to results of a survey of PD patients in Germany in the Journal of Parkinson's Disease, over 8% of patients with PD reported using cannabis products and more than half of those users (54%) reported a beneficial clinical effect. Cannabis products containing THC (tetrahydrocannabinol, the main psychoactive compound of cannabis) can be prescribed in Germany when previous therapies are unsuccessful or not tolerated, and where cannabis can be expected with not a very unlikely chance to relieve disabling symptoms. CBD (pure cannabidiol, derived directly from the hemp plant, a cousin of the marijuana plant) is available without a prescription from pharmacies and on the internet. "Medical cannabis was legally approved in Germany in 2017 when approval was given for therapy-resistant symptoms in severely affected patients independent of diagnosis and without clinical evidence-based data," explained lead investigator Prof. Dr. med. Carsten Buhmann, Department of Neurology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. "PD patients fulfilling these criteria are entitled to be prescribed medical cannabis, but there are few data about which type of cannabinoid and which route of administration might be promising for which PD patient and which symptoms. We also lack information about the extent to which the PD community is informed about medicinal cannabis and whether they have tried cannabis and, if so, with what result." Investigators aimed to assess patient perceptions of medicinal cannabis as well as evaluate the experiences of patients already using cannabis products. They performed a nationwide, cross-sectional, questionnaire-based survey among members of the German Parkinson Association (Deutsche Parkinson Vereinigung e.V.), which is the largest consortium of PD patients in German-speaking countries with nearly 21,000 members. Questionnaires were sent out in April 2019 with the association's membership journal and were also distributed in the investigators' clinic. Over 1,300 questionnaires were analyzed; results showed that interest in the PD community in medical cannabis was high, but knowledge about different types of products was limited. Fifty-one percent of respondents were aware of the legality of medicinal cannabis, and 28% were aware of the various routes of administration (inhaling versus oral administration), but only 9% were aware of the difference between THC and CBD.  More than 8% of patients were already using cannabinoids and more than half of these users (54%) reported that it had a beneficial clinical effect. The overall tolerability was good. Over 40% of users reported that it helped manage pain and muscle cramps, and more than 20% of users reported a reduction of stiffness (akinesia), freezing, tremor, depression, anxiety, and restless legs. Patients reported that inhaled cannabis products containing THC were more efficient in treating stiffness than oral products containing CBD but were slightly less well tolerated.  Patients using cannabis tended to be younger, living in large cities, and more aware of the legal and clinical aspects of medicinal cannabis. Sixty-five percent of non-users were interested in using medicinal cannabis, but lack of knowledge and fear of side effects were reported as main reasons for not trying it.  "Our data confirm that PD patients have a high interest in treatment with medicinal cannabis but lacked knowledge about how to take it and especially the differences between the two main cannabinoids, THC and CBD," noted Prof. Dr. med. Buhmann. "Physicians should consider these aspects when advising their patients about treatment with medicinal cannabis. The data reported here may help physicians decide which patients could benefit, which symptoms could be addressed, and which type of cannabinoid and route of administration might be suitable." "Cannabis intake might be related to a placebo effect because of high patient expectations and conditioning, but even that can be considered as a therapeutic effect. It has to be stressed, though, that our findings are based on subjective patient reports and that clinically appropriate studies are urgently needed," he concluded.  Bastiaan R. Bloem, MD, PhD, Director, Radboudumc Center of Expertise for Parkinson & Movement Disorders, Nijmegen, The Netherlands, and Co-Editor-in Chief of the Journal of Parkinson's Disease, added: "These findings are interesting in that they confirm a widespread interest among patients in the use of cannabis as a potential treatment for people living with PD. It is important to emphasize that more research is needed before cannabis can be prescribed as a treatment, and that guidelines currently recommend against the use of cannabis, even as self-medication, because the efficacy is not well established, and because there are safety concerns (adverse effects include among others sedation and hallucinations). As such, the present paper mainly serves to emphasize the need for carefully controlled clinical trials to further establish both the efficacy and safety of cannabis treatment."   Covid lockdown loneliness linked to more depressive symptoms in older adults University of Exeter (UK), January 22, 2021   Loneliness in adults aged 50 and over during the COVID-19 lockdown was linked to worsening depressive and other mental health symptoms, according to a large-scale online study.  Loneliness emerged as a key factor linked to worsening symptoms of depression and anxiety in a study of more than 3,000 people aged 50 or over led by the University of Exeter and King's College London, and funded by The National Institute for Health Research (NIHR) Maudsley Biomedical Research Centre (BRC) .  Researchers had access to data going back to 2015 for participants of the PROTECT online study. They also found that a decrease in physical activity since the start of the pandemic was associated with worsening symptoms of depression and anxiety during the pandemic. Other factors included being female and being retired.  Dr Byron Creese, of the University of Exeter Medical School, who led the study, said: "Even before the pandemic, loneliness and physical activity levels were a huge issue in society, particularly among older people. Our study enabled us to compare mental health symptoms before and after COVID-19 in a large group of people aged 50 and over. We found that during lockdown, loneliness and decreased physical activity were associated with more symptoms of poor mental health, especially depression. It's now crucial that we build on this data to find new ways to mitigate risk of worsening mental health during the pandemic." The study found that before the pandemic, lonely people would report an average of two symptoms of depression for at least several days over the previous last two weeks. During lockdown, lonely people reported either an increase in frequency of depressive symptoms, to more than half the days in the two week period, or a new symptom for at least several days in that timeframe. In people who were not lonely, levels of depressive symptoms were unaffected.  PROTECT began in 2011, and has 25,000 participants signed up. Designed to understand the factors involved in healthy ageing, the innovative study combines detailed lifestyle questionnaires with cognitive tests that assess aspects of brain function including memory, judgment and reasoning over time. In May, researchers included a new questionnaire designed to assess the impact of COVID-19 on health and wellbeing. Running from May 13 to June 8, the questionnaire was completed by 3,300 people, of which 1,900 were long-standing PROTECT participants. The study is continuing to run so that longer term outcomes can be assessed.  Zunera Khan, Research Portfolio Lead at Institute of Psychiatry, Psychology & Neuroscience said "We've found links between loneliness and a drop in physical exercise and worsening mental health symptoms. It should be within our power to find ways of keeping people socially engaged and active. Our online PROTECT platform ultimately aims to find new ways to engage people in their homes, however, technology can only be part of the picture. We need to ensure we can find new ways to help people stay active and social, whether they are online or not." Professor Clive Ballard, Executive Dean and Pro-Vice Chancellor of the University of Exeter Medical School, who leads PROTECT, said: "We are only just beginning to learn the impact that COVID-19 is having on the health and wellbeing of older people. For example, the effect of any economic impact may not yet have emerged. Our large scale study will span a number of years, and will help us understand some of the longer-term effects of COVID-19 on mental health and wellbeing, and ultimately, on whether this has any knock-on effect on aspects of ageing, such as brain function and memory. " The study plans to conduct further analysis on groups at particularly high risk, such as people with cognitive impairment and those with caring rolesG

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.07.21.213397v1?rss=1 Authors: Park, J. E., Guo, X., Liou, K. C. K., Lynn, S. E., Ng, S. S., Meng, W., Lim, S. C., Leow, M. K.-S., Richards, A. M., Pennington, D. J., McCarthy, N. E., de Kleijn, D. P. V., Sorokin, V., Ho, H. H., Sze, S. K. Abstract: Abnormal matrix deposition on vessels and recruitment of inflammatory cells into the arterial wall are critical events in atherosclerotic plaque formation. Fibronectin protein is a key matrix component that exhibits high levels of deamidation in atherosclerotic plaques and blood plasma, but it is unclear how this structural change impacts on endothelial function or modifies interactions with recruited leukocytes. This study aimed to determine how deamidation-induced isoDGR motifs in fibronectin influence extracellular matrix accumulation on endothelial cells, and to investigate possible effects on integrin outside-in signalling in matrix-bound monocytes which are key mediators of human atherosclerosis. Blood plasma fibrinogen and fibronectin displayed marked accumulation of isoDGR motifs in ischemic heart disease (IHD) as determined by ELISA analysis of patients undergoing coronary artery bypass grafting compared with age-matched healthy controls. Biochemical and functional assays confirmed that isoDGR-containing fibronectin promoted activation of integrin {beta}1 in monocytes and facilitated protein deposition and fibrillogenesis on endothelial cell layers. In addition, isoDGR interactions with integrins on the monocyte cell surface triggered an ERK:AP-1 signalling cascade that induced potent secretion of chemotactic mediators (including CCL2, CCL4, IL-8, and TNF), that promoted further leukocyte recruitment to the assembling plaque. Fibronectin deamidation forms isoDGR motifs that increase binding to {beta}1 integrins on the surface of endothelial cells and monocytes. Subsequent activation of integrin outside-in signalling pathways elicits a range of potent cytokines and chemokines that drive additional leukocyte recruitment to the developing atherosclerotic matrix and likely constitutes a key early event in progression to IHD. Copy rights belong to original authors. Visit the link for more info

In this episode our tramatized trio battle against unsee forces, Jay talks with ghosts, and Laura learns a joke.  Anxiety, Controlled Chaos, Evening of Chaos, Long Note 3, Night of Chaos, Professor and the Plant, and Steel and Seething by Kevin MacLeod (incompetech.com) Licensed under CCL4.0

Welcome to the season finale of Deaded Dominions. We hope you have enjoyed this season. We could not do it without your support! We will have bonus content during the hiatus, but will return for season 2 in January. Happy Holidays! I Am a Man Who Will Fight for Your Honor & Candlepower by Chris Zabriskie are licensed under CCL4.0 Artist: http://chriszabriskie.com/ Brittle Rille, Deck the Halls B, Creeping To Ship, Laid Back Guitars, & Colorless Aura by Kevin MacLeod are licensed under CCL4.0. Artist: http://incompetech.com/

Gwen Foster is a Hanna Kroeger practitioner, certified Master Neuro-Linguistic Programming (NLP) Practitioner, Neuro-Linguistic Hypnotherapist, Certified Biofeedback Technician and Personal Coach. Other modalities include Reiki, Matrix Energetics, SRT, EFT, and ECR. Gwen received her Bachelor of Natural Health Studies with Highest Honors from Clayton College of Natural Health in 2003. Her website is http://nuvisionusa.com/ Today's topics: her background and how you got into naturopathic medicine What is NuVision and how does it help you identify blocks and imbalances in clients? 1. My results and how it works based on resonances 2. What goes into the machine and how does it work? 3. How can it be used to help recover from injuries or illnesses? It is a cooperative component with healing but it does not diagnosis “Nu|Vision visualizes resonances between these holographic tokens, resulting in analytical insights. A Swiss psychologist named Carl Gustav Jung coined the word “synchronicity” to describe the experience of events that are apparently casually unrelated, yet occur together in a meaningful manner. Synchronistic events reveal an underlying pattern, a conceptual framework that encompasses, but is larger than any of the systems that display the synchronicity. Following discussions with both Albert Einstein and Wolfgang Pauli, Carl Jung believed that there were parallels between synchronicity and aspects of relativity theory and quantum mechanics. Synchronicity is perceived as being a law of attraction in a higher-dimensional space, but is actually caused by convergence in the lower-dimensional reference system.” · This machine, based on resonances from my blood type, my name, where I was born, and the hospital I was born in revealed that I need healing with friends, healing, and integrating shadow cells… And really revealed some personal stuff that has been going on in my life over the past couple years. What all does it reveal because it also offered nutritional options for me? · Polarity (division) issue · It showed that I resonated with weak muscles in my neck and shoulders, so she connected me with holistic chiropractor Dr. Marmostein, I emailed him, a busy dr, and the next day he called me, got me in, and in 1 visit helped me reduce some lingering symptoms · What all can these results help someone looking to make some changes do? · What is C60 and why might it be better taken than other supplements? o I started using it On December 30 and just got to the bottom of the bottle. I did not research extensively, but found that after a week or 2 I was feeling a bit more energized and more control of the lingering symptoms from the concussion. o Studies show: The effects of C60-olive oil solutions in an experimental model of CCl4 intoxication in rat strongly suggest that the effect on lifespan is mainly due to the attenuation of age-associated increases in oxidative stress. o Antioxidant qualities o C60 is one of the top 5 antioxidants you should be taking · WebMD defines them as substances that “protect the body from damage caused by harmful molecules called free radicals. Many experts believe this damage is a factor in the development of blood vessel disease (atherosclerosis), cancer, and other conditions.” Gwen's advice to her 22 year old self and her gift to share with the world.

Um den Wirkmechanismus verschiedener Krebstherapeutika aufzuklären bzw. besser zu verstehen wurden in der vorliegenden Arbeit deren Wirkungen auf Zelllinien untersucht. Hierfür wurde die Wirkung verschiedener kommerziell erhältlicher und einiger Roche-eigener Kinaseinhibitoren auf Leukämiezelllinien untereinander und mit der Wirkung von FLT3-siRNAs verglichen. Die Auswirkungen von Behandlungen mit anti-CD20- und anti-BCR-Antikörper wurden an Lymphomzelllinien analysiert. Für die FLT3-Inhibition konnte gezeigt werden, dass die Vorhersagen zur Spezifität aus der Display-Technologie in vier von fünf Fällen tendenziell richtig waren. In einem mehrstufigen Verfahren wurden verschiedene Eigenschaften der Inhibitoren getestet: Hemmung der Phosphorylierung von rekombinanter FLT3-Kinase, Hemmung der zellulären Phosphorylierung der Wildtyp-FLT3-Kinase, Hemmung der Phosphorylierung von FLT3 mit der ITD-Mutation. So konnte für die Substanzen VX-680, CHIR-265 und RKI-1 eine FLT3-Hemmung als primärer Wirkmechanismus in einer Zelllinie mit FLT3-ITD ausgeschlossen werden. Für die kommerziell erhältlichen Inhibitoren Sorafenib, CFI-2 und CFI-3 sowie die neue Substanz RKI-3 konnte bestätigt bzw. gezeigt werden, dass sie FLT3 / FLT3-ITD in biochemischen und zellulären Testsystemen spezifisch hemmen können. Die Expressionsprofilierung erwies sich für die Klärung dieser Fragestellung nur als bedingt geeignet, da die Expressionsmuster der Behandlungen mit verschiedenen Inhibitoren untereinander trotz unterschiedlicher Wirkungsweisen funktionell stark übereinstimmten. In diesen Profilen zeichnete sich bereits nach vierstündiger Behandlung ein Zellzyklusarrest ab, und im weiteren Verlauf wurden sie von Expressionsänderungen aus dem Umfeld der Apoptose dominiert. Die Inhibitoren konnten jedoch hinsichtlich der FLT3-Hemmung relativ zu einander aufgrund der Übereinstimmung mit dem Muster der Behandlung mit FLT3-siRNAs eingeordnet werden. Aus den bei beiden Behandlungsarten übereinstimmend deregulierten Genen wurden zeitabhängige FLT3-Inhibitionssignaturen abgeleitet.Die Untersuchungen zum Wirkmechanismus von Typ I anti-CD20-Antikörpern zeigten, dass der Signalweg downstream von CD20 in den getesteten Zelllinien zumindest teilweise mit dem der BCR-Aktivierung identisch ist. Obgleich die Übereinstimmung der BCR-Aktivierungsmuster der verschiedenen Zelllinien verhältnismäßig gering war, konnte gezeigt werden, dass die Transkriptionsmuster der Behandlungen mit anti-CD20- bzw. anti-BCR-Antikörpern untereinander in großen Teilen übereinstimmten. Zwei der besonders schnell und stark induzierten Gene waren CCL3 und CCL4. Die Kinase SYK ist als Signalüberträger downstream des BCR bekannt. Die Induktion der Cytokine CCL3 und CCL4 konnte durch SYK-Hemmung mittels spezifischer Inhibitoren und das siRNA-vermittelte Stilllegen von SYK deutlich vermindert werden. Somit deuten die Ergebnisse dieser Arbeit darauf hin, dass SYK auch im Signalweg von CD20 eine wichtige Rolle spielt. Durch die Behandlung von NHL-Zelllinien mit anti-CD20-Antikörpern wie Rituximab oder LT20 wird demzufolge eine zelluläre Antwort ausgelöst, die einer BCR-Aktivierung ähnelt.

Organic nanostructures are employed in various nonlinear optical applications including novel IR mode-locked fiber lasers, all-optical switching, and 3D updateable holographic display technology. This presentation will focus on our advances in this area including, 1. Sources: Using fiber taper based carbon nanotube saturable absorber, we have demonstrated an all-fiber thulium-doped wavelength mode-locked laser operating near 2 µm with over 50nm tuning range. 2. All-optical switching: Liquids such as CCl4, CS2, and organic solutions in liquid core optical fiber (LCOF) offer an effective platform to study nonlinear optical phenomena, e.g. Raman scattering, four-wave mixing and supercontinuum generation. In these devices the long interaction length is combined with a strong field confinement to enable extremely low power operation. Our observation of all-optical switching using inverse Raman scattering in LCOF with > 20dB contrast at a time scale < 5ps will be described. 3. 3D holographic display: The use of organics and nanostructures in holographic updateable 3D display will be summarized.