Podcasts about ppar

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This week's expert, Hepatologist and Key Opinion Leader Mazen Noureddin, joins Roger to discuss major advances in drug development over the past year. He covers a range of different drug classes, focusing on stages of development and the range of options within each class. First, Mazen discusses a tremendously exciting group of FGF-21 agents, specifically mentioning Akero Therapeutics's efruxifermin, 89bio's pegozafermin, and Boston Pharmaceuticals's efimosfermin. He points to efruxifermin's 96-week results to suggest that FGF-21s might be appropriate for a wide range of patients, the idea that the drug's duration of effect may make the idea of “induction therapy” less appropriate, and the exciting early data on cirrhosis patients. He also mentions pegozafermin's publication of data in the New England Journal of Medicine and efimosfermin's promising data based on monthly dosing. Next, Mazen provides some detail on the various incretin agonist options, why hepatologists are particularly excited about combinations that include a glucagon agent, and what kinds of results we might expect in upcoming trials. Finally, Mazen discusses other promising compounds in later-stage development, including the pan-PPAR lanifibranor and the FASN inhibitor denifenstat. He notes ongoing work on new classes and combination therapies. 

00:00:00 - Surf's Up: Season 6 Episode 4 Surfing the MASH Tsunami concludes its coverage of the AASLD Emerging Trends Conference on MASLD, MetALD and ALD. This week, the panelists focus on pivotal messages that attendees took away from the conference and what messages they would like to share with listeners. Our newsmaker, Fatty Liver Alliance and CEO Mike Betel, discusses the lessons he has taken from being invited to a far wider swath of conferences this year and shares the messages he delivers to these new audiences. Finally, our expert, hepatology research and key opinion leader Mazen Noureddin, discusses recent advances in drug development, focusing on agents in Phase 3 trials.00:04:24 - IntroductionHost Roger Green briefly describes this episode's three sections and one key lesson from each.00:06:03 - Roundtable: Highlights from the AASLD Emerging Trends Conference, Part 4This is the concluding portion of our Emerging Trends Conference Roundtable. The group focuses on key lessons they have learned and messages they would like listeners to take from this conversation.  The pivotal idea is that SLD is a spectrum running from MASLD through MetALD to ALD. Researchers and treaters will all do best in developing and implementing therapies and guidelines with this thought in mind. Aleksander Krag stresses this idea and notes that, with several different classes of drugs demonstrating positive impact, it will be an exciting decade ahead as we learn how to apply these drugs along the spectrum. Jenn Jones and Alex Lalos note the importance of identifying MetALD, although Jenn noted that it does not seem wise to conduct trials solely with MetALD patients at this time.  00:22:04 - Newsmaker: Mike Betel on the Increased Visibility of Patient AdvocatesThis week's newsmaker, Mike Betel, has experienced a significant increase in the number of conferences at which he is invited to speak or appear on a panel. This discussion centers around the reasons Mike believes this is happening and the message(s) he delivers. To Mike, his most important contribution lies in the amount of information he sends back from each event, many of which surpass 30% download rates (and some even hit 50%). He discusses his value in diabetes, endocrinology and obesity meetings, where he brings a "liver" perspective and co-education opportunity to these events. The entire experience has taught him about the need not to stigmatize patients and reinforced his belief in the importance of tailoring care to patients' needs and personalities. 00:49:28 - Expert: Mazen Noureddin on the Exciting MASLD Drug Development EnvironmentHepatologist and Key Opinion Leader Mazen Noureddin joins Roger to discuss major advances in drug development over the past year. He covers a range of different drug classes, focusing on stages of development and the range of options within each class. Specifically, he discusses the FGF-21 agents, the range of patients for whom they might be appropriate, how efruxifermin's 96-week results may make the idea of "induction therapy" less appropriate,  and the exciting early data on cirrhosis patients. He provides some detail on the various incretin agonist options, why hepatologists are particularly excited about combinations that include a glucagon agent, and what kinds of results we might expect in upcoming trials. He goes on to discuss the pan-PPAR lanifibranor, the FASN inhibitor denifenstat, and notes ongoing work on new classes and combination therapies. In general, he paints, I think, not a rosy, but an extremely optimistic picture of what the future will be for patients who need to be treated for fatty liver. 01:09:38 - Business Report Roger discusses the next Roundtable and provides some details on SurfingMASH's coverage of the upcoming EASL Congress.

In this podcast, expert faculty, Dr Stuart Gordon and Dr Nancy Reau, use an illustrative patient case to explore the roles of ALP and other biochemical markers in PBC management, and explain what to expect from treatment. Topics covered include: How baseline ALP can affect ALP normalization after second-line treatment with elafibranor and seladelparPotential outcomes if ALP normalization cannot be achievedThe importance of managing fatigue, pruritus, and sleep disturbances independently of the biochemical responsePresenters:Stuart C. Gordon, MDProfessor of MedicineWayne State University School of MedicineDirector, Division of HepatologyHenry Ford HealthDetroit, MichiganNancy Reau, MDProfessor of MedicineRichard B. Capps Chair of HepatologyChief, Section of HepatologyAssociate Director, Solid Organ TransplantationRush University Medical CenterChicago, IllinoisTo learn more about PBC management, check out our program, Curbside Consults: Expert Insights on Challenges in PBC Management.  

In this podcast, expert faculty, Dr Stuart Gordon and Dr Nancy Reau discuss an illustrative patient case to demonstrate how they individualize primary biliary cholangitis (PBC) therapy for patients ​with cirrhosis. Topics covered include:AASLD guideline recommendations for second-line therapy for PBCConsiderations when using newer agents for second-line treatment of PBC in patients with cirrhosis: elafibranor and seladelparPresenters:Stuart C. Gordon, MD Professor of MedicineWayne State University School of MedicineDirector, Division of HepatologyHenry Ford HealthDetroit, MichiganNancy Reau, MD Professor of MedicineRichard B. Capps Chair of HepatologyChief, Section of HepatologyAssociate Director, Solid Organ TransplantationRush University Medical CenterChicago, IllinoisTo learn more about PBC management, check out our program, Curbside Consults: Expert Insights on Challenges in PBC Management.

How do you decide when to move from first-line to second-line treatment for primary biliary cholangitis (PBC)? In this podcast, listen as experts Alan Bonder, MD, AGAF, and Aparna Goel, MD, discuss this question and more, including:How and when to measure treatment responseEvidence-based goals of therapyConsiderations for second-line treatmentNew agents for second-line treatment: PPAR agonistsPresenters:Alan Bonder, MD, AGAFAssociate Professor of MedicineMedical Director of Liver TransplantDepartment of GastroenterologyBeth Israel Deaconess Medical CenterHarvard Medical SchoolBoston, MassachusettsAparna Goel, MDAssociate Clinical Professor of MedicineDivision of Gastroenterology and HepatologyStanford UniversityPalo Alto, CaliforniaContent based on an online CME program supported by independent educational grants from Gilead Sciences, Inc., and Ipsen Biopharmaceuticals, Inc​.To learn more about PBC management, check out our program, Curbside Consults: Expert Insights on Challenges in PBC Management.Supported by educational grants from Gilead Sciences, Inc. and Ipsen Biopharmaceuticals, Inc

In this podcast, listen as experts Alan Bonder, MD, AGAF, and Aparna Goel, MD, discuss how they assess the symptoms of primary biliary cholangitis (PBC) and explore how new therapeutic agents may help alleviate symptom burden. Topics include:Strategies and tools for assessing pruritusNonpharmacologic and pharmacologic management of pruritusSecond-line agents and their impact on pruritusInvestigational treatments for pruritusPresenters:Alan Bonder, MD, AGAFAssociate Professor of MedicineMedical Director of Liver TransplantDepartment of GastroenterologyBeth Israel Deaconess Medical CenterHarvard Medical SchoolBoston, MassachusettsAparna Goel, MDAssociate Clinical Professor of MedicineDivision of Gastroenterology and HepatologyStanford UniversityPalo Alto, CaliforniaContent based on an online CME program supported by independent educational grants from Gilead Sciences, Inc., and Ipsen Biopharmaceuticals, Inc​.To learn more about PBC management, check out our program, Curbside Consults: Expert Insights on Challenges in PBC Management.

In this podcast, Sonal Kumar, MD, MPH, meets with patient advocate Maria Morais to discuss actionable steps that healthcare providers can incorporate into the care of people with primary biliary cholangitis (PBC). Listen as they discuss:The chronic nature of PBCGoing beyond biochemical markers to assess and address symptoms such as fatigue and pruritusThe importance of referral to patient support groupsPresenters:Sonal Kumar, MD, MPHAssistant Professor of MedicineDirector, General Gastroenterology and HepatologyWeill Cornell Medical CollegeNew York, New YorkMaria G. Morais, RNVP Patient AdvocacyCanadian PBC SocietyToronto, CanadaTo learn more, see the program Hear Me: Patient Perspectives on PBC

In this episode, Christopher L. Bowlus, MD, discusses recent advances in the management of primary biliary cholangitis (PBC), including:Treatment goalsUse of PPAR agonists for the treatment of PBCClinical trial results for elafibranor (ELATIVE), seladelpar (RESPONSE), and bezafibrate (BEZURSO)Presenter:Christopher L. Bowlus, MDLena Valente Professor and ChiefDivision of Gastroenterology and HepatologyUniversity of California Davis School of MedicineSacramento, CaliforniaLink to full program: https://bit.ly/41tvSDuGet access to all of our new podcasts by subscribing to the CCO Infectious Disease Podcast on Apple Podcasts, Google Podcasts, or Spotify.

In this episode, Christopher L. Bowlus, MD, discusses recent advances in the management of primary biliary cholangitis (PBC), including:Treatment goalsUse of PPAR agonists for the treatment of PBCClinical trial results for elafibranor (ELATIVE), seladelpar (RESPONSE), and bezafibrate (BEZURSO)Presenter:Christopher L. Bowlus, MDLena Valente Professor and ChiefDivision of Gastroenterology and HepatologyUniversity of California Davis School of MedicineSacramento, CaliforniaLink to full program: https://bit.ly/41tvSDuGet access to all of our new podcasts by subscribing to the CCO Infectious Disease Podcast on Apple Podcasts, Google Podcasts, or Spotify.

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CME credits: 1.00 Valid until: 08-11-2025 Claim your CME credit at https://reachmd.com/programs/cme/pbc-is-risky-business/29109/ Primary biliary cholangitis (PBC) is a chronic cholestatic autoimmune liver disease characterized by a destructive, small duct, and lymphocytic cholangitis, and marked by the presence of antimitochondrial antibodies. Outcomes largely depend on early recognition of the disease and prompt institution of treatment. First-line treatment consists of ursodeoxycholic acid, but not all patients sufficiently respond to treatment. It is thus important to monitor patients for response to therapy to know when to initiate second-line treatment. The recent approval of PPAR agonists has greatly improved second-line treatment options, as these therapies not only elicited significantly better biochemical responses and normalized bilirubin levels but also improved extrahepatic symptoms including pruritus and fatigue, leading to better quality of life.

CME credits: 1.00 Valid until: 08-11-2025 Claim your CME credit at https://reachmd.com/programs/cme/does-your-patient-have-pbc/29108/ Primary biliary cholangitis (PBC) is a chronic cholestatic autoimmune liver disease characterized by a destructive, small duct, and lymphocytic cholangitis, and marked by the presence of antimitochondrial antibodies. Outcomes largely depend on early recognition of the disease and prompt institution of treatment. First-line treatment consists of ursodeoxycholic acid, but not all patients sufficiently respond to treatment. It is thus important to monitor patients for response to therapy to know when to initiate second-line treatment. The recent approval of PPAR agonists has greatly improved second-line treatment options, as these therapies not only elicited significantly better biochemical responses and normalized bilirubin levels but also improved extrahepatic symptoms including pruritus and fatigue, leading to better quality of life.

CME credits: 1.00 Valid until: 08-11-2025 Claim your CME credit at https://reachmd.com/programs/cme/dont-forget-theres-a-sleepy-patient-behind-those-numbers/29112/ Primary biliary cholangitis (PBC) is a chronic cholestatic autoimmune liver disease characterized by a destructive, small duct, and lymphocytic cholangitis, and marked by the presence of antimitochondrial antibodies. Outcomes largely depend on early recognition of the disease and prompt institution of treatment. First-line treatment consists of ursodeoxycholic acid, but not all patients sufficiently respond to treatment. It is thus important to monitor patients for response to therapy to know when to initiate second-line treatment. The recent approval of PPAR agonists has greatly improved second-line treatment options, as these therapies not only elicited significantly better biochemical responses and normalized bilirubin levels but also improved extrahepatic symptoms including pruritus and fatigue, leading to better quality of life.

CME credits: 1.00 Valid until: 08-11-2025 Claim your CME credit at https://reachmd.com/programs/cme/pbc-target-practice-normalization-is-the-new-norm/29110/ Primary biliary cholangitis (PBC) is a chronic cholestatic autoimmune liver disease characterized by a destructive, small duct, and lymphocytic cholangitis, and marked by the presence of antimitochondrial antibodies. Outcomes largely depend on early recognition of the disease and prompt institution of treatment. First-line treatment consists of ursodeoxycholic acid, but not all patients sufficiently respond to treatment. It is thus important to monitor patients for response to therapy to know when to initiate second-line treatment. The recent approval of PPAR agonists has greatly improved second-line treatment options, as these therapies not only elicited significantly better biochemical responses and normalized bilirubin levels but also improved extrahepatic symptoms including pruritus and fatigue, leading to better quality of life.

CME credits: 1.00 Valid until: 08-11-2025 Claim your CME credit at https://reachmd.com/programs/cme/initiating-second-line-therapy-what-when-and-then-what/29111/ Primary biliary cholangitis (PBC) is a chronic cholestatic autoimmune liver disease characterized by a destructive, small duct, and lymphocytic cholangitis, and marked by the presence of antimitochondrial antibodies. Outcomes largely depend on early recognition of the disease and prompt institution of treatment. First-line treatment consists of ursodeoxycholic acid, but not all patients sufficiently respond to treatment. It is thus important to monitor patients for response to therapy to know when to initiate second-line treatment. The recent approval of PPAR agonists has greatly improved second-line treatment options, as these therapies not only elicited significantly better biochemical responses and normalized bilirubin levels but also improved extrahepatic symptoms including pruritus and fatigue, leading to better quality of life.

CME credits: 1.00 Valid until: 08-11-2025 Claim your CME credit at https://reachmd.com/programs/cme/dont-forget-theres-an-itchy-patient-behind-those-numbers/29113/ Primary biliary cholangitis (PBC) is a chronic cholestatic autoimmune liver disease characterized by a destructive, small duct, and lymphocytic cholangitis, and marked by the presence of antimitochondrial antibodies. Outcomes largely depend on early recognition of the disease and prompt institution of treatment. First-line treatment consists of ursodeoxycholic acid, but not all patients sufficiently respond to treatment. It is thus important to monitor patients for response to therapy to know when to initiate second-line treatment. The recent approval of PPAR agonists has greatly improved second-line treatment options, as these therapies not only elicited significantly better biochemical responses and normalized bilirubin levels but also improved extrahepatic symptoms including pruritus and fatigue, leading to better quality of life.

CME credits: 1.00 Valid until: 08-11-2025 Claim your CME credit at https://reachmd.com/programs/cme/advances-in-the-treatment-of-pbc-part-1/29114/ Primary biliary cholangitis (PBC) is a chronic cholestatic autoimmune liver disease characterized by a destructive, small duct, and lymphocytic cholangitis, and marked by the presence of antimitochondrial antibodies. Outcomes largely depend on early recognition of the disease and prompt institution of treatment. First-line treatment consists of ursodeoxycholic acid, but not all patients sufficiently respond to treatment. It is thus important to monitor patients for response to therapy to know when to initiate second-line treatment. The recent approval of PPAR agonists has greatly improved second-line treatment options, as these therapies not only elicited significantly better biochemical responses and normalized bilirubin levels but also improved extrahepatic symptoms including pruritus and fatigue, leading to better quality of life.

CME credits: 1.00 Valid until: 08-11-2025 Claim your CME credit at https://reachmd.com/programs/cme/advances-in-the-treatment-of-pbc-part-2/29115/ Primary biliary cholangitis (PBC) is a chronic cholestatic autoimmune liver disease characterized by a destructive, small duct, and lymphocytic cholangitis, and marked by the presence of antimitochondrial antibodies. Outcomes largely depend on early recognition of the disease and prompt institution of treatment. First-line treatment consists of ursodeoxycholic acid, but not all patients sufficiently respond to treatment. It is thus important to monitor patients for response to therapy to know when to initiate second-line treatment. The recent approval of PPAR agonists has greatly improved second-line treatment options, as these therapies not only elicited significantly better biochemical responses and normalized bilirubin levels but also improved extrahepatic symptoms including pruritus and fatigue, leading to better quality of life.

Chris Duffin sits down with expert Anthony Castor to dive into the controversial world of nicotine and its effects on our brain and body. We'll explore how nicotine impacts neurotransmitters like dopamine, acetylcholine, norepinephrine, serotonin, and glutamate—shedding light on its roles in mood regulation, cognitive enhancement, fat loss, and even immune support. Together, Chris and Anthony will discuss the benefits and risks of nicotine use, comparing different delivery methods like gum, patches, and inhalers, and emphasizing the importance of moderation. They'll also delve into the historical context of nicotine, its pharmacokinetics, and its potential for aiding conditions like Alzheimer's, Parkinson's, and autoimmune diseases. Additionally, we'll hear about cutting-edge treatments in neural therapy and the synergy between nicotine and other cognitive enhancers. So, whether you're curious about the scientific intricacies or practical applications of nicotine, stay tuned for an engaging and informative discussion on harnessing the power of this complex compound for resilience and peak performance.   Anthony Castor is a distinguished chemist and researcher, renowned for his work on the effects of alkaloids on the human nervous system. Inspired by the early 19th-century discoveries of Wilhelm Heinrich Posselt and Carl Ludwig Reinman, who first isolated nicotine, Anthony has dedicated his career to examining its profound impact on body chemistry. With a keen focus on how nicotine binds to nicotinic acetylcholine receptors, Anthony's research has advanced our understanding of this powerful alkaloid, positioning him as a leading figure in the field of neurochemistry. His work continues to shed light on the complexities of naturally occurring compounds like nicotine, caffeine, and morphine, all of which share the commonality of containing nitrogen. This episode of the ARCHITECT of RESILIENCE podcast is available on Apple, Spotify & YouTube, and is sponsored by  @naboso_technology : The Foundation of Movement.

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Avsnitt 238 - Sebbe tar semester och stjärnan stäppar in by jaktsnack

Biden och Trump igen. Hur kunde det bli så här? Live på Parkteatern i Stockholm 4 juli 2024. Lyssna på alla avsnitt i Sveriges Radio Play. Förutsatt att Joe Biden inte hoppar av kommer presidentvalet 2024 att stå mellan två historiskt impopulära kandidater i ett djupt polariserat land.I detta avsnitt utforskar vi hur Demokraterna kunde utse en 80-plussare till kandidat och sedan bli förvånade när han verkade märkt av sin ålder.Och hur det kommer sig att Republikanerna kunde sluta upp bakom Donald Trump efter att först ha förkastat honom för hans roll i stormningen av kongressen 2021?Avsnittet spelades in på Parkteaterns scen i Stockholm torsdag 4 juli 2024.Medverkande: Ginna Lindberg och Roger Wilson, Sveriges Radios USA-korrespondenter.Programledare: Sara StenholmProducent: Viktor MattssonTekniker: Christer Tjernell

BUFFALO, NY- July 10, 2024 – A new #research paper was #published in Aging (listed by MEDLINE/PubMed as "Aging (Albany NY)" and "Aging-US" by Web of Science) Volume 16, Issue 12, entitled, “Aging exacerbates oxidative stress and liver fibrosis in an animal model of Down Syndrome.” Down Syndrome (DS) is a common genetic disorder characterized by an extra copy of chromosome 21, leading to dysregulation of various metabolic pathways. Oxidative stress in DS is associated with neurodevelopmental defects, neuronal dysfunction, and a dementia onset resembling Alzheimer's disease. Additionally, chronic oxidative stress contributes to cardiovascular diseases and certain cancers prevalent in DS individuals. In this new study, researchers Sebastiano Giallongo, Jessica Ferrigno, Rosario Caltabiano, Giuseppe Broggi, Amer M. Alanazi, Alfio Distefano, Emanuela Tropea, Antonella Tramutola, Marzia Perluigi, Giovanni Li Volti, Eugenio Barone, and Ignazio Alberto Barbagallo from the University of Catania, King Saud University, and Sapienza University of Rome investigated the impact of aging on oxidative stress and liver fibrosis using a DS murine model (Ts2Cje mice). “Our results show that DS mice show increased liver oxidative stress and impaired antioxidant defenses, as evidenced by reduced glutathione levels and increased lipid peroxidation.” DS liver exhibited an altered inflammatory response and mitochondrial fitness as the researchers showed by assaying the expression of HMOX1, CLPP, and the heat shock proteins Hsp90 and Hsp60. DS liver also displayed dysregulated lipid metabolism, indicated by altered expression of PPARα, PPARγ, FATP5, and CTP2. Consistently, these changes might contribute to non-alcoholic fatty liver disease development, a condition characterized by liver fat accumulation. Consistently, histological analysis of DS liver revealed increased fibrosis and steatosis, as showed by Col1a1 increased expression, indicative of potential progression to liver cirrhosis. Therefore, their findings suggest an increased risk of liver pathologies in DS individuals, particularly when combined with the higher prevalence of obesity and metabolic dysfunctions in DS patients. “These results shed a light on the liver's role in DS-associated pathologies and suggest potential therapeutic strategies targeting oxidative stress and lipid metabolism to prevent or mitigate liver-related complications in DS individuals.” DOI - https://doi.org/10.18632/aging.205970 Corresponding author - Giovanni Li Volti - livolti@unict.it Video short - https://www.youtube.com/watch?v=8GlAruy0xfk Sign up for free Altmetric alerts about this article - https://aging.altmetric.com/details/email_updates?id=10.18632%2Faging.205970 Subscribe for free publication alerts from Aging - https://www.aging-us.com/subscribe-to-toc-alerts Keywords - aging, Down Syndrome, oxidative stress, liver About Aging-US The mission of the journal is to understand the mechanisms surrounding aging and age-related diseases, including cancer as the main cause of death in the modern aged population. The journal aims to promote 1) treatment of age-related diseases by slowing down aging, 2) validation of anti-aging drugs by treating age-related diseases, and 3) prevention of cancer by inhibiting aging. (Cancer and COVID-19 are age-related diseases.) Please visit our website at https://www.Aging-US.com​​ and connect with us: Facebook - https://www.facebook.com/AgingUS/ X - https://twitter.com/AgingJrnl Instagram - https://www.instagram.com/agingjrnl/ YouTube - https://www.youtube.com/@AgingJournal LinkedIn - https://www.linkedin.com/company/aging/ Pinterest - https://www.pinterest.com/AgingUS/ Spotify - https://open.spotify.com/show/1X4HQQgegjReaf6Mozn6Mc MEDIA@IMPACTJOURNALS.COM

Check out Nascentmc.com for medical writing assistance. visit learnAMAstyle.com for free downloads on medical writing and editing Adbry for Atopic Dermatitis The FDA has approved tralokinumab-ldrm (Adbry) as a 300 mg single-dose autoinjector for moderate-to-severe atopic dermatitis (AD) in adults, offering a more convenient delivery method. Adbry, which inhibits IL-13, was previously approved for adults in December 2021 and for pediatric patients aged 12 and older in December 2023. The approval was granted to LEO Pharma Inc.  Augtyro for NTRK Tumors The FDA has approved repotrectinib (Augtyro) for treating solid tumors with NTRK gene fusions in patients aged 12 and older, based on Phase 1/2 trials showing significant response rates in both TKI-naïve and previously treated patients. The approval was granted to Bristol Myers Squibb, with additional clinical data required to confirm safety and efficacy. Donanemab for Alzheimer's FDA advisors unanimously recommended the approval of donanemab for Alzheimer's disease, emphasizing its efficacy in slowing early-stage disease and manageable risks. Donanemab, targeting amyloid plaques, offers potential advantages over Leqembi with monthly infusions. The FDA decision is expected soon. Iqirvo for Primary Biliary Cholangitis The FDA granted accelerated approval to elafibranor (Iqirvo) for primary biliary cholangitis (PBC) to be used with ursodeoxycholic acid or as monotherapy. Elafibranor targets PPAR-α and PPAR-δ, with Phase 2 trials showing significant biochemical responses. The approval was granted to GENFIT and Ipsen.  Retevmo in Thyroid Cancer The FDA granted full approval to selpercatinib (Retevmo) for advanced or metastatic RET fusion–positive thyroid cancer in patients aged 2 years and older, based on the LIBRETTO-001 trial showing high response rates. The approval was granted to Eli Lilly and Company. OTC Continuous Glucose Monitors The FDA approved Abbott Laboratories' continuous glucose monitoring systems, Libre Rio and Lingo, for over-the-counter use. Libre Rio is for Type 2 diabetes patients not on insulin, while Lingo targets non-diabetic consumers for health improvement. These systems provide real-time glucose monitoring via a smartphone app. Check out Nascentmc.com for medical writing assistance.visit learnAMAstyle.com for free downloads on medical writing and editing  

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A new study entitled, “The Efficacy of Palmitoylethanolamide (Levagen+) on the Incidence and Symptoms of Upper Respiratory Tract Infection-A Double Blind, Randomised, Placebo-Controlled Trial” aimed to evaluate the effectiveness of a signaling lipid called Palmitoylethanolamide (PEA) in reducing the occurrence, duration, and severity of upper respiratory tract infections(URTIs). The results showed that participants who took PEA experienced fewer URTI episodes and had reduced symptoms compared to those who took a placebo, suggesting that PEA may be a safe and effective treatment option for URTIs. Palmitoylethanolamide (PEA) is a lipid compound that belongs to the N-acylethanolamine (NAE) family and has similar properties to endocannabinoids. In the context of cold and flu infections, PEA is suggested to regulate interleukins and inhibit mast cell production, thereby reducing inflammation. PEA activates NF-κB pathways through peroxisome proliferator-activated receptors (PPAR), particularly PPAR-α, and concentration-dependent mechanisms to decrease NLRP3 and inflammasome activation, ultimately leading to a decrease in the expression of cytokines and alleviation of upper respiratory tract infection symptoms. It is worth noting that the natural levels of PEA in the body and the use of PEA supplements have been found to be ineffective in producing significant clinical results due to poor absorption, resulting in low levels of PEA in the bloodstream. However, when PEA is combined with dispersion technology, such as Levagen+, the absorption of PEA is greatly improved, leading to higher concentrations in the bloodstream, which may enable a therapeutic effect. This study was conducted over a period of 12 weeks. It was a double-blind, randomized, placebo-controlled trial, where participants were divided into two groups: an active group receiving 300 mg of Levagen+ PEA twice a day and a placebo group receiving maltodextrin. The purpose of the study was to investigate the efficacy of Levagen+ PEA compared to the placebo in terms of the incidence, severity, and duration of upper respiratory tract infections (URTI).   During the study, 87 participants out of the total enrolled experienced at least one URTI, resulting in a total of 103 URTI episodes. The group receiving Levagen+ PEA reported significantly fewer URTI episodes (39) compared to the placebo group (64), and a lower number of participants who fell sick at least once during the study (32 vs. 55) when compared to the placebo group. Participants in the Levagen+ PEA group reported a significantly lower severity score for scratchy throat and cough. Overall, compliance with the study was high for both groups in terms of capsule consumption. The findings of the study indicate that individuals in the Levagen+ PEA group had a significantly lower number of upper respiratory tract infection (URTI) episodes compared to the placebo group. The study suggests that Levagen+ PEA could be a viable treatment for preventing upper respiratory tract infections (URTIs) and alleviating symptoms of cold and flu. The findings indicate that Levagen+ PEA is safe and effective in reducing the frequency of URTI episodes and relieving scratchy throats and coughing in individuals with URTI symptoms. I use PEA Luteolin Select from Moss Nutrition, which contains 300 mg of Levagen+ PEA and 50 mg of the flavonoid luteolin per capsule. PEA and luteolin have been shown to work synergistically in COVID-19-related illnesses such as Long COVID. I have patients take 1 capsule twice a day with meals of PEA Luteolin Select during COVID-19, cold, and flu season for prevention and then increase to 2 capsules three times a day when they feel like they're coming down with something. Hedberg Institute Members can download my latest upper respiratory tract infection protocols by logging in. Click here to learn more about the Hedberg Institute Membership.

References General and Comparative Endocrinology,2018-06-01, Volume 262, Pages 27-35 Pisendel JG 1735.Violin Concerto in D major, JunP I.5. https://youtu.be/dvwhXXvFiNg?si=YfS2waKLC5WHy0En --- Send in a voice message: https://podcasters.spotify.com/pod/show/dr-daniel-j-guerra/message Support this podcast: https://podcasters.spotify.com/pod/show/dr-daniel-j-guerra/support

References General and Comparative Endocrinology 2018-06-01, Volume 262, Pages 27-35. Immunohorizons. 2022 Jun 22; 6(6): 366–372. Biochem J. 2009 Dec 14;425(1):265-74. Nature. 2023; 614(7948): 530–538. Winwood,S. 1969 Blind Faith "Had to Cry Today". https://youtu.be/Z4Yo_VbGdMg?si=3whbMcoWNFtfgPwE --- Send in a voice message: https://podcasters.spotify.com/pod/show/dr-daniel-j-guerra/message Support this podcast: https://podcasters.spotify.com/pod/show/dr-daniel-j-guerra/support

During the 2023 American Association for the Study of Liver Diseases conference, exciting and important results from many primary biliary cholangitis (PBC) clinical trials were reported, including 3 late-breaking studies on the PPAR-δ agonist seladelpar, the dual PPAR agonist elafibranor, and the combination of the FXR agonist obeticholic acid and a fibrate.In this episode, Kris V. Kowdley MD, FAASLD, FACP, FACG, discusses topline results from several of these studies and more, including: A combination of 3 studies—HEROES, COBALT, and COBALT EC—that evaluated the real-world effectiveness and safety of second-line therapy in PBC where OCA was added to the treatment regimen of people with PBC with an incomplete response to ursodeoxycholic acid Lessons learned from a long-term outcomes study of people with PBCResults from 2 phase II studies of obeticholic acid plus bezafibrate in people with PBC who did not respond to or were intolerant of ursodeoxycholic acidPresenter:Kris V. Kowdley MD, FAASLD, FACP, FACGProfessor, Elson S. Floyd College of MedicineWashington State UniversityDirector, Liver Institute NorthwestSeattle, Washington      Link to reviews of other PBC studies from AASLD 2023: https://bit.ly/3RvXXEI

During the 2023 American Association of the Study of Liver Diseases (AASLD) conference, exciting and important results from many primary biliary cholangitis (PBC) clinical trials were reported, including 3 late-breaking studies on the PPAR-delta agonist seladelpar, the dual PPAR agonist elafibranor, and the combination of the FXR agonist obeticholic acid and a fibrate.In this episode, Stuart C. Gordon, MD, FAASLD, discusses topline results from one of these late-breaking studies and more, including: A phase III study of an investigational PPAR-delta agonist (seladelpar) in people with PBC who had failed to respond to ursodeoxycholic acidA study that explored racial differences as they relate to the presentation and diagnosis of PBCPresenter: Stuart C. Gordon, MD, FAASLDDirector of HepatologyHenry Ford Health SystemProfessor of MedicineWayne State University School of MedicineDetroit, MichiganLink to commentary:https://bit.ly/3GzRMt2Link to reviews of other PBC studies from AASLD 2023:https://bit.ly/3RvXXEI

During the 2023 American Association of the Study of Liver Diseases (AASLD) conference, exciting and important results from many primary biliary cholangitis (PBC) clinical trials were reported, including 3 late-breaking studies on the PPAR-delta agonist seladelpar, the dual PPAR agonist elafibranor, and the combination of the FXR agonist obeticholic acid and a fibrate.In this episode, Marlyn J. Mayo, MD, discusses topline results from several of these studies and more, including: A phase III study of an investigational dual PPAR α/δ agonist (elafibranor) in people with PBC who did not respond to or were intolerant of ursodeoxycholic acid (UDCA)A study that evaluated the effectiveness and safety of second-line therapy in PBC where obeticholic acid with or without a fibrate was added to the treatment regimen of people with PBC with an incomplete response to UDCAA retrospective review of the rates of hyperlipidemia, atherosclerosis, and/or hepatic steatosis in patients with PBCPresenter: Marlyn J. Mayo, MDProfessor of Internal MedicineDivision of Digestive & Liver DiseasesUT Southwestern Medical CenterDallas, TexasLink to commentary:https://bit.ly/47PmGdcLink to reviews of other PBC studies from AASLD 2023: https://bit.ly/3RvXXEI

Hepatology researchers and key opinion leaders Profs. Laurent Castera and Scott Friedman join Louise Campbell and Roger Green in the final element of our review coverage of TLM 2023. This far-ranging conversation moves beyond MASLD/NAFLD and MASH/NASH to consider an array of topics.The episode starts with Roger asking the other guests for their general impressions of the meeting. Three key insights: 1.    "Pre-pandemic" levels of interaction and discussion among attendees2.     Online meeting app was a "fail", becoming a topic of conversation in its own right while fostering confusion3.    In the "frenzy" about the anticipated resmetirom approval and other MASH drugs approaching market,  we shouldn't overlook that patients with PBC will soon have two new exciting PPAR agents, elafibranor and seladelpar. As Scott notes, we also learned about promising modes of action for PSC so, overall, a promising meeting for rare cholestatic diseases. The rest of this discussion covers multiple topics, key among them:  ·      Impact of FGF-21 and FGF-19 agents on patients with compensated cirrhosis. Roger is optimistic that agents might provide improvement. Scott is more pessimistic because we do not have agents addressing the unique mechanistic challenges in cirrhosis vs. advanced fibrosis. Both agree that agents on the horizon can buy time until curative or regressive medications arrive. ·      AI-based analysis. Roger bridges to Stephen Harrison's presentation of HistoIndex analysis of resmetirom that produces an estimate of 54% efficacy vs. 34% placebo. He comments that given this analysis and that bariatric surgery studies tell us fibrosis regression may take five years, the FDA one-year standard might be so stringent as to be misleading. ·      Bariatric surgery. Laurent refers to a presentation from Phillippe Mathurin's group demonstrating that in patients post-bariatric surgery, MASH resolution and fibrosis regression clearly lead to improved outcomes. ·      NITs. Laurent discusses a poster from a multi-country 16,000-patient cohort that did not confirm liver stiffness as leading to a decline in MALO over a two-year period but anticipates more robust findings over time. ·      VCTE-based analysis. Louise discusses two posters with analyses based on FibroScan. The first, from the Virginia Commonwealth University and the VA, found that liver stiffness correlates with success in liver transplant and that CAP can predict the risk of future MI in these patients. She notes that CAP of 270 served as "its own parameter" in predicting time to mortality. ·      Nomenclature. Roger notes that a Saturday morning session resolved the two most pivotal outstanding issues about the effect of nomenclature change on scientific development. FDA signaled that the agency views old and new nomenclature terms as interchangeable. NIMBLE and LITMUS analysis determined that patient mapping is also interchangeable.·      Impact of triple-agents. Presentations at this conference confirm that triple agents addressing GLP-1, glucagon and GIP can have bariatric surgery-level impact on liver fat and reduce the entire disease burden. Interspersed between these topics are a range of insights on cirrhosis disease models, regulatory slowness in moving on from current conditional efficacy metrics, treater supply vs. patient demand, "stigma", and basic science. This is a high-level view of an information-dense conversation. Listen to learn more and hear all the details.  

This month, Surfing NASH embarks on a series of episodes dedicated to takeaways emerging from June's two major conferences: the 2023 EASL Congress in Vienna and the American Diabetes Association's 83rd Scientific Sessions meeting in San Diego. In doing so, the Big Band of Surfers (Stephen Harrison, Jörn Schattenberg, Louise Campbell and Roger Green) are joined by Mazen Noureddin for a fascinating conversation which covers compelling data and ideas emerging from the drug development space. Jörn and Mazen begin by prompting Stephen with questions around the FASCINATE-2 study outlined in the previous conversation. Stephen confirms that the data presented was based on a planned interim analysis of a prespecified subset of patients at week 26 of a 52-week trial. Mazen next asks questions designed to challenge Stephen to reveal how excited he truly is about the drug (denifanstat) and surrounding data. Specifically, Mazen asks whether denifanstat feels like an add-on agent when compared to more 'mainstream' FGF-21 agents. Stephen responds by referring to a need for what he characterizes as a plethora of agents before commenting on possible and practical differences between orals and injectables. He suggests that injectables seem to produce faster drops in liver fat reduction and ALT improvements than orals, although orals may 'catch up' over time in a sort of 'tortoise and the hare' phenomenon. From here Stephen describes the ways which he might use injectables first in more severe patients before introducing orals after achieving the desired effect. He also talks about simply starting with orals in less severe patients. The group digs deeper into these ideas by introducing ACC inhibitors and pan-PPAR agonist, lanifibranor, to the conversation. Finally, concluding comments return to the theme that injectables might produce stronger efficacy results, although there are several agents yet to be clearly differentiated among orals. Each conversation covers a lot of ground on drug development, analysis of trial results, and the upcoming increases in importance of omics and artificial intelligence. If you have questions or comments around the EASL Congress or ADA meetings, or the themes and data discussed in this episode, we kindly ask that you submit reviews wherever you download the discourse. Alternatively, you can write to us directly at questions@SurfingNASH.com.Stay Safe and Surf On

Dr Gideon Hirschfield from the University of Toronto Centre for Liver Disease discusses the potential of new drugs, including selective PPAR agents such as seladelpar, for the treatment of primary biliary cholangitis.

Dr Gideon Hirschfield from the University of Toronto discusses the potential of new drugs, including selective PPAR agents such as seladelpar, for the treatment of primary biliary cholangitis.

Alexandra har anmält en taxichaufför, Dasha har gjort injektioner i både läppar och kinder för första gången i sitt liv och så diskuteras det om Ariel är en slampa och om man verkligen behöver manuellt körkort eller om det faktiskt bara räcker med automat. Följ oss på instagram @ordochallavisor!‘Ord och alla visor' är producerad av Silverdrake Förlag via Acastwww.silverdrakeförlag.seKlippare:Patrik Sundén@patriksundenRedaktör:Marcus Tigerdraake, marcus@silverdrakeforlag.se@marcustigerdraakeKoordinator: Victoria Tigerdraake, victoria.tigerdraake@gmail.com@victigerdraake Hosted on Acast. See acast.com/privacy for more information.

References Cells. 2019 Mar; 8(3): 227 Chest. 2016 Jul; 150(1): 91–101 JCI Insight. 2016 Nov 17; 1(19): e87748. --- Send in a voice message: https://podcasters.spotify.com/pod/show/dr-daniel-j-guerra/message

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This week, Surfing the NASH Tsunami celebrates its 3rd anniversary since the debut episode posted on April 15, 2020. We are offering a jam-packed special featuring individual interviews with guests Amy Articolo of Novo Nordisk, Donna Cryer of the Global Liver Institute, and Frédéric Cren of Inventiva Pharma.In this final interview, Frédéric, Louise Campbell and Roger Green exchange ideas around, among other topics, the history and development of Inventiva's lead product candidate, PPAR agonist lanifibranor.If you enjoy the special, have questions or interest around Fatty Liver disease, please let us know your ideas by writing to questions@SurfingNASH.com and leaving a review wherever you download the discourse.Stay Safe and Surf On!

A new research paper was published in Aging (listed by MEDLINE/PubMed as "Aging (Albany NY)" and "Aging-US" by Web of Science) Volume 15, Issue 6, entitled, “Selenium as a predictor of metabolic syndrome in middle age women.” Metabolic syndrome (MetS) is a widespread clinical entity that has become almost a global epidemic. Selenium plays an important role in metabolic homeostasis. It has been suggested that it may also affect the expression and activity of PPAR-γ—an important mediator in energy balance and cell differentiation. In this new study, researchers Daria Schneider-Matyka, Anna Maria Cybulska, Małgorzata Szkup, Bogumiła Pilarczyk, Mariusz Panczyk, Agnieszka Tomza-Marciniak, and Elżbieta Grochans from Pomeranian Medical University in Szczecin, West Pomeranian University of Technology and Medical University of Warsaw aimed to analyze the relationships between these variables in the context of the health of women, for whom the risk of MetS increases with age. “The aim of this study was to search for a relationship between selenium concentrations and MetS, and to assess the impact of PPAR-γ on the incidence of MetS with regard to the moderating role of selenium.” The study involved 390 women in middle age. The stages of study: a survey-based part; anthropometric measurements; analysis of biological material (blood) in terms of glycemia, triglyceride, HDL, and selenium levels, as well as genetic analysis of the PPAR-γ polymorphisms. The researchers found that selenium may moderate the effect of the G allele of the PPAR-γ gene on the occurrence of elevated waist circumference (OR=1.030, 95%CI 1.005-1.057, p=0.020); and the effect of the C (OR=1.077, 95%CI 1.009-1.149, p=0.026) and the G alleles (OR=1.052, 95%CI 1.025-1.080, p

Läppar kan inte bara visa upp hela vårt register av känslor; de har också inspirerat modeskapare, konstnärer och formgivare tack vare sina sensuella och skulpturala former. I veckans Stil ägnar vi oss därför åt sådant som våra läppar kan uttrycka och associeras med. Vi berättar om när Salvador Dali skapade en röd soffa i form av en pussmun. Den var inspirerad av skådespelerskan Mae Wests läppar. Vi pratar med regissören Amanda Adolfsson om hur man får till den perfekta filmkyssen. Vi tittar närmare på Rolling Stones kända läpp-logga som skapades 1971 av John Pasche. Honom har vi ringt upp. Och så berättar vi historien om när skönhetspionjären Elizabeth Arden skapade ett rött läppstift åt kvinnorna i den amerikanska marinkåren.Veckans programledare är Erik Sjölin.

This week, SurfingNASH is offering conversation segments to showcase our new series, The NASH Tsunami in Diabetes: Getting Ahead of the Rising Tide. Rising Tide, as we call it, is a subscription-only series targeted at the primary care physicians, endocrinologists and allied health professionals who provide front-line treatments for patients living with Type 2 Diabetes and/or obesity. This sample session comes from the just-released Season 2 debut which focuses comprehensively on a new chapter of the podcast and why 2023 might be “the best year ever” for Fatty Liver.The group considers what made 2022 special. Mazen highlights Madrigal's positive topline results from the Phase 3 trial of resmetirom for treatment of NASH and liver fibrosis. He also notes Intercept's study on evaluating the safety and efficacy of obeticholic acid in patients with compensated cirrhosis. Ken underscores the development of algorithms for identifying and diagnosing patients. He is optimistic about different societies aligning to define pathways because NAFLD and NASH are metabolic diseases at the center of converging fields. Roger states his highlight of 2022 to be movement toward noninvasive tests and away from biopsies.Conversation expands on the NASH drug pipeline. Mazen cites utility in GLP-1 medications, like semaglutide, and the pan-PPAR agonist, lanifibranor. Roger adds that efruxifermin, an FGF21, has the potential to regress fibrosis in pre-cirrhotic patients. Ken notes it was previously thought that a monotherapy would cure NASH. Today, the promise of combination therapies demonstrates benefits which positively impact weight and other cardiometabolic variables. Roger echoes the idea that the ability to stop progression and reduce steatosis is an achievable target today.Shifting to diagnostics, Roger explains the fading narrative of biopsy as a gold standard. Mazen emphasizes need to screen Type 2 diabetics and those with two or more metabolic risk factors. He introduces a simple test, called FIB-4, which helps to estimate the amount of scarring in the liver. FIB-4 is a basic computation that factors a patient's age, liver enzymes and platelet count. He also describes transient elastography FibroScan, a noninvasive method evaluating liver fibrosis by measurement of liver stiffness. Lastly, he details the enhanced liver fibrosis (ELF) test, a blood test that provides a score reflecting the severity of liver fibrosis. A key message: patients with Stage 2 fibrosis and higher need to be referred as this is the population with significant risk of facing severe complications. Ken builds on the idea behind criticality in screening and identifying early in disease progression. There are simply not enough hepatologists to treat the millions of patients with liver disease.After more notes around guidelines and practical, systemic approaches to navigate widespread prevalence, the panelists offer closing comments. The final points focus on: 1) biggest takeaways for frontline treaters, and 2) most exciting elements to emerge in this space in 2023.If you enjoy this preview, please visit our website and sign up to listen to the full episode and more exclusive content. We also kindly ask that you submit reviews wherever you download our discussions or, alternatively, write to us directly at questions@SurfingNASH.com.The Rising Tide podcast series and all episodes are produced under a non-restricted grant from Novo Nordisk. Novo Nordisk has neither influenced nor reviewed the contents of this podcast in any way. This content represents the views of the speakers and does not necessarily represent the views of Novo Nordisk. The content herein is for educational purposes only and should not be taken as medical advice.

This week, SurfingNASH is offering conversation segments to showcase our new series, The NASH Tsunami in Diabetes: Getting Ahead of the Rising Tide. Rising Tide, as we call it, is a subscription-only series targeted at the primary care physicians, endocrinologists and allied health professionals who provide front-line treatments for patients living with Type 2 Diabetes and/or obesity. This preview looks at drug choices prescribers can make today for patients with Type 2 Diabetes Mellitus and obesity that have positive impact on Fatty Liver disease. In addition to co-hosts Dr. Ken Cusi and Roger Green, panelists for this discussion include endocrinologist Dr. Scott Isaacs, second author of the recent AACE guidelines, and hepatology researcher Dr. Naim Alkhouri.Ken notes that we are living in a period where the paradigm around treating chronic metabolic conditions is shifting. In a world where one in five patients with T2DM lives with clinically significant fibrosis, Ken states providers can no longer ignore the liver when making treatment decisions about diabetes. He also suggests that hepatologists need to become more comfortable using medications that were previously reserved for diabetes.At this point, Naim and Scott join the conversation. Naim begins by discussing EDICT, a trial that compared the standard T2DM regimen of the day (metformin, followed by the sulfonylurea glipizide and then insulin) to a first-line combination therapy of metformin, the GLP-1 agonist exenatide and the PPAR pioglitazone. At the end of this six-year period, the researchers found meaningful, statistically significant differences in three key Fatty Liver parameters: prevalence of NAFLD (69% vs. 31%); clinically significant fibrosis (26% vs. 7%); and percentage fat in the liver (12.5% vs. 8.5%). It also found that patients achieved a lower HbA1c level (6.0% with the combination, vs. 6.8% in the standard treatment group).In response to a question from Roger, Ken identifies three majors lessons of the last 10 years:7 of 10 Americans with T2D have a fatty liver; those with NAFLD but not T2D see their chances of becoming diabetic and , separately, developing cardiovascular disease double.15-20% of Americans with T2D also exhibit moderate-to-advanced cirrhosis.GLP-1s, as a class, address multiple factors of chronic metabolic disease. They reduced HbA1c, promote and maintain significant weight loss, and slow progression of fibrosis.Naim expresses a concern that many doctors treating patients with T2D do not consider NASH. A Cleveland Clinic assessment of ICD-10 codes demonstrated that only 5% of T2D patients were coded for NAFLD. This means the 2/3 of the T2D patients in that system have fatty livers and were never evaluated! Similarly, ~2/3 of the patients who present with cirrhosis in his clinic were never told that they had NAFLD. In Naim's view, NAFLD should be a disease for primary care and endocrinology to treat, while it should be hepatologists that treat NASH.If you enjoy this preview, please visit our website and sign up to listen to the full episode and more exclusive content. We also kindly ask that you submit reviews wherever you download our discussions or write to us directly at questions@SurfingNASH.com.The Rising Tide podcast series and all the episodes are produced under a non-restricted grant from Novo Nordisk. Novo Nordisk has neither influenced nor reviewed the contents of this podcast in any way. This content represents the views of the speakers and does not necessarily represent the views of Novo Nordisk. The content herein is for educational purposes only and should not be taken as medical advice.

At least 5 agents that target the peroxisome proliferator-activated receptor (PPAR) are in clinical studies in primary biliary cholangitis (PBC). Are you aware of the latest data?    Credit available for this activity expires: 2/21/2024 Earn Credit / Learning Objectives & Disclosures: https://www.medscape.org/viewarticle/[articleID]?ecd=bdc_podcast_libsyn_mscpedu  

If you have been listening to the show for a while – then you know I am all about lifestyle and what we put into our bodies. The foods we eat are what will move the needle the fastest when looking to optimize our health. But – what about those times that we want a “convenience food”. What about those times we are at a social gathering or having family or friends over and we want to serve snacks. Today we are going to talk about processed foods. We're going to get into how to read food labels. Every day in my practice I go over this concept – how to read food labels – as it can shift our mindset and subsequently help us when we are looking to optimize our health. We are going to do a couple of side by side comparisons. We are going to talk about additives and preservatives. Then we are going to talk about better options – healthier choices for the times we want to snack. Just a quick disclaimer that this podcast is meant for educational purposes only and is not meant to diagnose or be a substitute for medical advice from your practitioner. ** Follow me on Instagram: https://www.instagram.com/thefunctionalnursepractitioner/ ** Level up your products: https://www.ewg.org/ewgverified/ ** Find a certified Functional Medicine Practitioner: https://www.ifm.org/find-a-practitioner/ ** Interesting articles for more information** The Potential of High-Anthocyanin Purple Rice as a Functional Ingredient in Human Health: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8225073/pdf/antioxidants-10-00833.pdf Nutritional and functional properties of coloured rice varieties of South India: a review: https://journalofethnicfoods.biomedcentral.com/articles/10.1186/s42779-019-0017-3 The Artificial Food Dye Blues: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2957945/pdf/ehp-118-a428.pdf Butylated hydroxyanisole: Carcinogenic food additive to be avoided or harmless antioxidant important to protect food supply?: https://www.sciencedirect.com/science/article/pii/S0273230021000271 Butylated Hydroxytoluene: https://www.sciencedirect.com/topics/immunology-and-microbiology/butylated-hydroxytoluene Alarming impact of the excessive use of tert-butylhydroquinone in food products: A narrative review: https://www.sciencedirect.com/science/article/pii/S2214750022001111 Effects of the food additives sodium acid pyrophosphate, sodium acetate, and citric acid on hemato-immunological pathological biomarkers in rats: Relation to PPAR-α, PPAR-γ and tnfα signaling pathway: https://pubmed.ncbi.nlm.nih.gov/29986283/ Assessing the Health Impact of Phosphorus in the Food Supply: Issues and Considerations : https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3884091/

Today, I am grateful to have here with me, Lara Adler, an Environmental Toxins Expert & Educator, a Certified Holistic Health Coach, and someone who is deeply passionate about changing the landscape of disease through addressing toxic exposures. This episode originally aired in November 2019. Lara Adler has been on a mission to help allied health professionals better support their clients & patients they serve by addressing exposures to environmental chemicals. She also guides her students on how to seamlessly integrate this topic into their practices and to leverage their education to distinguish themselves in their fields. Lara has worked with thousands of practitioners in over 26 countries in her online programs to help them understand the links between chemicals in our daily lives and their links to chronic health conditions like metabolic disorders, thyroid disease, fertility, and behavioral problems in children. Through her flagship course, Talking Toxins, Lara gives health professionals like nutritionists, health coaches, ND's, RN's and chiropractors, as well as healthy-minded consumers a deep education on where these toxic exposures are happening, along with actionable steps to take. The goal is action, not overwhelm. In this episode, Lara Adler starts by discussing how our cell metabolism can be causing resistance to weight loss. Genetics can play a significant role in this resistance, as well as the pharmaceuticals you may be taking. Then, Lara explains all the toxins and chemicals we are introducing to our lives without even knowing. These toxins can be detrimental to our health. However, the good news is there are ways to rid your body of these chemicals. The easiest way to get started with detox is by visiting the sauna every single day. Lara also reveals other ways to rid our bodies of toxins and why this process doesn't need to be overwhelming. Tune in! Take my FREE toxicity quiz to determine your level of toxicity. Visit www.toxicmiami.com for the free quiz. Order Keto Flex: http://www.ketoflexbook.com / / E P I S O D E   S P ON S O R S  Dr Phillips CBD Oil & Keto Fruit Chews. Visit www.drphillipscbd.com Good Idea Functional Sparkling Water Drinks. Visit http://www.goodidea.us and use the coupon code KETOKAMP at checkout.  Text me the words "Podcast" +1 (786) 364-5002 to be added to my contacts list.  [09:55] About Lara Adler Lara has always been interested in health. However, Lara never thought she would pursue anything professionally in the space. After eight years in another career, several people suggested she become a health coach. Lara got certified as a health coach. All of her clients were coming to her for weight loss advice. Some of Lara's clients had terrific results, whereas others had no results at all. What was she missing? Lara dove into the literature around resistance to weight loss. Lara learned about chemicals that mess with our metabolism and cause resistance weight loss. [14:15] Why You May Have Resistance to Weight Loss Genetic differences may predispose you to specific health conditions. Whereas, other people may not manifest these health conditions. For instance, two people who are smokers can have very different outcomes. [15:20] About the PPAR Pathway When PPAR gets activated, it changes the programming of our fat cells that lead toward weight gain. Our cells increase their capacity for fat storage. PPAR can also increase our number of fat cells. It happens at a cellular level completely absent from diet and exercise. This is referred to as chemically induced weight gain. Chemicals can make us fat. Antidepressants cause weight gain – it is a well-established side effect. [19:15] Fasting with Toxins We are burning fat while fasting. Normally, we are dumping our toxins into our fat. When we start losing weight rapidly, the toxins are dumped into our bloodstream. Our liver has to try and keep up with this load. Unless your liver is working perfectly, your liver can still be overloaded. People who have undergone rapid weight loss have shown a thousandfold increase of toxins flooding their systems. People often will get so sick that their hair even falls out. We want to be careful when we are fasting or losing weight. Toxins will desperately search for fat. Your metabolism cannot get rid of toxins – they get recycled back into the system. The body will rebound by adding fat to house the toxins. [22:15] Ways to Support the Liver Anything that supports the liver will be your friend on this journey. Lara's goal is to dial back the exposure and amp up what our body is getting rid of. We can do this by supporting the liver. Take activated charcoal – you need to know how to take a binder because it is a whole process. Sweat every day if you can in a sauna. Law enforcement is using sweat patches to see whether or not there are narcotics in someone's system. Sweat works! Some toxins will exit through sweat rather than any other pathway. You can measure chemicals in urine, but there are still toxins under your skin. A detox should be done every single day. We just want to support this process in all of the ways possible. [30:20] Chemicals to Look Out For BPA or bisphenol A can be found in cash register receipts, canned foods, the lining of canned foods, hard plastic materials. They are not found in soft plastics. Marketing from these companies is really misleading. If you look at a Ziploc bag, they all say BPA free – it never contained BPA. They manipulate the consumer's lack of understanding. BPA is only one chemical in a family of chemicals known as bisphenol. BPA got a bad rap in the public arena because a group of mothers saw it was in baby bottles. Companies swapped BPA for BPS – they are nearly identical. Studies about these substitutions are showing they may actually be worse. [39:45] There Is No Safe Water Bottle Brand Drink out of stainless steel. People don't want to use as much plastic, so they start reusing their plastic containers. The right thing to do is not to buy plastic. Our foods come packaged in plastic, and we can't avoid it. Avoid plastic when buying olive oil, coconut oil, and nut butter. There are 4 key things that increase the way chemicals migrate out of plastic: Heat Oil Acidity Abrasion If you have oily or fatty foods – it will increase the number of chemicals leaking out of the plastic and into the foods. [45:35] Cleaning Our Indoor Air Household cleaners cause a bigger percentage of air pollution than automobiles. You need to clean up what is happening in your house. Breathing this stuff every single day is harmful. House dust is actually lead, heavy metals, pesticides, and non-stick coating. These chemicals settle in the dust in our house. Dusting is so important to eliminate these harmful chemicals. [56:20] One Action Step at a Time When people come to this conversation and feel overwhelmed they need to take one action step. You can't occupy a space of being proactive and being overwhelmed. Action not overwhelm. Start doing stuff even if it's really small. Your first step can be visiting a sauna every day. It is easy to become obsessed with this topic and be afraid of touching anything. We do not need to be afraid of touching a plastic container. Take action on these things, and do not grab the receipt! AND MUCH MORE! Resources from this episode: Visit Lara's Website Read her Blog Enroll in Talking Toxins Connect with Lara Adler: Facebook Twitter Instagram Pinterest Take my FREE toxicity quiz to determine your level of toxicity. Visit www.toxicmiami.com for the free quiz. Order Keto Flex: http://www.ketoflexbook.com / / E P I S O D E   S P ON S O R S  Dr Phillips CBD Oil & Keto Fruit Chews. Visit www.drphillipscbd.com Good Idea Functional Sparkling Water Drinks. Visit http://www.goodidea.us and use the coupon code KETOKAMP at checkout.  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 ▸clubhouse | @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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This month on Episode 42 of Discover CircRes, host Cynthia St. Hilaire highlights four original research articles featured in the October 28 and November 11th  issues of Circulation Research. This episode also features an interview with Dr Miguel Lopez-Ramirez and undergraduate student Bliss Nelson from University of California San Diego about their study, Neuroinflammation Plays a Critical Role in Cerebral Cavernous Malformations.   Article highlights:   Jia, et al. Prohibitin2 Maintains VSMC Contractile Phenotype   Rammah, et al. PPARg and Non-Canonical NOTCH Signaling in the OFT   Wang, et al. Histone Lactylation in Myocardial Infarction   Katsuki, et al. PCSK9 Promotes Vein Graft Lesion Development   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 October 28th and our November 11th issues of Circ Res. I'm also going to have a chat with Dr Miguel Lopez-Ramirez and undergraduate student Bliss Nelson, about their study, Neuroinflammation Plays a Critical Role in Cerebral Cavernous Malformations. But, before I get into the interviews, here are a few article highlights.   Cindy St. Hilaire:        The first article is from our October 28th issue, and the title is, PHB2 Maintains the Contractile Phenotype of Smooth Muscle Cells by Counteracting PKM Splicing. The corresponding author is Wei Kong, and the first authors are Yiting Jia and Chengfeng Mao, and they are all from Peking University. Insults to blood vessels, whether in the form of atherosclerosis, physical injury, or inflammation, can trigger vascular smooth muscle cells to transition from a contractile state to a proliferative and migratory one. Accompanying this conversion is a switch in the cells' metabolism from the mitochondria to glycolysis. But what controls this switch? To investigate, this group compared the transcriptomes of contractile and proliferative smooth muscle cells.   Among the differentially expressed genes, more than 1800 were reciprocally up and down regulated. Of those, six were associated with glucose metabolism, including one called Prohibitin-2, or PHB2, which the team showed localized to the artery wall. In cultured smooth muscle cells, suppression of PHB2 reduced expression of several contractile genes. While in rat arteries, injury caused a decrease in production of PHB2 itself, and of contractile markers.   Furthermore, expression of PHB2 in proliferative smooth muscle cells could revert these cells to a contractile phenotype. Further experiments revealed PHB2 controlled the splicing of the metabolic enzyme to up-regulate the phenotypic switch. Regardless of mechanism, the results suggest that boosting PHB2 might be a way to reduce adverse smooth muscle cell overgrowth and conditions such as atherosclerosis and restenosis.   Cindy St. Hilaire:        The second article I'm going to highlight is also from our October 28th issue, and the first authors are Mayassa Rammah and Magali Theveniau-Ruissy. And the corresponding authors are Francesca Rochais and Robert Kelly. And they are all from Marseille University. Abnormal development of the heart's outflow track, which ultimately forms the bases of the aorta and the pulmonary artery, accounts for more than 30% of all human congenital heart defects. To gain a better understanding of outflow tract development, and thus the origins of such defects, this group investigated the role of transcription factors thought to be involved in specifying the superior outflow tract, or SOFT, which gives rise to the subaortic myocardium, and the inferior outflow tract, which gives rise to the subpulmonary myocardium. Transcription factor S1 is over-expressed in superior outflow tract cells and the transcription factors, TBX1 and PPAR gamma, are expressed in inferior outflow tract cells.   And now this group has shown that TBX1 drives PPAR gamma expression in the inferior outflow tract, while Hess-1 surpasses PPAR gamma expression in the superior outflow tract. Indeed, in mouse embryos lacking TBX1, PPAR gamma expression was absent in the outflow tract. While in mouse embryos lacking Hess-1, PPAR gamma expression was increased and PPAR gamma positive cells were more widespread in the outflow tract.   The team also identified that signaling kinase DLK is an upstream activator of Hess-1 and a suppressor of PPAR gamma. In further detailing the molecular interplay regulating outflow tract patterning, the work will shed light on congenital heart disease etiologies, and inform potential interventions for future therapies.   Cindy St. Hilaire:        The third article I want to highlight is from our November 11th issue of Circulation Research, and the title is Histone Lactylation Boosts Reparative Gene Activation Post Myocardial Infarction. The first author is Jinjin Wang and the corresponding author is Maomao Zhang, and they're from Harbin Medical University. Lactylation of histones is a recently discovered epigenetic modification that regulates gene expression in a variety of biological processes. In inflammation, for example, a significant increase in histone lactylation is responsible for switching on reparative genes and macrophages when pro-inflammatory processes give way to pro-resolvin ones.   The role of histone lactylation in inflammation resolution has been shown in a variety of pathologies, but has not been examined in myocardial infarction. Wang and colleagues have now done just that. They isolated monocytes from the bone marrow and the circulation of mice at various time points after induced myocardial infarctions, and examined the cells' gene expression patterns. Within a day of myocardial infarction, monocytes from both bone marrow and the blood had begun upregulating genes involved in inflammation resolution. And, concordant with this, histone lactylation was dramatically increased in the cells, specifically at genes involved in repair processes.   The team went on to show that injection of sodium lactate into mice boosted monocyte histone lactylation and improved heart function after myocardial infarction, findings that suggest further studies of lactylation's pro-resolving benefits are warranted. Cindy St. Hilaire:        The last article I want to highlight is titled, PCSK9 Promotes Macrophage Activation via LDL Receptor Independent Mechanisms. The first authors are Shunsuke Katsuki and Prabhash Kumar Jha, and the corresponding author is Masanori Aikawa, and they are from Brigham and Women's Hospital in Harvard. Statins are the go-to drug for lowering cholesterol in atherosclerosis patients. But the more recently approved PCSK9 inhibitors also lower cholesterol and can be used to augment or replace statins in patients where these drugs are insufficient.   PCSK9 is an enzyme that circulates in the blood and destroys the LDL receptor, thereby impeding the removal of bad cholesterol. The enzyme also appears to promote inflammation, thus potentially contributing to atherosclerosis in two ways. This group now confirms that PCSK9 does indeed promote pro-inflammatory macrophage activation and lesion development, and does so independent of its actions on the LDL receptor.   The team assessed PCSK9-induced lesions in animals with saphenous vein grafts, which are commonly used in bypass surgery but are prone to lesion regrowth. They found that LDL receptor lacking graft containing mice had greater graft macrophage accumulation and lesion development when PCSK9 activity was boosted than when it was not. The animal's macrophages also had higher levels of the pro-inflammatory factor expression. Together, this work shows that PCSK9 inhibitors provide a double punch against atherosclerosis and might be effective drugs for preventing the all too common failure of saphenous vein grafts.   Cindy St. Hilaire:        So, today with me I have Dr Miguel Lopez-Ramirez and undergraduate student Bliss Nelson from the University of California in San Diego, and we're going to talk about their study, Neuroinflammation Plays a Critical Role in Cerebral Cavernous Malformation Disease, and this article is in our November 11th  issue of Circulation Research. Thank you both so much for joining me today. Before we talk about the science, want to just maybe tell me a little bit about yourselves?   Bliss Nelson:                My name is Bliss Nelson. I'm a member of Miguel Lopez-Ramirez's lab here at UC San Diego at the School of Medicine. I'm an undergraduate student here at UC San Diego. I'm actually a transfer student. I went to a community college here in California and I got involved in research after I transferred.   Cindy St. Hilaire:        What's your major?   Bliss Nelson:                I'm a cognitive science major.   Cindy St. Hilaire:        Excellent. You might be the first undergrad on the podcast, which is exciting.   Bliss Nelson:                Wow. What an honor. Thank so much.   Cindy St. Hilaire:        And Miguel, how about you?   Miguel Lopez-Ramirez: Yes, thank you. Well, first thank you very much for the opportunity to present our work through this media. It's very exciting for us. My name is Miguel Alejandro Lopez-Ramirez, and I'm an assistant professor in the Department of Medicine and Pharmacology here at UCSD. Cindy St. Hilaire:        Wonderful. I loved your paper, because, well, first, I don't think I've talked about cerebral cavernous malformations. So what are CCMs, and why are they so bad?   Bliss Nelson:                Cerebral cavernous malformations, or CCMs for short, are common neurovascular lesions caused by a loss of function mutation in one of three genes. These genes are KRIT1, or CCM1, CCM2 and PDCD10, or CCM3, and generally regarded as an endothelial cell autonomous disease found in the central nervous system, so the brain and the spinal cord.   The relevance of CCMs is that it affects about one in every 200 children and adults, and this causes a lifelong risk of chronic and acute hemorrhaging. CCMs can be quiescent or dynamic lesions. If they are dynamic, they can enlarge, regress, or behave progressively, producing repetitive hemorrhaging and exacerbations of the disease.   Other side effects of the disease could be chronic bleedings, focal neurological deficits, headaches, epileptic seizures and, in some cases, death. There's no pharmacological treatment for CCMs. There's only one type of option some patients may have, which would be to have surgery to cut out the lesions. But of course this depends on where the lesion or lesions are in the central nervous system, if that's even an option. So sometimes there's no option these patients have, there's no treatment, which is what propels our lab to towards finding a pharmacological treatment or uncovering some of the mechanisms behind that.   Cindy St. Hilaire:        Do people who have CCM know that they have them or sometimes it not detected? And when it is detected, what are the symptoms?   Bliss Nelson:                Sometimes patients who have them may not show any symptoms either ever in their lifetime or until a certain point, so really the only way to find out if you were to have them is if you went to go get a brain scan, if you went to go see a doctor, or if you started having symptoms. But also, one of the issues with CCMs is that they're very hard to diagnose, and in the medical community there's a lack of knowledge for CCMs, so sometimes you may not get directed to the right specialist in time, or even ever, and be diagnosed.   Miguel Lopez-Ramirez: I will just add a little bit. It is fabulous, what you're doing. I think this is very, very good. But yes, that's why they're considered rare disease, because it's not obvious disease, so sometimes most of the patient, they go asymptomatic even when they have one lesions, but there's still no answers of why patients that are asymptomatics can become symptomatics. And there is a lot in neuro study, this study that we will start mentioning a little bit more in detail. We try to explain these transitions from silent or, quiescent, lesion, into a more active lesion that gives the disability to the patient.   Some of the symptoms, it can start even with headaches, or, in some cases, they have more neurological deficits that could be like weakness in the arms or loss of vision. In many cases also problems with the speech or balance. So it depends where the lesion is present, in the brain or in the spinal cord, the symptoms that the patient will experience. And some of the most, I will say, severe symptoms is the hemorrhagic stroke and the vascular thrombosis and seizure that the patients can present. Those would be the most significant symptoms that the patient will experience.   Cindy St. Hilaire:        What have been some limitations in the study of CCMs? What have been limitations in trying to figure out what's going on here?   Bliss Nelson:                The limitations to the disease is that, well, one, the propensity for lesions, or the disease, to come about, isn't known, so a lot of the labs that work on it, just going down to the basic building blocks of what's even happening in the disease is a major problem, because until that's well established, it's really hard to go over to the pharmacological side of treating the disease or helping patients with the disease, without knowing what's going on at the molecular level.   Cindy St. Hilaire:        You just mentioned molecular level. Maybe let's take a step back. What's actually going on at the cellular level in CCMs? What are the major cell types that are not happy, that shift and become unhappy cells? Which are the key players?   Bliss Nelson:                That's a great question and a great part of this paper. So when we're talking about the neuroinflammation in the disease, our paper, we're reporting the interactions between the endothelium, the astrocytes, leukocytes, microglia and neutrophils, and we've actually coined this term as the CaLM interaction.   Cindy St. Hilaire:        Great name, by the way.   Bliss Nelson:                Thank you. All props to Miguel. And if you look at our paper, in figure seven we actually have a great graphic that's showing this interaction in play, showing the different components happening and the different cell types involved in the CaLM interaction that's happening within or around the CCM lesions.   Cindy St. Hilaire:        What does a astrocyte normally do? I think our podcast listening base is definitely well versed in probably endothelial and smooth muscle cell and pericyte, but not many of us, not going to lie, including me, really know what a astrocyte does. So what does that cell do and why do we care about its interaction with the endothelium?   Miguel Lopez-Ramirez: Well, the astrocytes play a very important role. Actually, there are more astrocytes than any other cells in the central nervous system, so that can tell you how important they are. Obviously play a very important role maintaining the neurological synapses, maintaining also the hemostasis of the central nervous system by supporting not only the neurons during the neural communication, but also by supporting the blood vessels of the brain.   All this is telling us that also another important role is the inflammation, or the response to damage. So in this case, what also this study proposed, is that new signature for these reactive astrocytes during cerebral malformation disease. So understanding better how the vasculature with malformations can activate the astrocytes, and how the astrocytes can contribute back to these developing of malformations. It will teach us a lot of how new therapeutic targets can be implemented for the disease.   This is part of this work, and now we extend it to see how it can also contribute to the communication with immune cells as Bliss already mentioned.   Cindy St. Hilaire:        Is it a fair analogy to say that a astrocyte is more similar to a pericyte in the periphery? Is that accurate?   Miguel Lopez-Ramirez: No, actually there are pericytes in the central nervous system as well. They have different roles. The pericyte is still a neuron cell that give the shape, plays a role in the contractility and maintains the integrity of the vessels, while the astrocyte is more like part of the immune system, but also part of the supporting of growth factors or maintaining if something leaks out of the vasculature to be able to capture that.   Cindy St. Hilaire:        You used a handful of really interesting mouse models to conduct this study. Can you tell us a little bit about, I guess, the base model for CCM and then some of the unique tools that you used to study the cells specifically?   Bliss Nelson:                Yeah, of course. I do a lot of the animal work in the lab. I'd love to tell you about the mouse model. So to this study we use the animal model with CCM3 mutation. We use this one because it is the most aggressive form of CCM and it really gives us a wide range of options to study the disease super intricately. We use tamoxifen-regulated Cre recombinase under the control of brain endothelial specific promoter, driving the silencing of the gene CCM3, which we call the PDCD10 betco animal, as you can see in our manuscript. To this, the animal without the Cre system, that does not develop any lesions, that we use as a control, we call the PDCD10 plox. And these animals are injected with the tamoxifen postnatally day one, and then for brain collection to investigate, wcollected at different stages. So we do P15, which we call the acute stage, P50, which we term the progressive stage, and then P80, which is the chronocytes stage. And after enough brain collections, we use them for histology, gene expression, RNA analysis, flow cytometry, and different imaging to help us further look into CCMs.   Cindy St. Hilaire:        How similar is a murine CCM to a human CCM? Is there really good overlap or are there some differences?   Miguel Lopez-Ramirez: Yes. So, actually, that's a very good question, and that's part of the work that we are doing. This model definitely has advantages in which the lesions of the vascular formations are in an adult and juvenile animals, which represent an advantage for the field in which now we will be able to test pharmacological therapies in a more meaningful, way where we can test different doses, different, again, approaches. But definitely, I mean, I think I cannot say that it's only one perfect model for to mimic the human disease. It's the complementary of multiple models that give us certain advantages in another, so the integration of this knowledge is what will help us to understand better the disease.   Cindy St. Hilaire:        That's great. I now want to hear a little bit about your findings, because they're really cool. So you took two approaches to study this, and the first was looking at the astrocytes and how they become these, what you're calling reactive astrocytes, and then you look specifically at the brain endothelium. So could you maybe just summarize those two big findings for us?   Miguel Lopez-Ramirez: Yeah, so, basically by doing these studies we use trangenic animal in this case that they give us the visibility to obtain the transcripts in the astrocytes. And basically this is very important because we don't need to isolate the cells, we don't need to manipulate anything, we just took all the ribosomes that were basically capturing the mRNAs and we profile those RNAs that are specifically expressed in the astrocytes.   By doing this, we actually went into looking at in depth the transcripts that were altered in the animals that developed the disease, in this case the cerebral cavernous malformation disease, and what we look at is multiple genes that were changing. Many of them were already described in our previous work, which were associated with hypoxia and angiogenesis. But what we found in this work is that now there were a lot of genes associated with inflammation and coagulation actually, which were not identified before.   What we notice is that now these astrocytes, during the initial phase of the vascular malformation, may play a more important role in angiogenesis or the degradation of the vessels. Later during the stage of the malformation, they play a more important role in the thrombosis, in the inflammation, and recruitment of leukocyte   That was a great advantage in this work by using this approach and looking in detail, these astrocytes. Also, we identified there were very important signature in these astrocytes that we refer as a reactive astrocytes with neuroinflammatory properties. In the same animals, basically, not in the same animal, but in the same basically the experimental approach, we isolated brain vasculature. And by doing the same, we actually identified not only the astrocyte but also the endothelium was quite a different pattern that we were not seeing before. And this pattern was also associated with inflammation, hypoxia and coagulation pathways.   That lead us to go into more detail of what was relevant in this vascular malformations. And one additional part that in the paper this is novel and very impactful, is that we identify inflammasome as a one important component, and particularly in those lesions that are multi-cavernous.   Now we have two different approaches. One, we see this temporality in which the lesions forms different patterns in which the initial phase maybe is more aneugenic, but as they become more progressive in chronocytes, inflammation and hypoxy pathways are more relevant for the recruitment of the inflammatory cells and also the precipitation of immunothrombosis.   But also what we notice is that inflammasome in endothelial and in the leukocytes may play an important role in the multi-cavernous formation, and that's something that we are looking in more detail, if therapeutics or also interventions in these pathways could ameliorate the transition of phases between single lesions into a more aggressive lesions.   Cindy St. Hilaire:        That's kind of one of the follow up questions I was thinking about too is, from looking at the data that you have, obviously to get a CCM, there's a physical issue in the vessel, right? It's not formed properly. Does that form influence the activation of the astrocyte, and then the astrocytes, I guess, secrete inflammatory factors, target more inflammation in the vessel? Or is there something coming from the CCM initially that's then activating the astrocyte? It's kind of a chicken and the egg question, but do you have a sense of secondary to the malformation, what is the initial trigger?   Miguel Lopez-Ramirez: The malformations in our model, and this is important in our model, definitely start by producing changes in the brain endothelial. And as you mention it, these endothelium start secreting molecules that actually directly affect the neighboring cells.   One of the first neighboring cells that at least we have identified to be affected is the astrocytes, but clearly could be also pericytes or other cells that are in the neurovascular unit or form part of the neurovascular unit. But what we have seen now is that this interaction gets extended into more robust interactions that what you were referring as the CaLM interactions.   Definitely I think during the vascular malformations maybe is the discommunication that we identify already few of those very strong iteration that is part of the follow up manuscript that we have. But also it could be the blood brain barrier breakdown and other changes in the endothelium could also trigger the activation of the astrocytes and brain cells.   Cindy St. Hilaire:        What does your data suggest about potential future therapies of CCM? I know you have a really intriguing statement or data that showed targeting NF-kappa B isn't likely going to be a good therapeutic strategy. So maybe tell us just a little bit about that, but also, what does that imply, perhaps, of what a therapeutic strategy could be?   Bliss Nelson:                Originally we did think that the inhibition of NF-kappa B would cause an improvement potentially downstream of the CCMs. And unexpectedly, to our surprise, the partial or total loss of the brain endothelial NF-kappa B activity in the chronic model of the mice, it didn't prevent or cause any improvement in the lesion genesis or neuroinflammation, but instead it resulted in a trend to increase the number of lesions and immunothrombosis, suggesting that the inhibition of it is actually worsening the disease and shouldn't be used as a target for therapeutical approaches.   Miguel Lopez-Ramirez: Yes, particularly that's also part of the work that we have ongoing in which NF-kappa B may also play a role in preventing the further increase of inflammation. So that is something that it can also be very important. And this is very particular for certain cell types. It's very little known what the NF-kappa B actually is doing in the brain endothelial during malformations or inflammation per se. So now it's telling us that this is something that we have to consider for the future.   Also, our future therapeutics of what we propose are two main therapeutic targets. One is the harmful hypoxia pathway, which involves activation, again, of the population pathway inflammation, but also the inflammasomes. So these two venues are part of our ongoing work in trying to see if we have a way to target with a more safe and basically efficient way this inflammation.   However, knowing the mechanisms of how these neuroinflammation take place is what is the key for understanding the disease. And maybe even that inflammatory and inflammatory compounds may not be the direct therapeutic approach, but by understanding these mechanisms, we may come with  new approaches that will help for safe and effective therapies.   Cindy St. Hilaire:        What was the most challenging part of this study? I'm going to guess it has something to do with the mice, but in terms of collecting the data or figure out what's going on, what was the most challenging?   Bliss Nelson:                To this, I'd like to say that I think our team is very strong. We work very well together, so I think even the most challenging part of completing this paper wasn't so challenging because we have a really strong support system among ourselves, with Miguel as a great mentor. And then there's also two postdocs in the lab who are also first authors that contributed a lot to it.   Cindy St. Hilaire:        Great. Well, I just want to commend both of you on an amazing, beautiful story. I loved a lot of the imaging in it, really well done, very technically challenging, I think, pulling out these specific sets of cells and investigating what's happening in them. Really well done study. And Bliss, as an undergraduate student, quite an impressive amount of work. And I congratulate both you and your team on such a wonderful story.   Bliss Nelson:                Thank you very much.   Miguel Lopez-Ramirez: Thank you for Bliss and also Elios and Edo and Katrine, who all contributed      enormously to the completion of this project.   Cindy St. Hilaire:        It always takes a team.   Miguel Lopez-Ramirez: Yes.   Cindy St. Hilaire:        Great. Well, thank you so much, and I can't wait to see what's next for this story.   Cindy St. Hilaire:        That's it for the highlights from October 28th and November 11th issues of Circulation Research. Thank you so much for listening. Please check out the Circ Res Facebook page and follow us on Twitter and Instagram with the handle @circres and #discovercircres. Thank you to our guests, Dr Miguel Lopez-Ramirez and Bliss Nelson. This podcast is produced by Ashara Retniyaka, edited by Melissa Stoner, and supported by the editorial team of Circulation Research. Some of the copy text for our highlighted articles is provided by Ruth Williams. I'm your host, Dr Cindy St. Hilaire, and this is Discover CircRes, you're 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 speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more information, please visit ahagenerals.org.

References Circulation Research. 2008;102:283–294 Neurochemical Research volume 45, pages 972–988 (2020) Biochim Biophys Acta. 2008 Sep; 1781(9): 519–524. --- Send in a voice message: https://anchor.fm/dr-daniel-j-guerra/message

On Episode 17 of the Stroke Alert Podcast, host Dr. Negar Asdaghi highlights two articles from the June 2022 issue of Stroke: “Vitamin D Enhances Hematoma Clearance and Neurologic Recovery in Intracerebral Hemorrhage” and “Acute Ischemic Stroke, Depressed Left Ventricular Ejection Fraction, and Sinus Rhythm: Prevalence and Practice Patterns.” She also interviews Dr. Bruce Campbell on his article “Role of Intravenous Thrombolytics Prior to Endovascular Thrombectomy.” Dr. Negar Asdaghi:         Let's start with some questions. 1) Is vitamin D that golden key to recovery from intracerebral hemorrhage? 2) Endovascular therapies seem to have prevailed where thrombolytics have failed. In the era of fast and furious thrombectomy, what is the role of pre-thrombectomy thrombolysis? 3) And finally, 20 years of clinical research has failed to demonstrate the superiority of anticoagulation over antiplatelet therapies for treatment of patients in sinus rhythm with low left ventricular ejection fraction, and yet, our practice patterns have not changed. Why do we remain resolute in prescribing anticoagulation despite the lack of evidence? We're back here to tackle the toughest questions with our Stroke Alert Podcast because this is the latest in Stroke. Stay with us. Dr. Negar Asdaghi:         Welcome back to another extremely motivating Stroke Alert Podcast. My name is Negar Asdaghi. I'm an Associate Professor of Neurology at the University of Miami Miller School of Medicine and your host for the monthly Stroke Alert Podcast. The June 2022 issue of Stroke contains a number of interesting articles. As part of our Advances in Stroke, we have two articles, one on the topic of cost-effectiveness of stroke care to inform health policy and the second on the current state and the future of emerging stroke therapies. As part of our Original Contributions category, we have an interesting study by Dr. [Ben] Assayag and colleagues from the Department of Neurology at Tel Aviv Sourasky Medical Center, where we learned that just over 10% of patients with TIA and stroke developed post-traumatic stress disorder, or PTSD. Higher presenting stroke severity, preexisting white matter disease, and having anxious coping styles are risk factors for development of post-stroke PTSD. Dr. Negar Asdaghi:         In another Original Contribution, by Dr. Daehoon Kim and colleagues from Yonsei University College of Medicine in Seoul, South Korea, we read with interest on the topic of whether or not we should be anticoagulating frail patients with atrial fibrillation. In this large population-based cohort, which included patients with atrial fibrillation older than 65 years of age with frailty as defined by a score of equal or greater than five on Hospital Frailty Risk Score, we learned that despite their frailty, patients with atrial fibrillation still significantly benefit from oral anticoagulation therapy. In this study, those treated with anticoagulation had lower net adverse clinical events as compared to those untreated. We also learned that direct oral anticoagulants provided lower incidence of stroke, bleeding, and mortality over Coumadin. This paper really provided practical information on treatment of frail patients with atrial fibrillation. So, I encourage you to review these papers in addition to listening to our podcast today. Later in the podcast, I have the great pleasure of interviewing Dr. Bruce Campbell from University of Melbourne in Australia on an especially timely topic, that is the role of intravenous thrombolytics prior to endovascular therapy. Dr. Campbell is a leading authority on the topic, and his interview does not disappoint. But first, with these two articles. Dr. Negar Asdaghi:         In the setting of intracerebral hemorrhage, or ICH, aside from the primary brain insult that occurs at the time of hemorrhage, secondary brain injuries continue for days and sometimes to months mostly due to the pathological response of the brain to byproducts of hematoma lysis or RBC degradation products. Today, the majority of spontaneous ICH cases are not surgically evacuated, so we rely on the body's own ability to clear blood for hematoma clearance, and obviously the faster the clearance, the better the outcome. Erythrophagocytosis by monocyte-derived macrophages contributes to hematoma clearance and ultimately to the functional recovery from ICH. So, it's conceivable that therapeutic approaches to enhance the endogenous erythrophagocytosis can potentially improve ICH outcomes. Vitamin D has been known to have variety of functions within the central nervous system, and it turns out that it may also be one such therapeutic option to improve the much needed erythrophagocytosis in intracerebral hemorrhage. Dr. Negar Asdaghi:         In the current issue of the journal, in the study titled "Vitamin D Enhances Hematoma Clearance and Neurologic Recovery in Intracerebral Hemorrhage," a group of researchers led by Dr. Jiaxin Liu from the Department of Surgery at Queen Mary Hospital at the University of Hong Kong studied the effects of oral vitamin D administered two hours after the induction of hematoma in a rodent model of ICH using direct collagenase injection into the striatum of the mouse. Eighty-nine young mice and 78 middle-aged mice were included in the study and randomly divided into three groups. Group one were sham-operated mice; group two, ICH mice treated with vehicle, which was corn oil; and group three, vitamin D-treated ICH mice. In the third group, 1000 international unit per kg of vitamin D diluted in corn oil was administered orally using a pipette two hours after the induction of ICH to mice, and then daily afterwards. And here are their top three findings of this study. Dr. Negar Asdaghi:         Number one, vitamin D-treated mice did better than vehicle on two neurobehavioral tests that were completed in the study. On the cylinder test, treatment with vitamin D significantly alleviated the asymmetric usage of four limbs at day seven, and vitamin D elongated the duration that the mice could run on the accelerated rod at day 10 on the rotarod test. Dr. Negar Asdaghi:         Number two, in terms of hematoma resolution and perihematoma edema, it's an issue that we deal with, with ICH, they used MRI imaging for edema measurement on T2-weighted images, and then sacrificed the mice and used digital quantification of hematoma volume with fresh brain specimens. And they found that treatment with vitamin D significantly alleviated both the ICH-associated brain swelling on MR and resulted in significant reduction in hematoma volume on the fresh brain specimens when compared with the vehicle-treated group at day three and day five. Dr. Negar Asdaghi:         And finally, their third main finding is in terms of erythrophagocytosis. So, the pathway that is mediated by the monocyte-derived macrophages is an endogenous pathway, that is, PPAR-γ (which stands for peroxisome proliferator-activated receptor γ) and its downstream scavenger receptor CD36 mediated. This pathway is essential for directing the endogenous erythrophagocytosis. Using flow cytometry, they found that vitamin D-treated mice had more mature macrophages expressing the scavenger receptor CD36, which was not expressed by the undifferentiated monocytes. Dr. Negar Asdaghi:         Western blot analysis confirmed that vitamin D treatment increased the tissue levels of CD36 and the upstream PPAR-γ levels in the brain at day five after collagenase model. Locally, vitamin D-enriched phagocytes that were positive for PPAR-γ and CD36 in the perihematoma regions. So, in summary, vitamin D increased the number of mature macrophages rather than undifferentiated monocytes in the perihematoma region and accelerated the differentiation of reparative macrophages from bone marrow-derived monocytes. So, bottom line is that in vitamin D, we have a simple, accessible, and well-tolerated agent to improve both the ICH outcomes and enhance hematoma resolution, but this we all observed in rodents. So, we stay tuned with interest to find out whether the same success will be seen in humans treated with vitamin D after intracerebral hemorrhage. Dr. Negar Asdaghi:         Patients with depressed left ventricular ejection fraction, or low EF, are at risk of development of ischemic stroke even if they remain in sinus rhythm. The optimal antithrombotic treatment for these patients is still unknown. Over the past two decades, we have a number of randomized trials studying the efficacy of oral anticoagulation, predominantly Coumadin, over aspirin therapy in prevention of all forms of stroke, that is ischemic and hemorrhagic, and death in patients with a low EF in sinus rhythm. Dr. Negar Asdaghi:         The meta-analysis of WASH, HELAS, WATCH, and WARCEF trials showed that treatment of low ejection fraction patients in sinus rhythm with Coumadin does reduce the subsequent risk of stroke, but it comes at the cost of a higher major bleeding risk in this population. The COMMANDER HF clinical trial published in New England Journal of Medicine in October 2018 studied whether low-dose rivaroxaban at 2.5 milligram BID was superior to placebo in patients with recent worsening of chronic heart failure, reduced ejection fraction, coronary artery disease, but no atrial fibrillation, and very similar to its prior counterparts, it did not show that rivaroxaban was associated with a lower rate of combined death, myocardial infarction, or stroke as compared to placebo. But very similar to prior studies, it also showed that rivaroxaban-treated patients had a lower risk of subsequent ischemic stroke. This poses a conundrum for stroke neurologists treating patients with this condition, especially after they present with an embolic-appearing stroke. So, the question is, how often do we encounter this situation, and what do we do in routine practice? We know that when there is equipoise, there's practice variation. Dr. Negar Asdaghi: In the current issue of the journal, in the study titled "Acute Ischemic Stroke, Depressed Left Ventricular Ejection Fraction, and Sinus Rhythm," Dr. Richa Sharma from the Department of Neurology at Yale School of Medicine and colleagues examined the prevalence of heart failure with sinus rhythm among hospitalized patients with acute ischemic stroke and the physician's practice patterns with regard to the choice of antithrombotics in this population. Dr. Negar Asdaghi:         So, let's look at their study. The study was comprised of five separate study cohorts of hospitalized acute ischemic stroke patients in the Greater Cincinnati Northern Kentucky Stroke Study for the year 2005, 2010, and 2015, and then four additional academic hospital-based cohorts in the United States during different timeframes. These were the Massachusetts General Hospital from 2002 to 2016, Rhode Island Hospital from 2016 to 2018, Yale-New Haven Hospital 2015 to 2017, and Cornell Acute Stroke Academic Registry from 2011 to 2018. All of these cohorts combined contributed to the 19,155 total number of patients in this study, which included over 14,000 patients that had documented left ventricular ejection fraction. Amongst those, 1,426 had a depressed EF and were included in this study. The investigator obviously excluded those with documented atrial fibrillation and flutter. And so the sample size for this analysis was 805 patients. And here are their main results. Dr. Negar Asdaghi:         The overall prevalence of this condition, that is low ejection fraction and sinus rhythm, among hospitalized acute ischemic stroke patients was 5%. It varied slightly between the different cohorts in this study from 4 to 6%. In terms of the antithrombotic treatment patterns, this information was available in close to 500 patients in the cohort. Overall, 59% of patients were discharged on an antiplatelet treatment alone, and 41% on anticoagulation. But these percentages significantly varied between the different institutions and was as low as 22% in one of the cohorts and as high as 45% in another cohort. Dr. Negar Asdaghi:         So, what were the factors that were associated with the use of anticoagulation at discharge? They found that the absolute percentage of left ventricular ejection fraction and the presenting NIH Stroke Scales were associated with anticoagulation use. That is, the lower the percentage of EF and the higher the presenting NIH Stroke Scale, the more likely physicians were to discharge the patients on an anticoagulation in univariate analysis, but in multivariate analysis, only the study site and presenting NIH Stroke Scale over eight were independently associated with anticoagulation use. Dr. Negar Asdaghi:         Now, interestingly, 2002 to 2018, which was their overall study period, was a time during which some of the largest and neutral randomized trials on the topic of anticoagulation versus antiplatelet were published, including the WATCH and the WARCEF trial. But the authors found no temporal variation in anticoagulation practice patterns before and after the publication of the results of these trials. So, it appears that we didn't change our minds. So, overall, we have some important takeaway messages from this study. We learned that 5% of hospitalized acute ischemic stroke patients have low left ventricular ejection fraction and remain in sinus rhythm without atrial fibrillation. Today, over 40% of patients with this condition are anticoagulated at discharge despite the results of the randomized trials, but the practice is widely variable among different institutions, and a higher presenting NIH Stroke Scale is a significant predictor of anticoagulation use at discharge in this population. Dr. Negar Asdaghi:         Almost 20 years after the approval of intravenous thrombolysis for treatment of patients with acute ischemic stroke, endovascular therapy was approved for treatment of select ischemic stroke patients with a large vessel occlusion. The two treatments are, therefore, entangled, as one was the standard of care while the second one was being tested. Therefore, all endovascularly treated patients enrolled in randomized trials would've received intravenous thrombolysis if eligible. Now, with the overwhelming success of endovascular therapy in achieving reperfusion in areas where IV thrombolysis has drastically failed, there're still critical questions regarding the added value of IV thrombolysis to endovascularly treated patients. The critical question remains as to whether eligible ischemic stroke patients who have immediate access to endovascular thrombectomy should receive prior IV thrombolysis, or should we skip the thrombolysis step altogether and just move to the angio suite as fast as possible. And there are, of course, arguments for and against each approach. Dr. Negar Asdaghi:         In this issue of the journal, in an invited topical review titled "The Role of Intravenous Thrombolytics Prior to Endovascular Thrombectomy," we learn about these arguments as the authors go through a comprehensive review of the current literature on this issue. I'm joined today by the first author of this review, Dr. Bruce Campbell, to discuss this paper. Dr. Campbell absolutely needs no introduction to our Stroke listeners. He's a professor of neurology and head of neurology and stroke at Royal Melbourne Hospital, University of Melbourne, in Australia. He's a pioneer in the field of acute stroke therapies and acute neuroimaging. He has served as the lead investigator of multiple landmark randomized trials, including EXTEND-IA and EXTEND-IA TNK, and holds multiple leadership roles. He's the clinical director of the Stroke Foundation and co-chairs the Australian Stroke Guidelines Working Party and the coordinator of the National Brain School Training Program for Neurologists in Training. And, of course, last but not least, he's my friend. So, I'm delighted to welcome him to our podcast today. Top of the morning to you, Bruce, 6:00 a.m. in Melbourne. That's quite some dedication. Thank you for being here. Dr. Bruce Campbell:       It's great to be with you. Thanks for the invitation. Dr. Negar Asdaghi:         Congrats on the paper, really exciting topic. So, let's just start with this question as part of a case. We have a patient with an M1 occlusion, a large clinical syndrome presenting two hours out from their symptom onset, and we are at a hospital where the angio suite is ready. What are some of the benefits of basically spending time in giving IV thrombolytics first rather than quickly going to the angio suite? Dr. Bruce Campbell:       I think a key element of this case is that the patient has presented directly to a hospital with immediate access to thrombectomy. Thrombolytic used in drip-and-ship transfer patients really isn't controversial, and the recent randomized trials excluded them. So, the debate's all about this context of bridging thrombolytics in patients presenting directly to a comprehensive stroke center. And you mentioned spending time giving lytics, but in fact, if you do things in parallel, that shouldn't be the case. It shouldn't delay thrombectomy if you go and give thrombolysis. Dr. Bruce Campbell:       So, the general principle is that getting the artery open faster by any means is better, and IV thrombolytic certainly has the potential to open the artery before thrombectomy in a proportion of patients, perhaps not that many, but it may also facilitate the thrombectomy. So, in the randomized trials, reperfusion after the thrombectomy was significantly better when patients had had bridging thrombolytic despite a low rate of pre-endovascular reperfusion. Other reasons for giving the lytics are the potential safety net it provides if the thrombectomy procedure is unexpectedly delayed or fails to get the artery open, and there's also this potential for lytics to dissolve distal embolic fragments and perhaps improve microvascular reperfusion. Dr. Negar Asdaghi:         So, great. So, let me summarize for our listeners what you mentioned. First off, so these are arguments in favor of giving lytics. As you mentioned, we're not really wasting time. These processes occur in parallel, so it's not like we're wasting time in giving a therapy that is potentially not as efficacious as thrombectomy is. And number two, we have improved the possibility of early reperfusion, perhaps, with the lytics. And if there are some fragments or distal clots that thrombectomy wouldn't have reached, then the lytics would. And then also there is also the chance that the thrombectomy might have failed in difficult access, and so on and so forth, and at least the patient has some chance of revascularization with the lytics. So, if these are the arguments for giving lytics, what are the arguments against giving lytics in this scenario? Dr. Bruce Campbell:       The main argument is the potential to reduce both the intracerebral and systemic hemorrhagic complications. There's also potential cost saving by skipping thrombolytics. That's probably more relevant in low-resource settings, particularly when relatives may have to pay for the thrombolytic before treatment is initiated, and that can be burdensome and also potentially delay the thrombectomy. There's a theoretical concern about thrombus fragmentation with lytics and potential migration of the clot out of reach of the thrombectomy or to new territories. But final reperfusion, as I mentioned, was, on average, better with the patient having a lytic on board in the randomized trials. Dr. Negar Asdaghi:         Perfect. And I want to highlight this issue of thrombus fragmentation because I think our readers will read more and more about this idea of, as you mentioned, fragmentation will potentially make an accessible clot for thrombectomy inaccessible. But I see that later in our questions, we're going to address that as part of the findings of randomized trials as well. So, these are some of the arguments for and against. And before we go to the randomized trials, I'd like to get an overview of what we knew as part of observational studies and non-randomized studies prior to more recent randomized trials on this topic. Dr. Bruce Campbell:       There've been a couple of nice systematic reviews and meta-analyses of the observational data, and notably in most of these studies, the direct thrombectomy patients had contraindications to lytics, and that introduces confounding factors that are difficult to adjust for. For what that's worth, the functional independence, mortality outcomes were better in the bridging patients. Hemorrhage rates weren't always higher with the lytic, and one study by Jonathan Coutinho in JAMA Neurology for the SWIFT and STAR studies showed the opposite despite them having really careful adjustment for all the confounders they could think of. And the meta-analysis by Eva Mistry in Stroke did not detect a difference in symptomatic ICH between the direct and bridging strategies. One thing that should be less affected by the patient characteristics would be the technical efficacy outcomes, and it was interesting that in the observational data, the patients who'd had bridging lytic had higher mTICI 2b-3 rates and also fewer device passes. Dr. Negar Asdaghi:         Okay. And now we do have further information with all of these new randomized trials. So, why don't we start with some of the earlier studies, the three, SKIP, DEVT, and DIRECT-MT, and start with those studies first before we move to some more recent European trials. Dr. Bruce Campbell:       SKIP was performed in Japan, and it used the lower 0.6 milligram per kilogram dose of alteplase that's standard there, and DEVT and DIRECT-MT were performed in China. All three of them showed numerically similar functional outcomes with slight trends favoring direct thrombectomy. SKIP had a smaller sample size and did not meet its non-inferiority criteria, and the other two trials did meet their specified non-inferiority margin, but it could be argued those margins were overly generous. If you think about non-inferiority trials, we generally try to set a margin for non-inferiority such as lower 95% confidence interval for the trial intervention would sacrifice up to 50% of the reference treatment effect. And it's difficult to estimate the effect of alteplase in this specific population. But if you think of the Emberson meta-analysis of alteplase, overall zero to three hours alteplase versus placebo has a 10% effect size and mRS 0-1, three to four and a half hours of 5% effect size. And we regard that as clinically important. So, half of 5%, 2.5%, is a lot tighter margin than any of the direct randomized trials employed. Dr. Negar Asdaghi:         So, Bruce, let me recap what you just mentioned. Two out of the three earlier trials seem to suggest that perhaps skipping IV therapy is the way to go rather than bridging as these two trials met the non-inferiority criteria if we believe that non-inferiority margins you mentioned. And now we have a couple of more trials, more recent trials. Can you tell us about these trials please? Dr. Bruce Campbell:       MR CLEAN-NO IV in a European population did not demonstrate non-inferiority, and the point estimate slightly favored bridging. Interestingly, in that trial, the symptomatic intracerebral hemorrhage risk, which was one of the main drivers for trying this strategy, was 5.9% in the direct and 5.3 in the bridging group. So, there's no hint of benefit from dropping the lytic on that metric. SWIFT-DIRECT was more selective in only enrolling internal carotid and M1 occlusions, which had a lower chance of early recanalization with lytic. But the protocol also specified giving the full dose of lytic. In the other trials, it seems the alteplase infusion was often stopped once the patient was in the angio suite, so the full dose may not have been delivered. And despite very low pre-endovascular recanalization in that selected group in SWIFT-DIRECT, the end of procedure reperfusion was significantly better in the bridging group, which is a consistent finding across the trials and suggests that the lytic may improve the thrombectomy outcome. Dr. Bruce Campbell:       DIRECT-SAFE, the final of those trials, was interesting in that the patients were enrolled roughly 50:50 from Australia, New Zealand, versus Asia. And in contrast to the original three randomized trials in Asian patients, DIRECT-SAFE found a significant benefit of bridging lytic in Asian patients. So, it'd be very interesting to see the results of the IRIS individual patient data meta-analysis, but we may not find a difference in Asian versus Caucasian patients despite those initial trials and despite substantial differences in the prevalence of intracranial atherosclerosis, which has often been proposed as something that would increase the risk of having bridging thrombolytic on board. Dr. Bruce Campbell:       The original study level estimate of symptomatic hemorrhage had a borderline significant 1.8% absolute reduction in the direct group. Whether those data were not all core lab adjudicated and the final analysis may show a smaller difference than that. Notably, given that trend with symptomatic intracerebral hemorrhage, mortality did not differ significantly, and, in fact, the trend favored bridging patients. So, the symptomatic hemorrhage slight trend into increase did not translate into any hint of increased mortality. Dr. Negar Asdaghi:         So, Bruce, a lot of information, and I need a recap for me. So, let me try to recap some of the things you said, and please jump in. So, so far, the newer data really basically don't show us any convincing evidence that skipping is the way to go, and direct endovascular we really don't have data in favor of going directly to the angio suite. And the jury is still out regarding an increase in the symptomatic intracerebral hemorrhage rate amongst those that actually are pre-treated with IV therapy. Is that correct? Dr. Bruce Campbell:       That's correct. So, none of the three recent trials met their non-inferiority margins. And again, we had this issue of relatively generous non-inferiority margins, and the symptomatic hemorrhage, it would make sense that there's a small difference, but it's not really been borne out in the data to be statistically significant at this stage. And again, this individual patient data meta-analysis is keenly awaited to get the most accurate estimate on that. Dr. Negar Asdaghi:         So, while we wait that, I'm going to digress a little bit and ask you a question that's not addressed in the paper that you have in this issue of the journal, and that's the CHOICE trial. So, by now, we have the results of CHOICE trial. Do you mind first give us a brief overview of what CHOICE was and how you feel that the results of CHOICE would affect this field of direct versus bridging in general? Dr. Bruce Campbell:       CHOICE is a very interesting study in that it tested giving the intra-arterial lytic at the end of a thrombectomy procedure that had achieved an mTICI 2b or better, which is what we traditionally regarded as angiographic success. The idea was to improve microvascular flow, and that may be the case. The trial was terminated early due to logistic reasons and showed a very large effect size that requires replication. The subgroup analyses are interesting in that the benefits seem to mostly accrue in patients who'd not already had intravenous lytic. Dr. Bruce Campbell:       So, perhaps giving the IV lytic before thrombectomy can still benefit patients after the thrombectomy, as well as achieving early recanalization in a proportion of patients and perhaps facilitating the thrombectomy. The other issue to address with the DIRECT trials is that with the exception of a few patients in DIRECT-SAFE, the comparator was alteplase and not tenecteplase. And we have data from EXTEND-IA TNK that tenecteplase bridging is not just non-inferior, but superior to alteplase bridging. There's an ongoing Brazilian trial of exactly that, tenecteplase versus the direct approach, which will be very interesting. Dr. Negar Asdaghi:         So, great, Bruce. I just want to repeat this segment again for our listeners. So, CHOICE is a very interesting study, looked at giving intraarterial alteplase to patients after endovascular therapy was completed and after they'd already achieved the complete and successful revascularization, and the trial was terminated early because of logistic reasons. So, we have to keep in mind, this was a smaller study, early termination, but the effect size was pretty large in favor of giving lytics. Dr. Negar Asdaghi:         So, what you mentioned is interesting, and I think that it's really worth paying attention to, that the majority of the benefits seem to have occurred from intraarterial thrombolytics in patients that have not been given intravenous lytics prior to endovascular therapy. So, in other words, you need some sort of lytics either before or after the endovascular thrombectomy to achieve that ultimate improved outcome. So, moving forward now from the randomized trials that we have on bridging versus direct thrombectomy, you have mentioned in the paper some interesting subgroups that may benefit or not benefit as much from bridging versus direct thrombectomy. Do you want to elaborate a little more about those subgroup analyses? Dr. Bruce Campbell:       The idea of precision selection or individualized treatment is being talked about a lot given there didn't seem to be much overall difference between strategies in the randomized trials, but it's important to note that the randomized trial actually disadvantages the bridging group by delaying lytic until the patient was firstly confirmed eligible for thrombectomy and then consented and randomized. Putting that aside, if we could identify a subgroup who clearly benefit from skipping lytic and, importantly, identify them without delaying lytic for those who likely benefit, that's clearly attractive. Dr. Bruce Campbell:       Currently, I'd say we have not identified that kind of subgroup, and the planned IRIS individual patient data meta-analysis will be critical for that. Patients with a large ischemic core are one potential group where there's a high risk of bleeding hypothesized. To date, there is no definitive data to indicate the risk is lower with the direct approach. Patients who need stents certainly may benefit from not having a lytic on board because they often need adjuvant antithrombotics that could increase the bleeding risk. But the question there is whether we can confidently identify those patients before the procedure, and I think that's unclear at this stage. Patients with really large clot burdens and proximal occlusions have sometimes been said not to benefit from IV lytic based on the low rates of pre-endovascular reperfusion, but the randomized trials really hinted other benefits like this potential facilitative thrombectomy. So, that hypothesis may be insecure as well. Dr. Negar Asdaghi:         And how about age? Have you come across and has there been any signal towards an impact or interaction between age and benefit from pre-endovascular thrombectomy and thrombolytics? Dr. Bruce Campbell:       It's an interesting question because age has not generally been a treatment effect modifier in previous stroke studies with thrombolytics and thrombectomy, and the individual direct thrombectomy trials that have reported subgroups haven't shown any convincing heterogeneity by age. There's certainly no indication that older patients are at risk from bridging in what I've seen so far. Dr. Negar Asdaghi:         So, this question comes up in clinical practice all the time, that a person's older, perhaps more atrophy, more vascular risk factors and white matter disease, and they're more prone, so to speak, of having a symptomatic intracerebral hemorrhage. So, what you're saying is, from the data we have, there's really no signal in favor of withholding pre-thrombectomy lytics in this population. So, it's important to know this. Bruce, what should be our final takeaway message from this study? Dr. Bruce Campbell:       I tend to agree with the recent European Stroke Organization and ESMINT guideline that for now, patients should receive lytic as early as possible and in parallel with the decision to perform thrombectomy such that neither treatment delays the other. I think if we can identify a subgroup that benefits from direct thrombectomy, and that's confirmed in the individual patient data and meta-analysis, and we can identify them without disadvantaging the majority of patients, and also that the ongoing improvements in IV lytic strategies don't render the existing trial data obsolete, then we may, in future, skip lytic for some patients, but we are not there yet. Dr. Negar Asdaghi:         So, that's amazing, Bruce. We look forward to reviewing the paper and individual data meta-analysis and interviewing you, hopefully at a better hour your time, on that. Thank you very much for joining us on the podcast today. Dr. Bruce Campbell:       Thanks again for the invitation. It's been great talking to you. Dr. Negar Asdaghi:         Thank you. Dr. Negar Asdaghi:         And this concludes our podcast for the June 2022 issue of Stroke. Please be sure to check out this month's table of contents for the full list of publications, including three very interesting images that are presented as part of a new article type, Stroke Images, and a special report in Comments and Opinions section on "Bias in Stroke Evaluation: Rethinking the Cookie Theft Picture." June is the month of Pride, and in spirit of equality, we hope to do our part to reduce all biases in stroke processes of care, diagnosis, and outcomes as we continue to stay alert with Stroke Alert. Dr. Negar Asdaghi:         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, visit AHAjournals.org.