Podcast appearances and mentions of Joseph Berger

Dr. Joseph Berger explores the significance of drug infusion centers in modern healthcare. He discusses how these centers enhance patient care by providing efficient, cost-effective treatment options for various medical conditions.​

In this edition of the Mentorship Matters podcast, COL Rob Abbott, the U.S. Army JAG Corps's Leadership Center Director, interviews MG Joseph Berger, the 22nd Deputy Judge Advocate General. This interview provides insight on MG Berger's personal leadership philosophy, expectations he has for leaders, and personal lessons learned. To learn more about the Army JAG Corps' Leadership Center and to access additional resources please visit https://tjaglcs.army.mil/center/leadership-center or https://tjaglcs.army.mil/leapp. This episode is dedicated to our friend and teammate CW3 Melanie Sellars.

Ako svedok a obeť tragédie v Osvienčime podal Elie Wiesel v memoároch Noc mimoriadne silnú výpoveď o hrôzach holokaustu. Ako sa tento krehký a nenápadný spisovateľ z karpatského mestečka stal takým vplyvným aktérom na svetovej scéne? Joseph Berger sa v knihe Elie Wiesel – Prelomiť mlčanie pokúša zodpovedať túto otázkou prostredníctvom rozhovorov s jeho priateľmi, vedcami, kritikmi, ale aj pomocou jeho literárnej tvorby.

Ici, on parcourt avec Joseph toutes les idées qu'on peut se faire du métier de berger et du berger lui-même. Les points évoqués : La solitude Le kiff du plein air Bosser avec des animaux c'est une vraie chance Métier précaire Métier difficile physiquement Une philosophie de vie On dégomme plus ou moins, on affine, on rafraîchit. Découvrez ici la réalité derrière ces clichés ! Et si ça vous a plu, foncez découvrir la version longue :) Bonne écoute

Does evolution ever reverse itself? Regressive evolution means that animals or organisms lose some of the complexity they had in the past. There's one specific group of animals that really dived into reverse evolution: whales, dolphins, seals, and sea turtles. They've really changed a lot over the last 350 million years, moving from sea to dry land and back to sea! #brightside Credit: NASA/Earth Science and Remote Sensing Unit, Lyndon B. Johnson Space Center Black sheep: Jesus Solana, CC BY 2.0 https://creativecommons.org/licenses/..., https://commons.wikimedia.org/wiki/Fi... Ice age: Mauricio Antón, CC BY 2.5 https://creativecommons.org/licenses/..., https://commons.wikimedia.org/wiki/Fi... CC BY-SA 2.5 https://creativecommons.org/licenses/... Astrophytum asterias: Dr. David Midgley, https://en.wikipedia.org/wiki/File:As... Glomeris marginata: Stemonitis https://en.wikipedia.org/wiki/File:Gl... Rhagoletis pomonella: Joseph Berger, Bugwood.org, CC BY 3.0 https://creativecommons.org/licenses/..., https://en.wikipedia.org/wiki/File:Rh... CC BY-SA 3.0 https://creativecommons.org/licenses/... Toby Hudson: Labeotropheus https://commons.wikimedia.org/wiki/Fi... Maylandia https://commons.wikimedia.org/wiki/Fi... Cichlid blue https://commons.wikimedia.org/wiki/Fi... Pinicola enucleator: Cephas https://commons.wikimedia.org/wiki/Fi... Doc. RNDr. Josef Reischig, CSc.: Cyanobacteria https://commons.wikimedia.org/wiki/Fi... Cyanobacteria https://commons.wikimedia.org/wiki/Fi... Sphaeromyxa hellandi: Ivan Fiala https://commons.wikimedia.org/wiki/Fi... Cyprinidae: Hectonichus https://commons.wikimedia.org/wiki/Fi... Astyanax mexicanus: H. Zell, https://commons.wikimedia.org/wiki/Fi... Bottlenose dolphin: Peter Asprey, http://www.peter-asprey.com/, https://commons.wikimedia.org/wiki/Fi... Euphorbia obesa: Frank Vincentz, https://en.wikipedia.org/wiki/File:E_... Armadillidium vulgare: Franco Folini https://en.wikipedia.org/wiki/File:Ar... CC BY 4.0 https://creativecommons.org/licenses/... Homo neanderthalensis: Jakub Hałun https://commons.wikimedia.org/wiki/Fi... Symbiotic nitrogen: LegumeLover, https://commons.wikimedia.org/wiki/Fi... Parasite: Marcelo Knoff, Simone Chinicz Cohen, Melissa Querido Cárdenas, Jorge M. Cárdenas-Callirgos and Delir Corrêa Gomes https://commons.wikimedia.org/wiki/Fi... CC BY-SA 4.0 https://creativecommons.org/licenses/... Invertebrate montage: Dan Parsons, François Michonneau, Nhobgood, Sanjay Acharya, jbrasher, Jnpet, GlebK, Bernard DUPONT, Schokraie E, Warnken U, Hotz-Wagenblatt A, Grohme MA, Hengherr S, et al. (2012) https://commons.wikimedia.org/wiki/Fi... Lucy: Neanderthal-Museum, Mettmann https://commons.wikimedia.org/wiki/Fi... Shark eggs: Yohanes Wahyu Nurcahyo https://commons.wikimedia.org/wiki/Fi... Cladoselache: Armin Reindl https://commons.wikimedia.org/wiki/Fi... Saaser Mutte: Namma! https://commons.wikimedia.org/wiki/Fi... Animation is created by Bright Side. ---------------------------------------------------------------------------------------- Music by Epidemic Sound https://www.epidemicsound.com Check our Bright Side podcast on Spotify and leave a positive review! https://open.spotify.com/show/0hUkPxD... Subscribe to Bright Side: https://goo.gl/rQTJZz ---------------------------------------------------------------------------------------- Our Social Media: Facebook: / brightside Instagram: / brightside.official TikTok: https://www.tiktok.com/@brightside.of... Stock materials (photos, footages and other): https://www.depositphotos.com https://www.shutterstock.com https://www.eastnews.ru ---------------------------------------------------------------------------------------- For more videos and articles visit: http://www.brightside.me Learn more about your ad choices. Visit megaphone.fm/adchoices

MedLink Neurology Podcast is delighted to feature selected episodes from BrainWaves, courtesy of James E Siegler MD, its originator and host. BrainWaves is an academic audio podcast whose mission is to educate medical providers through clinical cases and topical reviews in neurology, medicine, and the humanities, and episodes originally aired from 2016 to 2021.Originally released: July 18, 2017In this episode of BrainWaves, Dr. Joseph Berger discusses the complications of HIV literally from head to toe. From neuropathy to myelopathy to neurocognitive disorders as well as the myriad of opportunistic infections. Definitely worth your time.BrainWaves podcasts and online content are intended for medical education only and should not be used to guide medical decision-making in routine clinical practice. The content in this episode was vetted and approved by Joseph Berger for broadcast.REFERENCESBoissé L, Gill MJ, Power C. HIV infection of the central nervous system: clinical features and neuropathogenesis. Neurol Clin 2008;26(3):799-819. PMID 18657727Di Rocco A, Simpson DM. AIDS-associated vacuolar myelopathy. AIDS Patient Care STDS 1998;12(6):457-61. PMID 11361993Dore GJ, Law MG, Brew BJ. Prospective analysis of seizures occurring in human immunodeficiency virus type-1 infection. J NeuroAIDS 1996;1(4):59-69. PMID 16873179Ellis R, Langford D, Masliah E. HIV and antiretroviral therapy in the brain: neuronal injury and repair. Nat Rev Neurosci 2007;8(1):33-44. PMID 17180161Garg RK. HIV infection and seizures. Postgrad Med J 1999;75(885):387-90. PMID 10474720Murdoch DM, Venter WD, Van Rie A, Feldman C. Immune reconstitution inflammatory syndrome (IRIS): review of common infectious manifestations and treatment options. AIDS Res Ther 2007;4:9. PMID 17488505We believe that the principles expressed or implied in the podcast remain valid, but certain details may be superseded by evolving knowledge since the episode's original release date.

Today's Great Quote in Franchising comes from Joseph Berger - President of You've Got Maids, Joseph has a unique perspective on the franchise industry as the residential cleaning concept was founded by his parents, Frank and Cynthia Berger.

Joseph Berger, formerly a New York Times journalist, discusses his book Elie Wiesel: Confronting the Silence, the first English-language biography of the iconic Jewish intellectual and Holocaust author.

Merriam-Webster's Word of the Day for June 27, 2023 is: pungent • PUN-junt • adjective Pungent typically describes things that have a strong, sharp taste or smell. It can also describe communication that has a strong effect on the mind because of being clever and direct. // Toni likes to add pungent habaneros to her chili to give it an extra spicy kick. // The Emmy-nominated series is a pungent satire of today's political climate. See the entry > Examples: "The archive paints a pungent portrait of the couple in their own words, a relationship marked by recrimination and anger but also mutual dependence and tender affection." — Joseph Berger, The New York Times, 6 Mar. 2023 Did you know? Things described as "pungent"—be they on the plate or on the page—have a bite to them, just as the word's Latin forbear suggests: the verb pungere means "to prick or sting." Some early uses of pungent described things that literally pricked, and the word is still used this way in the biological sciences for such purposes as identifying fish with pungent dorsal fins or plants (such as holly) with pungent leaves. But most often we reserve pungent for flavors and scents that don't actually pierce or poke us, even if they result in similar sensations—which many people enjoy! The word is also frequently applied to verbal prickings, in which sharp and incisive language brings a biting quality to satires, critiques, and the like. Not to put too fine a point on it, but we think pungent really cuts the mustard as an evocative word choice.

Elie Wiesel is the author of the seminal Holocaust memoir Night and recipient of the Nobel Peace Prize.Join us with Joseph Berger, author of the new Jewish Lives biography Elie Wiesel: Confronting the Silence, as we explore how a teenage survivor from a Hasidic family became the eloquent embodiment of Holocaust remembrance and of forceful opposition to indifference. 

MedLink Neurology Podcast is delighted to feature selected episodes from BrainWaves, courtesy of James E Siegler MD, its originator and host. BrainWaves is an academic audio podcast whose mission is to educate medical providers through clinical cases and topical reviews in neurology, medicine, and the humanities, and episodes originally aired from 2016 to 2021. Originally released: July 18, 2017 Clumsiness can be hard to localize. But in a patient with a remote history of cancer, you should be suspicious for a number of things. In this week's clinical case, we discuss a patient who was cured of Hodgkin lymphoma but returns with progressive dysmetria. BrainWaves podcasts and online content are intended for medical education only and should not be used to guide medical decision-making in routine clinical practice. The content in this episode was vetted and approved by Joseph Berger. REFERENCES Abate G, Corazzelli G, Ciarmiello A, Monfardini S. Neurologic complications of Hodgkin's disease: a case history. Ann Oncol 1997;8(6):593-600. PMID 9261529 Alstadhaug KB, Croughs T, Henriksen S, et al. Treatment of progressive multifocal leukoencephalopathy with interleukin 7. JAMA Neurol 2014;71(8):1030-5. PMID 24979548 Bellizzi A, Anzivino E, Rodio DM, Palamara AT, Nencioni L, Pietropaolo V. New insights on human polyomavirus JC and pathogenesis of progressive multifocal leukoencephalopathy. Clin Dev Immunol 2013;2013:839719. PMID 23690827 Cettomai D, McArthur JC. Mirtazapine use in human immunodeficiency virus-infected patients with progressive multifocal leukoencephalopathy. Arch Neurol 2009;66(2):255-8. PMID 19204164 Felli V, Di Sibio A, Anselmi M, et al. Progressive multifocal leukoencephalopathy following treatment with rituximab in an HIV-negative patient with non-hodgkin lymphoma. A case report and literature review. Neuroradiol J 2014;27(6):657-64. PMID 25489887 García-Suárez J, de Miguel D, Krsnik I, Bañas H, Arribas I, Burgaleta C. Changes in the natural history of progressive multifocal leukoencephalopathy in HIV-negative lymphoproliferative disorders: impact of novel therapies. Am J Hematol 2005;80(4):271-81. PMID 16315252 Hoppe RT, Advani RH, Bierman PJ, et al. Hodgkin disease/lymphoma. Clinical practice guidelines in oncology. J Natl Compr Canc Netw 2006;4(3):210-30. PMID 16507269 Pavlovic D, Patera AC, Nyberg F, Gerber M, Liu M; Progressive Multifocal Leukeoncephalopathy Consortium. Progressive multifocal leukoencephalopathy: current treatment options and future perspectives. Ther Adv Neurol Disord 2015;8(6):255-73. PMID 26600871 Van Assche G, Van Ranst M, Sciot R, et al. Progressive multifocal leukoencephalopathy after natalizumab therapy for Crohn's disease. N Engl J Med 2005;353(4):362-8. PMID 15947080  We believe that the principles expressed or implied in the podcast remain valid, but certain details may be superseded by evolving knowledge since the episode's original release date.

On today's podcast we have BG Joseph B. Berger, the Commanding General of The Judge Advocate General's Legal Center and School, the premier training, education, and analysis institution for military law. As the Commander, BG Berger is responsible for developing and executing our Army's (and in many cases, the Joint Force's) institutional level legal training of uniform and civilian attorneys, paralegals, and legal administrators. The Legal Center and School's mandate is not just limited to members of the JAG Corps; it is also responsible for legal training across the Army, from what our Soldiers learn about the law of war during basic combat training to what our most senior commanders learn during their Senior and General Officer Legal Orientations, mandatory courses before they can assume command of our Nation's sons and daughters.

On today’s podcast we have BG Joseph B. Berger, the Commanding General of The Judge Advocate General’s Legal Center and School, the premier training, education, and analysis institution for military law. As the Commander, BG Berger is responsible for developing and executing our Army’s (and in many cases, the Joint Force’s) institutional level legal training of uniform and civilian attorneys, paralegals, and legal administrators. The Legal Center and School’s mandate is not just limited to members of the JAG Corps; it is also responsible for legal training across the Army, from what our Soldiers learn about the law of war during basic combat training to what our most senior commanders learn during their Senior and General Officer Legal Orientations, mandatory courses before they can assume command of our Nation’s sons and daughters. In mid-May, MAJ Coffey and MAJ Wellemeyer interviewed BG Berger via Zoom to discuss a number of topics including decision-making by lawyers as leaders, lessons learned from his time with special operations units, the speed of decision-making under the OODA loop process, under-writing failure as a leader, and lessons from the COVID-19 pandemic. Below is a timeline of some of the subject-areas discussed during the episode: 00:00 Introduction 01:05 Decision-making and lessons from SOF assignments 04:50 OODA loop, risk, and mistakes: how leaders under-write failure 06:45 Confusing “energy” with “progress” 07:49 OODA loop applied to the shift in distributed learning at TJAGLCS 13:44 How the OODA loop ties into mission command 16:10 Comfort with risk and how leaders can underwrite failure to build success 20:47 Lessons from the COVID-19 pandemic 23:07 How stress increases at lower echelons 25:06 Closing comments by BG Berger 27:05 Book recommendations 31:55 End notes If you’re interested in learning more about some of the topics covered during this episode, we recommend the following additional reading and resources: Early Lessons from the U.S. Army’s Campaign to Conquer COVID-19 by Loren Thompson Explanation of the OODA Loop BG Berger’s Book Recommendations: “Barking Up the Wrong Tree: The Surprising Science Behind Why Everything You Know About Success Is (Mostly) Wrong” by Eric Barker “Why We Write: Craft Essays on Writing War” edited by Randy Brown and Steve Leonard “Pale Rider: The Spanish Flue of 1918 and How it Changed the World” by Laura Spinney For more information related to FCD you can follow us on Twitter @jagfcd or by visiting our webpage. If you have recommendations or suggestions about future topics or guests, please send us an email at usarmy.pentagon.hqda-tjaglcs.list.tjaglcs-doctrine@mail.mil, or you can leave us a comment by signing in below. Finally, if you like what you hear, please leave us a review on iTunes and subscribe to “Battlefield Next” on your favorite podcast app. While this is a podcast created by US Army Judge Advocates from Future Concepts Directorate, our goal is to reach other judge advocates and lawyers across the DoD, law students, and members of academia. Your reviews help make this possible. For more information about the US Army JAG Corps, you can go here. If you’re interested in joining the Army JAG Corps, you can get more information by contacting the Judge Advocate Recruiting Office (JARO) or by visiting their webpage. *Music by Joseph McDade **The views expressed on the podcast are the views of the participants and do not necessarily represent those of The Judge Advocate General’s Legal Center and School, the Army, the Department of Defense, or any other agency of the US Government.

Today Franchise Interviews celebrates Thanksgiving, our 650th podcast, and 13th year anniversary.  We start our show with our most recent Great Quotes in Franchising podcast.  Today’s Great Quote in Franchising comes from Joseph Berger – President of You’ve Got Maids, Joseph has a unique perspective on the franchise industry as the residential cleaning concept was founded by his parents, Frank and Cynthia Berger. Joseph discusses why franchising is similar to taking an open book test. Next we play one of our earliest interviews with Scott Haner of the Yum! Brands franchise opportunity. Yum! Brands, Inc., based in Louisville, Kentucky, has over 48,000 restaurants in more than 145 countries and territories primarily operating the company’s restaurant brands – KFC, Pizza Hut and Taco Bell – global leaders of the chicken, pizza and Mexican-style food categories. Worldwide, the Yum! Brands system opens over eight new restaurants per day on average, making it a leader in global retail development. In 2018, Yum! Brands was named to the Dow Jones Sustainability North America Index and ranked among the top 100 Best Corporate Citizens by Corporate Responsibility Magazine. In 2019, Yum! Brands was named to the Bloomberg Gender-Equality Index for the second consecutive year.

We are meeting with Joseph Berger - President of You’ve Got Maids, Joseph has a unique perspective on the franchise industry as the residential cleaning concept was founded by his parents, Frank and Cynthia Berger. Joseph will discuss the You Got Maids franchise, the benefits of working in a family run business and his best advice for maintaining a healthy professional and personal relationship with those you work with. In part two, we play a clip from our popular Great Quotes in Franchising podcast.  

In this episode, Neil, Niki, and Natalia discuss the anxiety over automation, new treatments for male baldness, and the controversial Trump spiritual advisor Paula White. Support Past Present on Patreon: https://www.patreon.com/pastpresentpodcast Here are some links and references mentioned during this week’s show:  Automation and its effect on American jobs was a core theme at this month’s Democratic debate. Natalia referred to Rick Wartzman’s book The End of Loyalty: The Rise and Fall of Good Jobs in America, excerpted in POLITICO. Natalia also referenced this timeline chronicling fears of automation, at A raft of new products has emerged to fight an old problem: baldness. Natalia recommended Danielle Friedman’s InStyle article about the rebranding of baldness remedies by the wellness industry. Trump spiritual advisor Paula White has written a new book, endorsed by several evangelical leaders who once distanced themselves from her. Niki drew on Kelsey McKinney’s Buzzfeed article about televangelist Jim Bakker. In Episode 24, we discussed “Trump’s Evangelicals.”   In our regular closing feature, What’s Making History: Natalia recommended a podcast on which she appears at a comedy club, “Nevertheless, She Existed.” Neil discussed Joseph Berger’s New York Times article, “How Amazon Has Transformed the Hasidic Economy.” Niki shared Austin Grossman’s Atlantic article, “Monocles Were Never Cool.”

Clumsiness can be hard to localize. But in a patient with a remote history of cancer, you should be suspicious for a number of things. In this week's clinical case, we discuss a patient who was cured of Hodgkins Lymphoma but returns with progressive dysmetria. BrainWaves podcasts and online content are intended for medical education only and should not be used to guide medical decision making in routine clinical practice. The content in this episode was vetted and approved by Joseph Berger. REFERENCES 1. Bellizzi A, Anzivino E, Rodio DM, et al. New insights on human polyomavirus JC and pathogenesis of progressive multifocal leukoencephalopathy. Clin Dev Immunol 2013;1-17. 2. Garcia-Suarez J, de Miguel D, Krsnik I, et al. Changes in the natural history of progressive multifocal leukoencephalopathy in HIV-negative lymphoproliferative disorders: Impact of novel therapies. Am J Hematol 2005;80(4):271-81. 3. Felli V, DiSibio A, Anselmi M, et al. Progressive multifocal leukoencephalopathy following treatment with Rituximab in an HIV-negative patient with non-Hodgkin lymphoma: A case report and literature review. Neuroradiol J 2014;27(6):657-64. 4. Van Assche G, Van Ranst M, Sciot R, et al. Progressive multifocal leukoencephalopathy after natalizumab therapy for Crohn’s disease. N Engl J Med 2005;353:362-8. 5. Abate G, Corazzelli G, Ciarmiello A, et al. Neurologic complications of Hodgkin’s disease: A case history. Ann Oncol 1997;8(6):593-600. 6. Hoppe RT, Advani RH, Bierman PJ, et al. Hodgkin disease/lymphoma. Clinical practice guidelines in oncology. J Natl Compr Canc Netw 2006;4(3):210-30. 7. Pavlovic D, Patera AC, Nyberg F, et al. Progresive multifocal leukoencephalopathy: current treatment options and future perspectives 2015;8(6):255-73. 8. Cettomai D and McArthur JC. Mirtazapine use in human immunodeficiency virus-infected patients with progressive multifocal leukoencephalopathy. Arch Neurol 2009(2):255-258. 9. Alstadhaug KB, Croughs T, Henriksen S, et al. Treatment of progressive multifocal leukoencephalopathy with interleukin 7. JAMA Neurol 2014;71(8):1030-35.

Host: Jennifer Caudle, DO Guest: Joseph Berger, MD, FACP, FAAN, FANA Multiple sclerosis is a notoriously difficult disease to diagnose early on. With no singular confirmatory tests yet available, physicians often become reluctant to identify MS in their patients, leading to years of diagnostic and treatment uncertainty. But new innovations are helping doctors establish earlier diagnoses and start more targeted treatments for MS patients. Dr. Jennifer Caudle welcomes Dr. Joseph Berger, Professor of Neurology at Penn Medicine, to explore some of these innovations advancing MS diagnosis and treatment.

Host: Jennifer Caudle, DO Guest: Joseph Berger, MD, FACP, FAAN, FANA Multiple sclerosis is a notoriously difficult disease to diagnose early on. With no singular confirmatory tests yet available, physicians often become reluctant to identify MS in their patients, leading to years of diagnostic and treatment uncertainty. But new innovations are helping doctors establish earlier diagnoses and start more targeted treatments for MS patients. Dr. Jennifer Caudle welcomes Dr. Joseph Berger, Professor of Neurology at Penn Medicine, to explore some of these innovations advancing MS diagnosis and treatment.

Host: Jennifer Caudle, DO Guest: Joseph Berger, MD, FACP, FAAN, FANA Multiple sclerosis is a notoriously difficult disease to diagnose early on. With no singular confirmatory tests yet available, physicians often become reluctant to identify MS in their patients, leading to years of diagnostic and treatment uncertainty. But new innovations are helping doctors establish earlier diagnoses and start more targeted treatments for MS patients. Dr. Jennifer Caudle welcomes Dr. Joseph Berger, Professor of Neurology at Penn Medicine, to explore some of these innovations advancing MS diagnosis and treatment.

Host: Jennifer Caudle, DO Guest: Joseph Berger, MD, FACP, FAAN, FANA Multiple sclerosis is a notoriously difficult disease to diagnose early on. With no singular confirmatory tests yet available, physicians often become reluctant to identify MS in their patients, leading to years of diagnostic and treatment uncertainty. But new innovations are helping doctors establish earlier diagnoses and start more targeted treatments for MS patients. Dr. Jennifer Caudle welcomes Dr. Joseph Berger, Professor of Neurology at Penn Medicine, to explore some of these innovations advancing MS diagnosis and treatment.

In this episode of BrainWaves, Dr. Joseph Berger discusses the complications of HIV literally from head to toe. From neuropathy to myelopathy to neurocognitive disorders as well as the myriad of opportunistic infections. Definitely worth your time. BrainWaves podcasts and online content are intended for medical education only and should not be used to guide medical decision making in routine clinical practice. The content in this episode was vetted and approved by Joseph Berger for broadcast. REFERENCES 1. Ellis R, Langford D and Masliah E. HIV and antiretroviral therapy in the brain: neuronal injury and repair. Nat Rev Neurosci. 2007;8:33-44. 2. Boisse L, Gill MJ and Power C. HIV infection of the central nervous system: clinical features and neuropathogenesis. Neurol Clin. 2008;26:799-819, x. 3. Garg RK. HIV infection and seizures. Postgraduate medical journal. 1999;75:387-90. 4. Dore GJ, Law MG and Brew BJ. Prospective analysis of seizures occurring in human immunodeficiency virus type-1 infection. J NeuroAIDS. 1996;1:59-69. 5. Di Rocco A and Simpson DM. AIDS-associated vacuolar myelopathy. AIDS Patient Care STDS. 1998;12:457-61. 6. Murdoch DM, Venter WD, Van Rie A and Feldman C. Immune reconstitution inflammatory syndrome (IRIS): review of common infectious manifestations and treatment options. AIDS Res Ther. 2007;4:9.

It's 2016 - have you considered joining the AFA? We've got memberships where you can not only support future projects like billboards, media releases and events - but also get a fantastic magazine, network with other like-minded atheists, get some pretty snappy merchandise, and have a say in the future of the association. We're holding our AGM in March in Sydney - so consider starting your year off right and join now at www.atheistfoundation.org.au/membership. ***** Founded in 2012, the Women without Religion forum began with women without religion - and has since grown to be inclusive of feminists, rationalists, atheists, LBGTQI and cis gendered folk. The page primarily acts as a billboard that advocates for changes to make the world a better place for everyone regardless of race, ethnicity, gender, sexual orientation, ableness and age. The Women without Religion page is without religion for a large number of reasons but two main reasons are that we are without bigotry, and we value evidence based reasoning. We understand that without religion and with more evidenced based reasoning, the world would be a better place for everyone. I spoke to Annie, the founder and one of the administrators of the page - you can find it at: https://www.facebook.com/WomenWithoutReligion/ ******* Paul Fidalgo is our international correspondent on the show; he is the communications director for the skeptic and humanist organization the Center for Inquiry, where he writes the daily news roundup The Morning Heresy, among a bazillion other things. He blogs at iMortal over on the Patheos network and podcasts with Brian Hogg at www.thinkerypodcast.com. - The coming of the Depp to the Reason Rally is making news - is it a sign of a cultural acceptance of atheism in the entertainment industry? - A bishop in the Philippines says folks should keep away from Madonna's tour for being suggestive and vulgar - it also happens to be one year since the murder of Avijit Roy and Salman Rushdie is again being targeted. - NYT publishes two letters to the editor reacting to Susan Jacoby's recent piece on atheists and the language of politics and Joseph Berger at NYT looks at how Bernie Sanders talks about (or doesn't talk about) being Jewish. - We also talk about Tim Minchin's Cardinal Pell song and what's involved in the investigation in Rome. ***** In Australian and AFA forum board news – our correspondent GoldenMane gives us the lowdown on what’s happened this month on the boards. Join him and the lively crowd at atheistfoundation.org.au/forums. ***** For more information visit: atheistfoundation.org.au/podcast/ All Atheist Aus Podcast episodes are under the Creative Commons license. You are free to distribute unedited versions of the episodes for non-commercial purposes. If you would like to edit the episode please contact us. The views expressed are not necessarily representative of the Atheist Foundation of Australia, its affiliates, sponsors or advertisers. Continue the conversation with atheists, the like-minded and the not-so-like minded at the AFA forums, found at atheistfoundation.org.au/forums or tweet us at twitter.com/atheistaus. Contact the show at atheistauspodcast@gmail.com. “Backed Vibes Clean” Kevin MacLeod (incompetech.com) Licensed under Creative Commons: By Attribution 3.0 creativecommons.org/licenses/by/3.0/ “Base Walker” Kevin MacLeod (incompetech.com) Licensed under Creative Commons: By Attribution3.0creativecommons.org/licenses/by/3.0/ You can find all the previous episodes of Atheist Aus over on the SoundCloud site and on iTunes!

[intro music]   Host – Dan Keller Hello, and welcome to Episode Thirty-Nine of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.   This week’s podcast features the second part of our interview with Joseph Berger of the University of Pennsylvania. But to begin, a couple of updates.   Last week we told you about our Drug-Development Pipeline, which includes continually updated information on 44 investigational agents for MS. Since last week’s podcast we added two new trials, we updated information on 10 other trials, and we added 10 other pieces of information. The drugs with important additions and changes are dimethyl fumarate, fingolimod, glatiramer acetate, interferon beta-1a, interferon beta-1b, and phenytoin. To find information on all 44 compounds, visit msdicovery.org and click first on Research Resources and then on Drug-Development Pipeline   Two weeks ago we described how we curate a weekly list of all newly published scientific papers on MS and related disorders. Last Friday’s list included 53 papers. We selected two of them as Editor’s Picks: One is a Cochrane meta-analysis of dimethyl fumarate – trade name Tecfidera – for treating MS. The other is a study from Paul Tesar’s group at Case Western Reserve University. That study, which appeared in Nature, is entitled “Drug-based modulation of endogenous stem cells promotes functional remyelination in vivo.” To find the full weekly list and the Editor’s Picks, click on the Papers tab at msdiscovery.org.   [transition music]   Now to the interview. Dr. Joseph Berger is a professor of neurology at the Hospital of the University of Pennsylvania. In part one of his interview we talked about risk of progressive multifocal leukoencephalopathy. This week, Dr. Berger discusses diagnostic dilemmas in MS.   Interviewer – Dan Keller Dr. Berger, how do these present, and what are some of them?   Interviewee – Joseph Berger They’re legion, actually. There are a lot of different diseases that can look very much like multiple sclerosis both in terms of the history and physical examination as well as in terms of the radiographic findings. And the question is, do you want to avoid treatment that is not very helpful and expensive? You know, once you’ve made a diagnosis of multiple sclerosis you tend to put the patient on a disease-modifying therapy that they would remain on for the rest of their lives. And there’s an expense and some risk depending on what you put them on, associated with that. Secondly, there are diseases that, if you miss the diagnosis, these are diseases that can be aggressive in and of their own right, and if you’ve misdiagnosed it there’s a concern that disease may go on and create its own problems for the patient. So there are a variety of reasons why you want to ensure that what you’re dealing with is truly MS and not one of the MS mimics.   Among the common MS mimics, one that we’ve had increasing experience with in the recent past, is neuromyelitis optica. So, neuromyelitis optica was a disease that we lumped together with multiple sclerosis, but we’ve realized recently that not only is the pathogenesis different than multiple sclerosis, it being a humoral immune disorder, but that the therapies that we employ for multiple sclerosis may actually aggravate neuromyelitis optica. So that’s a common concern and one of the reasons why we frequently obtain neuromyelitis optica antibodies in patients, particularly when they present with optic neuritis or transverse myelitis, and certainly when they present with both of them.   MSDF That would be aquaporin-4 antibodies?   Dr. Berger That’s correct. It’s an aquaporin-4 antibody, but not everybody with neuromyelitis optica has the aquaporin-4 antibody that’s demonstrable. A certain percentage of them have what appears to be an anti-MAG antibody, and others we simply don’t know what the antigen is. And that’s being worked out. So there’s this whole spectrum of neuromyelitis optica that you certainly want to sort out from multiple sclerosis. But there are also a wide variety of other illnesses that can look like multiple sclerosis. In fact, if you take any broad classification of diseases – infection, vascular, neoplastic, toxic, metabolic, genetic, etc. – if you do that and say, are there diseases in these categories that can appear like multiple sclerosis and be mistaken for multiple sclerosis, there are. So every single one of these broad categories can have within it a disease that can be mistaken for multiple sclerosis.   MSDF Would they be mistaken for multiple sclerosis on many measures or mainly signs and symptoms or is it radiologic on imaging? How do you sort out this kind of gamish of different diseases and how they present, and really nailing down an MS diagnosis, not even considering a diagnosis of what else it could be?   Dr. Berger So it can be enormously difficult to do so. And I’ll give you some examples from my own practice. I have, for instance, seen individuals with a disorder called hereditary spastic paraparesis where you were unaware of their hereditary nature of their disease. And the patient has come in with a progressive myelopathy. And you say, well, could this be primary progressive multiple sclerosis? And could be extraordinarily difficult to sort out, particularly if they don’t have common mutations, and they don’t have a family history. And you say, well, which is it? The spinal fluid can be very helpful in that regard.   The MRIs can be very helpful in that regard, but not always. I’ve seen individuals who’ve had vascular disease where the MRI abnormalities have looked very much like multiple sclerosis. They’ve had recurrent episodes of neurologic symptoms be it numbness or weakness or visual problems, and it be mistake for MS. I’ve seen individuals with intravascular lymphoma, a rare disease, but one where they’ve presented with both clinical picture and MRI that looks very much like multiple sclerosis.   Although we have good diagnostic criteria, there is no single test that tells you that this is MS. But there are times when all of us, even the very best clinicians, scratch our heads when a patient’s reappeared in the office; nothing new has happened to him. Ten years have elapsed, and you say to yourself, did they really have multiple sclerosis? So, again, it’s a matter of comprehensive history and physical; the appropriate radiographic studies; looking at the spinal fluid when that’s indicated; and doing the appropriate laboratory studies to rule out things that may mimic multiple sclerosis.   MSDF Is that why there is a diagnosis of CIS? If it never returns, then it was CIS?   Dr. Berger I guess one could say that, but I use the term CIS to mean the very first episode of multiple sclerosis. So when I label somebody with CIS, I already believe that they have multiple sclerosis. I think that if they have CIS in the absence of any radiographic findings, I’d be unlikely to label them CIS. CIS to me is in the continuum of MS, so you have CIS, relapsing/remitting multiple sclerosis, secondary progressive multiple sclerosis. So that’s how I use the term.   MSDF Can you definitely rule in or rule out multiple sclerosis?   Dr. Berger I think that there are probably rare instances where people fulfill all the criteria for multiple sclerosis. And at the time of autopsy you say, how about that? That wasn’t multiple sclerosis. There’s an old expression in medicine that you can never be a 100% certain. You can never have a 100% certainty. So I think that you do the best you can. And I think that probably the rate’s 99% or better, but in these people fulfilling the criteria that have been established. However, you can never be entirely certain.   And it is not that uncommon in my practice, and I’ve been practicing medicine nearly 40 years, where an individual has presented the office after a long hiatus. And the chart is unavailable to me, and they come in with a diagnosis of multiple sclerosis, and I say, who made the diagnosis of multiple sclerosis in you? And they go, you did, Dr. Berger. So I think go down to the cave where they keep the charts that are over seven years old only to find out that they had all the criteria for multiple sclerosis; that they had oligoclonal bands, and they had hyperintense signal abnormalities on their MRI, and they had relapsing symptoms, but, you know, over the course of the last 10 years they’ve had little. And you scratch your head and say, geeze I wonder if this is truly MS?   There are probably people who carry this diagnosis, and there’s literature on it, that carry it incorrectly.   MSDF Those criteria, even though it never turned out to be MS, satisfied a diagnosis of MS. When you see something like radiologically isolated syndrome, do you work it up for MS, or only once it presents later does it become MS?   Dr. Berger This is a very difficult question, and we see this with some regularity, that is, the individual that has hit his head in a car accident or developed a headache that somebody’s decided to do an MRI on. And they come in with an MRI that looks all the world like a patient with multiple sclerosis, yet they have no symptoms and no signs on physical examination that is suggestive of multiple sclerosis. And the question then becomes, what do you do with them?   There’s currently a study in which that question is being addressed. However, I will tell you what I do, currently. I do look for multiple sclerosis. I look for lesions in their spinal cords because I think that if they have that, the prognosis can’t be good, and I would likely start somebody with lesions in their spinal cord, who I’m convinced has MS, on a disease-modifying drug.   I look their spinal fluid. And I look at their spinal fluid for oligoclonal bands, and, if I see that, I’m increasingly convinced that that’s what we’re dealing with. And I would be inclined to treat those people as well. Now whether I’m doing the right thing or not, I don’t know, but for others in whom there are no spinal cord lesions, there are no signs or symptoms, and the spinal fluid is pristine, I’ve elected to wait. That is not necessarily the consensus among the MS community. That’s simply how I practice, currently.   MSDF People don’t need oligoclonal bands to have MS, though, do they?   Dr. Berger No, not at all. So, we certainly see a fair number of people – and it depends on the study – who have pristine spinal fluids. That means no oligoclonal bands, no cells, no increased protein, no elevated myelin basic protein or IgGs who still have multiple sclerosis.   MSDF What about fatigue as an initial symptom of multiple sclerosis? A lot of people have fatigue – tiredness. Is there a way to differentiate the fatigue of multiple sclerosis from just being tired or a sleep apnea or an insomnia or they just don’t feel good?   Dr. Berger Well, I think your history is very helpful because the sleep deprivation and excessive daytime sleepiness is not the same as the fatigue that people with MS report. The fatigue that people with MS report is akin to the fatigue that one experiences when they have a viral illness. So when you have the flu you go, oh man, I just can’t get out of bed. I feel terrible. And that’s precisely what the people with multiple sclerosis have. And what’s so interesting is how common it is. So it’s been said to be the greatest cause of disability in the MS population. It’s an acceptable cause of disability; not blindness, not incoordination, not weakness, but fatigue.   And it’s curious, when I practiced in Kentucky, I had a number of patients who were wheelchair-bound, had very poor vision or had double vision because of paralysis ocular palsies, who went to work every single day. And then I had patients that looked as healthy as you and I, and they were on disability. And I said, well, why is it that you can’t work? They said, I’m just too fatigued. I can’t do anything. It’s affected everything.   So the fatigue is different, and getting back to the frequency of it, so in individuals who have been diagnosed with multiple sclerosis, and I was part of this study, if you look at large numbers of individuals diagnosed with MS or who are on disease-modifying drugs for MS and go back and look at their medical records prior to the time of the diagnosis, you will see that about a third of them had been labeled by their family physician or their internist as having one of two diagnoses: chronic fatigue syndrome or fatigue and malaise. They’re the only two diagnoses with fatigue in them that you could put into the ICD-9 classification.   So, this is striking that so many individuals have fatigue recognized, yet it’s an advance of their having any neurologic symptoms that were believed to be the consequence of multiple sclerosis. It’s not to say that they didn’t have them. You know, it might have been some transient numbness or transient tingling or slight weakness that went away that nobody ever thought was due to multiple sclerosis. So that we don’t know about. But what I can tell you is that prior to an established diagnosis of multiple sclerosis, roughly a third of individuals have been labeled by their family physicians with fatigue.   MSDF It’s interesting that you make the analogy between this sort of fatigue and that with a viral illness like the flu. Could this be a prodrome telling there’s an inflammatory process going on? I mean, is there interferon release or are there other mediators that seem to be unique to this kind of fatigue?   Dr. Berger I would like to think that that’s the case. I would like to think that this is due to the very same cytokines that cause the fatigue that’s associated with viral illness. That’s not been convincingly demonstrated, although it’s been proposed. I think it makes a lot of sense. Coming full circle, eventually, although most of my colleagues classify multiple sclerosis as an autoimmune disease, there must be a trigger for the autoimmune disease. And my own belief, coming to this from virological angles as opposed to coming at it from an immune angle, is that there’s probably some infectious origin.   One of the things that’s so striking is the association between Epstein-Barr virus and multiple sclerosis where virtually every adult patient with multiple sclerosis has evidence serologically of having been exposed to Epstein-Barr virus. Now I’m not saying that that’s necessarily the cause, but in some way it must contribute to the development of the disease perhaps in a way that low vitamin D levels contribute to the genesis of the disease.   MSDF Is there anything you’d like to add about diagnostic dilemmas or any kind of a mental framework for approaching this sort of thing, in nutshell?   Dr. Berger Yes. The one thing that I would say is never be too confident. Never be too confident. I found that my highest confidence levels were right before I took boards in neurology, which was a long time ago. And I thought I knew everything. And the more I practice neurology, the more humble I’ve become in terms of establishing diagnoses and selecting right therapies for patients. So I always have a healthy skepticism. I have a healthy skepticism of things that I feel certain about. And when patients represent to office I always question myself, particularly if there’s something that doesn’t fit with the diagnosis. And I think that that’s good advice to anybody practicing medicine.   MSDF Very good! Thank you.   Dr. Berger My pleasure.   [transition music]   Thank you for listening to Episode Thirty-Nine of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Robert Finn. Msdiscovery.org is part of the non-profit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is vice president of scientific operations.   Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.   We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.   [outro music]

[intro music]   Hello, and welcome to Episode Thirty-Eight of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.   This week’s podcast features part one of a two-part interview with Joseph Berger of the University of Pennsylvania. But to begin, we’d like to tell you about MSDF’s Drug-Development Pipeline.   Twelve drugs are currently approved in the US for the treatment of MS, but there are many more drugs in various stages of clinical and pre-clinical development. We’re keeping daily track of 44 of them in our Drug Development Pipeline.   To visit the pipeline just go to msdiscovery.org and click on Research Resources, and then Drug-Development Pipeline. You’ll find a finely detailed, fully referenced, and easily searchable database of all 44 of those drugs. The database includes details on each drug candidate’s physiology, its progress through pre-clinical and clinical trials, and its regulatory and commercial status.   Science journalist Heather McDonald has managed this database since its inception, and she updates it continuously, whenever new information becomes available. In just the last week, for example, she added one new clinical trial to the database, she updated information on two other clinical trials, and she added 5 other pieces of information. The drugs with important additions and changes were dimethyl fumarate, fingolimod, glatiramer acetate, interferon beta-1a, interferon beta-1b, mitoxantrone, natalizumab, and RPC1063.   [transition music]   Now to the interview. Dr. Joseph P Berger is a professor of neurology and Chief of the MS Division at the University of Pennsylvania in Philadelphia. In part one of our discussion with Dr. Berger, we’re talking about the risk of progressive multifocal leukoencephalopathy (PML), a rare but serious brain infection that occasionally arises in people being treated for multiple sclerosis.   Interviewer – Dan Keller The topic of quantifying risk and mitigating risk comes up with certain immunosuppressive drugs, notably natalizumab in MS but also with other drugs as well in other conditions. What are some of the confounding factors? Why is this not an easy thing to approach?   Interviewee – Joseph Berger Well, it’s not easy because it’s so unpredictable. Nobody would have thought that natalizumab would have uniquely predisposed to the development of progressive multifocal leukoencephalopathy. In fact, when natalizumab was introduced, if one would have attempted to predict what would have happened, you might have said, well, we’ll see a wide variety of opportunistic infections of the central nervous system, since this is a drug that prevents the neural immunosurveillance that is necessary to prevent these diseases from occurring. However, that’s not what we see. We don’t see the opportunistic infections of the central nervous system that we see in the AIDS patient; for instance, things like cryptococcal meningitis and toxoplasma and tuberculous meningitis, it simply doesn’t happen. What we see, on the other hand, is this unique increased risk for the development of progressive multifocal leukoencephalopathy. This was an entirely, in my mind, unpredictable event. I suspect that this is true of many of the other drugs that are now coming to market; that our experience with them is limited, they have what we think is a well-defined effect on the immune system – they’re not broadly immunosuppressant – yet our knowledge of the immune system is such that we don’t understand fully the downstream effects they have. And it’s only after we’ve used these drugs for a number of years do we have a comfort level with what sort of risks that are engendered by their use.   MSDF But it’s not unique to natalizumab; other drugs can induce this whether in neurologic conditions or even rheumatologic conditions. Is that right?   Dr. Berger Yes. In talking about PML, that is true that there are other drugs that carry black box warnings for the development of PML; however, there’s something unique about natalizumab and another drug that is somewhat related to it and now off the market called efalizumab, which was a drug which went by the name of Raptiva and was used for the treatment of psoriasis. So there are drugs that uniquely increase the risk of PML and there are those that marginally increase the risk of PML, and one shouldn’t conflate them. And though a drug carries a black box warning for PML, it doesn’t necessarily mean that the risk is the same as it is with another drug that may also carry such a warning.   And let me explain this a little further. If you look at natalizumab and you look at efalizumab, those are drugs that have been used for conditions that had never previously been associated with progressive multifocal leukoencephalopathy. So despite the fact… And natalizumab, as you know, is used in the treatment of MS and used in the treatment of inflammatory bowel disorders, in particular Crohn’s disease, efalizumab used in the treatment of psoriasis; these are autoimmune diseases. And prior to the availability of these compounds, we did some aggressive immunosuppressive therapies in the treatment of these diseases. We would treat them with drugs like Cytoxan and azathioprine and high-dose steroids; a wide variety of things were employed. Yet until the PML experience with natalizumab and efalizumab, we had never seen PML in the setting of multiple sclerosis, in the setting of inflammatory bowel disease, or in the setting of psoriasis. So that tells you that there’s something unique about the drugs that we’re using and that it’s not necessarily the underlying condition that is responsible.   The second is when you start the drug, you do not see PML develop immediately; it takes some time. So the experience with efalizumab was three or more years, the experience with natalizumab is typically 12 months; actually the vast majority of cases – over 80% - have been on natalizumab for 24 months, so they’re on the drug for a long time. The shortest latency from initiation to the development of PML has been a single case in which it developed within eight months; everything else is 12 or more months. So what is that telling you? That tells you that the drug is doing something fundamentally to overcome the barriers to the development of this disease and that it’s not simply opening up a gate and letting the horses out; it’s doing something to the pathobiology of the disease.   And then lastly, the incidence with which we see PML with natalizumab – and presumably with efalizumab, although the numbers were much smaller – is extraordinarily high in the appropriate context. So for natalizumab, the risk of developing PML, provided you’re on the drug for two years, you’ve seen prior immunosuppressive therapy, and you’re JC virus antibody-positive so that you have been exposed to the virus that causes this disease, if you have all three of those, your risk is on the order of 1 in 90 or thereabouts. That is a risk that is commensurate with what we see with HIV-associated PML, so it’s very, very high.   However, if one looks at these other drugs which I have called Class 2 agents in several papers now; drugs like rituximab, also a monoclonal antibody though directed against CD20, drugs like brentuximab vedotin or mycophenolate mofetil – which is CellCept – those drugs, too, carry black box warnings for the development of PML; however, the setting in which PML occurs with their use is almost always with a condition that already predisposes you to the development of PML. So with rituximab, for instance, it’s seen with lymphoproliferative disorders, or with transplantation, or with autoimmune diseases in which PML had already been described long before the use of rituximab for the condition. And the same is true with these other drugs.   The second is there’s no latency to the development of the disease, so this is strictly a stochastic event; you may start rituximab today and in two weeks’ time develop PML. There’s no way that somebody’s developed PML in two weeks’ time. What that indicates is that individual was predisposed to developing PML, that virus was already in their brain, it was percolating there, your immune system was suppressing it adequately so it wasn’t expressing itself. And now you’ve done something, you’ve tweaked it a bit and the PML is now expressing itself because you’ve introduced the drug, but the drug fundamentally is not changing the pathobiology of the disease.   Lastly, although we do not have good figures on this, but the best data that I have is that we’re talking about orders of magnitude lower risk with these other drugs. So rituximab, for instance, the risk is probably on the order of 1 in 30,000, or something to that effect. That compared to 1 in 90 when you have all the risk factors that I described with natalizumab. So we’re talking orders of magnitude difference. So I’d suggest that we avoid conflating these drugs when talking about PML risks, and I think that this is something that is generalizable for other risks; I mean, PML is just one risk, but we see other infections and other things that have occurred with other drugs that we’ve employed tweaking the immune system, and I don’t think that one should necessarily put all these drugs that cause these things in the same boat.   MSDF These drugs that are used in other conditions that do in themselves predispose to PML, when they’re used in MS which as a disease does not, on its own, predispose to PML, these same drugs – azathioprine, cyclophosphamide, mycophenolate – add to the risk when you give natalizumab?   Dr. Berger That’s what it looks like. So when Biogen looked at the data that they had available from the initial cases of natalizumab-associated PML, one of the risks that they identified was the increased risk of the development of PML in those individuals that had previously received immunosuppressive therapy. And it really didn’t seem to matter which immunosuppressive therapy it was, it was any immunosuppressive therapy. However, it may be different with the different immunotherapies, it’s simply that the numbers weren’t large enough for one to say that this was particularly associated with azathioprine. People in Europe like to use azathioprine often very early in the course of the disease, so they were seeing a bit more PML than we had seen in the United States at least initially. And it wouldn’t surprise me if there aren’t certain immunosuppressive agents that increase the risk significantly compared to others, but we simply don’t have that data. And what is known is that it really doesn’t matter, any of them can do that.   MSDF Without really having a firm understanding of the pathogenesis of PML – you know the risks but maybe not exactly why it’s occurring – how do you come up with a framework for mitigating risk; is it purely empiric?   Dr. Berger That’s an excellent question. So it turns out that this was a back-of-the-textbook disease; this was the disease that occurred very, very rarely. Between 1958 and 1984 in a review published by Ben Brooks and Deward Walker, there were only 230 cases that they were able to come up with; 1958, of course, is when the disease was first described. So this was a very, very rare disease until the AIDS pandemic where people developed some interest in it, and then it really became interesting when we saw it with natalizumab. And there’s been more resources put into the study of this disease since then, so that we do have a better understanding of the pathogenesis. But in identifying these risks, we’ve worked backwards; you know, we say, alright, what does natalizumab do? So why is it that we see this increased risk?   So in getting back to your question, we know that immunosurveilling the brain is important; so if you have a drug that prevents appropriate immunosurveillance of the central nervosus system, it should not surprise you that the risk of PML is increased. And we do think that the alpha-4 beta-1 integrin inhibition that occurs preventing the entry of JC virus-specific cytotoxic T lymphocytes into the brain is in a large measure – but not completely – contributing to the development of PML. We also know other things. For instance, the virus that we are likely infected with – and the infection occurs very early in our lives; seroepidemiologic studies indicate that most individuals that are infected are infected before the age of 20 – that that virus is a virus that is ubiquitous but incapable of growing effectively in glial tissues; it is a virus found in urine and found in the urinary tract, it’s found in kidney and renal pelvis and bladder, and it’s found in high concentrations in some people’s urine. That virus will not grow in the brain. So something has to happen to the virus.   Does natalizumab change that in some way? Well, we think it does. We think it does that by causing the release of immature B cells; these immature B cells can harbor JC virus, and that virus as these B cells mature there is an upregulation of transcriptional factors that transactivate the virus, it is occurring in a milieu that may uniquely predispose to a genetic rearrangement of the virus enabling it to become a form of the virus referred to as a prototype strain or a neurotropic strain that can grow in the brain. So we think that there are at least two very large barriers that prevent PML that are affected by natalizumab; there may be others. And as we investigate this disease further, our understanding may improve and these explanations I’m telling you will likely be expanded. And, in fact, it may be that some of the thoughts that we have are wrong, because the story with the B cells is actually somewhat hypothetical; there’s some preliminary evidence supportive of it, and that’s why I tell people that I’m fond of Ralph Waldo Emerson’s comment, that consistency is the hobgoblin of small minds. If I stand before you a year from today and tell you something different, it’s only because we’ve learned more about it.   MSDF So how do you mitigate risk and how do you get the point across to patients to let them make informed decisions with you?   Dr. Berger So this is difficult, but we lay the facts out to them. And the facts are that there is this risk of PML, the risk in individuals that are JC virus antibody-negative are very small, the product label puts the risk at less than 1 in a thousand; the belief is that it’s significantly less than that. The fact is that we do see individuals who are JC virus antibody-negative months before the development of PML – it’s rare but it occurs – and there have been studies, including my own, that have indicated that the antibody study doesn’t necessarily mean you’ve never been infected by the virus. So one shouldn’t conflate JC virus antibody negativity with never having been infected, but it is a very good marker for the development of PML, and it is one that needs to be monitored carefully at six month intervals.   So we lay out to the patients that if you’re antibody-negative your risk is infinitesimal and an acceptable risk, and that we monitor you carefully. The second is this is a disease that can be life-threatening, and if not life-threatening certainly severely debilitating – multiple sclerosis I’m talking about – and there are people that have very aggressive disease and will accept the risk of developing PML, knowing that the risk may be 1 in 100, but their risk of developing something that was going to leave them wheelchair-bound and totally disabled is very, very high, and they say I’d rather take the risk of the development of PML.   So we do know what the numbers are. There’s a table that’s been published and gets revised periodically that puts into it JC virus antibody positivity, duration of therapy broken up into 24-month epochs, and prior immunosuppressive use. So we know what the risks are; the highest are in individuals that are treated more than 24 months with the drug, are JC virus antibody-positive, and had previously received immunosuppressive therapies.   MSDF What about monitoring for signs and symptoms of PML if someone does choose to go on some of these drugs?   Dr. Berger Yes, so that’s very, very important. And we do have patients that even in the face of JC virus antibody positivity, we and the patient elect to continue them on the drug. And patients on natalizumab need to be monitored very carefully for the development of PML, and that is a combination of both clinical screening – there is a TOUCH program that queries for the development of symptoms that may be concordant with PML – unfortunately, you also see symptoms of that nature develop in MS patients, as well, so it’s sometimes difficult to tell whether it’s MS or PML – and at that point in time you definitely want to survey them with an MRI. And, in fact, many of us do MRIs at regular intervals in patients on Tysabri attempting to identify the disease – PML – when it is asymptomatic. And those people seem to do best; the prognosis both in terms of disability and in terms of survival is better when you pick the disease up while they’re still asymptomatic, and they have what one would refer to as radiographically isolated PML.   So it’s a combination of vigilance, asking the right questions, performing your physical examination, and obtaining period MRIs, and in those that are JC virus antibody-negative – or even the antibody-positive – repeating that study periodically. And the reason I say that repeating it periodically even in the positive patients is because what’s been demonstrated is that the higher your antibody titer, the greater the risk of developing PML. So there’s a threshold now that’s been identified and individuals above that range have a significantly higher risk of developing PML than individuals who are seropositive but below that level.   MSDF And just to clarify; the TOUCH program is the Tysabri Outreach Unified Commitment to Health? This is what you’re referring to in terms of monitoring for signs and symptoms of PML?   Dr. Berger That is correct. That is the risk mitigation strategy that is FDA-approved and that Biogen has implemented in an effort to decrease the likelihood of PML developing.   MSDF Very good, thank you.   Dr. Berger My pleasure.   [transition music]   Thank you for listening to Episode Thirty-Eight of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Robert Finn. Msdiscovery.org is part of the non-profit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is vice president of scientific operations.   Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.   We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.    [outro music]

1) PML diagnostic criteria: Consensus statement from AAN Neuroinfectious Disease Section and 2) Topic of the month: Stroke trials. This podcast for the Neurology Journal begins and closes with Dr. Robert Gross, Editor-in-Chief, briefly discussing highlighted articles from the print issue of Neurology. In the second segment Dr. Andy Southerland interviews Dr. Joseph Berger about the consensus paper from the PML Guidelines Committee of the AAN Neuroinfectious Disease Section. Dr. Andy Numis is reading our e-Pearl of the week about spinal epidural abscesses. In the next part of the podcast Dr. Brett Kissela interviews Dr. Marc Chimowitz about SAMMPRIS trial. The participants had nothing to disclose except Drs. Berger, Numis, Kissela and Chimowitz.Dr. Berger serves as an Associate Editor for the Journal of Neurovirology, serves as an editorial board member of ISRN Education, Neuroscience, World Journal of Rheumatology and MS and other related disorders; serves on the PML adjudication committees of Millenium/Takeda and Amgen; has served as a consultant to Millennium/Takeda, Amgen, Genzyme, Eisai and Novartis; and receives honoraria from Genzyme. Dr. Numis serves on the editorial team for the Neurology® Resident and Fellow Section. Dr. Kissela serves on scientific advisory board for Allergan, Inc.; has received funding for travel and speaker honoraria from Allergan, Inc.; has received research support from the NIH, will receive compensation from Reata Pharmaceuticals, Inc. for serving on the Event Adjudication Committee for the BEACON study, which they are sponsoring. and provides medico-legal reviews.Dr. Chimowitz serves as an editorial board member for the journals Stroke and Neurosurgery; has received grant support from NIH/ NINDS to lead multicenter trials on the treatment of intracranial arterial stenosis; for these NIH funded trials, he has also received research support from Stryker Corporation (donation of intracranial stents, payments for 3rd party monitoring of trial), AstraZeneca Corporation (donation of statin), Bayer (donation of aspirin and placebo) and Bristol Myers Squibb (donation of warfarin and placebo); serves on the data safety monitoring board for an industry funded PFO closure study sponsored by Gore Corporation and on a stroke event adjudication panel for an osteoporosis trial funded by Merck and has also provided medico-legal reviews on stroke related cases.

Aaron Lansky and Justin Cammy explore the who, the why, and the little-known of Chaim Grade the Litvak Yiddish writer par excellence. Professor Justin Cammy (Smith College), Professor David Fishman (Jewish Theological Seminary), and New York Times reporter Joseph Berger presented a three-day program, "Sabbath Days and Extinguished Stars: The Life and Work of Chaim Grade," on April 20-22, 2012, at the Yiddish Book Center. The lectures and discussions from that weekend formed the basis for an online course offered October, 2012. To learn more about onsite and online learning opportunities visit http://www.yiddishbookcenter.org/adult-learning. Episode 0009 February 21, 2012 Yiddish Book Center Amherst, Massachusetts