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Local and remote interactions between macrophages and microglia in neurological conditions – DocWire News

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Curr Opin Immunol. 2021 Dec 1;74:118-124. doi: 10.1016/j.coi.2021.11.006. Online ahead of print.

ABSTRACT

In the central nervous system (CNS) parenchymal macrophages are called microglial cells and have a distinct developmental origin and can self-renew. However, during pathological conditions, when the blood-brain-barrier becomes leaky, including after injury, in multiple sclerosis or with glioblastoma, monocyte-derived macrophages (MDM) infiltrate the CNS and cohabit with microglia. In neurodegenerative diseases such as Alzheimers disease or ALS, MDM mostly do not enter the CNS, and instead microglia take several identities. In the specific case of ALS, the affected motor neurons are even surrounded locally by microglia, while along the peripheral nerves, by MDM-derived macrophages. The specific functions and interactions of these different myeloid cells are only starting to be recognized, but hold high promise for more targeted therapies.

PMID:34864338 | DOI:10.1016/j.coi.2021.11.006

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20 Years Later, Neurology Training Transitions with New… : Neurology Today – LWW Journals

Article In Brief

Neurology residency directors reflect back on the way training has shifted in the last 20 yearsfrom training and work limits for residents to new models for assessing skills.

With the understanding of a host of neurologic diseases growing at an impressive pace, neurology residency programs have plenty of new discoveries and topics to consider.

Just 20 years ago, stroke care was in its infancy and neurologists were only starting to experience the potential of tissue plasminogen activator (tPA) to limit the devastating effects of acute stroke. Now with the introduction of mechanical thrombectomy, stroke care has evolved even more, as have therapies for everything from multiple sclerosis (MS) to epilepsy.

It used to be that residency programs could teach residents the field of neurologythis is what's out there and this is what you should know is comingbut now that's impossible, said Shannon M. Kilgore, MD, FAAN, who serves as the site director of the Stanford University neurology residency program. The depth and breadth of neurology is so big at this point that there is no way to cover everything.

Exposing residents to a spectrum of neurologic diseases and degrees of illness remains at the heart of clinical rotations in neurology training, Dr. Kilgore said, but there also is a shift toward the goal of creating learners, life-long learners. It's about teaching trainees how to access information, how to recognize when they don't know something and seek out information from someone else or another resource.

Other key changes in neurology training in recent years include limitations on how many hours residents can work each week (80 is the magic number); the use of milestones to track residents' advancement through levels of mastering skill sets (such as diagnosis and management of neurologic emergencies); and more attention to broader societal issues such as diversity, inclusion, cultural awareness, inherent bias, and health care access and inequities.

A lot has changed and a lot has not changed, said Ralph Jzefowicz, MD, FAAN, who at the end of this year will step down after 25 years as program director of the neurology residency program at the University of Rochester School of Medicine and Dentistry.

On the change side, Dr. Jzefowicz said neurology is shedding its image of being a kind of laid-back specialty where there isn't much for practitioners to do besides making diagnoses and managing symptoms as best they can. When he began training residents, stroke was not considered a medical emergency, and largely involved admitting a patient to the hospital, providing physical and occupational therapy, and transferring the patient to a rehabilitation facility or a nursing home depending upon the severity of the neurologic deficit.

Dr. Jzefowicz, professor of neurology and medicine, said, What hasn't changed is the aim to turn out residents who are physicians foremost with the knowledge to care for patients with neurologic disorders, outstanding teachers, as well as leaders who are kind, compassionate, and have humanistic skills.

Pierre Fayad, MD, FAAN, FAHA, who served as neurology residency program director for more than 12 years at the University of Nebraska Medical Center and is currently a member of the neurology residency review committee for the American Council for Graduate Medical Education (ACGME), said, The key shift in neurology training, as in other specialties, has been to move away from a very structured, prescriptive approachthe prescriptive do these rotations, cover these core subjects toward assessing a training experience focused on clinical competencies and milestone achievement.

There are various milestones for what we feel are important things for a neurology resident to achieve in training, said Dr. Fayad, professor of neurological sciences and chief of vascular neurology and the stroke division of the University of Nebraska Medical Center. Assessing residents using 27 milestones, which began in 2013 and was updated this year, gives us a much bigger and better picture of the progress of residents, he said.

The 27 milestones, grouped under six major domains of physician competency, are each rated from 1 (novice) to 5 (expert). For instance, in a milestone for Interpretation of Neuroimaging, residents advance from Level 1 (identifies basic neuroanatomy on brain and vascular anatomy of the head and MRI and CT) to Level 5 (interprets advanced neuroimaging).

The specialty of neurology has grown tremendously because of the massive expansion in knowledge and therapeutics that led to subspecialization within neurology to carry forward the science and clinical practice, said Dr. Fayad, who noted there are now 10 ACGME-approved neurology subspecialties and many others that are not yet approved by the ACGME.

A big challenge for the neurology residency is parceling out the knowledge from each of the subspecialties and integrating them to a general neurologist's need, he said. An example is incorporating some of the critical content and practice from endovascular surgical neuroradiology into the neurology residency. Other subspecialties with such challenges include MS and neuro-oncology, which require a significant knowledge and comfort with managing immune therapies, or movement disorders and epilepsy, which are heavy in surgical therapies, procedures, and pharmacotherapies.

He said telehealth, which became quite common in neurology during the early months of the pandemic, will eventually need to be officially incorporated into neurology residency training.

Dr. Fayad said residency directors have a lot of balls to juggle: They need to consider the professional interests and goals of individual residents, the on-call demands of a given servicevascular and endovascular neurology require availability 24 hours a day on an urgent basiswhile other specialties do not have such needs, the impact of urgent calls on residents' well-being, and compliance to the 80-hour work requirement.

Carlo S. Tornatore, MD, professor and chair of neurology at Georgetown University Medical Center, was residency director from 1998 to 2015. He believes the decision to limit residents' hours has led to mostly positive results, though he said there needs to be extra attention on good communication when handing a patient off from one doctor to the next. The adoption of electronic medical records helps.

There is no question that work hours are more humane and respectful of our learners, and the whole purpose of residency is to learn, he said.

Dr. Tornatore said that with advances in stroke care, spending time on stroke service is all the more critical for residents, but he said inpatient, acute-care experience shouldn't be emphasized at the expense of outpatient services because that is where most neurologic care is delivered.

Our goal is to train somebody who is highly competent as a general neurologist and who can easily pass the boards, he said, though most residents do go on to specialty training.

I think a general trend (in training) has been to have residents spend more time in the outpatient setting, he said, which helps connect residents with the everyday practice of neurology and the dynamics outside the walls of the hospital.

Dr. Tornatore, who specializes in MS, said the COVID-19 pandemic brought front and center to his residents the pressing issue of health disparities and inequities in health care access in low income and minority communities.

What we learned during the pandemic is that lack of access to care and the incredible inequities in care absolutely had an impact on patients' risk of developing COVID-19 or being hospitalized and dying from COVID, he said. He said part of medical education and training has to focus on what doctors can do within their institutions and communities to address health inequities and disparities, including being cognizant of the inherent biases they may bring into patient encounters.

It's getting at the idea that when you see a person don't immediately jump to the conclusion, I know this person and what they are about, he said.

He said Georgetown University Medical Center has undertaken multiple initiatives to address issues of diversity, inclusion, and equity, including the establishment of the Racial Justice Committee for Change, which consists of attending staff, fellows, residents, medical students, patients, and staff. Dr. Tornatore said the committee has been tasked to make tangible and meaningful changes over the next year to address diversity, inclusion, and equity concerns.

Wendy Peltier, MD, associate professor of neurology and medicine at the Medical College of Wisconsin, said she wonders whether the holistic side of being a doctor is being shortchanged amid the need to teach all sorts of new developments in neurology while still keeping training hours in check.

I think it is important for medicine as a whole to have a broader approach for doctors in training, to focus on not just what they learn but how they grow as humans, she said.

Dr. Peltier, who was neurology residency director for a decade and now specializes in palliative care, said she's not advocating a return to the days when she once worked 100 days in a row as an intern during the HIV/AIDS epidemic, but said today's trainees may be perhaps missing a little of that lived and shared experience with a patient.

I can look back and say my (training) experiences brought me so close to patients and families and made me the doctor I am today, she said. The joy I got from the patientdoctor relationship empowered me to stay active in neurology.

Dr. Peltier said that one trend in neurologic care that she finds particularly exciting is the growth in using multidisciplinary care teams in field such as amyotrophic lateral sclerosis, MS and memory care, so there needs to be an emphasis on residents learning how to be a leader of a team.

Stanford's Dr. Kilgore, who has served on the ACGME's Review Committee for Neurology, said neurology training of the future needs to be organized in such a way to help address the unmet need for neurologists in many communities, including rural America, which contributes to inequities in care.

Training is inherently tied to hospital care [due to Medicare funding of GME], but we have historically woefully undertrained in the outpatient clinics, she said. Residents are really uncomfortable going into practice where they are going to see patients mostly in a clinic because that's not what they've been doing for four years.

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20 Years Later, The Pressures and Opportunities Facing… : Neurology Today – LWW Journals

Article In Brief

The loss of protected time for research and a focus on clinical revenue and relative value units has changed the traditional balance of academic neurology from the traditional triad of research, teaching, and clinical practice. But some of the changes in the last 20 years are for the better, academic neurology chairs told Neurology Today.

With great advances comes greater pressure to deliver clinical care to patients.

Twenty-one years into the 21st century, neurology chairs across the United States say that academic medicine has seen vast changesmany of them exciting, some not so much.

On the plus side, new discoveries and treatments offer neurologists new tools and subspecialties to treat more patients.

When I was a student and resident, I would hear people say, Neurology is diagnose and adios, said Matthew Rizzo, MD, FAAN, professor and chair of the department of neurological sciences at the University of Nebraska. It's not that at all now. So many treatments are available for the acute and chronic diseases we treat. And there are more and more people who seek neurologic care. What I see is opportunity upon opportunity.

At the same time, he and four other chairs who spoke to Neurology Today agreed, demands on academic neurologists to spend more time treating patients and less time on research and teaching have led to increased stress and, for some, burnout.

The emphasis on high throughput has definitely hurt academic neurology, said Clifton Gooch, MD, FAAN, professor and chair of neurology at the University of South Florida's (USF) Morsani College of Medicine. Neurology has more complicated patients than most other areas of medicine to begin with, and the most challenging patients from within this group are referred to academic neurology departments. So when some health systems say, We want you to spend 30 minutes on a new patient with severe Alzheimer's disease and 15 minutes to follow up a complex Parkinson's disease patient, you simply can't provide adequate care, and that puts you under tremendous stress. Department leadership is critical to mitigate demands such as these on faculty, but it can be challenging.

On balance, though, all five chairs said the positives in today's academic neurology far outweigh the negatives.

I finished my fellowship in 1987, when there was more protected time for research and teaching, said Kathleen M. Shannon, MD, FAAN, FANA, professor and chair of neurology at the University of Wisconsin School of Medicine and Public Health. Since then, she said, The pressure for patient care has really, really gone up. That has led to a lot of burnout issues. But don't get me wrong. Academic neurology is a wonderful place. It still attracts the very best people, who are 100 percent committed to taking care of their patients and making their lives better. I really love what I do. It's just hard to know the struggles that my folks are facing.

To help neurologists in every career path better handle the challenges of practicing in an academic setting, the AAN established an Academic Neurology Initiative under its past president, Ralph L. Sacco, MD, FAAN, FAHA, professor and chair of neurology at the University of Miami Leonard Miller School of Medicine.

Many people went into academic medicine to do research and teaching, but the clinical mission is growing more rapidly, Dr. Sacco said. The revenue for academic health systems is much more dependent now on clinical revenues. The AAN felt strongly there was more help needed for neurologists in academic medical centers to deal with the new realities.

Back in the day, Dr. Rizzo said, Neurology departments were basically fiefdoms. Department chairs had a lot of power and leverage over the way money got spent, how the clinic was organized. What I've seen over the course of my career is the corporatization of medicine. You have C-suites and CFOs and CEOs. When I started out, all we had were doctors, nurses, ward clerks, and patients. It was pretty simple.

Dr. Gooch, who in 2017 published a survey of academic neurology departments, described the last couple of decades of the 20th century as a fiscal golden age for neurologists and other physicians.

There was a lot more money in medicine at that time, he said. The baby boomers were younger and healthier, working and paying into the health insurance system while consuming fewer services and clinical reimbursement was good. States provided a much greater portion of most medical school budgets. There was funded time to teach and do research, including small exploratory and/or descriptive clinical research projects. The clinical productivity metric of RVUs [relative value units] were first introduced in 1989, and were not yet an unyielding standard of performance .

Changes accelerated with the advent of managed care, Dr. Gooch said. As we approached the year 2000, the baby boomers started retiring and began consuming health care rather than working and paying into the system. This and other factors, including the development of more expensive technologies and treatments, contributed to rising health care costs, causing Medicare and businesses to look for ways to rein in expenses. Consequently, managed care was born, with a major focus on cutting reimbursement for clinical services, he said. At the same time, state support fell. When I became chair here at USF in 2008, 40 percent of the medical school's budget was from the state. Now it's below 10 percent and continues to fall.

Steven Galetta, MD, FAAN, professor and chair of neurology at NYU Grossman School of Medicine, said that back in the 1990s, Most of us were doing general neurology. As the decade progressed, subspecialty fellowships emerged, particularly for stroke and neurocritical care. We started off with no headache medicine specialists. Now we have six.

As more medicines became available for headaches, multiple sclerosis, stroke, and other disorders, the demand for neurological care became tremendous, Dr. Galetta said. As NYU has taken over smaller health systems in nearby Brooklyn and Long island, he said, We went from seeing 7,000 outpatients in 2012 to nearly 100,000 this year. We've hired over a hundred neurologists in those years.

Even as total US spending on health care has grown vastly in the 21st century, reaching $3.8 trillion in 2019amounting to 17.7 percent of the nation's gross domestic productthe portion going to academic neurologists has hardly kept pace.

The pie has gotten bigger, Dr. Gooch said, but pharma is consuming a much bigger percentage of the pie, and the insurance industry is taking its cut too.

Another irony in the evolution of academic medicine is that while the total amount of research money available from the National Institutes of Health (NIH) has grown, getting an NIH grant for a clinical trial has become increasingly difficult.

While the NIH is the major source of funding for critical basic biomedical researchmouse models of disease, cell cultures, etc., only a very small percentage of the NIH budget is dedicated to human clinical trials, which are very expensive, Dr. Gooch said.

In the past, much of this work, especially exploratory therapeutic studies in humans, was funded by excess clinical revenues, which dried up in the late 90s, Dr. Gooch said. This means a lot of this very important early phase clinical research has been pared back. At the same time, NIH-funded basic research has become the coin of the realm in most academic centers, with broad influence on metrics such as the US News medical school rankings.

As with so many other workers in the 21st century, academic neurologists are now gauged by measures of their productivity.

In the old days, you got a salary and you did your workclinical, teaching, research, and administration, Dr. Sacco said. Now each component is measured. And the measure of clinical productivity is by RVUs. When a clinician sees a patient, or reads an EEG or EMG, they generate a certain amount of RVUs. It's become more metrics-driven. If you're not making your clinical RVUs, your salary could be reduced or you might have to do more clinical time to support your salary.

Despite all the pressures, Dr. Rizzo said, It's crazy to be negative. We have so much opportunity. More and more people need neurological care.

That optimistic view was echoed by Frances E. Jensen, MD, FAAN professor and chair of neurology at the University of Pennsylvania's Perelman School of Medicine.

Academic neurology is in an incredibly dynamic state right now, she said. I am unbelievably excited. I pinch myself every day that I'm actually in the field I'm in. We are moving ahead at a pace that is unprecedented for our field. Twenty-five years ago, neurology was more of a watch and wait and document field. What's happening now, because so many treatments are translating to direct patient care, is we're seeing new opportunities and career paths emerge. We're seeing interactions with industry. There are people looking at population-based studies, public health, operations, safety, and quality.

That's not to say it's all gumdrops and unicorns. Yes, of course, my faculty have to mind their RVUs, Dr. Jensen said. But we also focus on having them participate at the top of their licensure. If you continually ask people to work below their licensure, it becomes demoralizing for them, and you are not tapping their potential for program growth. So we work hard to think about how to use physician assistants and advanced practice nurses. The documentation required in electronic medical records is not going to go away. The question is: How do we automate or find other professionals to handle some of it? We have to be adaptive.

Dr. Gooch said he sees hope for reducing the pressure on academic neurologists to see ever more patients in less time is by moving away from a fee-for-service model.

The movement to population health management changes the whole paradigm, he said. It means each health system gets a set amount of money each year to treat a defined population in their area. So the game becomes here's the money, this is it, use it wisely. Now you want to do fewer expensive procedures. You want to invest in internists, neurologists, and family practitioners to keep your population healthy so that they don't need surgery or emergency medical care. In this model, which is more logical, cost effective, and most importantly, better for the patient, the value of clinical neurology will soar, along with the other cognitive specialties.

The move to population health management is already well underway and is a major strategy of the Affordable Care Act in the form of Accountable Care Organizations ( ACOs). Existing large health maintenance organizationtype health systems are best positioned to transition to the ACO model, and many academic medical centers are actively expanding to enter this space.

For all the changes that have affected academic neurology in the past 20 years and will continue to do so, Dr. Rizzo said, What hasn't changed is the neurologist's diligence, aptitude, and appetite for solving really hard clinical problems and digging into the science to find cures. Neurologists remain a very special group of people.

Dr. Sacco said he, too, remains optimistic. With every challenge comes a new opportunity, he said. We will remain resilient and work collectively together to chart a new course forward.

None of the sources quoted in this stories had conflicts of interest to report.

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Outlook on the Neurology Clinical Trials Global Market to 2028 – Size, Share & Trends Analysis Report – Yahoo Finance

DUBLIN, Nov. 2, 2021 /PRNewswire/ -- The "Neurology Clinical Trials Market Size, Share & Trends Analysis Report By Phase (Phase I, Phase II, Phase III, Phase IV), By Study Design (Interventional, Observational, Expanded Access), By Indication, By Region, and Segment Forecasts, 2021-2028" report has been added to ResearchAndMarkets.com's offering.

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The global neurology clinical trials market size is expected to reach USD 7.4 billion by 2028. The market is expected to expand at a CAGR of 5.5% from 2021 to 2028.

This is largely attributed to big pharma companies conducting innovative trials in neurology, increased government funding from the National Institute of Neurological Disorders and Stroke (NINDS), and stringent regulatory requirements pertaining to clinical trials.

Neuroscience continues to receive a healthy level of early investment. It received USD 1.5 billion in venture capital funding in 2018, second only to cancer, indicating that investors expect a large pharma acquisition to pay off in the near future. As the industry strives to move past the many late-stage clinical failures of recent years, early diagnosis of diseases is attracting investment and driving deal-making in the complex neuroscience sector, particularly for pain and Alzheimer's disease.

In terms of deal volume, no other therapy area comes close to matching oncology, but neuroscience is among the nearest contenders. Despite a drop in total expected value in 2017, the number of neuroscience-related licensing deals has gradually climbed over the last decade.

The vast majority of neuroscience agreements ~90%have a primary neurological focus, which corresponds to the level of R&D activity in the two disciplines.

Many experimental therapeutics require dosage by on-site administration and carefully scheduled outcome measure evaluations hence, the COVID-19 pandemic has significantly harmed the implementation of the precise procedures required to establish proof of safety and efficacy.

Story continues

The COVID-19 has resulted in the shutdown of the network of centers conducting stroke clinical trials. This was followed by a phased research restart plan that took local circumstances and regulatory oversight into account. This approach was successful in a reengaging research effort to some extent in all but one of the ongoing investigations within 55 days.

Neurology Clinical Trials Market Report Highlights

The phase II segment dominated the market and accounted for a maximum revenue share of 36.7% in 2020. Between 1999 and 2020, 8,205 CNS trials were conducted, with 609 trials being conducted in 2020.

The interventional segment held the largest market revenue share of 81.1% in 2020.

The Huntington's disease segment is anticipated to register the fastest CAGR of 6.0% over the forecast period. This is largely due to the high prevalence of the disease around the world.

North America dominated the market and accounted for a revenue share of 45.8% in 2020. The rising prevalence of neurological disorders and the presence of a large number of players in clinical trials drive the market in the region.

Key Topics Covered:

Chapter 1 Methodology and Scope

Chapter 2 Executive Summary

Chapter 3 Neurology Clinical Trials Market: Variables, Trends, & Scope3.1 Market Segmentation and Scope3.2 Market Dynamics3.2.1 Market Driver Analysis3.2.1.1 Increasing neurological disease, such as dementia, stroke, and peripheral neuropathy3.2.1.2 Increasing R&D investments3.2.1.3 Stringent Regulatory Requirements3.2.2 Market Restraint Analysis3.2.2.1 High Failure Rates of Trials3.2.2.2 Rising Cost of Clinical Trials3.3 Penetration & Growth Prospect Mapping3.4 COVID-19 Impact on the Market3.5 Major Deals and Strategic Alliances Analysis3.6 Neurology Clinical Trials: Market Analysis Tools3.6.1 Industry Analysis - Porter's3.6.3 PESTEL Analysis

Chapter 4 Neurology Clinical Trials Market: Phase Segment Analysis4.1 Neurology Clinical Trials Market: Phase Market Share Analysis, 2020 & 20284.2 Phase I4.2.1 Phase I Market, 2016 - 2028 (USD Million)4.3 Phase II4.3.1 Phase II Market, 2016 - 2028 (USD Million)4.4 Phase III4.4.1 Phase III Market, 2016 - 2028 (USD Million)4.5 Phase IV4.5.1 Phase IV Market, 2016 - 2028 (USD Million)

Chapter 5 Neurology Clinical Trials Market: Study Design Segment Analysis5.1 Neurology Clinical Trials Market: Study Design Market Share Analysis, 2020 & 20285.2 Interventional5.2.1 Interventional Market, 2016 - 2028 (USD Million)5.3 Observational5.3.1 Observational Market, 2016 - 2028 (USD Million)5.4 Expanded Access5.4.1 Expanded Access Market, 2016 - 2028 (USD Million)

Chapter 6 Neurology Clinical Trials Market: Indication Segment Analysis6.1 Neurology Clinical Trials: Indication Market Share Analysis, 2020 & 20286.2 Epilepsy6.2.1 Epilepsy Market, 2016 - 2028 (USD Million)6.3 Parkinson's Disease6.3.1 Parkinson's Disease Market, 2016 - 2028 (USD Million)6.4 Huntington's Disease6.4.1 Huntington's Disease Market, 2016 - 2028 (USD Million)6.5 Stroke6.5.1 Stroke Market, 2016 - 2028 (USD Million)6.6 Traumatic Brain Injury6.6.1 Traumatic Brain Injury Market, 2016 - 2028 (USD Million)6.7 Amyotrophic Lateral Sclerosis6.7.1 Amyotrophic Lateral Sclerosis Market, 2016 - 2028 (USD Million)6.8 Muscle regeneration6.8.1 Muscle regeneration Market, 2016 - 2028 (USD Million)6.9 Others6.9.1 Others Market, 2016 - 2028 (USD Million)

Chapter 7 Neurology Clinical Trials Market: Regional Analysis

Chapter 8 Company Profiles8.1 IQVIA8.1.1 Company Overview8.1.2 Service Benchmarking8.1.3 Financial Performance8.1.4 Strategic Initiatives8.2 Novartis8.2.1 Company Overview8.2.2 Financial Performance8.2.3 Service Benchmarking8.2.4 Strategic Initiatives8.3 Covance8.3.1 Company Overview8.3.2 Service Benchmarking8.3.3 Strategic Initiatives8.4 Medpace8.4.1 Company Overview8.4.2 Financial Performance8.4.3 Service Benchmarking8.5 Charles River Laboratories8.5.1 Company Overview8.5.2 Financial Performance8.5.3 Service Benchmarking8.6 Icon Plc8.6.1 Company Overview8.6.2 Financial Performance8.6.3 Service Benchmarking8.7 GlaxoSmithKline8.7.1 Company Overview8.7.2 Financial Performance8.7.3 Service Benchmarking8.7.4 Strategic Initiatives8.8 Aurora healthcare8.8.1 Company Overview8.8.2 Financial Performance8.8.3 Service Benchmarking8.9 Charles River Laboratories8.9.1 Company Overview8.9.2 Financial Performance8.9.3 Service Benchmarking8.9.4 Strategic Initiatives8.10 Biogen8.10.1 Company Overview8.10.2 Financial Performance8.10.3 Service Benchmarking8.10.4 Strategic Initiatives

For more information about this report visit https://www.researchandmarkets.com/r/c0upuj

Media Contact:

Research and Markets Laura Wood, Senior Manager press@researchandmarkets.com

For E.S.T Office Hours Call +1-917-300-0470 For U.S./CAN Toll Free Call +1-800-526-8630 For GMT Office Hours Call +353-1-416-8900

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This Neuromuscular Specialist Keeps Life Humming with… : Neurology Today – LWW Journals

Article In Brief

When neuromuscular specialist Zach London, MD, FAAN, is not at work, he engages in other passions like music and game board development. Here he talks about what drives these interests and why he has pursued them since his busiest days as intern in medical school.

In his professional endeavors and personal life, Zach London, MD, FAAN, relishes the opportunity to be creative. Dr. London's innovative nature has come in handy as professor and director of the neurology residency program at the University of Michigan Medical School in Ann Arborthe same institution where he completed his training and a fellowship in clinical neurophysiology.

Among the interactive educational tools he has designed is a web-based training simulator called EMG Whiz. And his efforts were instrumental in developing two mobile applicationsNerve Whiz and Neuro Localizerto teach neuroanatomic localization.

For Dr. London, the goal is to engage learners any way he can, no matter how boring or challenging the subject may be. He credits his former neuroanatomy professor John K. Harting, PhD, at the University of Wisconsin School of Medicine and Public Health in Madison with instilling this belief in him.

With textbooks, workbooks, educational handouts, flash cards, and whatever else he could devise, he would teach the same material in 20 different ways, Dr. London recalled. All that mattered was that at least one of those ways clicked with his students. That was really inspirational to me.

A neuromuscular specialist, Dr. London has published online learning modules for the AAN and other national organizations. He also has received many teaching awards, including the the Consortium of Neurology Program Directors Recognition Award in 2014, the American Neurological Association's Distinguished Teacher Award in 2017, and the American Association of Neuromuscular and Electrodiagnostic Medicine Innovation Award in 2020.

The AAN recently tapped his expertise to promote an upcoming conference in a novel way. He posted this recording on Twitter.

Neurology Today spoke with Dr. London about his musical hobby as well as his interest in developing board games. One of those inventions is The Lesion: Charcot's Tournament, a tabletop strategy board game about neuroanatomy that he co-designed and published.

I was 14 years old when I first started playing. I took one or two lessons and hated it, so I put it down for a few years. Then, when I was a senior in high school, I read a modern translation of Beowulf, and for some reason, I got in my head that I was going to write a rock opera about Beowulf for my English class. I enjoyed that so much that it got me hooked on songwriting and recording. I've never really been a performer. I like the recording process more than anything else.

It's a great instrument for people who are learning to play music. The reason it's so popular is that it's easy to become good enough to play a few songs. It's also portable. You can pick it up and take it with you.

I have a few guitars hanging up on the wall. I have five guitars, a ukulele, a banjo, a mandolin, a bass guitar, and an Irish bouzouki.

I play a little piano, bass, mandolin, and accordion at the novice to intermediate level. I like to pick up new instruments and play them well enough that I can record something once.

The real turning point was when I was an intern. Your life suddenly becomes very busy. A lot of people lose their hobbies when they get into residency. It was a now-or-never moment. I decided I'm either going to stick with it or dedicate myself only to my career. It was really important for my mental health to have a creative outlet.

I record exactly one song per month and post it online at http://www.hardtaco.org. That's a realistic goal for the rest of my life. Having this self-imposed deadline has helped me focus. Some of the songs are throwaways, and some of them are ones I'm proud of. The fact that I stuck with that schedule is something I'm most proud of.

They're mostly simple pop, rock, folk, hip hop, and electronica. I don't have a classical music background. I know some music theory, but I'm not good enough to compose classical or jazz. They're the kind of songs you could hum in your head and put music to. I try to experiment with different genres, so they don't all sound the same. If there's a common thread, half of the songs tend to be silly or clever. I'm always thinking about rhyming words while I'm in the shower or I'm in the car.

My wife, Lauren London, is a trained singer with a musical theater background. She probably is on 75 percent of the songs as a lead or background singer. Professionally, she is a lawyer and the general counsel for Eastern Michigan University, while serving as executive director of a local professional theater company in Ann Arbor.

Our kidsScarlett, 16, and Malcolm, 13occasionally do vocals on the songs. Sometimes I'll write songs that have different characters in them. A few years ago, we did a song about a court trial for a bee who had murdered an elephant. One of the kids played the judge and one played the attorney. They rapped about what happened to this particular elephant.

I've been a board game player my whole life. I got into the modern board game in the mid- or late 1990s, and since then, I've been into trying out new games, especially complex ones. There's definitely a market for more complex games. Board game sales have skyrocketed in the last 20 years.

As a family, we have been involved in making games. We are also board game reviewers. When the pandemic started last year and we were all on lockdown, we decided as a family project we would play one new board game a day. We bought some and borrowed others from friends who are board game enthusiasts. Michigan's stay-at-home order was in place. We called it the Play-At-Home Order [www.theplayathomeorder.com]. The kids and my wife and I would write reviews. By now, we have reviewed up to about 130 games. Some are ones you can play in 10 minutes. It has been a wonderful family activity. Since the kids are back in school, it's harder to convince them to play a new game.

One is a board game called The Lesion: Charcot's Tournament, named after Jean-Martin Charcot, the French physician often considered to be the father of modern neurology. I developed it about five years ago with a colleague, Jim Burke, MD, MS, associate professor of neurology, who is also a board game fanatic. It's essentially based on the concept of neurologic localization on a map of the central nervous system. With any neurologic symptom in the bodysuch as weakness in the arm or facea pathway is interrupted somewhere between the brain and peripheral nerve.

The game's strategy involves looking at a bunch of symptoms and finding where those pathways overlap and where the most likely source of the problem is, where the lesion is.

There's also a non-neurological game we just published that was invented by my son. It's called Battle Thunder Worm (three words in the game), and it's a family-friendly party game. [For more information about the game, visit http://www.battlethunderworm.com.] Players have to put together a combination of two random words to name an invention that would solve a specific problem. And then they have to do a sales pitch as to why their invention is better than everyone else's.

Another game in the works is a card game about the brachial plexus called The Plexus. I'm just putting the final touches on the graphics.

We've sold over 1,000 copies of the Lesion, which has been out for five years. I use a print-on-demand board company called The Game Crafter. People order it through their website. I posted about it on Twitter a couple of months ago, and we sold over 50 copies in a few days. A bunch of neurologists and medical students were interested. It's definitely a target market for sure, very niche. I haven't made any profit. I'm not much of a businessman. I think of this as more of a fun academic project.

At my house every year for the last 25 years, we have done the fortress party. We convert our entire house into a giant maze of sheets. You can't see the walls or the ceiling of the house because everything is covered with sheets. It's a private event and not a good pandemic party.

You have to make time. That's kind of that crossroad I was at as an intern. It's really easy to let things go that are important to you when you're busy. I don't watch as much TV as I used to. I don't read as many books as I would like to. It's important to me and my family to support it, and they've been really wonderful in helping.

Definitely. It helps keep me centered. When I finish writing a song, I record it and I upload it to the website. It's a real sense of accomplishment. In academic medicine, it's good to have several irons in the fire in life, so when one of them isn't succeeding, maybe another one is. Usually, something is going well. Whether it's a work project or a home project, it keeps me engaged and helps me through the stuff that's harder.

Making board games about neurology is fun for me, but I'm also doing it as career development tool. I have to learn the material well, which probably makes me a better doctor. It's an academic niche for me. Some people do research on Alzheimer's. It's totally at opposite ends of the spectrum of what you can do as an academic neurologist.

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COVID-19 and Neuropsychiatric Symptoms in Teenagers : Neurology Today – LWW Journals

Article In Brief

Investigators reported anti-SARS-CoV-2 autoantibodies in the cerebrospinal fluid of three teens who came to the emergency department with neuropsychiatric symptoms. The scientists believe that emergency department doctors should be open to the possibility that young people presenting for the first time with unexplained neuropsychiatric problems could have an autoantibody response to the COVID-19 infection, and should be evaluated accordingly.

Scientists have identified anti-SARS-CoV-2 antibodies and anti-neuronal auto-antibodies in the cerebrospinal fluid (CSF) of two of three teenagers who presented to an emergency department with subacute neuropsychiatric problems, including paranoid delusions, suicidal ideation, anxiety, obsessive behavior, and cognitive slowing.

While many teenagers present to the emergency department with neuropsychiatric symptoms, these three teens were the only ones who presented to the University of California, San Francisco (UCSF) with these symptoms in the setting of a recent COVID-19 infection and for whom a neurology consult was called. Two tested positive with direct detection tests, and one was seropositive (antibody testing) with a recent exposure.

All three also had abnormal CSF with restricted oligoclonal bands, elevated protein, and/or an elevated immunoglobulin G (IgG) index. None of them met the criteria for multisystem inflammatory syndrome in children, which has been associated with some cases of COVID-19 in young patients.

The findings, published online on October 25 in JAMA Neurology, suggest that the virus could be associated with central nervous system inflammation and leave some pediatric COVID-19 patients with new onset neuropsychiatric symptoms that do not respond to traditional psychiatric medications.

One of the teenagers seemed to improve after immunotherapy, another had a modest response, while the third teens' symptoms improved after treatment with lorazepam and olanzapine without immunotherapy.

The scientists believe that emergency department doctors should be open to the possibility that young people presenting for the first time with unexplained neuropsychiatric problems could have an auto-antibody response to the COVID-19 infection, and should be evaluated accordingly.

We don't know if this could be a more general phenomenon, said the senior study author Michael R. Wilson, MD, FAAN, associate professor and Debbie and Andy Rachleff Distinguished Chair in neurology at the UCSF Weill Institute for Neurosciences. Scientists at UCSF are now analyzing CSF from more young people.

Together with Samuel J. Pleasure, MD, PhD, the Glenn W. Johnson, Jr. Memorial Endowed Chair in Neurology at UCSF, Dr. Wilson, and first co-author Christopher Bartley, MD, PhD, have been using multiple technologiesgenomics, immune system sequencing techniques, and phage displayto characterize the immune system's response to pathogens and to screen for antibodies in the CSF of COVID-19 patients with neurologic symptoms.

For this latest study, the scientists conducted a detailed analysis of CSF and blood from three teenagers presenting to UCSF Benioff Children's Hospital with neurological or psychiatric symptoms during a five-month period in 2020.

In the first case, UCSF pediatric resident Claire Johns, MD, had evaluated a teenager who presented with acute delusions and psychosis, and called on the neurology service to help assess the patient. The teenager had erratic and paranoid-like behavior, insomnia and social withdrawal. The teen had a history of marijuana use and unspecified anxiety and depression, was initially treated with psychiatric medications, but was discharged after 11 days. The teen was readmitted a day later with persistent delusions.

The teenager had tested positive for COVID-19 during the first hospitalization, although the teen had no respiratory symptoms. On readmission, a lumbar puncture showed elevated protein and elevated IgG index. An MRI of the brain showed non-specific T2/FLAIR white matter hyperintensities in the frontal lobes. The pediatric specialists ordered intravenous immunoglobulin (IVIg) and the teen quickly improved enough to be discharged from the hospital. The teen's blood and CSF were later sent for further analysis to Dr. Wilson and his colleagues who identified abnormal antibody production in the teen's CSF.

The second teen had a history of anxiety and motor tics and a foggy brain,: according to the description in the paper. The teen's father had just been diagnosed with COVID-19, and a week later the teen developed fever and respiratory symptoms and improved without treatment. Over the next six weeks, the teen experienced a host of neuropsychiatric symptoms, including word-finding difficulty and problems concentrating, insomnia, mood swings, and it morphed into aggression and suicidal ideation. The teen was treated without success with psychiatric medications, and admitted to the hospital ten weeks after the neuropsychiatric symptoms began.

Back in the hospital, the patient tested positive for SARS-CoV2 antibodies. The teen's slowed thinking and memory problems improved after IV methylprednisolone, and was discharged on lithium and risperidone. Six days later, still in the throes of aggression and suicidal ideation, the teen was readmitted. Another lumbar puncture showed elevated CSF protein and IVIg was administered for three days. The patient was discharged with psychiatric medicines but six months later there was still lingering forgetfulness and attention problems. A third lumbar puncture at six months still showed elevated protein.

The third teenager was taken to the emergency department after four days of extremely erratic and odd repetitive behaviors, insomnia, and anorexia. There was no previous history of psychiatric symptoms. In the ED, a SARS-CoV-2 test came back positive. The teen had an elevated white blood cell count, creatine kinase, and C-reactive protein as well as ideomotor apraxia, a lack of motivation, disorganized behavior, and agitation. Psychiatric medications were administered for a few days and then stopped. The patient's symptoms improved during the weeklong hospitalization, and the teen was discharged without any psychiatric medications.

One important difference is that the teen who improved was treated soon after their symptoms started whereas the second patient's treatment was delayed by over two months, said Dr. Johns. The third young person had mania and insomnia and tested positive for SARS-CoV2 but did not have evidence of auto-antibodies in the CSF.

You get to one underlying question: SARS-CoV-2 is infecting millions and millions of people, and a great majority don't get critically ill. The ones who do tend to be older and/or have co-morbidities. What we don't know is if there are underlying issues that put certain people at risk for neuropsychiatric problems or long COVID, said Dr. Pleasure.

Merely identifying these autoantibodies and some of their antigens does not causally link them to these young peoples' symptoms, added Dr. Bartley. In some patients, the specific regions of the SARS-CoV-2 proteome targeted by the serum antibodies differed from the antigens in the CSF, suggesting that a compartmentalized immune response might be occurring in the CNS.

But we won't build more confidence about a potential link until we've been able to assess additional patients to determine whether these autoantibodies consistently track with particular clinical phenotypes. Ultimately, these autoantibodies may be reflective of a broader immune dysregulation that is related to their symptoms, but it's too early to tell. These teenagers were treated as psychiatric patients and COVID was found incidentally. We should definitely have this on our radar. Some of these patients may have subtle evidence of neuroinflammation and warrant a different treatment approach.

The scientists published previous studies in 2020 that led up to this latest work. In a paper Cell Reports Medicine done in close collaboration with Shelli Farhadian, MD, PhD, and Serena Spudich, MD, at Yale University, they identified early evidence for CSF anti-neural autoantibodies using mouse brain tissue to look for immunofluorescence. They identified some of the antibody targets using a combination of immunoprecipitation-mass spectrometry with rodent brain lysates and phage display. Then, they validated their finding in tissue culture cells engineered to express these antigens. Ultimately, five of the seven adults had evidence for CSF autoantibodies.

The immune response was so jazzed up, said Dr. Pleasure. It is not at all clear yet whether these antibodies, some of which appear to be cross-reactive between SARS-CoV-2 and neural antigens, are responsible for any of the neuropsychiatric symptoms.

The UCSF team now has samples from more than 50 COVID-19 patients who have unexplained neuropsychiatric symptoms. UCSF scientists are also studying patients with long-haul COVID, and Dr. Bartley said that they want to run the same types of experiments to see if they can identify auto-antibodies that may correlate with their enduring symptoms.

This is an important study that links infectious SARS-CoV-2 with neurological and neuropsychiatric complications in young people, said Carlos A. Pardo, MD, professor of neurology and pathology at Johns Hopkins Medicine and division of neuroimmunology and neuroinfectious disorders. The finding of auto-antibodies in spinal fluid is fascinating. It implicates the immunological responses in the brain, or unmasks the immunological responses against the brain.

We need to better characterize the mechanism of how the antibody triggers acute and long-term neuropsychiatric problems, added Dr. Pardo, who also studies CSF in patients with difficult neurological complications, including COVID-19. His laboratory recently published a study in The Journal of Neurological Sciences showing that almost 77 percent of patients with COVID-19 neurological complications had anti-SARS-CoV2 antibodies in their CSF.

The new study in JAMA Neurology opens the door to see how COVID triggers neurological and neuropsychiatric symptoms, he added. We are still a bit far away from recommending immune-based treatments.

There is currently great interest among neurologists regarding the potential for COVID infections to stir up an autoinflammatory process and induce autoimmunity resulting in a targeted immune attack against proteins in the brain, said Sean J. Pittock, MD, director of Mayo Clinic's center for multiple sclerosis and autoimmune neurology and of Mayo's neuroimmunology laboratory. Patients with COVID infections may develop encephalopathies but the immunopathological mechanisms underlying these remain unclear.

In this study, the UCSF scientists used their human phage display immunoprecipitation sequencing (testing for antibodies targeting the entire human proteome) and identified a multitude of autoantigens. The heterogenous autoantigen signature identified between patients indicates complexity and makes conclusions difficult, Dr. Pittock said. The identification of two potential novel targets in Case 1 is of interest but again the clinical implications remain unclear.

Many patients without autoimmune disease harbor autoantibodies (organ and non-organ specific).The two protein targets reported in this paper are intracellular proteins, thus it is unlikely that antibodies targeting such proteins are pathogenic, he added. Antibodies targeting intracellular proteins can indicate a pathogenic T cell response, however, if this were the case one would expect a more persistent and less responsive disorder than transient, as in these patients.

Overall, these findings are interesting and raise lots of questions which should stimulate more research in this area, Dr. Pittock said. Future studies investigating larger numbers of patients with COVID-associated encephalopathies will hopefully define the antibody, chemokine and cytokine signatures of this and other viral encephalopathies. This will further our understanding of these conditions and potentially identify therapeutic targets allowing repurposing of biologics for therapy.

He also said that although not applicable in this study, we must be careful in drawing too many conclusions: young patients develop primary psychiatric illness frequently, and when this diagnosis is combined with high levels of concomitant infection, there may or may not be a causal relationship.

The findings are pointing us in an intriguing direction, added Sarosh Irani, MD, associate professor at University of Oxford and head of the Oxford Autoimmune Neurology Group. These young people had atypical forms of encephalitis. The patients were identified retrospectively and it's not known if their neuropsychiatric symptoms would have occurred anyway or were due to COVID. Nevertheless, this is a very interesting preliminary finding and now needs validation in a larger consecutive cohort, ideally the pre-and post-COVID era.

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