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ROCHESTER, Minn. -- Research on a genetic heart disease has uncovered a new and unexpected mechanism for heart failure. This landmark discovery found a correlation between the clumping of RNA-binding proteins long linked to neurodegenerative disease ? and the aggregates of protein found in the heart tissue of patients with RBM20 dilated cardiomyopathy.

Dilated cardiomyopathy is a disease of the heart muscle that makes it harder for the heart to pump blood to the rest of the body. A decade ago, Timothy Olson, M.D., a pediatric cardiologist at Mayo Clinic, traced the disease to a genetic mutation in a gene called RBM20. Unlike most heart disease, this form of cardiomyopathy can affect patients as early as young adulthood, and they are at particularly high risk for sudden cardiac death.

For the past decade, heart failure in RBM20 cardiomyopathy was attributed to abnormalities in the splicing of genes for proteins that help the heart contract. However, the new discovery finds another way that mutant RBM20 damages heart muscle cells: through accumulation of pathological ribonucleoprotein granules, affecting everything in the cells and leading to a new form of disease.

"It's important to realize that there are kids and young adults that have heart failure because of this exact mutation," says Tim Nelson, M.D., Ph.D., director of Mayo Clinic's Todd and Karen Wanek Family Program for Hypoplastic Left Heart Syndrome and lead author of the study. "We have taken these findings back into the lab and developed cell cultures to test new therapeutics. The future of this research is focused on moving discoveries out of the lab and into clinical trials to make new therapies available to our patients. This research is a very important catalytic step to do that."

Through gene editing technology, Dr. Nelson's team produced the first large animal model displaying all the typical clinical signs and symptoms of human heart failure: a pig born with the human gene for RBM20 dilated cardiomyopathy. This model allowed them to study development of the heart disease in the animal in a matter of months. It takes 20 years or more for the disease to progress in humans.

A simple staining test performed on the pig heart tissue samples discovered clumps full of RNA-binding protein. Archived tissue samples from Dr. Olson's RBM20 dilated cardiomyopathy human patient tissue confirmed this discovery. They were likewise flooded with the same protein granules. This supports a new concept that beyond splicing caused by the gene mutation, RBM20 is an RNA-binding protein granule disease similar to diseases like Lou Gehrig's disease, or amyotrophic lateral sclerosis, and Alzheimer's disease.

"To my knowledge, this overload of protein granules in cells has only previously been seen in the brain or spinal cord, and some very rare skeletal muscle diseases. Now we have found it in the heart, a large organ that is much more accessible to study than spinal neurons or brain tissue. Most importantly, we can study and develop therapies to prevent the buildup of these toxic granules at the beginning of life instead of waiting 50 years or more for degenerative disease to appear clinically. This is a huge advantage that should accelerate drug discovery in ribonucleoprotein granule degenerative diseases of the heart and nervous system," says Jay Schneider, M.D., Ph.D., a Mayo Clinic cardiologist and first author of the study.

Bottom Line: A computational method that combines clinicodemographic variables with deep learning of pre-treatment histology images could predict response to immune checkpoint blockade among patients with advanced melanoma.

Journal in Which the Study was Published:
Clinical Cancer Research, a journal of the American Association for Cancer Research

Authors: Corresponding study author Iman Osman, MD, medical oncologist in the Departments of Dermatology and Medicine (Oncology) at New York University (NYU) Grossman School of Medicine and director of the Interdisciplinary Melanoma Program at NYU Langone's Perlmutter Cancer Center; and corresponding study author Aristotelis Tsirigos, PhD, professor in the Institute for Computational Medicine at NYU Grossman School of Medicine and member of NYU Langone's Perlmutter Cancer Center

Background: "While immune checkpoint inhibitors have profoundly changed the treatment landscape in melanoma, many tumors do not respond to treatment, and many patients experience treatment-related toxicity," said Osman. "An unmet need is the ability to accurately predict which tumors will respond to which therapy. This would enable personalized treatment strategies that maximize the potential for clinical benefit and minimize exposure to unnecessary toxicity."

"Several recent attempts to predict immunotherapy responses do so with robust accuracy but use technologies, such as RNA sequencing, that are not readily generalizable to the clinical setting," said Tsirigos. "Our approach shows that responses can be predicted using standard-of-care clinical information such as pre-treatment histology images and other clinical variables."

How the Study was Conducted: The researchers used data from a training cohort of 121 patients with metastatic melanoma who received immune checkpoint blockade treatment between 2004 and 2018. All patients were treated with first-line anti-CTLA-4 therapy, anti-PD-1 therapy, or a combination of both, and clinical outcomes were recorded as progression of disease or response, which included complete or partial responses (patients with stable disease were excluded for this proof-of-principle study). The researchers used computer algorithms called deep convolutional neural networks (DCCN) to analyze digital images of metastatic tumors of melanoma and identify patterns associated with treatment response. Through this approach, they developed a response classifier, which aimed to predict if a patient's untreated tumor would respond to immune checkpoint blockade or progress following treatment. This DCCN response classifier was validated in an independent cohort of 30 patients with metastatic melanoma treated at Vanderbilt-Ingram Cancer Center between 2010 and 2017.

Results: The performance of the DCCN response classifier was evaluated by calculating the area under the curve (AUC), a measure of the model's accuracy, where a score of 1 corresponds to perfect prediction. The DCCN prediction model achieved an AUC around 0.7 in both the training and validation cohorts.

To augment the prediction accuracy of the model, the researchers performed multivariable logistic regressions that combined the DCCN prediction with conventional clinical characteristics. The final model incorporated the DCCN prediction, Eastern Cooperative Oncology Group (ECOG) performance status, and treatment regimen (either anti-CTLA-4 monotherapy, anti-PD-1 monotherapy, or combination therapy). In both the training and validation cohorts, the multivariable classifier achieved an AUC around 0.8. In the validation cohort, the classifier could stratify patients into high versus low risk for disease progression, with significantly different progression-free survival outcomes between the two groups.

While the majority of patients in the training cohort received anti-CTLA-4 monotherapy (roughly 64 percent of patients), the majority of patients in the validation cohort received anti-PD-1 agents (roughly 53 percent of patients). The results suggested that some predictive patterns are not specific to the immune checkpoint target, Osman noted. Class activation mapping, which can identify regions within the digital images that the neural network uses to generate predictions, suggested that cell nuclei were important for the DCCN predictions, where larger and more numerous nuclei correlated with progression of disease. "These results suggest that ploidy might be one of the biologic determinants detected by DCCN," she added.

Author Comments: "There is potential for using computer algorithms to analyze histology images and predict treatment response, but more work needs to be done using larger training and testing datasets, along with additional validation parameters, in order to determine whether an algorithm can be developed that achieves clinical-grade performance and is broadly generalizable," Tsirigos said.

Study Limitations: Limitations of the study include the relatively small number of images used to train the computer algorithm, which included 302 images in the training cohort and 40 images in the validation cohort. "There is data to suggest that thousands of images might be needed to train models that achieve clinical-grade performance," said Tsirigos.

Children born with a common genetic condition, familial hypercholesterolemia (FH), are at increased risk for atherosclerotic cardiovascular disease (ASCVD) early in life. Despite long-standing national guidelines, cholesterol screening -- for children at age 2 for those with a family history of heart disease and between the ages of nine to 11 for all children -- is not being implemented .

New data from the FH Foundation's CASCADE FH Registry highlights the gaps in care for children with FH, published online today in The Journal of Pediatrics. Among nearly 500 children and adolescents with FH, diagnosis occurred on average at nine years of age, seven years later than cholesterol screening guidelines.

"It is critical to identify children with familial hypercholesterolemia in order to prevent cardiovascular disease through early treatment intervention," said Sarah de Ferranti, MD, MPH, chief, division of ambulatory cardiology, Boston Children's Hospital, and CASCADE FH Registry principal investigator. "The U.S. guidelines are clear but there is a low level of implementing these guidelines that put nearly 300,000 children at risk."

FH causes a high level of low-density lipoprotein cholesterol (LDL-C) from birth, that left untreated can cause early ASCVD including heart attacks and strokes. Treatment can begin as early as eight years old and is recommended to start no later than 10 years of age. One recent long-term study published in the New England Journal of Medicine demonstrated that initiating statins in childhood and continuing statins into adulthood led to a reduction of cardiovascular events as compared to their parents with the same genetic disorder.

Youth in the registry began lipid-lowering therapy on average at 11 years of age, with statins the most frequently reported medication (n=271; 56.2%). In addition, 23.5% of children eligible for treatment were not receiving therapy at enrollment. Only 39% of the youth achieved recommended LDL-C reduction according to U.S. and international guidelines (LDL-C

"Consequences are devastating when familial hypercholesterolemia is missed, with one in ten heart attacks under 45 caused by FH. Yet evidence shows that we can dramatically change this paradigm with early identification and treatment," said Katherine Wilemon, founder and CEO of the FH Foundation. "We will continue to advocate for increased research and awareness of FH as a common cause of premature heart disease in all members of affected families."

Amsterdam, NL, November 18, 2020 - There have been significant advances in knowledge regarding the pathology, etiology, assessment, and treatment of several significant neurogenic pain disorders regularly encountered by neurorehabilitation professionals in both inpatient and outpatient care. In a collection of articles published in NeuroRehabilitation, experts describe the latest advancements in neurogenic classification and pain management and treatment of these disorders.

Neurogenic pain results from injury to or disease of the central and/or peripheral nervous system. Types of neurogenic pain include neuropathic pain (due to nerve damage or disease), central pain (arising from a lesion in the central nervous system - such as thalamic pain following stroke), and deafferentation pain (the interruption or destruction of the afferent connections of nerve cells), among other mechanisms.

"There are multiple emerging trends in neurogenic pain management with particular reference to complex regional pain syndrome (CRPS), neuropathic pain, and cranial neuralgias," explains Guest Editor and co-Editor-in-Chief Nathan Zasler, MD, Concussion Care Centre of Virginia Ltd. and Tree of Life Services, Inc. Dr. Zasler is also a clinical professor in the Department of Physical Medicine and Rehabilitation at Virginia Commonwealth University in Richmond, VA, USA. "The topic of post-traumatic cephalalgia (headache) remains highly debated as does the area of functional/psychogenic pain disorders, both of which are elaborated on in this thematic issue of NeuroRehabilitation along with other more common, controversial, and/or challenging neurogenic pain disorders."

Articles in this issue provide in-depth reviews of:

Diagnosis and treatment of CRPS (Allison Kessler, Min Yoo, Randy Calisoff)

Classification, pathology, etiology, and treatment of neuropathic pain (Douglas Murphy, Denise Lester, F. Clay Smither, Ellie Balakhanlou)

Central pain syndromes (Deena Hassaballa, Richard L. Harvey)

Treatment options for craniofacial neuralgias (Sheryl D. Katta-Charles)

Residual limb pain or "phantom" pain/sensation after amputation (Gary Stover, Nathan Prahlow)

Post-traumatic cephalalgias or headache (Brigid Dwyer and Nathan Zasler)

Functional pain disorders (Stoyan Popkirov, Elena K. Enax-Krumova,Tina Mainka, Matthias Hoheisel, Constanze Hausteiner-Wiehle)

Highlighted contributions in this issue include:

Douglas Murphy, MD, Regional Amputation Center, Central Virginia Veterans Health Center; and Physical Medicine & Rehabilitation, Virginia Commonwealth University Medical Center, Richmond, VA, USA, and colleagues review the epidemiology, classifications, pathology, non-invasive and invasive treatments of peripheral neuropathic pain. Neuropathic pain occurs in up to 10% of the general population and in patients with neck and back pain and diabetes. Chemotherapy can also be associated with the development of painful neuropathies in 19%-85% of cases. Characteristic symptoms are burning, tingling, lightning bolts of pain, sharp sensations, unpleasant cold sensations, and electric-like sensations. Secondary symptoms and problems can include anxiety, depression, sleep disturbances, and impairment of quality of life.

"Peripheral neuropathic pain has a cost to the patient and society in terms of emotional consequences, quality of life, lost wages, and the cost of assistance from the medical system, and thus deserves serious consideration for prevention, treatment, and control," notes Dr. Murphy. "There is a wide range of pharmacologic options to control this type of pain, and when such measures fail, numerous interventional methods can be employed such as nerve blocks and implanted stimulators. It is an evolving therapeutic arena. Physicians providing these therapies need to use diligent patient selection processes and a multimodal, individualized pain program that supports a strong risk/benefit ratio."

Brigid Dwyer, MD, Department of Neurology, Boston University, Boston, MA, USA, and Nathan Zasler, MD, review the highly-debated topic of post-traumatic cephalalgias (PTC) or post-traumatic headache. They note that PTC remains controversial on a number of levels and provide an overview and discussion of current classification and limitations, epidemiology, and risk factors for PTC, subtypes of PTC and associated pain generators, as well as pathophysiology.

They contend that the current classification using the International Headache Society's International Classification of Headache Disorders has significant limitations that warrant reassessment. They also review the clinical course of PTC and prognostic risk factors for pain persistence. The authors discuss clinical management and limitations of the existing literature on PTC, noting that medication overuse may paradoxically exacerbate headache symptoms and prolong recovery times when superimposed upon pre-existing headache pathology.

According to Dr. Dwyer and Dr. Zasler, "A multifactorial diagnostic and treatment approach, cognizant of biopsychosocial factors as well as the unique interplay between central and musculoskeletal pain, sleep, mood, cognition and exertional limitations, continues to be most successful."

"The most significant challenges are dissemination of new knowledge, in particular practice guidelines, to clinicians in the trenches treating neurogenic pain disorders," concludes Dr. Zasler. "As guest editor of this issue, I am very grateful to all the contributors and their high quality of work, which will hopefully be appreciated by readers and advance knowledge in this area of neurorehabilitation."

Organ and stem cell transplants are proven and frequently used methods in everyday modern clinical practice. However, even when performed regularly in specialized centers, some patients still experience a number of serious complications afterwards. Among other things, infections with fungi and viruses can jeopardize therapeutic success. For example, coinfection with cytomegalovirus, which belongs to the family of Herpes viruses, and the fungus Aspergillus fumigatus can be critical. This combination of pathogens poses a serious medical threat in organ and stem cell transplantation.

When viruses and fungi join forces

A team of scientists from several German research institutions and clinics has now developed a new method to examine these two pathogens, their interaction with each other and with the human cells infected by them. The central result: coinfection with the two pathogens is more "than the sum of its parts". Viruses and fungi interact synergistically in the human organism, where they trigger certain genes that only become active when infected with both pathogens simultaneously.

The study involved scientists from the Julius Maximilian University of Würzburg (JMU), the Würzburg University Hospital (UKW), the Leibniz Institute for Natural Product Research and Infection Biology in Jena and the Helmholtz Institute for RNA-based Infection Research (HIRI) in Würzburg, a site of the Braunschweig Helmholtz Centre for Infection Research (HZI). The results have now been published in the journal Cell Reports.

New insights thanks to a novel technology

"For our study, we have developed a method called Triple RNA-seq," explains Alexander Westermann. He is junior professor at the Chair of Molecular Infection Biology I at JMU, as well as group leader at the HIRI. Together with Jürgen Löffler from UKW and Sascha Schäuble he is one of the senior authors of the study. The scientists have advanced an established method that has been an integral part of infection research for years: dual RNA-seq.

The term "RNA-seq" is short for RNA-sequencing: This technique enables the simultaneous and precise determination of the activities of thousands of genes at the RNA level in a high-throughput process, thus enabling the identification and better understanding of the changes occurring in the course of diseases. The development of dual RNA sequencing has made it possible to document not only the gene activity of a pathogen, but also the reaction of the host cell affected by it. This has enabled scientists to trace complex causal chains over the course of an infection.

Research on immune cells

Now, Triple RNA sequencing dissects the gene expression of three players and their interplay in infection processes. "Up to now, science has in many cases not known why an infection with a certain pathogen can make the affected person more susceptible to an infection with a second pathogen," explains Jürgen Löffler, molecular biologist at the Medical Clinic II of the UKW. In such cases, dual RNA-seq was insufficient to provide the desired answers.

In their study, the researchers used the triple RNA-seq method they developed to investigate what happens when certain cells of the immune system (known as monocyte-derived dendritic cells) are infected with both Aspergillus fumigatus and the human cytomegalovirus.

They were able to prove that the two pathogens influence each other, whilst also simultaneously affecting the immune cell in a different way than one pathogen alone otherwise would. For example, the cytomegalovirus weakened the fungal-mediated activation of pro-inflammatory signals, while Aspergillus affects viral clearance - the time it takes for the virus to become undetectable in tests.

Hope for a biomarker

At the same time, the team has identified specific genes in immune cells whose expression profiles differ significantly during an infection with both pathogens, compared to a single infection. These genes could thus serve as biomarkers for the timely identification of a co-infection after transplantation.

The scientists now hope that the triple RNA-seq technology will also help to better understand other cases of common infections, such as viruses and bacteria, and to prevent their potentially serious consequences. "Promising models for understanding how an infection makes the host more susceptible to another pathogen include certain strains of Salmonella and the human immunodeficiency virus (HIV), streptococci and influenza virus, or Chlamydia and human herpes virus," says Westermann. As a next step, Westermann plans to use the triple RNA-seq technique to investigate infections in which two different types of bacteria jointly influence the course of the disease.

DARIEN, IL – A study found a significant increase in the number of online search queries for “insomnia” between April and May 2020, when governments across the U.S. and around the world implemented stay-at-home orders in response to the COVID-19 pandemic.

Results show there were 2.77 million Google searches for insomnia in the U.S. for the first five months of 2020, an increase of 58% compared with the same period from the previous three years. While searches for insomnia trended downward from January through March 2020, consistent with prior years, they surged upward in April and May 2020. This increase also was associated with the cumulative number of COVID-19-related deaths in the spring.

“I think it’s safe to say, based on our findings as well as those from survey studies showing an increased level of insomnia symptoms in certain populations, that a lot of people were having trouble sleeping during the first months of the pandemic,” said lead author Kirsi-Marja Zitting, who has a doctorate in physiology and neurobiology and is an instructor in medicine and associate neuroscientist at Brigham and Women’s Hospital in Boston.

The study is published online as an accepted paper in the Journal of Clinical Sleep Medicine.

Insomnia involves difficulty falling asleep or staying asleep, or regularly waking up earlier than desired, despite allowing enough time in bed for sleep. Daytime symptoms associated with insomnia include fatigue or sleepiness; feeling dissatisfied with sleep; having trouble concentrating; feeling depressed, anxious or irritable; and having low motivation or energy.

The researchers analyzed Google search data in the U.S and worldwide between Jan. 1, 2004, and May 31, 2020. Data for the number of daily deaths from COVID-19 were downloaded from the freely available COVID-19 Data Repository maintained by the Center for Systems Science and Engineering at Johns Hopkins University.

Consistent with prior years, searches for insomnia in 2020 occurred most frequently during typical sleeping hours between midnight and 5 a.m., peaking around 3 a.m.

“This is the prime time for sleeping, so all these people were awake and probably wondering why they couldn’t sleep,” said Zitting.

Due to concern about the potential long-term impact of the pandemic on sleep quality, Zitting said that she plans to continue tracking searches for insomnia.

“While acute insomnia, typically triggered by stress or a traumatic event, will often go away on its own, I am worried that the longer this pandemic drags on, the greater the number of people who go on to develop chronic insomnia,” she said. “And unlike acute insomnia, chronic insomnia can be difficult to treat.”

In a new clinical practice guideline, the American Academy of Sleep Medicine recommends that clinicians use multi-component cognitive behavioral therapy for insomnia for the treatment of chronic insomnia disorder in adults. Another AASM clinical practice guideline indicates that several medications can be considered for the treatment of chronic insomnia in adults, mainly in patients who are unable to participate in CBT-I or still have symptoms despite treatment, or in select cases as a temporary adjunct to CBT-I.

Epigenetic marks do not change the DNA sequence but can affect the activity of genes. "Although in animals, including humans, these marks are believed to be completely reset in gametes, in plants, they can be stably inherited for many generations," says Frank Johannes, Professor of Population Epigenetics and Epigenomics at the Technical University of Munich (TUM), whose research team has been trying to understand how epimutations arise in plant genomes, how stable they are across generations, and whether they can affect important plant characteristics.

Trees are natural epimutation accumulation systems

"Given their extraordinary longevity, trees act as natural epimutation accumulation systems, and therefore offer unique insights into epigenetic processes over long time-scales," says Professor Johannes. Together with co-senior author Professor Robert J. Schmitz (University of Georgia, USA), who is also a Hans Fisher Fellow at the TUM-IAS, he recently published two companion papers on this topic.

In their studies, the team focused on a 330 year-old poplar tree. By comparing DNA methylation (an important epigenetic mark) of leaves from different branches of the tree, they were able to show that epimutations accumulate continuously as a function of the tree's age. The researchers found that the further apart two leaves are from each other, in terms of developmental time, the more dissimilar their DNA methylation patterns are. From this, the researchers were able to conclude that the rate of somatic epimutations is about 10,000 times higher than the genetic mutation rate in this same tree.

An epigenetic ageing clock in trees?

This discovery led to the intriguing insight that epimutations can serve as a kind of molecular clock to determine the age of a tree. "Only some branches had been dated by counting tree rings, but unfortunately not the main stem. We really needed this information for our analysis, so we decided to treat the total age of the tree as an unknown parameter and let the DNA methylation data of the leaves tell us how old the tree is. This gave an estimate of about 330 years," says Professor Johannes.

The estimate later turned out to be consistent with diameter-based dating of the main stem and with other information on the life history of this particular tree. "This was the first indication that there is something like an epigenetic clock in trees."

A window into the past

The team around Prof. Johannes is now pursuing the question whether environmental changes that trees experience over their long life-times leave epigenetic signatures that can be read and interpreted to learn something about their past.

"Our goal is to integrate historical environmental data with our epigenetic work. We think this may offer a window into the past which can help us to understand how trees have dealt with specific environmental challenges such as droughts and temperature fluctuations. This type of information may be useful when considering the future, particularly in light of global climate change."

Rates of both periodontal disease and cardiovascular disease are elevated in individuals with rheumatoid arthritis. New research published in Arthritis & Rheumatology suggests that immune responses to certain bacteria that cause periodontal disease may play a role in patients' higher cardiovascular disease risk.

Among 197 patients with rheumatoid arthritis, those with antibody responses to common periodontal pathogens were more likely to also show signs of atherosclerosis.

"Evidence of exposure to a particular periodontal pathogen called Aggregatibacter actinomycetemcomitans had the strongest associations with atherosclerosis in the patients with rheumatoid arthritis that we studied," said lead author Jon T. Giles, MD MPH, of Columbia University. "Moreover, it was associated with measures of coronary, carotid, and peripheral atherosclerosis, over and above other risk factors for atherosclerosis. Further studies are needed to determine if eliminating exposure to this pathogen might modify the increase in cardiovascular disease known to be part of rheumatoid arthritis."

Exercise-induced respiratory symptoms are common in childhood, and it can be difficult to diagnose their cause. A study published in Pediatric Pulmonology found that the diagnoses proposed by primary care physicians are often not the same as the final diagnoses after specialist referrals.

In the study of 214 children, the final diagnosis was asthma in 54% of cases, extrathoracic dysfunctional breathing in 16%, thoracic dysfunctional breathing in 10%, asthma plus dysfunctional breathing in 11%, insufficient fitness in 5%, chronic cough in 3%, and other diagnoses in 1%.

Final diagnosis differed from referral diagnosis in 54% of cases. Ninety-one percent of the children with a final diagnosis of asthma were prescribed inhaled medication and 50% of children with dysfunctional breathing were referred to physiotherapy.

Researchers have used machine learning, a type of artificial intelligence, to develop a prediction model for the early diagnosis of opioid use disorder. The advance is described in Pharmacology Research & Perspectives.

The model was generated from information in a commercial claim database from 2006 through 2018 of 10 million medical insurance claims from 550,000 patient records. It relied on data such as demographics, chronic conditions, diagnoses and procedures, and medication prescriptions.

The tool led to a diagnosis of opioid use disorder that was on average 14.4 months earlier than it was diagnosed clinically.

"Opioid use disorder has led a very serious epidemic in the U.S. and many other countries, with devastating rates of morbidity and mortality due to missed and delayed diagnoses. The novel ability of our algorithm to identify affected individuals earlier will likely save lives and health care costs," said senior author Gideon Koren, MD, of Ariel University, in Israel.

A scientific breakthrough has enabled experts to predict relapse in a common childhood cancer and means doctors can tailor treatment for each individual child and improve prognosis.

Research by Newcastle University, UK, has revealed that experts can identify the time, nature and outcome of medulloblastoma relapse from the biology of the disease at diagnosis and the initial therapy received.

The study, published today in The Lancet Child & Adolescent Health, shows that different biological and treatment groups within the disease relapse at different times and with different patterns of spread throughout the body.

High relapse rate

Medulloblastoma is the most common malignant brain tumour in children and relapse following initial treatment - surgery, radiotherapy and chemotherapy - has a grave prognosis.

Around 70 children are diagnosed with the cancer each year in the UK. Relapse occurs in around 30% of children, usually within five years of diagnosis.

The Newcastle research identifies which patients are most at risk of continuing problems with the disease and provides the ability to fine-tune treatment and surveillance to improve the child's prognosis.

Professor Steve Clifford, Director of Newcastle University's Centre for Cancer, who led the research, said the findings can be applied immediately in medical clinics to help disease monitoring, advance treatment decisions and improve quality of life after relapse.

He said: "Our research is a very exciting development for the treatment of medulloblastoma patients and it will help improve clinical outcomes.

"Our study allowed us to undertake biology-directed disease surveillance after initial treatment, in other words to gather and analyse a large amount of data on patients' tumours, looking out for particular types of relapse in particular groups of patients.

"This revealed that some patient biological groups relapse later and therefore need to be monitored longer as it is not a one-size-fits-all approach to tackling this kind of brain tumour.

"Our findings also mean that we can now predict the course of the disease following a relapse and tailor treatments, enabling us to improve how we manage these patients through more personalised approaches based on understanding their individual disease."

Hundreds of patients

For the study, 247 young patients around the globe with relapsed medullblastoma were monitored.

Professor Clifford explained: "For a while we thought these differences in medulloblastoma relapse might exist. To test this we gathered the largest set of data worldwide on these relapsed patients to allow us to investigate possible relationships and define the nature of the cancer accurately for clinical application.

"We now need to understand the biological mechanisms which underlie these findings, and whether these give rise to opportunities to develop new, more effective therapies for the disease."

The lead author of the study, Dr Rebecca Hill, has been awarded an MRC Clinician Scientist Fellowship to work on this area for the next five years.

Patient case study

Little Evan Wharton is a bundle of joy and lives life to the full the best he can.

But it has been a difficult start for the four-year-old, as at the age of just 15-months he was given the shock diagnosis of medulloblastoma following severe balance problems.

Within 24 hours of the discovery, Evan spent nine hours in surgery at Newcastle's Great North Children's Hospital to remove a brain tumour the size of a golf ball.

Months of intense chemotherapy followed and in September 2018 he was given the all clear. Yet, sadly just 10 months later, his cancer relapsed - more surgery and a course of proton therapy were needed.

His parents, Lindsey Sparrow, 38, and Scott Wharton, 43, a project construction manager, from Morpeth, Northumberland, had their lives turned upside down as they watched their happy son battle the brutal disease.

Lindsey said: "Just a month after Evan turned one, we noticed that he had stopped pulling himself up on the furniture, was unsteady when crawling and would topple over frequently.

"At first doctors thought it was an ear infection, but when he didn't improve and began to regress with his development, he was sent to hospital for tests.

"We were in shock when we were told it was medulloblastoma as it was a cancer we hadn't heard of before. Evan was still eating, was a happy boy and not sick, so it was a bolt out of the blue.

"There is always a grey cloud hanging over your head and when we were told his cancer had relapsed it was again upsetting as we knew he would have to go through more surgery and intense treatment."

In October this year, Evan had a brain scan to monitor his health and there was no sign of the cancer.

He has hearing problems, is not yet walking or talking, but is back at nursery and enjoying spending time with his friends which is helping with his development.

Lindsey said: "It is amazing and encouraging to hear of this breakthrough by scientists at Newcastle University.

"Evan has a lot of long-term health issues due to the type of treatment he received which, yes, saved his life but has also altered his life.

"With more tailor-based options available, this will hopefully lessen the long-term side effects and harsh treatments that children have to endure.

"It is a massive step forwards and it is fantastic that this breakthrough has happened at Newcastle."

YOUNGEST COVID-19 PATIENTS MOST LIKELY TO AVOID SEVERE ILLNESS, RECOVER WITH CARE

Media Contact: Michael E. Newman, mnewma25@jhmi.edu

In a comprehensive review of research studies looking at infections from SARS-CoV-2 -- the virus that causes COVID-19 -- in infants less than 3 months old, Johns Hopkins Medicine researchers found that the majority of these tiny patients experience mild to moderate cases of the disease and usually recover with supportive care.

The findings were reported online Sept. 8, 2020, in the Journal of Pediatrics.

According to the U.S. Centers for Disease Control and Prevention (CDC), children ages 0 to 4 years were the population least impacted by COVID-19 between Jan. 21 and Oct. 15, 2020, both in number of cases (98,216 or 1.7%) and deaths (34 or less than 0.1%). The counts and percentages were calculated from CDC's totals for that time span of nearly 6 million cases and greater than 155,000 deaths in the United States for which age-specific data were available.

Nonetheless, the youngest members of that group -- infants less than 3 months old -- have still-developing immune systems and frequently come in close contact with their caretakers. This makes them disproportionally vulnerable to infection with the SARS-CoV-2 virus compared with older infants and other young children.

To more accurately assess the virus' impact on very young infants, the Johns Hopkins Medicine team conducted a systemic review of reports and studies published between Nov. 1, 2019, and June 15, 2020, on laboratory-confirmed community-onset (where symptoms are first seen outside of the hospital) SARS-CoV-2 infections in children less than 3 months of age. Thirty-eight publications describing 63 infants met the criteria for being included in the study.

The researchers used data from the documents to define several variables about the youngest group infected by SARS-CoV-2, including age, exposure to COVID-19, past medical history, clinical symptoms, SARS-CoV-2 testing, laboratory findings, clinical course, and resulting outcome after hospital discharge or end of care (disposition).

Most of the infants evaluated in the study -- 58 out of 63, or 92% -- were hospitalized upon confirmation of SARS-CoV-2 infection. Along with the most common characteristic, fever (46, or 73%), the patients presented with various degrees of respiratory, gastrointestinal, cardiac and neurological symptoms. Eventually, most of the cases proved mild to moderate and improved with supportive care. Three infants were asymptomatic. Of the 63 patients, only 13 (21%) were admitted to an intensive care unit and two (3%) required invasive mechanical ventilation. No deaths were reported.

"Our results demonstrate a need for physicians to suspect SARS-CoV-2 infection in young infants presenting with generalized symptoms, such as fever or decreased desire to feed, even in the absence of respiratory problems," says Johns Hopkins Children's Center pediatrician Julia Johnson, M.D., Ph.D., associate director of clinical research in the Division of Neonatology and assistant professor of pediatrics at the Johns Hopkins University School of Medicine. "Further studies of SARS-CoV-2 infection in this special population are needed to address unanswered questions about how infants acquire the virus and what impacts it may have on their future health."

AUTOPSIED HEARTS SHOW MYOCARDITIS LINK TO COVID-19 RARER THAN PREVIOUSLY BELIEVED

Media Contact: Michael E. Newman, mnewma25@jhmi.edu

The suspected link between the SARS-CoV-2 virus -- the cause of the COVID-19 pandemic -- and myocarditis, an inflammation of the heart muscle (myocardium), made news this past August when a German research study claimed that 60 out of 100 patients who had recovered from the coronavirus showed signs of the dangerous heart condition via MRI. Shortly after that announcement, stories arose about several athletes with possible COVID-19-related myocarditis -- including major league pitcher Eduardo Rodriguez, who was sidelined for the entire 2020 season -- that appeared to support the connection.

However, following a recent review of clinical findings from 277 hearts autopsied from people in nine countries who died from COVID-19, researchers at Johns Hopkins Medicine and the Louisiana State University Health Sciences Center, New Orleans suggest otherwise, saying their evaluation provides evidence that myocarditis related to the viral disease may actually be a rare occurrence.

The study was published online Oct. 29, 2020, in the journal Cardiovascular Pathology.

The data from the autopsied hearts were published in 22 papers. After careful review, the researchers determined that the rate of myocarditis found in these patients is between 1.4% and 7.2%. Earlier studies, using imaging of hearts rather than a physical examination of the organs following death, reported rates ranging between 14% and 60%.

"What we have learned is that myocarditis is not nearly as frequent in COVID-19 as has been thought," says Marc Halushka, M.D., Ph.D., professor of pathology at the Johns Hopkins University School of Medicine and one of two study authors. "This finding should be useful for our clinical colleagues when considering how to best interpret blood tests and heart radiology studies."

"By bringing the data together from this large number of autopsy cases, we have better defined the spectrum of histologic findings that can be seen in the hearts of people with COVID-19," adds co-author Richard Vander Heide, M.D., Ph.D., M.B.A., professor of pathology at the LSU Health New Orleans School of Medicine.

The researchers say that even a low myocarditis rate of 1.4% would predict hundreds of thousands of worldwide cases of myocarditis following severe COVID-19. Low rates of myocarditis, they add, do not indicate that individuals infected with SARS-CoV-2 are not having cardiovascular problems, but rather those complications are likely due to other factors such as immune responses or electrolyte imbalances.

Based on the results of their study, the researchers have created a checklist for pathologists to use when evaluating COVID-19 at autopsy to provide consistency in investigating and reporting cardiovascular pathologic findings.

"This study demonstrates the importance of the autopsy in helping us determine what is occurring in the hearts of individuals passing away due to COVID-19," says Halushka.

DALLAS, Nov. 17, 2020 — Using a remotely-delivered, algorithm-driven program for disease management, patients experienced significant improvement in cholesterol and blood pressure levels, according to late-breaking research presented today at the American Heart Association’s Scientific Sessions 2020. The virtual meeting is Friday, November 13-Tuesday, November 17, 2020, and is a premier global exchange of the latest scientific advancements, research and evidence-based clinical practice updates in cardiovascular science for health care. The manuscript of this study is simultaneously published today in Circulation, the American Heart Association’s flagship journal.

Failure to appropriately treat hypercholesterolemia (high cholesterol) and hypertension (high blood pressure) remains an ongoing clinical challenge that increases the risk of heart attacks, stroke and cardiovascular death. Using digital tools, clinicians at Brigham and Women's Hospital in Boston, Massachusetts, initiated and continue to conduct a remote, algorithmically driven, hypercholesterolemia and hypertension management program.

Between January of 2018 and May of 2020, researchers screened 18,810 patients and enrolled 5,000 patients into either the cholesterol program, the hypertension program – or both. Among the 3,939 patients enrolled in the cholesterol program, 35% had established atherosclerotic cardiovascular disease (ASCVD); 25% had diabetes but no ASCVD; and 31% had a low-density lipoprotein cholesterol (LDL-C) >190 mg/dL. Doctors, pharmacists and support specialists helped design these management programs to initiate and adjust the medication doses, also known as titration, to achieve maximum benefits for patients while minimizing clinically important side effects.

“To better control cholesterol and blood pressure, both of which are major cardiovascular risk factors, we need new end-to-end treatment solutions that improve patient identification, data collection, education and care delivery, including standardizing medication regimens. We are redefining treatment pathways to address persistent gaps in health care, overcome clinical inertia and address the problems of limited access to physicians by expanding remotely-delivered care,” says the study’s lead author Benjamin M. Scirica, M.D., M.P.H., a cardiologist at Brigham and Women’s Hospital and associate professor of medicine at the Harvard School of Medicine, both in Boston.

Using electronic health records and doctor referrals, the program identified people with uncontrolled LDL-C and/or high blood pressure. Patients received digitally connected blood pressure cuffs for use at home, and pharmacists and support staff used the clinical algorithms to initiate and titrate medications at preset intervals until treatment goals were achieved.

Results of the study include:

An overall LDL-C reduction of 52 mg/dl (42%) occurred in patients who completed the titration phase of the program.

Significant LDL-C reductions were achieved in patients who met one of four cholesterol-risk categories – established atherosclerotic cardiovascular disease, diabetes, severe hypercholesterolemia (LDL >190 mg/dL) or high-risk primary prevention.

The average reduction in blood pressure was 14 mmHg systolic and 6 mmHg diastolic reduction.
An overall LDL-C reduction of 24 mg/dl (18%) was achieved in all patients enrolled.

“This is an effective and efficient strategy to care for high-risk yet undertreated patients and to optimize guideline-directed therapy. Specialized out-of-office treatment for cholesterol and blood pressure control reduces the need for in-person visits and allows for collaborative decision-making in-patient care. The results of our study provide a model for expanding remote health care delivery to increase access to care, to help reduce health inequities and to improve health care quality,” said Scirica.

Presentation: LBS.09 - High Tech or High Touch: Creative Strategies to Optimize Patient Care

"The urgent need for COVID-19 vaccines must be balanced with the imperative of ensuring safety and public confidence in vaccines by following the established clinical safety testing protocols throughout vaccine development, including both pre- and post-deployment," write David M. Knipe and colleagues in this Perspective. The authors highlight how historical experience with vaccine development has paved the way for a well-developed path for preclinical and clinical testing to ensure vaccine safety and efficacy. COVID19 vaccines will be safe if regulatory agencies maintain their well-documented safety testing protocols, as informed by history, they say. As part of this process, all batches of vaccines must be tested for safety. Also, it is critical for developers to understand a vaccine's mechanism of action and immune correlates of protection; understanding these can ensure that vaccines induce the optimal immune response for protection while avoiding nonproductive or counterproductive immune responses. Another lesson learned from historical vaccine development, Knipe and colleagues write, is that if serious adverse events are detected in a clinical trial, then additional clinical testing is indicated. Current regulatory practices require monitoring of rare adverse events pre- and post-licensure of a vaccine, with detection of serious adverse events triggering a pause to trial or use. Indeed, Knipe et al. note, such safety pauses have occurred in current COVID-19 vaccine trials, underscoring the value of extensive regulatory safety protocols, which should not be rushed or undermined. "There is an urgent need for COVID-19 vaccines and exciting progress to that end," write Knipe et al., "but there remains a critical public health obligation to conduct rigorous evaluation to ensure safety as well as efficacy."

November 17, 2020 - Can early-stage prostate cancer "vanish" during follow-up? More likely the cancer is just "hidden"--either way, negative biopsies during active surveillance for prostate cancer are associated with excellent long-term outcomes, reports a study in The Journal of Urology®, an Official Journal of the American Urological Association (AUA). The journal is published in the Lippincott portfolio by Wolters Kluwer.

"For men undergoing active surveillance, negative biopsies indicate low-volume disease and lower rates of disease progression," comments lead author Carissa E. Chu, MD, of University of California, San Francisco (UCSF) "These 'hidden' cancers have excellent long-term outcomes and remain ideal for continued active surveillance."

'Excellent' long-term outcomes with negative biopsies on active surveillance

`During active surveillance, prostate cancer is carefully monitored for signs of progression through regular prostate-specific antigen (PSA) screening, prostate exams, imaging, and repeat biopsies. The goal is for men to avoid or delay treatment-related side effects without compromising such long-term outcomes as cancer progression or survival.

Sometimes, men undergoing active surveillance have negative biopsies showing no evidence of prostate cancer. While these patients may believe their cancer has "vanished," they most likely have low-volume or limited areas of prostate cancer that were not detected in the biopsy sample. Dr. Chu comments, "While a negative biopsy is good news, the long-term implications associated with such 'hidden' cancers remain unclear."

To evaluate the long-term significance of negative biopsies, the researchers analyzed 514 men undergoing active surveillance for early-stage prostate cancer at UCSF between 2000 and 2019. All patients had at least three surveillance biopsies after their initial prostate cancer diagnosis (total four biopsies). Median follow-up time was nearly ten years.

Thirty-seven percent of patients had at least one negative biopsy during active surveillance, including 15 percent with consecutive negative biopsies. Men with negative surveillance biopsies had more favorable clinical characteristics, including low PSA density and fewer samples showing cancer at the initial prostate biopsy.

Negative biopsies were also associated with good long-term outcomes. At 10 years, rates of survival with no need for prostate cancer treatment (such as surgery or radiation) were 84 percent for men with consecutive negative biopsies, 74 percent for those with one negative biopsy, and 66 percent for those with no negative biopsies. After adjustment for other factors, men with one or more negative biopsies were much less likely to have cancer detected on a later biopsy.

However, having negative biopsies didn't mean that the cancer had "vanished" - even some men with consecutive negative biopsies later had positive biopsies or were diagnosed with a higher stage of cancer. Therefore surveillance, although less intense, is still recommended rather than "watchful waiting" for men in good health. Higher PSA density and suspicious findings on prostate magnetic resonance imaging (MRI) scans were associated with a higher risk of cancer detected on later biopsies.

"Negative surveillance biopsies in men on active surveillance indicate low-volume prostate cancer with very favorable outcomes," Dr. Chu and colleagues conclude. "A less-intensive surveillance regimen should be supported in these patients after discussion of risks and benefits, particularly in those with low PSA density and adequate MRI-targeted sampling."