COVID viruses are losing parts of their genome

Why it matters that COVID viruses are losing parts of their genome

Why it matters that COVID viruses are losing parts of their genome

Again and again, the new coronavirus has sloughed off small chunks of its genome, leading to changes in a viral protein that is frequently targeted by antibodies.

When evolution snips out a stretch of an organism’s genome, the change is called a deletion. Kevin McCarthy and Paul Duprex at the University of Pittsburgh School of Medicine in Pennsylvania and their colleagues searched a database of SARS-CoV-2 genome sequences and identified more than 1,000 viruses with deletions in the genomic region that encodes a protein called spike (K. R. McCarthy et alScience https://doi.org/10.1126/science.abf6950; 2021). The virus uses the spike protein to invade cells.

Further analysis showed that the deletions tended to crop up at a few distinct sites in the genomic region coding for spike. Some of the deletions have arisen independently multiple times, and some show evidence of spread from one person to another.

A powerful antibody against SARS-CoV-2 could not latch onto spike proteins harboring some of the deletions that the team identified. But antibody mixtures collected from people who had recovered from COVID-19 could disable viral variants that had deletions.

Source: Nature.com

Pediatric Minority Patients

Pediatric Minority Patients Less Likely to Undergo ED Imaging

Pediatric Minority Patients Less Likely to Undergo ED Imaging

Significant racial and ethnic differences in diagnostic imaging rates exist among children receiving care in pediatric EDs across the United States, Jennifer R. Marin, MD, of the University of Pittsburgh Medical Center Children’s Hospital of Pittsburgh, and associates reported.

Specifically, visits with non-Hispanic Black and Hispanic patients less frequently included radiography, CT, ultrasonography, and MRI than those of non-Hispanic White patients. The findings persisted across most diagnostic groups, even when stratified according to insurance type, Marin and colleagues reported in a multicenter cross-sectional study in JAMA Network Open.

The authors collected administrative data from the Pediatric Health Information System on 44 tertiary care children’s hospitals in 17 major metropolitan areas across the United States. They evaluated a total of 13,087,522 ED visits by 6,230,911 patients that occurred between Jan. 1, 2016, and Dec. 31, 2019. Of these, 28.2% included at least one imaging study. Altogether, 33.5% were performed on non-Hispanic White children, compared with just 24.1% of non-Hispanic Black children (adjusted odds ratio, 0.82) and 26.1% of Hispanic children (aOR, 0.87). After adjusting for relevant confounding factors, non-Hispanic Black and Hispanic children were less likely to have any imaging at all during their visits.

“Our findings suggest that a child’s race and ethnicity may be independently associated with the decision to perform imaging during ED visits,” Marin and associates said, adding that “the differential use of diagnostic imaging by race/ethnicity may reflect underuse of imaging in non-Hispanic Black and Hispanic children, or alternatively, overuse in non-Hispanic White children.”

Overuse vs Underuse: Racial Bias or Parental Anxiety?

Overuse of imaging carries its own risks, but underuse can lead to misdiagnosis, the need for additional care, and possibly worse outcomes in the long run, Marin and colleagues explained. “Although we were unable to discern underuse from overuse using an administrative database, it is likely that much of the imaging in White children is unnecessary.”

Higher parental anxiety was just one of the explanations the authors offered for excessive imaging in White children. Especially in cases of diagnostic imaging for head trauma, one survey of adult ED patients showed that the peace of mind CT offers with its more definitive diagnosis was worth the additional possible risk of radiation.

Language barriers in non–English-speaking patients may also affect likelihood of testing as part of an ED visit.

Implicit physician racial bias, which can be amplified under the stress of working in an ED, can affect patient interactions, treatment decisions and adherence, and ultimately overall health outcomes, the authors noted. The goal in ensuring parity is to routinely follow clinical guidelines and use objective scoring tools that minimize subjectivity. At the institutional level, internal quality assurance evaluations go a long way toward understanding and limiting bias.

Historically, White patients are more likely than minority patients to have a medical home, which can influence whether ED physicians order imaging studies and whether imaging of White patients may have been triggered by a primary care physician referral, Marin and associates said.

Source: Medscape.com

influenza vaccine

Intranasal influenza vaccine spurs strong immune response in Phase 1 study

Intranasal influenza vaccine spurs strong immune response in Phase 1 study

What

An experimental single-dose, intranasal influenza vaccine was safe and produced a durable immune response when tested in a Phase 1 study published in the Journal of Clinical Investigation. The investigational vaccine, called Ad4-H5-VTN, is a recombinant, replicating adenovirus vaccine designed to spur antibodies to hemagglutinin, a protein found on the surface of influenza viruses that attaches to human cells.

The investigational vaccine was developed by Emergent Biosolutions Inc., (Gaithersburg, Maryland). It was administered intranasally (28 study participants), as an oral capsule (10 participants) and via a tonsillar swab (25 participants) to healthy men and non-pregnant women ages 18 to 49 years.

The participants who received the vaccine intranasally or via tonsillar swab showed significantly higher H5-specific neutralizing antibody levels compared to the group receiving the vaccine capsule orally. The participants who received the intranasal vaccine shed viral DNA for two-to-four weeks, but virus could be cultured for a median of only one day. Participants had evidence of H5-specific CD4+ and CD8+ T-cell responses. Additionally, volunteers who received the intranasal vaccine had high levels of serum neutralizing antibodies at 26 weeks after vaccination, and this level was unchanged at three to five years after a single intranasal dose of the vaccine. The duration of viral shedding correlated with a high magnitude of neutralizing antibody response at week 26. In addition, the intranasal vaccine induced a mucosal antibody response in the nose, mouth, and rectum.

The study authors speculate that replication-competent vector vaccines may have advantages over other types of vaccines because they can express viral proteins at higher levels and for longer durations. Additionally, this type of vaccine induces a mucosal immune response that is critical for limiting transmission of viruses that infect mucosal tissues.

The vaccine platform could be highly adaptable for use against other viruses including HIV and SARS-CoV-2, according to the authors.

Article

K Matsuda et al. A Replication Competent Adenovirus-Vectored Influenza Vaccine Induces Durable Systemic and Mucosal Immunity. Journal of Clinical Investigation DOI: doi.org/10.1172/JCI140794.

Who

Mark Connors, M.D., chief of the HIV-specific Immunity Section in NIAID’s Laboratory of Immunoregulation and principal investigator for the Phase 1 study, is available for interviews. 

NIAID conducts and supports research — at NIH, throughout the United States, and worldwide — to study the causes of infectious and immune-mediated diseases, and to develop better means of preventing, diagnosing and treating these illnesses. News releases, fact sheets and other NIAID-related materials are available on the NIAID website.

Source: NIH.gov

Sleep Problems in Autism

Study Links Gene to Sleep Problems in Autism

Study Links Gene to Sleep Problems in Autism

Up to 80 percent of children with autism spectrum disorder (ASD) experience sleep problems. The source of these problems has been as much of a mystery as the exact causes of ASD, which scientists are still working to unravel. A new study led by a team of neuroscientists at Washington State University has brought scientists closer to identifying the causes of disturbed sleep in autism, which could open the door to future treatment that would bring relief to children with autism and their caregivers.

“Poor sleep is not only a problem for individuals with autism but is also one of the top concerns among caregivers,” said Lucia Peixoto, an assistant professor in the WSU Elson S. Floyd College of Medicine and the principal investigator and senior author on the study. “In addition, there is a clear link between sleep problems and severity of core autism symptoms such as social and communication challenges and repetitive behaviors. If we can get to the root of these sleep issues, this could potentially help ease other autism symptoms as well.”

Published in the open access journal eLife, the team’s findings suggest that sleep problems in patients with autism spectrum disorder may be linked to a mutation in the gene SHANK3 that in turn regulates the genes of the body’s 24-hour day and night cycle. Their study showed that people who were missing the SHANK3 gene and mice that lacked part of the gene had difficulty falling asleep. Their study in mice also strongly supported one possible explanation as to why individuals with autism have trouble falling asleep: It’s not that they are not sleepy. They are sleepy, but they simply cannot fall asleep.

Peixoto and her colleagues took a multistep approach to their study. First, they analyzed sleep data from patients with Phelan-McDermid syndrome (PMS), a genetic disorder that often goes hand in hand with autism and is thought to be related to the SHANK3 gene. They found that PMS patients who are missing the SHANK3 gene have trouble falling asleep and wake up multiple times during the night, starting at age five.

“Many kids with Phelan-McDermid syndrome sleep less than six hours a night, and their sleep is really poor across their lifespan so it’s an ongoing source of difficulty for them,” said postdoctoral research associate and co-first author Hannah Schoch.

Schoch along with co-first author and postdoctoral research associate Ashley Ingiosi did much of the hands-on work for the study. For the next step, Ingiosi studied sleep in a mouse model of PMS, which used mice that are missing a part of the Shank3 gene and wild-type control mice.

When kept on a light-dark cycle of 12 hours each and allowed to sleep normally, mice with the Shank3 mutation spent more time awake at the end of the dark period, when nocturnal mice would normally take a nap. The data also suggested that the quality of their deep sleep was reduced.

In a subsequent sleep deprivation experiment, all mice were kept awake for the first five hours of their main sleep phase.

“What we found is that the Shank3 mutant mice were able to build up a need for sleep to the same extent as wild-type mice, which tells us that they were sleepy,” Ingiosi said. “But it actually took them twice as long to fall asleep.”

A gene expression analysis of these mice showed decreased activity in a group of genes related to the body’s circadian clock, which helps to maintain a 24-hour day/night rhythm. Sleep deprivation made this worse–the team found that the number of genes that didn’t turn on correctly was twice as high in sleep deprived mutant mice. This suggests that sleep deprivation exaggerates the genetic differences between Shank3 mutants and wild-type mice, Peixoto said, which may translate to a worsening of symptoms in people who have conditions associated with SHANK3 mutations, such as PMS and autism.

The final experiment looked at how changes in circadian clock genes affected daily activity patterns in Shank3 mutant mice. They showed that the decrease in circadian clock gene activity did not change the timing of daily rest-activity rhythms in the mice, but–surprisingly–did make them less active.

Follow-up studies to be conducted by the research team will delve deeper into two questions: whether the sleep issues in mice with Shank3 mutations are present at birth or develop over time and what the mechanism is by which SHANK3 mutations cause sleep issues.

“If we are able to understand the molecular mechanisms underlying the sleep problem in Shank3 mutant mice, we expect that this will also strongly relate to sleep problems in autism in general,” Peixoto said. “And that would suggest novel points of intervention.”

 

Source: Drug, Discovery & Development

autism diagnoses

A new biomarker panel could accelerate autism diagnoses

New biomarker panel could accelerate autism diagnoses

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Ut elit tellus, luctus nec ullamcorper mattis, pulvinar dapibus leo.Investigators at the UC Davis MIND Institute and NeuroPointDX, a division of Stemina Biomarker Discovery, have identified a group of blood metabolites that could help detect some children with autism spectrum disorder (ASD). Part of the Children’s Autism Metabolome Project (CAMP), the largest metabolomic ASD study ever attempted, these findings are a key step toward developing an ASD biomarker test. The research was published September 6 in the journal Biological Psychiatry.

“With this panel of alterations in amino acid metabolism, we can detect about 17 percent of kids with ASD,” said David G. Amaral, founding director of research at the MIND Institute and senior author on the paper. “This is the first of hopefully many panels that will identify other subsets of kids with autism.”

No biomarker tests for ASD currently exist. Children are diagnosed based on their altered behaviors, which may not become evident until children are 2-4 years old. Families often must wait over a year or more for an appointment with a specialist, delaying diagnosis even further.

CAMP researchers believe the answer lies in the metabolome – the molecules that remain after larger molecules have been broken down (metabolized). Metabolomics has the advantage of monitoring both genetic and environmental contributions to the development of autism.

“By the time you’re getting to metabolomics, you’re looking at how the body is working, not just the genes it has,” said Amaral, a professor of Psychiatry and Behavioral Sciences.

The team hopes to use these and other CAMP findings to accelerate diagnosis and move kids into intensive behavioral therapy at an earlier age, which has proven quite effective. The multisite study has collected blood samples from 1,100 children – about two-thirds having been diagnosed with ASD – between 18 months and 4 years old. This is the first publication from the CAMP effort.

“One of the major goals of the MIND Institute is the development of early biological markers for detecting the risk of autism spectrum disorder,” Amaral said. “It would have been difficult for the MIND Institute to carry out the CAMP study on its own.”

Amaral added that CAMP is an excellent example of an academic/corporate partnership that has the promise of benefitting the autism community.

“It is unlikely that a single marker will detect all autism,” he said. “This paper demonstrates that alterations in metabolic profiles can detect sizable subsets of individuals with autism. The hope is that we will be able to generate a panel of biomarkers that will detect a large proportion of people at risk. Moreover, this approach highlights metabolic pathways that may be targets of intervention.”

In their work the research team compared blood metabolites – specifically, amino acids – in 516 kids with ASD and 164 children showing typical development. They found that 17 percent of the ASD children had unique concentrations of specific amino acids (metabotypes) in their blood. Though a 17 percent subgroup may seem small, it is actually quite significant. ASD encompasses a complex array of symptoms, and no one expected to find a single group of markers that would diagnose all subsets. Rather, the researchers hope to create a number of metabolomic assays that cover all variations.

“The long-term vision is, once we’ve been able to analyze all the data from CAMP, we would have a series of panels,” said Amaral. “Each of these would be able to detect a subset of kids with autism. Ultimately, metabolomics may be able to identify most children with autism.”

In addition to enabling earlier diagnosis, this work also could help generate targeted interventions for specific ASD groups. Amaral points to phenylketonuria (PKU) as a possible template. PKU is a rare disease in which the amino acid phenylalanine builds up, causing brain damage. However, relatively small dietary adjustments can make a big difference.

“With just a simple dietary modification, a child can move from being profoundly disabled to one who lives a reasonably normal life,” said Amaral. “That’s the hope with autism as well.”

The CAMP researchers will continue to validate these results while simultaneously investigating other metabotypes.

“I’m optimistic this is not a one-off,” said Amaral. “There are going to be other panels that can detect other groups of kids with ASD.”

###

Other researchers included Alan M. Smith, Joseph J. King, Paul R. West, Michael A. Ludwig, Elizabeth L. R. Donley and Robert E. Burrier at Stemina.

This work was supported by the National Institutes of Health (NIH 5 R44 MH107124-03 and 1R01MH103371), the Nancy Lurie Marks Family Foundation and The Robert E. and Donna Landreth Family Fund.

David G. Amaral receives research funding from Stemina and is on the Scientific Advisory Boards of Stemina Biomarker Discovery, Inc. and Axial Therapeutics

Source: EurekAlert.com 

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World Autism Awareness Day

World Autism Awareness Day

Autism spectrum disorder (ASD) is a developmental condition that can affect social, communication, and behavioral challenges. Autism affects the nervous system and affects how someone interacts, communicates or behaves. Early detection and educational therapies may reduce symptoms and support development. People with ASD might have trouble communicating and repeat certain behaviors. Most signs of Autism begin at an early age and may last a lifetime. Join us on Friday, April 2nd for World Autism Awareness Day.

  • ASD affects 1 in 68 children
  • Boys are nearly 5 times more likely than girls to be diagnosed with ASD
  • Autism generally appears before the age of 3
  • There is no current cure for Autism
  • ASD is not degenerative and diagnosed individuals can continuously improve
  • Up to 1/3 of people with ASD also develop seizures disorders
  • Hyperlexia commonly accompanies ASD

#AutismAwarenessDay

Source: CDC, Autism Speaks, Mayo Clinic

genetic disorder

NIH researchers identify new genetic disorder that affects the brain, craniofacial skeleton

NIH researchers identify new genetic disorder that affects the brain, craniofacial skeleton

Researchers at the National Institutes of Health have discovered a new genetic disorder characterized by developmental delays and malformations of the brain, heart and facial features. Named linkage-specific-deubiquitylation-deficiency-induced embryonic defects syndrome (LINKED), it is caused by a mutated version of the OTUD5 gene, which interferes with key molecular steps in embryo development. The findings indicate that the newly identified pathway may be essential for human development and may also underlie other disorders that are present at birth. The information will help scientists better understand such diseases — both common and rare — and improve patient care. The results were reported Jan. 20, 2021 in Science Advances.

“Our discovery of the dysregulated neurodevelopmental pathway that underlies LINKED syndrome was only possible through the teamwork of geneticists, developmental biologists and biochemists from NIH,” said Achim Werner, Ph.D., an investigator at the National Institute of Dental and Craniofacial Research (NIDCR) and lead author. “This collaboration provided the opportunity to pinpoint the likely genetic cause of disease, and then take it a step further to precisely define the sequence of cellular events that are disrupted to cause the disease.”

The project began when David B. Beck, M.D., Ph.D., a clinical fellow in the laboratory of Dan Kastner M.D., Ph.D., at the National Human Genome Research Institute (NHGRI) and co-first author, was asked to consult on a male infant who had been born with severe birth defects that included abnormalities of the brain, craniofacial skeleton, heart and urinary tract. An in-depth examination of siblings’ and family members’ genomes, combined with genetic bioinformatics analyses, revealed a mutation in the OTUD5 gene as the likely cause of the condition. Through outreach to other researchers working on similar problems, Beck found seven additional males ranging from 1 to 14 years of age who shared symptoms with the first patient and had varying mutations in the OTUD5 gene.

The gene contains instructions for making the OTUD5 enzyme, which is involved in ubiquitylation, a process that molecularly alters a protein to change its function. Ubiquitylation plays a role in governing cell fate, where stem cells are instructed to become specific cell types in the early stages of embryo development.

“Based on the genetic evidence, I was pretty sure OTUD5 mutations caused the disease, but I didn’t understand how this enzyme, when mutated, led to the symptoms seen in our patients,” said Beck. “For this reason we sought to work with Dr. Werner’s group, which specializes in using biochemistry to understand the functions of enzymes like OTUD5.”

To start, the NIH team examined cells taken from patient samples, which were processed at the NIH Clinical Center. Normally, OTUD5 edits or removes molecular tags on certain proteins (substrates) to regulate their function. But in cells from patients with OTUD5 mutations, this activity was impaired.

Using a method to return mature human cells to the stem cell-like state of embryo cells, the scientists found that OTUD5 mutations were linked to abnormalities in the development of neural crest cells, which give rise to tissues of the craniofacial skeleton, and of neural precursors, cells that eventually give rise to the brain and spinal cord.

In further experiments, the team discovered that the OTUD5 enzyme acts on a handful of protein substrates called chromatin remodelers. This class of proteins physically alters the tightly packed strands of DNA in a cell’s nucleus to make certain genes more accessible for being turned on, or expressed.

With help from collaborators led by Pedro Rocha Ph.D., an investigator at the National Institute of Child Health and Human Development (NICHD), the team found that chromatin remodelers targeted by OTUD5 help enhance expression of genes that control the cell fate of neural precursors during embryo development.

Taken together, the researchers concluded, OTUD5 normally keeps these chromatin remodelers from being tagged for destruction. But when OTUD5 is mutated, its protective function is lost and the chromatin remodelers are destroyed, leading to abnormal development of neural precursors and neural crest cells. Ultimately, these changes can lead to some of the birth defects seen in LINKED patients.

“Several of the chromatin remodelers OTUD5 interacts with are mutated in Coffin Siris and Cornelia de Lange syndromes, which have clinically overlapping features with LINKED syndrome,” said Werner. “This suggests that the mechanism we discovered is part of a common developmental pathway that, when mutated at various points, will lead to a spectrum of disease.”

“We were surprised to find that OTUD5 elicits its effects through multiple, functionally related substrates, which reveals a new principle of cellular signaling during early embryonic development,” said Mohammed A. Basar, Ph.D., a postdoctoral fellow in Werner’s lab and co-first author of the study. “These findings lead us to believe that OTUD5 may have far-reaching effects beyond those identified in LINKED patients.”

In future work, Werner’s team plans to more fully investigate the role that OTUD5 and similar enzymes play in development. The researchers hope the study can serve as a guiding framework for unraveling the causes of other undiagnosed diseases, ultimately helping clinicians better assess and care for patients.

“We’re finally able to provide families with a diagnosis, bringing an end to what is often a long and exhausting search for answers,” said Beck.

This research was supported by NIH intramural research programs at NIDCR, NICHD, NHGRI and the NIH Undiagnosed Diseases Program. Support also came from the Estonian Research Council, Japan Society for the Promotion of Science and the Japan Agency for Medical Research and Development.

Source: NIH.gov

Type 2 Diabetes

What’s the Best Second-Line Drug Class for Type 2 Diabetes?

What’s the Best Second-Line Drug Class for Type 2 Diabetes?

Sodium-glucose cotransporter 2 (SGLT2) inhibitors to treat type 2 diabetes appear to confer greater cardiovascular benefit than glucagon-like peptide-1 (GLP-1) receptor agonists among older adults with a history of cardiovascular disease (CVD), according to a new study.

But in those with no history of CVD, the two newer drug classes appear equally effective.

The findings, from an analysis of Medicare beneficiaries, were published online January 25 in Diabetes Care by Elisabetta Patorno, MD, and colleagues.

The analysis included more than 90,000 adults aged 66 years and older who started a GLP-1 agonist or SGLT2 inhibitor between April 2013 and December 2016. Use of an SGLT2 inhibitor compared with a GLP-1 agonist was associated with similar rates of major adverse cardiovascular events (MACE), fewer hospitalizations for heart failure and acute kidney injury, and greater risks for diabetic ketoacidosis (DKA), lower-limb amputations, and genital infections.

The head-to-head comparison reinforces findings from recent meta-analyses of cardiovascular outcomes trials (CVOTs) showing greater benefit for SGLT2 inhibitors than GLP-1 agonists in prevention of heart failure, while also shedding light on two type 2 diabetes populations who were not well-represented in the CVOTs, Patorno and colleagues say.

Study Fills a Knowledge Gap

“Our study focuses on routinely treated patients on average 10 years older than the patients included in these trials, providing information on a subset of the population with diabetes underrepresented in CVOTs,” say Patorno, of the Division of Pharmacoepidemiology and Pharmacoeconomics, Harvard Medical School, Boston, Massachusetts, and colleagues.

“It includes patients across a broader spectrum of CVDs at baseline, allowing for the exploration of drug effectiveness among patients with and without established CVD,” they add.

And, they note, the database includes a far larger population than do the CVOTs, thus enabling a closer investigation of safety issues in a more vulnerable population.   

Asked to comment, Rozalina G. McCoy, MD, an endocrinologist and primary care physician at the Mayo Clinic, Rochester, Minnesota, told Medscape Medical News, “It’s really important to compare these two classes of medications to each other because over the past 5 years they have come to the forefront as the ideal medications for the management of type 2 diabetes because of these additional benefits that we see in terms of cardiovascular disease, heart failure, and kidney disease progression.”

“It’s really important to know if these medications are comparable to each other, or if one should be preferred over the other for a particular benefit, in our patients depending on what they’re at highest risk for. So, I think this fills an important knowledge gap.”

Overall, McCoy said the data suggest that older adults with baseline CVD would be the most likely to benefit from SGLT2 inhibitors or GLP-1 agonists.

Among those individuals, “If I’m trying to decide which of these two drugs to start a patient on — after confirming they can afford them — this helps us with that shared decision-making conversation. If they have heart failure, I should give them an SGLT2 inhibitor. But if they don’t have heart failure, it really doesn’t matter…between those two.”

Source: medspace.com

Remote patient monitoring

Remote patient monitoring poised for further growth in clinical trials

Remote patient monitoring poised for further growth in clinical trials

Remote patient monitoring (RPM) is among the trends that will have the greatest impact on the pharma sector in 2021, according to the recent report, “The State of the Biopharmaceutical Industry, 2021 Edition,” from GlobalData. After a period of gradual uptake, RPM “witnessed a massive uptake in the life-sciences sector in 2020,” according to the GlobalData report.

The technology offers several advantages. It can help pharmaceutical companies continue making progress with clinical trials during a pandemic. The ability to gather data from patients remotely can also reduce the burden on medical staff while reducing gaps in clinical trial data. “One of the advantages when you have frequent measurements from remote patient monitoring is that, even if you have missing data, you tend to have so many data points that it doesn’t interfere with your judgment,” said Dr. Arik Eisenkraft, chief medical officer of BioBeat.

Remote data gathering for COVID-19 and vaccines

Remote patient monitoring can also help researchers better understand COVID-19 and other viral infections. Data from wearable devices can detect physiological changes in the early stages of viral infections, according to a 2020 article published in The Lancet.

“We were involved in two different flu studies, and definitely you can see physiological changes, using wearable technology in people who got the flu,” Eisenkraft said. “You sometimes see dramatic changes between men and women” in response to influenza-like illness, he added. “We’ve seen some dramatic cardiovascular changes among these patients far earlier than anyone would have thought — sometimes even before you see any respiratory changes.”

Remote patient monitoring can also shed light on potential adverse events from COVID-19 vaccines. Vital signs gathered via wearable technology can establish a baseline before a patient receives an initial vaccine dose, Eisenkraft said. After the baseline is established, clinical trials can identify the effect of the prime and boost vaccine doses.

Remote trials tend to be more patient-centric

Decentralized clinical studies not only help reduce COVID-19 transmission, but they also happen to be more convenient for patients. The benefits of remote clinical trials are especially high when it comes to chronic diseases such as congestive heart failure, diabetes and hypertension. Even before the pandemic, one of the top clinical trial hurdles in monitoring these diseases and drugs related to them was an inconvenience for patients. “And because a clinic is not a patient’s natural environment, it can make it difficult to measure the effects of drugs,” Eisenkraft said.

For instance, physicians have long known about white coat hypertension, a phenomenon in which some patients’ blood pressure rises when in a doctor’s office.

“Another aspect with remote patient monitoring is the fact you might find things you didn’t expect because you have so much data,” Eisenkraft said. One example is discovering clinically significant hypertension during dialysis. “We have an early warning score that triggers an alert if something goes wrong during dialysis,” Eisenkraft said. Finding such problems in the past was difficult given that measurements were usually collected before or after dialysis.

Ultimately, similar alerts can be applied for an array of physiological parameters in pharmaceutical clinical trials, Eisenkraft said. Data from wearable devices can help researchers understand how a given drug performs in specific patient populations. It’s even possible that physiological monitoring can lead to custom instructions for patients taking a particular drug. “Some patients with high blood pressure benefit more if they take a hypertension drug at night while others fare better when taking it in the morning,” Eisenkraft said.

Wearable device data could accelerate the detection of troubling signals from drugs during clinical trials and post-marketing surveillance.

The potential to provide medically relevant alerts continues to grow, thanks to increasing machine learning adoption (ML). “Artificial intelligence enables us to update algorithms and provide continually better monitoring,” Eisenkraft said. “Especially when you’re looking at large scale studies, this can be a huge advantage when you need to analyze so many data points.” Even in small studies, Biobeat gathers several million data points throughout a trial. “You really need to use AI/ML systems and tools to analyze everything,” Eisenkraft said.

Source: drugdiscoverytrends.com

 

Coronavirus Spike change enhances replication and transmition

SARS-CoV-2 spike enhances replication

SARS-CoV-2 spike enhances replication

A new SARS-CoV-2 spike enhances replication. During the evolution of SARS-CoV-2 in humans a D614G substitution in the spike (S) protein emerged and became the predominant circulating variant (S-614G) of the COVID-19 pandemic. However, whether the increasing prevalence of the variant represents an advantage that improves replication and/or transmission in humans or merely due to founder effects remains elusive. Isogenic SARS-CoV-2 variants were generated and showed that the S-614G variant has enhanced binding to human host cell surface receptor angiotensin-converting enzyme 2 (ACE2), ) increased replication in primary human bronchial and nasal airway epithelial cultures as well as in a novel human ACE2 knock-in mouse model, and markedly increased replication and transmissibility in hamster and ferret models of SARS-CoV-2 infection. Collectively, data shows that while the S-614G substitution results in subtle increases in binding and replication in vitro, it provides a real competitive advantage in vivo, particularly during the transmission bottle neck, providing an explanation for the global predominance of S-614G variant among the SARS-CoV-2 viruses currently circulating.

In late 2019, severe acute respiratory syndrome coronavirus 2(SARS-CoV-2) emerged in Wuhan, Hubei province, China, and rapidly developed into the COVID-19 pandemic. By December 2020, 70 million cases and 1.5 million deaths have been confirmed. In vulnerable groups of people, SARS-CoV-2 causes a life-threatening pneumonia. Cell entry of SARS-CoV-2 is dependent on the interaction of the spike glycoprotein and ACE23, a homotrimeric class I fusion protein consists of two subunits S1 and S2, separated by a protease cleavage site. S1 forms a globular head and is essential for receptor binding, while S2 mediates fusion of the viral envelope with host cell membranes. During entry, the receptor-binding domain (RBD) within the S1 subunit binds ACE2, generating conformational changes in the S2 subunit, facilitating virus internalization. S-D614G, a protein variant containing a substitution in the S protein outside of the RBD, is thought to cause a conformational change, improving ACE2 binding and increasing the
probability of infection.

As the pandemic progressed, the SARS-CoV-2 S-614G variant rapidly superseded the parental S-614D variant in frequency to become globally dominant. Such a shift in genotype frequency might be
caused by a founder effect following introduction into a highly
interconnected population. However, the S-614G variant may confer a fitness advantage compared to S-614D. However, some studies
suggest the S-614G substitution may confer a fitness advantage by
improving entry. To address the role that the S-D614G substitution
has played in the dissemination and predominance of this SARS-CoV-2
variant during the COVID-19 pandemic, we characterized S protein
binding to human ACE2 (hACE2) and replication kinetics in vitro and
evaluated infection and transmission dynamics in vivo using three
different animal models. The data show that the S-D614G substitution confers increased binding to the hACE2 receptor and increased
replication in primary human airway epithelial cultures. Moreover,
comparison of recombinant isogenic SARS-CoV-2 variants demonstrates that S-614G substitution provides competitive advantage in
a hACE2 knock-in mouse model, and markedly increases replication
and transmission in Syrian hamster and ferret models. To address the
role that the S-D614G substitution has played in the dissemination
and predominance of this SARS-CoV-2 variant during the COVID19 pandemic, we characterized S protein binding to human ACE2
(hACE2) and replication kinetics in vitro and evaluated infection and
transmission dynamics in vivo using three different animal models.

Source: https://www.nature.com/articles/s41586-021-03361-1