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Genetic Linkage

Down Syndrome Tied to Tenfold Risk for Death From COVID-19

People with Down syndrome who contract COVID-19 face a fivefold increased risk for hospitalization and a tenfold increased risk for death compared with infected individuals who do not have the syndrome, researchers report in the Annals of Internal Medicine.


Since the pandemic began, public health and infectious disease experts have identified comorbidities that elevate the risk for serious complications or death from COVID-19. In the United Kingdom and the United States, Down syndrome hasn't been on that list. The authors of the new report argue that it should be.


Down syndrome might be associated with more severe COVID-19, owing to "the immune dysregulation, such as differences in T cell function," said first author Ashley Kieran Clift, MA, MBBS, clinical research fellow at the University of Oxford, Oxford, United Kingdom. "People with Down syndrome have a higher risk of pneumonia and viral respiratory tract infections, which may also apply to this novel coronavirus. They have high rates of other conditions that may make them more vulnerable, such as heart and lung disease. There could also be a role for their environment, such as living in care homes or other institutions."

The researchers analyzed data from a UK government-sponsored cohort study of 8.26 million adults older than 19 years. The data included information on COVID-19 test results; records of associated hospitalizations and deaths; whether or not a person also had Down syndrome; and information on age, sex, ethnicity, alcohol intake, smoking status, body mass index (BMI), comorbidities, and medications.


The cohort included 4053 people with Down syndrome. Of those, during the study period, from January 24 until June 30, 2020, 68 died ―39.7% of COVID-19, 25.0% of pneumonia or pneumonitis, and 35.3% of other causes. By contrast, among the 8,252,105 people who did not have Down syndrome, 41,685 died; the cause of death was listed as COVID-19 for 20.3%, pneumonia or pneumonitis for 14.4%, and other causes for 65.3%.


The hazard ratio (HR) for death related to COVID-19 was 10.39 (CI, 7.08 – 15.23) and for hospitalization, 4.94 (CI, 3.63 – 6.73) after adjusting for age, sex, ethnicity, BMI, dementia diagnosis, living in a care home, congenital heart disease, and other comorbidities and treatments. For individuals who had learning disabilities but not Down syndrome, the adjusted HR for COVID-19–related death was only 1.27 (CI, 1.16–1.40).


Corresponding author Julia Hippisley-Cox, MD, professor of clinical epidemiology and general practice, St. Anne's College, University of Oxford, said that although the study was observational and did not identify reasons for the elevated risk, "we feel that clinicians, policymakers, and other healthcare workers should be aware of potential risks. These findings could be used by healthcare workers within the context of other factors to have a more nuanced risk assessment for their patients." 

That might entail weighing the relative risks and benefits of measures that protect against infection vs the values of socialization in day care programs and physical and occupational therapies. It's a balancing act, Hippisley-Cox said.


Preston McCormack, MD, assistant professor or internal medicine and pediatrics at the University of Arkansas for Medical Sciences College of Medicine, Little Rock, Arkansas, agreed that caution is warranted in navigating care during this challenging time.


"It's well known that Down syndrome patients are at increased risk. However, with these data surfacing, it may be a good time to reassess how we plan to move forward," McCormack said. "The risk, even after adjustment for age, sex, and associated comorbidities, remains impressive and demands attention as we approach another viral season this fall and upcoming winter.


"The fact that most in this population require more frequent medical follow-up, therapy, and other ancillary services further compounds this risk," he continued. "The decision to restrict patients from these care providers will likely have to be determined on an individual basis, though it is imperative that we are continually informed of the risks vs benefits of these decisions. Without a doubt, we are unable to optimize therapy and socialization in this pandemic landscape. However, this expense is offset with minimization of significant risk quantified in this recent study."


Originally published at Medscape Medical News

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Can Some Antibodies Worsen COVID-19? The Odd Situation of Enhancement

Antibodies are supposed to be the good guys. The proteins, built of distinctive Y-shaped pieces, enter the bloodstream early in infection, pouring out from plasma cells. They then latch onto molecules festooning pathogens and alert natural killer cells, which release a torrent of cytokines and complement, which are the biochemical weapons of an immune response.


Fighting infection is a complex business.


In a mysterious phenomenon called "antibody-dependent enhancement," the proteins actually make matters worse, intensifying symptoms. When a vaccine elicits the errant antibodies, the backfiring is called "vaccine enhancement of disease." We know these reactions exist, but still do not completely understand them.


The turncoat antibodies can be coaxed to appear in test tube experiments, but are elusive in a patient who is getting sicker. That is, there's no clinical way to distinguish antibody-dependent enhancement from just a severe case of an infectious disease. And that can complicate analysis of a candidate vaccine. "Vaccine enhancement of disease" would show up in a clinical trial as more people receiving a vaccine getting sick than the participants getting placebo.


Reportedly that hasn't happened for the candidate COVID-19 vaccines, but the data won't be published until the phase 3 trials are completed.


To continue reading, please go to my blog DNA Science at Public Library of Science. 

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Final weeks to approval: NIH’s Anthony Fauci and FDA’s Peter Marks on what’s ahead before we can expect a safe COVID vaccine

As tens of thousands of people participate in phase 3 clinical trials on COVID-19 vaccine candidates, the focus is turning to the approval process: Will the approved vaccines be safe and effective? For how long? Has politics been injected into the process?


To reassure the public that the checks and balances that regulatory agencies have always had in place will prevail, Anthony Fauci, MD, Director of the National Institute of Allergy and Infectious Diseases, and Peter Marks, MD, PhD, director of the FDA's Center for Biologics Evaluation and Research, discussed the current state of the science with Howard Bauchner, MD, at JAMA Live Q+A webinars for the media on September 25 and October 5.


Their comments interweaved into a compelling narrative is like visiting with two scientific maestros.


To continue reading, go to Genetic Literacy Project, where this post first appeared.

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A Drug Trio for COVID-19: Precedents in Cystic Fibrosis, HIV/AIDS, and Hepatitis C

(University of Washington Medicine)

Teaming treatments has long been a strategy to quell cancer, override mutations, and fight viruses. Will that be a winning strategy against SARS-CoV-2, the virus that causes COVID-19?


Surgery, chemo, and radiation are the traditional triple-punch against cancer, with more recent targeted therapies moving to the frontline. The same road has unfolded for cystic fibrosis (CF).


Fixing Errant Ion Channels


The first treatments for CF were simple: pounding on the chest to dislodge sticky mucus, sprinkling digestive enzymes on applesauce, and using old drugs to combat inflammation and infection.


The new CF drugs that have revolutionized treatment for most patients are small molecules that interact with the malformed ion channels that lie behind the disease. The channels are tiny tubes built of cells festooned with proteins that regulate the balance of water and salts in many body parts – hence the diverse symptoms of breathing difficulty, poor fat digestion, salty sweat, lung infections, and male infertility.


The new drugs work in three related ways.


To continue reading, go to my blog DNA Science, where this post first appeared. 

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Long-Awaited Drug for Alkaptonuria (AKU), the First “Inborn Error,” On the Way to Approval in Europe

The European Medicines Agency has just recommended extending use of an existing drug, nitisinone (Orfadin), to treat alkaptonuria (AKU). AKU holds a special place in the history of genetics as the first "inborn error of metabolism" described. It affects one in 250,000 to one in a million people.


The route to impending approval took two decades, illustrating factors that make the quest to discover, develop, and deliver a treatment for a very rare disease so challenging. There's no "Operation Warp Speed" for the rare disease community. Sometimes there aren't even enough participants to carry out a clinical trial that is controlled, relying instead on comparisons to the natural history of a disease, or enrolling one patient at a time in an "N+1" study.


I last wrote about AKU in 2014, calling it "black pee disease." I'm happy to report now on the progress in Europe, but won't use that attention-grabbing descriptor, because it minimizes the severity.

A Peculiar Condition and an Astute Physician


To continue reading, go to my DNA Science blog at Public Library of Science.

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‘Challenge studies’: Should we be testing COVID vaccines by intentionally infecting volunteers?

To those who've never thought about volunteering to be intentionally infected to test a vaccine, the idea may at first seem a bit bonkers. But such "challenge" studies not only have a rich history, but nearly 40,000 people have already checked the box "I am interested in being exposed to the coronavirus to speed up vaccine development" at 1daysooner, a website and non-profit organization that launched in April.


Challenge studies go by other names: "controlled human infection models," "human viral challenge," and "purposeful infection." Dripping virus-tainted saltwater into a volunteer's nostrils enables researchers to track infection, and the immune system's response to it, right from the start. The approach complements phase 3 clinical "field" trials of efficacy that await natural infection in the community.


To continue reading, go to Genetic Literacy Project, where this post first appeared.

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Can Gene-Edited Stem Cells Treat Cystic Fibrosis?

Drugs that restore the shape of the errant protein behind cystic fibrosis (CF) have, over the past eight years, helped the majority of patients, who have certain mutations. Gene-corrected stem cells might offer a "mutation agnostic" option to CF.


CF results from a glitch in a glycoprotein with the unwieldy name "cystic fibrosis transmembrane conductance regulator", or CFTR. The proteins normally fold into channels that regulate the flow of ions into and out of cells, controlling the balance of water and salts in linings and barriers of the respiratory tract, pancreas, intestines, and elsewhere. If the proteins can't fold correctly, or can't migrate to the cell's surface and then open and stay that way, the resulting ion imbalance allows too much water into lining cells and secretions thicken. CF symptoms ensue, such as difficulty breathing and digesting. The Cystic Fibrosis Foundation has a helpful video (see below) both on why CF develops and the promise of gene-editing.


The most common CF mutation, F508del, removes just one of the protein's 1,480 amino acids (a phenylalanine), and that's enough to wreck the ion channels. Ninety percent of patients have at least one F508del variant. Researchers have identified more than 2,000 variants in the CFTR gene, about 350 of which are pathogenic.


To continue reading go to The Niche, where this post first appeared.

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5 COVID-19 Updates: Cats, Kids, Seniors, Blood, and an Old Vaccine

Times have been strange for us all, weird indeed for science journalists.


The initial manageable flow of news alerts to the media back in January quickly became an unceasing torrent. Every day now I receive dozens of news releases and heads-ups from science and medical journals. Many papers are preprints (not yet peer-reviewed) or embargoed, meaning we agree to not report findings until a certain date and time.


This is COVID article #42 for me. Today's post covers 5 news releases that seemed intriguing. Cats first!


Cats Get COVID From Owners


When four-year-old Negrito's human died of COVID-19, relatives took in the bereft European/Persian mix, who lived in Barcelona. Then Negrito developed difficulty breathing, so the new owners, who also had COVID, took him to the vet. Negrito's shortness of breath was due to an enlarged heart from a pre-existing condition, and he humanely crossed the rainbow bridge. But his bloodwork revealed a low viral load of SARS-CoV-2, although the cat had no other symptoms of COVID-19.


To continue reading go to DNA Science, where this post first appeared.

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A Cloned Przewalski’s Horse Evokes Memories of the Catskill Game Farm

On August 6, the first cloned Przewalski's horse was born in Texas. Kurt began with a cell nucleus from another of his kind frozen 40 years ago at the San Diego Zoo, and a surrogate run-of-the-mill domestic horse mother.

The cloning is a project of San Diego Zoo Global, Revive & Restore, and Viagen Equine.


"This new Przewalski's colt was born fully healthy and reproductively normal. He is head butting and kicking, when his space is challenged, and he is demanding milk from his surrogate mother," said Shawn Walker, chief science officer at ViaGen.


I was excited at this news, because these last surviving wild horses had made quite a lasting impression on me when I was very young.


To continue reading, please go to DNA Science, where this post first appeared.

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How the Various COVID Vaccines Work

COVID vaccine hesitancy is on the rise, perhaps in the wake of pressure to speed approval beyond scientific reason. But I think some of the hesitancy might be due to confusion over how so many different vaccines can target the same pathogen – and why this is a good idea.


The ultimate voice of scientific reason, Anthony Fauci said in a media webinar:


"I'm cautiously optimistic that with the multiple candidates with different platforms that we're going to have a vaccine with a degree of efficacy that would make it deployable. The overwhelming majority of people make an immune response that clears the virus and recover. If the body can mount an immune response and clear the virus in natural infection, that's a pretty good proof-of-concept that you'll have an immune response against a vaccine."


Having choices would provide options for people not covered by some of the vaccines, like those over age 65 and people with certain medical conditions. "It's a misperception that vaccine development is a race to be a winner. I hope more than one is successful, with equitable distribution," Fauci said.


The vaccines work in what can seem to be mysterious ways, but all present a pathogen in some form, or its parts, to alert the immune system to mount a response. Understanding how it all happens isn't like learning "how the sausage gets made." Knowledge may quell fears.


To continue reading, go to my blog DNA Science.

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