Reed Berkowitz

Reed is a Health Science student and published virology researcher at the University of Florida. His areas of interest are immunology and general biomedical research. Reed founded OneResearch.org as a free online source to highlight biomedical research and combat medical disinformation.

Categories
Commentary COVID-19

Debunked: RFK Jr. Claims COVID is ‘Ethnically Targeted’

RFK Jr. speaking at press event in NYC. / NYPost

Recent statements from 2024 Democratic presidential candidate Robert F. Kennedy Jr. have drawn great public attention. Speaking at a press event in New York City, he claimed that COVID-19 “disproportionately attacks certain races,” particularly Caucasians and Black people, with Ashkenazi Jews and Chinese being seemingly more immune. Kennedy attributed these disparities to genetic variations of the host cell receptor, ACE2, a key player in the virus’s infectious cycle. He insinuated that this is proof that SARS-CoV-2, the virus that causes COVID-19, was a biological weapon designed to target certain ethnicities. But how sound are these alarming claims?

First, let’s look at the specific study Kennedy linked to on Twitter to validate his claim. The paper investigated the correlation between allele frequencies of certain ACE2 variants and their predicted effects on its ability to bind the SARS-CoV-2 spike protein, a crucial step in the infectious cycle of the virus. For instance, the p.Met383Thr and p.Asp427Tyr variants, which the article alleges are linked to worse COVID outcomes, have frequencies of just 0.003% and 0.01%, respectively. Their rarity suggests that they are unlikely to meaningfully affect large population groups. Not only are these variants incredibly rare, but they are also based on alleles associated with adverse outcomes for SARS-CoV-1, not SARS-CoV-2, the virus causing the COVID-19 pandemic. Hence, the information from this study should not be directly applied to the current pandemic and certainly cannot prove an ethnic targeting of the virus.

Another critical study that disproves Kennedy’s claim revolves around ACE2 variants but examines them in relation to SARS-CoV-2 susceptibility, unlike the former study. Even in this research, the ACE2 variants that could affect susceptibility to SARS-CoV-2 are extremely rare, with maximum prevalence values ranging from 0.00003 to 0.006. For example, an ACE2 variant that was found to increase spike protein binding was found at a frequency of only 3 in 10,000 Latino/Admixed American samples. Consequently, the low occurrence rates of these variants indicates that their impact on broad racial or ethnic groups is statistically insignificant when it comes to widespread racial or ethnic susceptibility.

Upon close examination, it’s clear that Kennedy’s claims lack robust scientific backing. While it’s true that COVID-19 has impacted different communities in different ways, it’s not due to any supposed “genetic targeting” inherent in the virus. Instead, this disparity arises from a multitude of factors, including access to healthcare, occupation types, living conditions, systemic racial disparities in healthcare, and perhaps biological variations unrelated to host cell receptor ACE2.

The assertion that COVID-19 is “ethnically targeted” is not only scientifically unsound but also has the potential to sow confusion and fear among the public. As we continue to grapple with this global health crisis, let’s keep the discourse grounded in verifiable science and promote unity rather than divisive misinformation.

References
  • Hou, Y., Zhao, J., Martin, W., Kallianpur, A., Chung, M. K., Jehi, L., Sharifi, N., Erzurum, S., Eng, C., & Cheng, F. (2020). New insights into genetic susceptibility of COVID-19: An ACE2 and TMPRSS2 polymorphism analysis. BMC Medicine, 18(1), 216. https://doi.org/10.1186/s12916-020-01673-z
  • Levine, J. (2023, July 15). RFK Jr. Says COVID was “ethnically targeted” to spare Jews. New York Post. https://nypost.com/2023/07/15/rfk-jr-says-covid-was-ethnically-targeted-to-spare-jews/
  • MacGowan, S. A., Barton, M. I., Kutuzov, M., Dushek, O., Van Der Merwe, P. A., & Barton, G. J. (2022). Missense variants in human ACE2 strongly affect binding to SARS-CoV-2 Spike providing a mechanism for ACE2 mediated genetic risk in Covid-19: A case study in affinity predictions of interface variants. PLOS Computational Biology, 18(3), e1009922. https://doi.org/10.1371/journal.pcbi.1009922
Categories
Public Health

Animal Tranquilizer ‘Xylazine’ Is Making the Fentanyl Crisis Even Worse

In recent years, the devastating impact of the fentanyl crisis has been felt by many Americans. The opioid epidemic, led by this potent synthetic drug, has claimed thousands of lives and shows no signs of abating. But now, a new threat lurks in the shadows, poised to exacerbate an already dire situation — a veterinary sedative known as xylazine.

First synthesized in the 1960s, xylazine is a non-opioid sedative, analgesic, and muscle relaxant used primarily in veterinary medicine for large animals such as horses1. However, it has started to creep into illicit drug markets, often used as an adulterant for opioids like heroin and fentanyl2. The rise of this trend is concerning, and it’s crucial to shed light on this development as it continues to evolve.

Xylazine vial. / Randlab Veterinary Medications
Chemical structure of xylazine. / PubChem

Xylazine, when used in humans, can induce effects similar to those of opioids — a deep sense of relaxation, sedation, and pain relief1. This might explain its allure for those entrenched in substance misuse, but these effects come at a steep price. Unlike traditional opioids, xylazine is not reversed by naloxone (Narcan), the standard emergency treatment for opioid overdoses3. This significantly complicates matters for first responders, who may be unaware that xylazine is present and find that their typical lifesaving interventions are ineffective.

Moreover, xylazine possesses several harmful side effects, including hypotension, bradycardia, respiratory depression, and, in some cases, even death4. Coupled with fentanyl — a substance already notorious for its fatal potency — the presence of xylazine is a ticking time bomb.

The issue of xylazine adulteration in the opioid supply is gaining recognition, yet its severity remains underestimated. According to a 2023 report in the New England Journal of Medicine, xylazine was found in more than 90% of illicit drug samples tested in Philadelphia in 20215. The report found that xylazine is typically found as an adulterant in polydrug mixtures, usually containing simulants like cocaine and amphetamines or opioids like heroin or fentanyl. Alarmingly, the report estimates that the number of xylazine-involved drug-poisoning deaths in the United States increased by 13 times from 2018 to 2021 (an increase from 250 to 3500 deaths).

This rapidly growing and evolving crisis calls for a broad, multi-faceted response involving policymakers, healthcare providers, researchers, and communities. Actions include tightening regulation of veterinary substances, amplifying harm reduction services, and research and development of new overdose drugs that work against xylazine.

The already formidable challenge of the fentanyl and opioid crises is deepened by the introduction of xylazine, adding another lethal layer to the issue. To protect those grappling with substance misuse, it’s crucial to adapt our strategies to this emerging reality. Through a combination of awareness, education, vigilance, and research, we can start to tackle the profound impact of xylazine on the opioid crisis.

References
  1. Ruiz-Colón, K.; Chavez-Arias, C.; Díaz-Alcalá, J. E.; Martínez, M. A. Xylazine Intoxication in Humans and Its Importance as an Emerging Adulterant in Abused Drugs: A Comprehensive Review of the Literature. Forensic Sci. Int. 2014, 240, 1–8. https://doi.org/10.1016/j.forsciint.2014.03.015.
  2. Kacinko, S. L.; Mohr, A. L. A.; Logan, B. K.; Barbieri, E. J. Xylazine: Pharmacology Review and Prevalence and Drug Combinations in Forensic Toxicology Casework. J. Anal. Toxicol. 2022, 46 (8), 911–917. https://doi.org/10.1093/jat/bkac049.
  3. National Institute on Drug Abuse. Xylazine. National Institutes of Health. https://nida.nih.gov/research-topics/xylazine (accessed 2023-05-25).
  4. Andrew McAward. Xylazine, an Emerging Adulterant. American College of Emergency Physicians. https://www.acep.org/talem/newsroom/oct-2021/xylazine-an-emerging-adulterant (accessed 2023-05-25).
  5. Gupta, R.; Holtgrave, D. R.; Ashburn, M. A. Xylazine — Medical and Public Health Imperatives. N. Engl. J. Med. 2023, 0 (0), null. https://doi.org/10.1056/NEJMp2303120.
Categories
COVID-19 Public Health

COVID Disease Severity Lower Than Ever, Most People Infected Unaware of Status

woman blowing nose
Photo by Karolina Grabowska on Pexels.com

As the omicron BA.5 subvariant has become dominant, many countries are heading into their third wave of Omicron cases. Japan reports its largest-ever surge in cases, recording over 200,000 new cases in one day.

Though omicron BA.5 has become the most dominant subvariant of COVID (accounting for 88% of new cases in the US) and is highly contagious, CDC data shows disease severity at its lowest point ever.

Intensive Care Unit (ICU) admission among hospitalized COVID-19 patients. (cdc.gov)

Among hospitalized COVID patients, about 1 in 10 are admitted to the ICU as of July 2022. This figure was as high as 1 in 3 in March 2020, and 1 in 5 as recently as December 2021.

Mortality among hospitalized COVID-19 patients. (cdc.gov)

Similarly, mortality among hospitalized COVID patients has decreased appreciably from 1 in 5 in March 2020 to 1 in 40 in July 2022.

These decreases in COVID disease severity follow the emergence of the omicron variant in November 2021 and its ever-growing share of new infections. The omicron variant, while of high concern and contagion, does not appear to be of proportionally high consequence compared to earlier variants.

The most common symptoms of COVID include cough, fever, and chills. Many report symptoms resembling a common cold with symptoms like upper respiratory congestion. Most people (56%) who are infected with the omicron variant are not aware of their positive status according to a recent Cedars-Sinai study.

Multiple factors could explain omicron’s lower severity, including widespread vaccination or immunity gained from prior exposure and infection. It is also possible that omicron has mutations that decrease severity while favoring infectivity.

Categories
Genetics

Antisense Therapy Explained: How Blocking mRNA Can Treat Genetic Disorders

Photo by Warren Umoh on Unsplash

Antisense therapy has proven to be effective at treating previously untreated genetic disorders including Duchenne muscular dystrophy and familial hypercholesterolemia. The therapy has also demonstrated promising results in Phase III clinical trials for amyotrophic lateral sclerosis (ALS).

What is antisense therapy, and how are antisense oligonucleotides used to treat genetic disorders?

Contents

Background

Genetic Disorders and Proteins

Genetic disorders are diseases caused by abnormal changes in our DNA sequence (mutations). Many diseases have a genetic basis, with mutations either being a direct cause or one of many contributors to a disease’s proliferation.

Some people are born with genetic disorders, acquiring mutations from one or both parents, while others acquire them during their lifetime due to mistakes made by their own cells or exposure to viruses, radiation, or mutagenic chemicals. Most mutations do not result in genetic disorders.

The reason why mutations can affect biological processes is because our DNA provides our cells with the blueprints necessary to build proteins, which are complex molecules responsible for carrying out the chemical reactions that occur within our bodies.

Humans are believed to have 25,000 unique proteins (some copied trillions of times throughout our bodies) that have very specific tasks and functions pertaining to growth, maintenance, structure, metabolism, immune defense, and much more. It follows that a mutation, which creates an error in the genetic instructions to create a specific protein, can have profound impacts on our health.

Genetic disorders that cause the creation of harmful proteins are notoriously difficult to treat. New genes can be introduced into cells to result in the creation of non-mutated proteins, but it is not yet possible to completely stop the production of specific proteins.

This limitation even applies with the recently discovered CRISPR-Cas9 gene editing technology, which can add, remove, inhibit, and activate genes–but not in all cells of the body, meaning some cells will still produce the harmful target protein. Therefore, gene therapy that could inhibit the expression of harmful mutated genes would benefit patients with such disorders.

Antisense Therapy

How It Works

When cells use our DNA’s instructions to build new copies of a protein, it must first be processed into a form that can be read by the ribosome, which is the site of protein synthesis in our cells. Messenger RNA (mRNA) is the final form into which a part of the DNA sequence is processed before the ribosome uses its instructions to build new proteins.

Antisense oligonucleotides (ASOs) are strands of DNA or RNA that are complementary to an mRNA strand that encodes for a mutated protein. Due to this complementary nature, the ASO and the faulty mRNA strand will bind together. This prevents the ribosome from ever translating the specific mutated mRNA strand into the harmful, mutated protein that is the basis of the target genetic disorder.

Implications and Discussion

Many genetic disorders are caused by single mutated proteins that have harmful effects. Some of the most serious neurodegenerative diseases like Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis (ALS) are caused by harmful mutated proteins.

Using ASOs to stop these proteins from being built by our cells can offer significant therapeutic effects in patients with this kind of genetic disorder.

For example, a mutation in the gene that encodes for the huntingtin protein causes the protein to take on an elongated shape. When metabolized, these mutated huntingtin proteins bind together and accumulate into increasingly large deposits in the brain, eventually becoming large enough to affect normal brain function. This is the basis for Huntington’s disease. Using ASOs to decrease expression of the mutated Huntingtin protein could provide therapeutic effects.

Antisense therapies could also treat diseases by inhibiting non-mutant proteins. For hypertriglyceridemia (excess triglycerides), ASOs could be used to inhibit the production of the APOC3 gene which encodes for a protein that regulates triglyceride metabolism.

Certain cancers could also be targeted by ASOs, as they could be used to block the production of proteins that facilitate the growth of a cancerous or precancerous mass of cells.

Solely using the antisense oligonucleotide is around 50% effective at preventing synthesis of a target protein. However, when combined with an enzyme that degrades the complex between the mRNA and ASO, this synthesis-blocking efficacy reaches 95%. This can slow the progression of or provide lasting relief from symptomatic disorder.

Limitations

Antisense therapy can not be used for all genetic disorders. Only those which are caused by a single protein mutated into a harmful form could theoretically be treated by the therapy. Also, stopping the production of an implicated protein could have unexpected side effects due to the discontinuation of normal functions of the protein. In one available ASO therapy, nusinersen (Spinraza), patients experienced varied side effects including increased risk of respiratory infection, congestion, constipation, and stunted growth in children–potentially related to the decreased presence of the target protein.

Another limitation of oligonucleotides is that it is very difficult to deliver them to the interior of our cells. However, surrounding them with fatty particles, like what is used to surround the mRNA in COVID-19 vaccines, can protect them from degradation and help them enter our cells. Though, it can still prove difficult to deliver antisense agents to places like the brain, where a drug must make it through the difficult-to-permeate ‘firewall’ that is the blood-brain barrier. For nusinersen (Spinraza), which has a target protein in the central nervous system, the antisense agent must be injected directly into the spinal canal.

In general, antisense therapy research faces an uphill battle. Since the prospect of using ASOs as drugs was first conceived by Harvard scientists in 1978, less than 10 antisense therapies have been approved by the FDA–the first was approved in 1998. Many antisense therapies have failed in the early phases of clinical trials due to low efficacy. Ionis Pharmaceuticals is the most notable biotechnology company researching antisense therapy, with nine current antisense drug candidates reaching Phase III trials as of June 2022.

Whether ASOs will play a wide role in the treatment of genetic disorders has yet to be determined, though recent innovations in drug delivery systems as well as dozens of such therapies being in advanced clinical trials makes them more promising than ever.

References
Categories
Commentary Genetics

Dog Behavior Unrelated to Breed? Researchers Respond to Controversy, Misleading Media Coverage

brown and white american pit bull terrier with brown costume
Photo by Gilberto Reyes on Pexels.com

Key Points

– A dog genomics study that found a smaller-than-expected relationship between dog breed and behavior has become widely controversial.
– Critics of the study’s methodology were not satisfied with its rationale for the use of dog-owner surveys to determine behavioral traits due to the possibility of rater bias.
– A well-known psychologist and dog behaviorist believes the study’s data actually proves that breed does, in fact, predict behavior to an appreciable extent–and that the researchers came to an erroneous conclusion.
– Media coverage of the study, even by the journal in which it was published, used absolute language that severely downplayed or outright denied any correlation that was established between breed and behavior.
– The researcher’s most significant finding that distinct genes were associated with individual behavior “at finer resolution than ever before” was largely overlooked.

Contents

Introduction

A recent dog genomics study from UMass Chan School of Medicine researchers claims to challenge popular breed stereotypes, concluding that dog breed is a poor predictor of individual behavior. According to the study, which was the feature article in the April 29 issue of Science, just 9% of variation in dog behavior can be explained by breed.

The study received widespread acclaim, making headlines in publications including The New York Times and The Associated Press. Many dog lovers were pleased with the results that showed a high degree of individuality in dogs. In fact, advocates for pit bull terriers largely rejoiced, as the study seemed to disprove negative stereotypes of the breed that might keep people from adopting them.

The CEO of Best Friends Animal Society said in a press release that “these findings could have far-reaching positive impacts in animal welfare,” and that the study’s findings “could be especially positive for pit bull type dogs, Rottweilers, Dobermans, German Shepherds and Chows, which often have an unfair stigma attached to their breed.”

Headlines of media reports of the study, including those from popular science publications, made generalizing claims that dog behavior is unrelated to breed.

They’re All Good Dogs, and It Has Nothing to Do With Their Breed

The New York Times

Massive study of pet dogs shows breed does not predict behaviour

Nature

Dog Breed Doesn’t Affect Behavior, According to New Genetic Research

Smithsonian Magazine

Even in Science, where the study was published, editors added the following generalization to the summary:

…dog breed is generally a poor predictor of individual behavior and should not be used to inform decisions relating to selection of a pet dog.

Science

While the study did receive positive acclaim, it also provoked significant controversy. Critics called into question the claims of the media as well as the methodology and conclusions of the study. After all, it is widely believed that breed is the most important factor in determining a dog’s behavior and temperament.

Is the criticism justified? Are the media’s generalizing claims supported by the study? First, it is important to understand the methods used by the researchers to come to their conclusion.

OneResearch dives headfirst into the media coverage, methodology, and critiques of the popular study, featuring quotes from an interview with the lead researcher.

Methodology of the Study

To determine whether dog breed could predict behavior, the research team sequenced the DNA of thousands of dogs, including pure-breds and mutts, and surveyed their owners with questions about their pet’s behavior.

The researchers used the survey responses to measure eight factors:

  • Human sociability (less sociable to highly sociable)
  • Arousal level (aroused to composed)
  • Toy-directed motor patterns (toy-directed to not toy-directed)
  • Biddability [responsiveness to human direction] (biddable to independent)
  • Agonistic threshold (assertive to diffident)
  • Dog sociability (less sociable to highly sociable)
  • Environmental engagement (engaged to not engaged)
  • Proximity seeking (affectionate to aloof)

Then, correlations were calculated to determine to what extent breed explains the values of these factors in individual dogs. They also measured physical traits like size, ear shape, and fur length as well as motor pattern behaviors like howling, retrieving, and pointing.

Another aspect of the study, which will be discussed later in this article, sought to link distinct genes with behaviors.

Discussion of Methodology

Rater Bias

Perhaps the most common critique of the study is the use of pet owner surveys to determine dog behavior. Specifically, the possibility of rater bias did not go unnoticed to skeptics of the study.

Voluntary self reporting is unscientific. Anyone who owns a pitbull is going to know the stereotypes and resist them. Questions about aggression they’ll decide to interpret how they want in their responses.

Reddit comment

Of course, nobody would assess the behavior of schoolchildren by asking their mommies, so the whole enterprise strikes me as less than scientific.

Gene Lyons for the Vallejo Times-Herald

Rater bias is addressed within the study. First, the authors claimed that by using mutts and determining their breed composition via DNA sequencing, breed-stereotype biases of surveyed owners should not largely affect the results. This claim was supported by other data within the study which shows that people are inaccurate at guessing the breed composition of mutts. Though, pure-bred dogs were also used in the study.

The authors admit to the limitation that pet owner survey responses “are susceptible to rater bias, including the influence of breed stereotypes.” Also, the authors prefaced findings regarding the relationship between breed and human sociability factor with a disclaimer that owner survey data “may be influenced by breed stereotypes and other factors, and differences are not necessarily genetic in origin.”

Kathleen Morrill, a Ph.D. candidate at UMass Chan Medical School, is the first author of the study. Morrill told OneResearch in a written interview that rater bias “can never be fully mitigated,” elaborating further:

Rather, we expect to overcome noise generated from rater bias by larger and larger samples. Strong effects are the first to appear at any given sample size. Real but small effects become more and more evident and supported at larger sample sizes.

…nor does rater bias need to be fully accounted for us to achieve our initial goal for the project: to genetically map behavioral traits.

Kathleen Morrill for OneResearch

It was not clear how larger samples would decrease the effect of rater bias. When seeking to genetically map behavioral traits, it seems that only traits not affected by rater bias could be reliably mapped.

Survey Validation

Further concerns regarding the survey focused on the validation of the questions for the context of determining large-scale trends in dog behavior and temperament. Readers wondered how they determined which questions to ask, and how accurately those questions could quantify personality traits and behaviors.

In a Reddit AMA (Q&A), Morrill addressed this concern.

Owner surveys are a widely accepted method of assessing a dog’s behavior in its home environment and allow us to achieve the scale necessary to study traits that derive from the interaction of genetics and environment. They are generally considered to be reliable, and previous work comparing survey data and professional assessments confirm this. They are widely used in veterinary medicine. Dog behaviorists will often implement these prior to in-person consultations, because a dog can behave differently in a clinical context.

Kathleen Morrill via Reddit

Though owner surveys are considered to be reliable in the context of veterinary medicine, they may not be as reliable when seeking to determine large-scale, long-term personality and behavioral trends of groups rather than making simple assessments about individuals.

A columnist for the Vallejo Times-Herald was not convinced.

Limiting a behavioral study to suburban backyard behavior tells you very little about what dogs really are.

Gene Lyons for the Vallejo Times-Herald

In terms of deciding which questions to ask, Morrill said that they chose to use previously validated questionnaires, including the Dog Personality Questionnaire (DPQ), Dog Impulsivity Assessment Scale (DIAS), Quality of Life assessment (CHQLS-15), and Canine Cognitive Dysfunction Rating (CCDR). The researchers also used questions added by dog behavior consultants.

The use of such surveys remains controversial in biological and medical research, in general, due to the myriad of biases that can compromise data. These specific surveys were not validated for the novel purpose used in the study. It can’t be determined with the available data whether this affected the results of the study.

Still, survey use is at least insightful as a starting point for generating new hypotheses that can be tested more thoroughly in follow-up validation studies. This is supported by previous use of digital phenotyping in genetic studies of human diseases.

The Dog Personality Questionnaire, developed to assess individual dog’s personality and temperament, is a good starting point for assessing the personality and temperament of individual dogs, as our project sought to do.

Kathleen Morrill for OneResearch

Results & Conclusions of the Study

The study found that for all eight factors, breed explained more of the behavioral variance than size, sex, or age. However, only 3% to 25% of variance in factor scores could be explained by breed, averaging only 9% across all tested factors. The majority of breeds scored within one standard deviation of the average for all behavioral factors, with few breeds over- or underrepresented in the highest-scoring quartiles.

Behavioral factors show high variability within breeds, suggesting that although breed may affect the likelihood of a particular behavior to occur, breed alone is not, contrary to popular belief, informative enough to predict an individual’s disposition.

Morrill et al.

The researchers hypothesized that this surprising conclusion could be due to the lack of breeding for function in favor of appearance during the past few centuries since modern dog breeds were established.

Interestingly, when grouping breeds by their historically given working roles according to characterizations by the American Kennel Club, more behavioral correlations could be drawn. For example, breeds known for herding were found to be more interested in toys, more biddable, more engaged, and more aloof. Working breeds were more dog social. Toy breeds were more independent and less dog social.

Heritability explained more behavioral variance than breed. The authors found that certain behaviors were up to 67% heritable, averaging 25% across behaviors. Motor pattern behaviors like howling, retrieving, and pointing were among the most heritable behaviors, while human sociability was the most heritable factor. 46% of the behavioral questions from the survey could be explained mostly by heritability.

Physical traits were found to be much more heritable than behavioral traits, as most measured physical traits exceeded 85% heritability.

Discussion of Conclusions

Dr. Stanley Coren Article

As quoted above from the study, the authors concluded that even though breed can affect the likelihood of certain behaviors to occur, breed alone does not provide enough information to reliably predict behavior. The study’s conclusion expanded upon past research that noted “mixed consistency” between empirical evidence and widely-recognized breed standards.

A prominent critique of this conclusion was published in Psychology Today by Dr. Stanley Coren, a psychology professor and neuropsychological researcher who is well known for his books about dog behavior.

Dr. Coren alleged that the researchers “misread” their own data. Using the study’s data, he found that breed is a “pretty good” indication of behavioral differences between groups of dogs, but that it is not a guarantee for the behavior of any particular individual.

To support his own conclusion from the data, Dr. Coren mentioned the following statistics from the study’s supplemental materials:

  • 62% of golden retrievers will fall into the highest quartile for human sociability
  • 72% of border collies fall into the top quartile for biddability (responsiveness to human direction)

While Dr. Coren noted that 16% of border collies will actually fall into the lowest quartile for biddability, he said that the data means that your odds are still “better than 4 to 1” that any given border collie will be highly intelligent and trainable. Thus, he believes that breed can, in fact, be a useful indicator of a dog’s behavior for prospective dog owners.

Dr. Jessica Hekman, who co-authored the study, expressed an idea similar to Dr. Coren’s in a statement to the American Kennel Club.

…you’ll definitely improve your chances of getting the right dog for you if you are also thoughtful about what breed you bring home.

Dr. Jessica Hekman for American Kennel Club

Since Dr. Coren concluded from the data that breed can be a useful predictor of a dog’s behavior, why did the study conclude otherwise?

Kathleen Morrill, first author of the study, answered questions from OneResearch about Dr. Coren’s article.

The data [visualization] tool explored by Dr. Coren indeed supports that for assertions of one or two facets of canine behavior, breed can be informative. Though, it depends on the breed and the behavior, as the relationship is far from extensive.

Kathleen Morrill for OneResearch

Morrill then brought attention to a figure in the study that shows instances in which age is “just as informative” as breed. She mentioned how the data shows that the benefits that breed offers when determining behaviors “quickly dissolve given a wider array of behaviors asserted.”

She then invoked an excerpt from the study itself–the first conclusion drawn in the Discussion, which highlights the inconsistency and “modest value” of using breed to predict behaviors in individual dogs. It states that for heritable and more breed-differentiated traits like biddability, breed can make predictions “somewhat more accurate” for purebred dogs. Though, for other factors, like agonistic threshold, they found breed to be “almost uninformative.”

Aggressive Breeds

Internet comments on news websites reporting on the study widely criticized the paper’s conclusion due to their belief that breed strongly determines behavior. Among countless anecdotes, many commentors questioned how the study could find that breed did not explain behavior despite certain breeds dominating the charts for the most bites–implying that these breeds are highly or disproportionately prone to aggression compared to others.

Pit bulls are reportedly the top breed responsible for fatal dog attacks on humans. A 2020 study from a level 1 trauma center also found that for dog bite incidents, pit bulls were much more likely than other breeds to bite without provocation and to go off property to attack. Dog bite data collected by the government of New York City shows that pit bull bites are by far the most commonly reported.

These facts caused internet users to doubt the study’s conclusions that breed can’t predict individual dog’s disposition and that breed did not explain agonistic threshold, which the study’s authors defined as “how easily [a] dog is provoked by a frightening, uncomfortable, or annoying stimulus.”

Dr. Benjamin Hart, animal behaviorist and professor emeritus at the UC Davis School of Veterinary Medicine, told SFGate that pit bulls often show no signs of aggression before an attack.

It’s quite common for a pit bull to show no signs of aggression. People will call it a nice dog, a sweet dog, even the neighbors–and then all of a sudden something triggers the dog, and it attacks a human in a characteristic way of biting and hanging on until a lot of damage is done.

Dr. Benjamin Hart for SFGate

Alarmingly, this means that owner surveys could never indicate the possibility that certain breeds are predisposed to such spontaneous dangerous behaviors. Notably, the researchers did not attempt to account for such behavior.

Morrill said that aggression was not measured because it is not a unitary behavior and can’t be well-defined scientifically, or even colloquially. Also, she explained that agonistic threshold is distinctly a fear response unrelated to predation, meaning spontaneous aggressive behaviors could not have been well accounted for, anyway.

When asked if the study had anything to say about the role of genetics or breed in predatory biting leading to severe or fatal injuries, Morrill responded succinctly, “No.”

Thus, the widely held beliefs regarding dangers of the pit bull terrier cannot be discounted by the study, regardless of conclusions that breed is not usually a reliable indicator of individual behavior.

Discussion of Media Coverage

Best Friends Animal Society Press Release

Best Friends Animal Society, an animal welfare nonprofit, is perhaps the largest advocacy group for stigmatized dog breeds. The nonprofit strongly believes that “all dogs are individuals,” and according to their latest press release, “this study proves it.” BFAS lobbies government bodies to end breed-specific legislation and prevent insurance from denying homeowners coverage due to “dangerous dog” ownership, disgustingly likening this “discrimination” to racism (see: Human races are not like dog breeds: refuting a racist analogy).

They use this study to claim that there is no such thing as a dangerous dog breed in order to support their positions against breed-specific legislation. Importantly for BFAS and its donors, this study should not influence breed-specific legislation.

We did not seek to address the validity of breed-specific legislation and its effectiveness for meeting public health goals to minimize dog bites and attacks on people. We don’t study dangerous interactions or dog bites.

Kathleen Morrill for OneResearch

Morrill did note that the limited predictive value of breed for inferring individual behavior could still have some relevance to breed-specific legislation. Nevertheless, the reason why pit bull terriers attack at much higher rates than other breeds was not elucidated by the study, possibly because it could not be measured using survey-based methodology. Additionally, the basis of the pit bull terrier’s relatively frequent and severe attacks is likely to be independent from the tested personality factors.

It follows that neither supporters nor detractors of breed-specific legislation should look to this study to support their position.

Breed Completely Unrelated to Behavior?

Absolute statements that breed has nothing to do with behavior are widespread across media coverage of the study. As established within the study and this article, this is not the case.

The study itself mentions not only through data but explicitly in the very beginning of the discussion that there is at least a correlation between breed and certain behaviors–but these correlations might not be strong enough to reliably predict behavior from breed. As Dr. Coren pointed out, the data shows that any given border collie has a 4 to 1 chance of scoring high in biddability. Still, as Morrill said, this is a narrow use case for predicting behaviors from breed.

Regardless, the media’s portrayal of the study’s results as showing that breed has no effect on behavior is not supported by the study. Morrill agreed with this in a statement to OneResearch.

Any headline that suggests no effects on behavior would be a misrepresentation. Headlines with scale qualifiers like “little effect” walk the delicate line of nonspecific enough to be technically in line with our findings and attention-grabbing to a large audience, whether they agree with the scale of “little” or not.

Kathleen Morrill for OneResearch

Misleading statements were not limited to headlines, either.

Breed means very little in predicting the behavior and personality of an individual dog, the researchers found. That appears to be especially true for traits that are most commonly associated with a dog’s personality, qualities such as cuddliness, friendliness toward strangers and aggression.

The Washington Post

Of course, aggression was not measured by the study. In fact, the word “aggression” is not written at all in the text.

The summary of the study that appears before its text on Science concludes that “dog breed is generally a poor predictor of individual behavior and should not be used to inform decisions relating to selection of a pet dog.” Dr. Hekman clarified to the Cog Dog Radio podcast that this take was written by Science editors, not the authors of the study.

I don’t want to speak for anybody else but myself, but I disagree with that statement. And I have no power to have it taken down.

Dr. Jessica Hekman for Cog Dog Radio

Media Coverage Overview

Dr. Elinor Karlsson, another key researcher and co-author of the paper, said that she was “for the most part quite happy” with the media coverage. “Our assertion that breed is not a reliable predictor of behavior in dogs was pretty clearly stated in our paper.” Dr. Karlsson clarified that even if breed is not a reliable predictor, there can still be differences between breeds. Also, traits can be heritable without being different between breeds. The study does not say that behavior lacks genetic basis.

Dr. Karlsson said she would expect more behaviorally distinct results from working dogs instead of the pet dogs used in the study, since they were more recently bred for performance rather than aesthetics.

Unfortunately, some sensationalist journalists and special interest groups misrepresented the results of the study to establish a narrative that no dog behaviors can be explained or predicted by breed. Popular science coverage is highly prone to cherry picking of data as journalists offer incomplete evidence to draw conclusions that scientists often don’t have the opportunity to correct or dispute before it’s too late.

The Buried Lede

Morrill expressed similar dismay that publications covering her study did not focus on–or even mention, in most cases–one of her most important findings.

The buried lede of our publication–one which didn’t get nearly as much media attention–is that we do successfully find genes associated with individual behavior, at finer resolution than ever before, largely thanks to all the mixed-breed dogs. 

Kathleen Morrill for OneResearch

The researcher’s ability to pinpoint these genes marks an apparent methodological success that could have implications on the study of human genetics. Improvements in methodology could perhaps reveal more genes associated with distinct individual behaviors.

In human genetics, we are always thinking about genes through the lens of “What goes wrong?”–it’s all very disorder-focused.

Kathleen Morrill for OneResearch

Morrill mentioned how, in laboratory settings, researchers must “break” genes and then measure the behavioral effects in order to understand their functions.

In dog genetics, we gain a new perspective on genetic variation and its behavioral effects, which is often more subtle. In this way, we can learn more about the biological functions of genes and gene regulators.

For example, we map common genetic variation that correlates with howling frequency in dogs. This variation exists nearby a gene that, in people, mutations in the same gene causes developmental disorders. In laboratory animals, mutations in that gene cause defects in the cortical regions of the brain pertaining to speech development. But, in dogs? We might get a better sense for how vocalization varies — it’s less all-or-nothing.

Kathleen Morrill for OneResearch

This finding also has implications on studies of human genetics and subsequent medical applications.

Human susceptibility to neuropsychiatric conditions is shaped by many genes and gene regulators, and large interactive effects of genes, environment, and life experiences. We have a limited understanding of the normal functions of genes that we do find associated with human disorders, and we’re also severely under-equipped to treat and manage neuropsychiatric conditions, like obsessive compulsive disorder or severe agoraphobia, with existing psychotropic medications. Comparative medicine and genomics in dogs has highlighted many genetic contributions to disease already, and will offer the opportunity to treat canine and human disorders in tandem.

Kathleen Morrill for OneResearch
Categories
Pharmacology

Clascoterone, First Novel Acne Therapy in 38 Years, Treats Acne By Blocking Facial Androgen Receptors

Topical medication cream. // Marco Verch, CC BY 2.0

In 1982, the FDA approved isotretinoin (Accutane), a Vitamin A derivative, for use in patients with acne. No new methods of acne medication had been approved from 1982 until the approval of topical clascoterone in August 2020, almost 40 years later.

Topical clascoterone is a cream that is applied directly to the skin of areas affected by acne. Clascoterone is an antiandrogen, which is a class of drug that blocks androgen receptors. The drug is the first antiandrogen to be approved by the FDA for acne medication, earning it the title of first-in-class medication. Androgens, which are male sex hormones present in males and lower levels in females, play an important role in the pathogenesis of acne.

During puberty, both males and females have increased levels of androgens like testosterone or dihydrotestosterone (DHT). Higher levels of testosterone can cause increased production of sebum, an oily substance secreted by sebaceous glands under the skin. Excessive amounts of sebum in a skin pore can cause a blockage (known as a comedo, blackhead, or whitehead) that may become infected.

Clascoterone was shown in vitro to have higher affinity for androgen receptors than DHT. This blockage of local androgen receptors by clascoterone was then shown by clinical trials to reduce the acne-causing effects of androgens.

The Investigator’s Global Assessment Scale (IGA) is a scale of acne severity that goes from 0 (clear) up to 4 (severe). Two clinical trials found that at least 18% of patients achieved a drop of at least 2 points on the IGA scale (resulting in a score of 0 or 1) at 12 weeks into treatment with topical clascoterone. One trial showed that patients, on average, saw a 39% decrease in total lesion count after 12 weeks of treatment.

The FDA listed the most common side effects of topical clascoterone as reddening, itching, and scaling or dryness of treated skin. The FDA-approved brand of topical clascoterone is Winlevi.

References
  • Piszczatoski, C. (2021, October 2). Topical Clascoterone: The First Novel Agent for Acne Vulgaris in 40 Years. https://doi.org/10.1016/j.clinthera.2021.08.007
  • U.S. Food and Drug Administration. (2020, September 3). Drug trial snapshot: Winlevi. https://www.fda.gov/drugs/drug-approvals-and-databases/drug-trial-snapshot-winlevi
Categories
Neuroscience

Transparent Zebrafish Study Reveals How Sleep Repairs Damaged Neuronal DNA

Using transparent zebrafish, Israeli researchers were able to confirm neuronal DNA repair as a function of sleep, also identifying a protein that triggers both DNA repair and sleep.

Background

The functions of sleep, though widely researched, have largely remained a mystery. It is known that sleep influences cognition, benefitting learning and memory, but proposed physiological functions have had little strong evidence. Proposed functions of sleep include removing toxic byproducts in the brain caused by wakefulness, replenishing energy and supplies for cells, and remediating neural damage and cellular stress.

Prior research showed that wakefulness and neuronal activity causes DNA double-strand breaks. These lesions are accumulated during wakefulness, contributing to homeostatic sleep drive (the pressure to sleep that builds up as time awake increases). Sleep has been demonstrated to decrease this DNA damage.

Researchers from Israel’s Bar-Ilan University and Tel Aviv University used zebrafish to study neuronal DNA repair as a potential novel function of sleep. The zebrafish is a tiny freshwater fish that has been widely used as a model organism due to their 70% genetic homology (similarity) to humans. Among other parallel physiologies, zebrafish exhibit a diurnal sleep cycle with states closely resembling mammalian slow-wave sleep (SWS) and rapid eye movement (REM) sleep. A mutated type of zebrafish is transparent, enabling researchers to observe the previously unobservable.

Confocal microscopy image showing the developing face of a 6 day old zebrafish larva. / Oscar Ruiz and George Eisenhoffer, University of Texas MD Anderson Cancer Center

By inducing neuronal DNA damage in zebrafish, they were able to determine its relation to sleep as well as causal proteins.

Results

First, the researchers confirmed a significant positive correlation between levels of neuronal DNA damage and total sleep time (R = 0.76). During wakefulness, zebrafish larvae were treated with pentylenetetrazol, which stimulated their neuronal activity. Consequently, the larvae had increased neuronal DNA damage and a 5-fold increase in total sleep time.

Because neuronal DNA damage is not only caused by cell activity, the researchers then exposed the larvae to UV radiation, which damaged their DNA without increasing their neuronal activity. Their subsequent increased sleep further confirmed that DNA damage was the cause.

By testing the rates at which genes involved in the DNA damage response (DDR) were expressed during sleep, they found that the RAD52 and Ku80 proteins were responsible for repairing double-strand breaks during sleep.

Further analysis uncovered that the PARP1 protein, a DNA damage detector that organizes the DDR, was immediately recruited and activated upon neuronal DNA damage.

When the researchers provoked greater expression of PARP1, total sleep time and depth increased—demonstrating that the protein is what connects the DNA damage response to homeostatic sleep drive. PARP1 was also shown to promote sleep regardless of damage.

Discussion

The study confirms in multiple experiments that neuronal DNA repair is a function of sleep regulated by the PARP1 enzyme and carried out by the DNA repair proteins RAD52 and Ku80.

Triggering neuronal DNA damage via cellular excitation and UV light both caused the expected result of increased sleep, with PARP1 as the protein responsible for detecting the damage, provoking a repair response, and causing increased sleep drive.

The study authors noted their intrigue that FDA-approved PARP1 inhibitors used as antitumor agents all caused fatigue as the prominent side effect, suggesting that inhibiting PARP1 masks its sleep-promoting signals. The use of PARP1 inhibitors was also found to cause increased DNA damage. These results, separate from their study, align with their findings regarding the functions of PARP1 as observed in zebrafish.

References
  • Frank, M. G. (2006, August 1). The mystery of sleep function: Current perspectives and future directions. De Gruyter. https://doi.org/10.1515/revneuro.2006.17.4.375
  • Yourgenome. (2021, July 21). Why use the zebrafish in research? https://www.yourgenome.org/facts/why-use-the-zebrafish-in-research
  • Zada, D., et al. (2021, December 16). Parp1 promotes sleep, which enhances DNA repair in neurons. Molecular Cell. https://doi.org/10.1016/j.molcel.2021.10.026
Categories
Cardiology Immunotherapy

CAR T Cells Produced by mRNA Injection Reduce Cardiac Fibrosis, Restore Function to Heart

Two individual CAR T cells attacking fibroblast activation protein (FAP)-producing cells. / Rurik et al., 2022

Researchers at the University of Pennsylvania’s Perelman School of Medicine have published a method to treat cardiac fibrosis using an mRNA injection that enables an individual’s own CAR T cells to fight the disease.

Background

Cardiac fibrosis is a medical condition caused by many different types of heart disease that can lead to scarring and stiffening in the muscle wall of the heart. Normally, cells in the heart called cardiac fibroblasts help to develop the heart and maintain its homeostasis (that is, it helps the heart stay in a stable condition). However, in a patient with cardiac fibrosis, these cells no longer perform their normal function. Following a cardiac injury, fibrosis can progress from scarring to complete heart failure.

T cells are a type of white blood cell that play a key role in immune response, killing cells that they recognize to be infected with viruses, cancers, or certain other pathogens. Chimeric antigen receptor (CAR) T cells are T cells that have been engineered to recognize specific proteins as harmful. This enables them to target and kill cells that have proteins from diseases that they otherwise would not recognize as harmful.

Innovation

The Penn researchers developed a CAR T-cell therapy that works by engineering T cells to recognize and kill cells that express (create) the fibroblast activation protein (FAP), a protein key to the pathology of cardiac fibrosis. Killing FAP-expressing cells consequently treats cardiac fibrosis.

By encoding a messenger RNA (mRNA) strand that results in the creation of CAR T cells that target FAP, the researchers had the idea to deliver them to a patient’s cells through an injection containing the mRNA within a lipid nanoparticle.

Lipid nanoparticles (LNP) are a relatively new technology discovered in the 1990s. To deliver an mRNA strand into cells to provoke a protein-expressing response, the mRNA is inserted into a sphere made of lipids that is injected into a patient. This then allows cells to uptake the LNP through endocytosis (bringing material into the cell). The mRNA then exits the LNP, causing the cell to read the mRNA instructions to create the desired protein.

09908-feature1-nanoparticle.jpg
Structure of the LNP. / Genevant Sciences via ACS.org

Without the LNP, mRNA would be unable to enter cells. mRNA vaccines for COVID-19 are a prominent use of this technology, as the mRNA that gives cells instructions to create the spike protein is protected and brought into cells by LNP.

Results

In rodents with cardiac fibrosis, the Penn researchers revealed that their mRNA injection successfully resulted in the creation of FAP-targeting CAR T cells. Observing the hearts of rodents before and after treatment showed notable improvements in cardiac function. This means that as the CAR T cells killed cells that expressed FAP, fibrosis was reduced.

Video of rodent echocardiograph recorded two weeks after treatment with CAR T-cell therapy that was given after an injury that caused cardiac fibrosis. / Rurik et al., 2022

In rodents with injuries causing cardiac fibrosis, the CAR T-cell treatment halved the percentage of fibrosis in the ventricles.

Discussion

The implications of this new treatment are of great significance. Reduction of fibrosis and restoration of cardiac function in rodents with cardiac fibrosis reveals a promising new form of treatment for human patients with the potentially fatal disease.

According to the CDC, about 659,000 people in the United States die from heart disease each year, accounting for 1 in every 4 deaths–all costing the country hundreds of billions of dollars each year. Thus, biotechnological innovations in treatment of cardiac disease can have a great impact.

Earlier CAR T-cell therapies have required a patient’s T cells to be extracted from blood, sent to a lab, engineered to find and kill certain targets, then returned intravenously to the patient. This is an extremely time-consuming and cost-prohibitive process, potentially costing patients hundreds of thousands of dollars.

The innovation of using mRNA injections to create CAR T cells within a patient’s own body instead of a lab may greatly reduce the time and financial burdens associated with CAR T-cell therapies. Rather than extracting, modifying, and replacing T cells from each patient, mRNA shots that provoke the creation of CAR T cells can be mass-produced and given to any patient.

The scope of this innovation reaches far beyond cardiac fibrosis, as it can potentially be applied to CAR T-cell therapies for cancer and other diseases.

References
Categories
COVID-19 Immunology

As Antibodies Wane in Quantity and Efficacy, T Cells Remain Effective Against Omicron

Killer T cells surround a cancer cell // NIH Image Gallery

Background

As the Omicron variant of COVID-19 becomes increasingly dominant among skyrocketing cases, including in vaccinated individuals, concerns of the variant’s immune escape abilities have grown.

Vaccines provoke important responses in the immune system to prevent disease, including creation of T cells and antibodies specific to the pathogen they introduce. In the case of mRNA vaccines for COVID-19, genetic code (mRNA) for the spike protein enters our cells, causing them to manufacture spike proteins. Our immune system then recognizes these proteins as foreign to our bodies, promptly destroying them while creating T cells and antibodies that can work against them in the future.

Antibodies and T cells play different roles in the event of an infection. Antibodies work by creating sites that bind to certain parts of a pathogen. As they pertain to mRNA COVID-19 vaccines, the antibodies will bind strongly to the spike protein. Since the spike protein is what enables SARS-CoV-2 to enter cells, binding antibodies to them will prevent infection.

On the other hand, T cells help fight infection by injecting poison into cells that are already infected, killing both the cell and the pathogen. mRNA vaccines help T cells recognize when a cell is infected with SARS-CoV-2. This means that antibodies are more useful for preventing infection via neutralization while T cells are better at stopping an infection that has already infected some cells.

These figures model T cell and antibody responses to viral infection. In an average SARS-CoV-2 infection, T cells have a greater response than antibodies, and this response effectively decreases viral load. In a severe infection, antibodies are far more prominent than T cells, and this response is ineffective at decreasing the viral load. T cells are more effective at managing instead of preventing an infection, so they would be more useful than antibodies in an already severe infection. (Sette, Crotty 2021)

Much of the focus surrounding COVID-19 vaccines and their efficacy has related to antibody quantity and binding affinity to the changed spike proteins of new variants in order to prevent infection instead of the role of T cells in managing infection. Researchers sought to quantify both antibody and T cell counts and efficacy in unvaccinated, twice vaccinated, and three-times vaccinated patients.

Results

A preprint study from Erasmus University Medical Center in the Netherlands detected high antibody levels against the original SARS-CoV-2 spike protein following receipt of the Pfizer or Moderna mRNA vaccines. Lower (but still significant) antibody levels were detected from the Johnson & Johnson viral vector vaccine. However, antibody levels from the mRNA vaccines decreased significantly within 6 months, while those from the viral vector vaccine did not. Though, even if neutralizing antibody levels remained high, researchers from Beijing’s Peking University found that Omicron escapes most SARS-CoV-2 neutralizing antibodies.

Studies from the Icahn School of Medicine at Mount Sinai in New York supported earlier reports that convalescent (unvaccinated, previously infected) and twice-vaccinated individuals had nonexistent protection against symptomatic infection from the Omicron variant. Boosted (three-times vaccinated) individuals had about 75% protection against symptomatic disease from Omicron, though it is unknown how long this protection will last.

Importantly, the Erasmus study found that unlike neutralizing antibodies, SARS-CoV-2-specific T cells were still detected in the blood 6 months after mRNA and viral vector vaccination as well as natural infection.

In contrast to findings that most neutralizing antibodies are largely ineffective against Omicron, data from Pfizer and BioNTech showed that 80% of spike-specific T cells in vaccinated individuals retained function. The Erasmus researchers corroborate this, finding that vaccinated individuals retain T cell immunity to the Omicron variant.

Discussion

Results from multiple studies now support a consensus that naturally infected and twice-vaccinated individuals have nonexistent protection against symptomatic infection due to depleted and ineffective neutralizing antibodies.

However, both populations can reattain significant protection against symptomatic infection by receiving initial vaccinations or a booster–though it is still unknown how long this protection will last.

These data indicate that convalescent individuals greatly benefit from vaccination, an observation that is of significant public health importance.

Carreño et al., 2021

Even though it has become significantly more difficult to prevent symptomatic infection due to the waning quantity and efficacy of neutralizing antibodies in convalescent and vaccinated individuals, T cells have been shown to remain active and are expected to still help prevent severe infection.

This is supported by new data that has shown that SARS-CoV-2-specific T cells remain present in the long-term and are still mostly effective against the Omicron variant in convalescent and vaccinated individuals.

Well-preserved T cell immunity to Omicron is likely to contribute to protection from severe COVID-19, supporting early clinical observations from South Africa.

Keeton et al., 2021
References
  • BioNTech. “Update – Omicron Variant (B.1.1.529).” BioNTech Investors & Media, 8 Dec. 2021, https://investors.biontech.de/static-files/47b4131a-0545-4a0b-a353-49b3a1d01789.
  • Cao, Yunlong, et al. “Omicron Escapes the Majority of Existing SARS-COV-2 Neutralizing Antibodies.” Nature, 23 Dec. 2021, https://doi.org/10.1038/d41586-021-03796-6.
  • Carreño, Juan Manuel, et al. “Activity of Convalescent and Vaccine Serum against SARS-COV-2 Omicron.” Nature, 31 Dec. 2021, https://doi.org/10.1038/d41586-021-03846-z.
  • Geurts van Kessel, Corine H., et al. “Divergent Sars Cov-2 Omicron-Specific T- and B-Cell Responses in COVID-19 Vaccine Recipients.” MedRxiv, 29 Dec. 2021, https://doi.org/10.1101/2021.12.27.21268416.
  • Keeton, Roanne, et al. “SARS-COV-2 Spike T Cell Responses Induced upon Vaccination or Infection Remain Robust against Omicron.” MedRxiv, 28 Dec. 2021, https://doi.org/10.1101/2021.12.26.21268380.
  • Sette, Alessandro, and Shane Crotty. “Adaptive Immunity to SARS-COV-2 and COVID-19.” Cell, 18 Feb. 2021, https://doi.org/10.1016/j.cell.2021.01.007.
  • Wu, Katherine J. “T Cells Might Be Our Bodies’ Best Shot against Omicron.” The Atlantic, 14 Dec. 2021, https://www.theatlantic.com/science/archive/2021/12/t-cells-omicron-vaccine-immunity/620995/.
Categories
COVID-19 Public Health

Recovered Patients of Severe COVID-19 Infection 233% More Likely To Die Within Year Than Negative Counterparts

a grieving man kneeling on a grave with red flower
Photo by RODNAE Productions on Pexels.com

Research published by University of Florida scientists in Frontiers in Medicine reported that patients (aged 18-65) who recovered from severe COVID-19 infection were 233% more likely to die within 12 months than COVID-19-negative counterparts.

Methodology

The study analyzed 13,638 patients in the University of Florida Health system over a 12-month period, including positive (mild, severe) and negative cases. A severe case was defined as one requiring hospitalization within 30 days of a positive COVID-19 test. The 12-month risk of mortality was adjusted for age, sex, race, and comorbidities–meaning these factors did not affect the data.

Results

Survival curve showing probability of survival over time following mild, severe, and lack of COVID-19 illness. / Mainous 2021

Patients aged 18 to 65 who recovered from an initial episode of severe COVID-19 had a 233% increased incidence of mortality in a 12-month period compared to negative counterparts. Recovered patients aged over 65 also had increased mortality compared to negative counterparts, but to a lesser extent.

The difference in 12-month mortality between COVID-negative and mild COVID patients was not statistically significant.

Only 20% of the deaths in the 12-month period were attributed to cardiovascular or respiratory conditions.

Discussion

These results show that those who recover from severe COVID-19 infections are much more likely to die within 12 months of recovery compared to those with mild or no infection. This reveals that the increased risk of death from COVID-19 is not limited to the initial episode of infection, indicating that the biological and physiological insult from severe infection is significant. This is further demonstrated by the unexpectedly low portion of deaths caused by cardiovascular or respiratory conditions.

Arch G. Mainous III, Ph.D., first author of the study and University of Florida College of Medicine faculty member, said in a statement to the University of Florida Health Newsroom that “patients may feel that if they are hospitalized and recover from COVID-19 then they have beaten COVID-19. Unfortunately, having a substantially increased [risk] of death in the next year after recovery from a severe episode of COVID-19 shows that this is not the case. Preventing severe COVID-19 should be our primary focus.”

The study mentions that nearly all hospitalizations and severe infections are preventable. Pfizer and Moderna’s COVID-19 vaccines prevent severe infection in more than 95% of cases.

Mainous hopes that the data, which he described as devastating, will “make everyone rethink the impact of COVID-19.”

References