The complex patterns of genetic ancestry uncovered from genomic data in health care systems can provide valuable insights into both genetic and environmental factors underlying many common and rare diseases — insights that are far more targeted and specific than those derived from traditional ethnic or racial labels like Hispanic or Black, according to a team of Mount Sinai researchers.
In a study in the journal Cell, the team reported that this information could be used to better understand and predict which populations are more susceptible to certain disorders — including cancers, asthma, diabetes, and cardiovascular disease — and to potentially develop early interventions.
“This is the first time researchers have shown how genetic ancestry data could be used to enhance our understanding of disease risk and management at a health system level,” says senior author Eimear Kenny, PhD, Professor of Medicine, and Genetics and Genomic Sciences, at the Icahn School of Medicine at Mount Sinai. “By linking this data directly to health outcomes, we believe we’re contributing to an ongoing conversation to move beyond the current role of race and ethnicity in medicine.”
The research team drew from Mount Sinai’s BioMe™ BioBank program, recognized as one of the world’s leading repositories of genomic information for diverse populations, for its study. Using machine learning methodology, scientists identified 17 distinct ethnic communities from among the 30,000 participants in the BioMe BioBank. They then linked this data to thousands of health outcomes residing in Mount Sinai’s electronic health records. Among the findings was that 25 percent of BioMe participants had genetic links to populations — such as Ashkenazi Jewish and Puerto Rican — that predisposed them to certain genetic diseases.
“The traditional use of demographic data by health systems fails to capture the rich ethnic heritage of patients, and thus all the genetic and environmental factors that can affect rates of disease even within the same population,” says Dr. Kenny, who is Founding Director of the Institute for Genomic Health at Mount Sinai. “Our study used genomic data embedded in health system records to show how patients with origins from different countries in the Americas can have different rates of disease. For example, people of Puerto Rican and Mexican descent are broadly classified as Hispanic or Latinx, yet the former population has one of the highest rates of asthma in the world, while the latter population has one of the lowest.”
The Mount Sinai study cited the APOL1 gene, which can confer a significantly greater risk of kidney and cardiovascular disease, as another reason for moving beyond the traditional demographic labels used by health care systems. The risk variants of APOL1 are most frequently seen in populations across the Americas that share African genetic ancestry. However, there are many populations around the world of African descent that might not self-identify as African, and thus be unaware that they might harbor those risk variants. Furthermore, that knowledge gap may result in these populations being underrepresented in APOL1 research.
“Our study underscores that there are limits to the narrow demographic labels used in medicine and research today — and society in general, for that matter — to attempt to characterize disease and its risk factors,” says Dr. Kenny. “The types of information that can be derived from using biological markers of ancestry, however, convey a much richer and more sophisticated layer of understanding of disease risk and burden, one that could have enormous implications for health care systems globally.”

More than 20 years after the launch of a landmark clinical trial, follow-up examinations and analyses found that not all patients with elevated eye pressure need pressure-lowering treatment to prevent vision loss from glaucoma.
When the study was launched, it was universally accepted that all patients with elevated eye pressure should be given medication to lower that pressure. The Ocular Hypertension Treatment Study — funded by the National Eye Institute of the National Institutes of Health (NIH) and led by researchers at Washington University School of Medicine in St. Louis — recruited more than 1,600 patients nationally who were at moderate to high risk for glaucoma because of elevated eye pressure. The purpose was to evaluate how successful medication was at preserving vision.
Half of the patients were randomly selected to receive daily treatment with eye drops to lower intraocular pressure, and the other half were observed without treatment. After seven years, when the treatment had been shown to be highly effective, patients in both groups were given the treatment. In this latest phase of the study, researchers evaluated which patients went on to develop glaucoma after the initial study had concluded.
As reported online April 15 in the journal JAMA Ophthalmology, the researchers found that about 25% of study participants went on to develop vision loss from glaucoma in at least one eye, a lower rate than what was expected. The conventional thinking had been that most patients with elevated eye pressure probably should receive treatment.
“But treating elevated eye pressure can be expensive and inconvenient, so we wanted to determine whether all individuals with high pressure should be treated,” said Michael A. Kass, MD, the Bernard Becker Professor of Ophthalmology & Visual Sciences. “With only 25% of the individuals in the study developing vision loss in one or both eyes after all these years, we know now that not all of those patients needed to be treated.”
Glaucoma is one of the leading causes of blindness in the United States and the No. 1 cause of blindness in Black Americans. Elevated eye pressure develops in 4% to 7% of the people in the United States over age 40, and the conventional wisdom prior to the study had been to prescribe pressure-lowering drops. But those medications can cost hundreds of dollars per year; they can cause side effects in some people; and many people, especially older individuals, find it difficult to put drops in their eyes every day.

Researchers from Kumamoto University (Japan) have found that the anti-diabetic drug metformin significantly prolongs the survival of mice in a model that simulates the pathology of non-diabetic chronic kidney disease (ND-CKD) by ameliorating pathological conditions like reduced kidney function, glomerular damage, inflammation and fibrosis. Metformin’s mechanism is different from existing therapeutics which only treat symptoms, such as the blood pressure drug losartan, so the researchers believe that a combination of these medications at low dose will be highly beneficial.
CKD (chronic kidney disease) is a general term for kidney damage that results from persistent decline in kidney function due to proteinuria, kidney inflammation, or fibrosis. As CKD progresses, patients are forced to undergo dialysis, and diabetes is one of its biggest risk factors. CKD can also occur in association with lifestyle-related conditions such as hypertension, insufficient exercise, smoking, hyperuricemia, and mutations in kidney-related genes. This type of CKD is classified as non-diabetic chronic kidney disease (ND-CKD) and has limited treatment options.
Alport syndrome is an inherited kidney disease that falls under the ND-CKD umbrella. In Alport syndrome, abnormalities in type 4 collagen, a constituent of the membrane responsible for urine filtration in the kidney, cause abnormal glomerular filtration which results in chronic loss of kidney function. It is a serious disease that eventually progresses to end-stage renal failure, requiring dialysis or kidney transplant. As with diabetic kidney disease and ND-CKD, Alport syndrome is currently treated by maintaining kidney function using blood pressure-lowering drugs but patients eventually transition to end-stage renal failure. Therefore, a new therapeutic agent that is effective and safe enough to be administered to patients for a long period of time is needed.
Metformin is used as a treatment for type 2 diabetes because it improves insulin sensitivity. It is an inexpensive and safe drug that has been used by diabetics for many years. Interestingly, because of its mechanism of action, metformin was also known to be protective against many diseases involving inflammation and fibrosis, and was known to improve the renal pathology of diabetic kidney disease. However, it was unclear whether metformin also had a protective effect on ND-CKD, which is not caused by diabetes.
Researchers selected an Alport syndrome mouse model for their ND-CKD experiments and worked to identify novel therapeutic targets based on pathogenic mechanisms. They focused on drugs traditionally used for CKD patients, metformin and losartan — which works by lowering blood pressure and inhibiting proteinuria caused by increased glomerular filtration.
Administration of metformin or losartan to ND-CKD model mice significantly suppressed proteinuria and serum creatinine, which are indicators of CKD. Inflammation and fibrosis, which also reduce kidney function, significantly improved. Furthermore, metformin was found to have a nephroprotective effect similar to losartan.
The results of a detailed gene expression analysis found that the renal pathology of the ND-CKD mouse model was caused by abnormal expression of genes related to glomerular epithelial cell podocytes (cells responsible for kidney filtering) and genes involved in intracellular metabolism. Interestingly, the improvement caused by losartan was limited to genes involved in podocyte abnormalities. Metformin, on the other hand, improved the expression of genes related to podocyte abnormalities and those related to intracellular metabolism. In other words, metformin clearly has a different target of action (also improved targeting of metabolic abnormalities) from that of losartan.
Finally, they found that administration of low-dose metformin and losartan to model mice significantly prolonged their survival. Researchers also found that in studies using doses at which metformin alone was not effective, the combination of metformin and losartan significantly prolonged mice survival. Put plainly, this study showed that an appropriate combination of the two therapeutic drugs could effectively treat the ND-CKD (Alport syndrome) mouse model.
This study raises the possibility that metformin, a proven and inexpensive diabetic drug, may delay the progression of kidney pathology in ND-CKD, including Alport syndrome. Metformin is currently available for use in patients with diabetes in clinical practice, but not in non-diabetic patients.
“This study appears to show that metformin has therapeutic effects for both diabetic and non-diabetic kidney disease,” said Professor Hirofumi Kai, who led the research project. “However, metformin is contraindicated in patients with severe renal dysfunction (eGFR < 30) due to the development of lactic acidosis as a side effect and should be administered with caution to patients with mild to moderate renal dysfunction." This research found that the appropriate combination of metformin and losartan significantly improved renal pathology and prolonged survival in a ND-CKD mouse model. This suggests that the old inexpensive drug metformin could become a new inexpensive drug for patients with chronic kidney disease.

The causes of the serious muscle disease ALS still remain unknown. Now, researchers at Karolinska Institutet and KTH Royal Institute of Technology, among others, have examined a type of cell in the brain blood vessels that could explain the unpredictable disease origins and dynamics. The results indicate a hitherto unknown connection between the nervous and vascular systems. The study, which is published in Nature Medicine, has potential implications for earlier diagnoses and future treatments.
ALS (amyotrophic lateral sclerosis) is a neurodegenerative disease of the motor neurons that eventually causes muscular atrophy, paralysis and death. There is currently no cure.
The cause of ALS is only understood in the 5 to 10 per cent of patients who have an inherited form of the disease. To help in its early detection and to develop efficacious therapies, researchers are avidly seeking a clearer picture of the disease’s pathogenesis.
ALS patients demonstrate high variability of age at onset, non-motor symptoms and survival. In recent years, research has shifted focus from neurological explanations to these differences, and has taken an interest, for example, in the cerebral vascular system, which delivers oxygen and nutrients to brain tissue.
Researchers at Karolinska Institutet, KTH Royal Institute of Technology, SciLifeLab, London’s Imperial College and Umeå University have now studied whether a possible connection exists between perivascular fibroblast cells and the time of disease onset and survival.
Studies on mice with ALS showed that genes for perivascular fibroblasts were active already in an early asymptomatic stage of the disease and months before neuronal damage began to appear.
The researchers then examined the levels of a large number of potential marker proteins in the plasma of 574 patients with a recent ALS diagnosis and 504 healthy controls from four countries.
Their results suggest a correlation between elevated levels of the protein marker SPP1 for perivascular fibroblasts and an aggressive disease process and shorter survival. This is the first time a connection between the vascular and nervous systems in sporadic ALS has been observed.
“It is exciting to see how the results from our protein profiling could be connected to the long range of cellular and molecular analysis that we have done and reveal the identified association to disease progression,” says the first author Anna Månberg, researcher at the Department of Protein Science, at KTH and SciLifeLab.
“Our results indicate that vascular events are a factor in the disease’s heterogeneity and can improve our knowledge of early stage ALS,” says the study’s last and senior author Sebastian Lewandowski, researcher at the Department of Clinical Neuroscience and the Centre for Molecular Medicine at Karolinska Institutet. “More studies are now needed on vascular disease mechanisms for better prognostic tools and future treatments.”
The research was financed by the Olle Engkvist Foundation, the Ulla-Carin Lindquist Foundation for ALS Research, the Swedish FTD Initiative and others, and received strategic support from the Knut and Alice Wallenberg Foundation and the Erling-Persson Family Foundation for the KTH Center for Applied Precision Medicine (KCAP). 
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Even the mention of parasites can be enough to make some people’s skin crawl. But to recent UC Santa Barbara doctoral graduate Dana Morton these creepy critters occupy important ecological niches, fulfilling roles that, in her opinion, have too often been overlooked.
That’s why Morton has just released the most extensive ecological food web that includes parasites. Eight years in the making, the dataset includes over 21,000 interactions between 942 species, all thoroughly annotated. The detailed description, published in the journal Scientific Data, is a boon for basic research, conservation efforts and resource management.
Understanding who eats whom, or trophic interactions, in an ecosystem is prime information for biologists. These relationships alone can tell researchers a great deal about a system, its complexity and even its overall health. However, ecologists often overlook parasites when investigating these interactions, perhaps because parasitology only recently joined the sphere of ecology, emerging from the medical sciences.
“But you can’t overlook parasite interactions once you know about them,” said Morton. “If you’re ignoring half of the interactions in the system, you don’t really know what’s going on in that system.”
Previous work led by her mentors, Armand Kuris and Kevin Lafferty in the Department of Ecology, Evolution, and Marine Biology, found that parasites were common in estuarine food webs. But Morton wanted to tackle a more diverse ecosystem. Given the body of research conducted on California’s kelp forests, she thought it would be easy enough to simply add parasites and small, free-living invertebrates to an existing network. But she quickly realized that previous food webs compiled for the kelp forest were too coarse to build on. They focused on big fish eating little fish, but gave less attention to mammals, birds and invertebrates. She’d need to start from scratch.
An exhaustive endeavor
First Morton compiled a list of species that call the kelp forest home. She and her co-authors used basically every credible source they could find. They pored over literature reviews and got data from long-term research projects, like the Santa Barbara Coastal Long Term Ecological Research Program and the Channel Islands National Park Kelp Forest Monitoring program. She also sought out fellow divers, and when that wasn’t enough, Morton and her team conducted their own field sampling.

Being constantly hungry, no matter how much you eat — that’s the daily struggle of people with genetic defects in the brain’s appetite controls, and it often ends in severe obesity. In a study published in Science on April 15, researchers at the Weizmann Institute of Science, together with colleagues from the Queen Mary University of London and the Hebrew University of Jerusalem, have revealed the mechanism of action of the master switch for hunger in the brain: the melanocortin receptor 4, or MC4 receptor for short. They have also clarified how this switch is activated by setmelanotide (Imcivree), a drug recently approved for the treatment of severe obesity caused by certain genetic changes. These findings shed new light on the way hunger is regulated and may help develop improved anti-obesity medications.
The MC4 receptor is present in a brain region called the hypothalamus — within a cluster of neurons that compute the body’s energy balance by processing a variety of energy-related metabolic signals. When the MC4 is activated, or “on” — as it normally is — it sends out commands that cause us to feel full, which means that from the brain’s perspective, our default state is satiety. When our energy levels drop, the hypothalamic cluster produces a “time to eat” hormone that inactivates, or turns off the MC4 receptor, sending out a “become hungry” signal. After we eat, a second, “I’m full” hormone is released. It binds to the same active site on the MC4, replacing the hunger hormone and turning the receptor back on — bringing us back to the satiety default. Mutations that inactivate the MC4 cause people to feel constantly hungry.
MC4 is a prime target for anti-obesity drugs, such as setmelanotide, precisely because it’s a master switch: turning it on can control hunger while bypassing all other energy-related signals. But until now it was unknown how exactly this hunger switch works.
The new study began with the predicament of one family, in which at least eight members, plagued by persistent hunger, were severely obese — most of them with a body mass index of over 70, that is, about triple the norm. Their medical history came to the attention of Hadar Israeli, a medical student pursuing PhD studies into the mechanisms of obesity under the guidance of Dr. Danny Ben-Zvi at the Hebrew University of Jerusalem. Israeli was struck by the fact that the family’s plight was due to a single mutation that ran in the family: one affecting the MC4 receptor. She turned to Dr. Moran Shalev-Benami of Weizmann’s Chemical and Structural Biology Department, asking whether new advances in electron microscopy could help explain how this particular mutation could produce such a devastating effect.
Shalev-Benami decided to launch a study into the structure of MC4, inviting Israeli to join her lab as a visiting scientist. Together with Dr. Oksana Degtjarik, a postdoctoral fellow in the lab, Israeli isolated large quantities of pure MC4 receptor from cell membranes, let it bind with setmelanotide and determined its 3D structure using cryogenic electron microscopy. The study was conducted in collaboration with the teams of Dr. Peter J. McCormick from the Queen Mary University of London and of Prof. Masha Y. Niv from the Hebrew University of Jerusalem.
The 3D structure revealed that setmelanotide activates the MC4 receptor by entering its binding pocket — that is, by directly hitting the molecular switch that signals satiety, even more potently than the natural satiety hormone. It also turned out that the drug has a surprising helper: an ion of calcium that enters the pocket, enhancing the drug’s binding to the receptor. In biochemical and computational experiments, the scientists found that similarly to the drug, calcium also assists the natural satiety hormone.

People who have recovered from COVID-19 had a robust antibody response after the first mRNA vaccine dose, but little immune benefit after the second dose, according to new research from the Penn Institute of Immunology. The findings, published today in Science Immunology, suggest only a single vaccine dose may be needed to produce a sufficient antibody response. The team found that those who did not have COVID-19 — called COVID naïve — did not have a full immune response until after receiving their second vaccine dose, reinforcing the importance of completing the two recommended doses for achieving strong levels of immunity.
The study provides more insight on the underlying immunobiology of mRNA vaccines, which could help shape future vaccine strategies.
“These results are encouraging for both short- and long-term vaccine efficacy, and this adds to our understanding of the mRNA vaccine immune response through the analysis of memory B cells,” said senior author E. John Wherry, PhD, chair of the department of Systems Pharmacology and Translational Therapeutics and director of the Penn Institute of Immunology in the Perelman School of Medicine at the University of Pennsylvania.
The human immune response to vaccines and infections result in two major outcomes — the production of antibodies that provide rapid immunity and the creation of memory B cells, which assist in long-term immunity. This study represents one of the first to uncover how memory B cell responses differ after vaccination in people who previously experienced infection, compared to those who have not have COVID-19.
“Previous COVID-19 mRNA vaccine studies on vaccinated individuals have focused on antibodies more than memory B cells. Memory B cells are a strong predictor of future antibody responses, which is why it’s vital to measure B cell responses to these vaccines,” Wherry said. “This effort to examine memory B cells is important for understanding long-term protection and the ability to respond to variants.”
The researchers recruited 44 healthy individuals who received either the BioNTech/Pfizer or Moderna mRNA COVID-19 vaccine at the University of Pennsylvania Health System. Of this cohort, 11 had a prior COVID-19 infection. Blood samples were collected for deep immune analyses four times prior to and after vaccine doses.

The list of known genetic mitochondrial disorders is ever-growing, and ongoing research continues to identify new disorders in this category. In an article recently published in Brain, a Japanese-European team of scientists, including researchers from Fujita Health University, describe mutations in the LIG3 gene, which plays a crucial role in mitochondrial DNA replication. These mutations cause a previously unknown syndrome characterized by gut dysmotility, leukoencephalopathy, and neuromuscular abnormalities.
DNA ligase proteins, which facilitate the formation of bonds between separate strands of DNA, play critical roles in the replication and maintenance of DNA. The human genome encodes three different DNA ligase proteins, but only one of those proteins — DNA ligase III (LIG3) — is expressed in mitochondria. LIG3 is therefore crucial for mitochondrial health, and inactivation of the homologous protein in mice causes profound mitochondrial dysfunction and early embryonic mortality. In an article recently published in the peer-reviewed journal Brain, a team of European and Japanese scientists, led by Dr. Mariko Taniguchi-Ikeda from Fujita Health University Hospital, describes a set of seven patients with a novel mitochondrial disorder caused by biallelic variants in the gene that encodes the LIG3 protein, called the “LIG3” gene. Their report provides a description of the patients’ symptoms and a mechanistic exploration of the mutations’ effects.
For Dr. Taniguchi-Ikeda, the investigation began with her desire to help a young patient. “I wanted to make a distinct clinical and genetic diagnosis for the affected patient,” she explains, “because his elder brother had passed away and the surviving boy was referred to my outpatient ward for detailed genetic tests.” By performing whole-exome sequencing of DNA from the surviving patient, Dr. Taniguchi-Ikeda discovered that he had inherited a p.P609L LIG3 variant from his father and a p.R811Ter LIG3 variant from his mother. The parents had kept the deceased brother’s dried umbilical cord, and by analyzing DNA extracted from that source, Dr. Taniguchi-Ikeda confirmed that the brother had carried the same LIG3 variants.
Having detected a novel genetic mitochondrial disorder, Dr. Taniguchi-Ikeda wished to conduct further research by identifying other patients with pathogenic LIG3 variants. She could find no other such cases in Japan, but through a collaboration with Dr. Makiko Tsutsumi from Fujita Health University and researchers in Europe, including Professor Elena Bonora from the University of Bologna and Professor Roberto De Giorgio from the University of Ferrara, she learned of two European families also affected by such variants. One was an Italian family in which three brothers had all inherited a p.K537N variant from their father and a p.G964R variant from their mother, and the other was a Dutch family in which two daughters had inherited a p.R267Ter variant from their father and a p.C999Y variant from their mother.
These patients experienced a complex syndrome involving severe gut dysmotility and neurologic abnormalities as the most consistently observed clinical signs. The neurologic abnormalities included leukoencephalopathy, epilepsy, migraine, stroke-like episodes, and neurogenic bladder. The prominent changes in the gut were decreased myenteric neuron counts and elevated fibrosis and elastin levels. Muscle pathology assessments revealed decreased staining intensities for cytochrome C oxidase.
To better characterize how the patients’ LIG3 mutations could lead to such phenotypes, the researchers conducted experiments both in vitro and on zebrafish. The in vitro experiments with patient-derived fibroblasts showed that the mutations resulted in reduced LIG3 protein levels and diminished ligase activity. The consequent deficits in mitochondrial DNA maintenance would do much to explain the patients’ presentations. Experiments with zebrafish showed that disrupting the lig3 gene produced brain alterations and gut transit impairments analogous to those observed in the patients.
The study brings to light a novel disorder resulting from disruption of a gene that plays a critical role in the maintenance of mitochondrial DNA. In describing the importance of these findings, Dr. Taniguchi-Ikeda concludes, “Our study may facilitate efforts to diagnose patients with mitochondrial diseases. Our findings will also be beneficial to future investigations into the mitochondrial DNA repair system.”
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SharecloseShare pageCopy linkAbout sharingimage copyrightGetty ImagesThe risk of developing a serious brain clot – known as a cerebral venous sinus thrombosis (CVST) – is 8 to 10 times higher in people with Covid than those who get a vaccine, a study suggests.Based on US data, the Oxford research team says people being vaccinated should be reassured by the findings.It follows investigations into links between the AstraZeneca vaccine and rare blood clots.The study only looked at those who had had a Pfizer or Moderna vaccine.The research, which involved electronic health records of 81 million people in the US, looked at the number of CVST cases seen in the two weeks following a diagnosis of coronavirus and the number of cases occurring in the two weeks after people had their first coronavirus vaccine.It estimates that while these blood clots are uncommon after Covid – with 39 in every million people developing one within two weeks of being ill – they are much rarer still after a vaccine.’Work in progress’But researchers say their study – which has not been through a formal review and is separate from the Oxford vaccine group – is still a work in progress and must be interpreted cautiously because it is difficult to calculate with certainty how common CVSTs are in the general population, partly because of just how rare they are. The study also found:Clots were more common in people who already had cardiovascular disease80% of people who have the clots surviveSome cases were seen in under-30s, showing they are not immune to serious complications from coronavirusIn those who had an mRNA vaccine – such as the Pfizer or Moderna jab – they estimate CVSTs occurred in around four in a million people. Scientists say their study cannot identify whether vaccines are linked to these clots and much larger studies are needed to address this. They say a more complete database would be needed because as in cases it was unclear exactly which mRNA vaccine had been given There are no directly comparable figures for the AZ vaccine because this jab has not been used in the USThe European Medicines Agency says a particular type of CVST occurs in around five in a million people after the first dose of the Oxford-AstraZeneca vaccine – but the populations vaccinated were not the same as in the US and the rates cannot be compared.Paul Harrison, professor of psychiatry at the University of Oxford, said their study had important conclusions for people deciding on vaccines.He said: “Firstly, Covid-19 markedly increases the risk of CVST, adding to the list of blood clotting problems this infection causes. “Secondly, the Covid-19 risk is higher than seen with the current vaccines, even for those under 30; something that should be taken into account when considering the balances between risks and benefits for vaccination.”Rare blood clots – what you need to knowWhere is there surge testing for Covid variants?Is the Oxford-AstraZeneca vaccine safe?From their database they were unable to investigate whether the CVST clots they were seeing had similar features to those seen in rare cases after vaccines – which all had a peculiar pattern of blood cells associated with them, where certain cells called platelets were diminished.Prof Beverley Hunt, of Thrombosis UK, said the mechanisms behind people getting clots after Covid and those experiencing clots after vaccines were likely to be different. She said: “Patients who are hospitalised with Covid-19 have very pro-thrombotic (sticky) changes in their blood, which persist after they have been discharged. This will lead to an increased rate of blood clots. “The mechanism for the very rare blood clots and low platelet counts seen after the AstraZeneca vaccine is different. It is associated with an immune response.”Related Internet LinksOSF COVID-CVT-paper.pdf.websiteThe BBC is not responsible for the content of external sites.