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HIV VACCINE EFFORTS ARE UNDERMINED BY OFF-TARGET ANTIBODIES

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Some proof-of-concept HIV vaccines in early human trials generate antibodies that actively hinder protection by degrading the vaccine’s payload, suggests a new study from Scripps Research.

Their study was published in the journal Science Advances. While scientists have had rapid success engineering vaccines against the pandemic coronavirus in less than a year’s time, HIV, the virus responsible for the AIDS epidemic, has proven significantly more challenging. Understanding how “off-target” antibodies may be undermining HIV vaccine prototypes allows for design improvements, says the study’s lead author, Andrew Ward, PhD, a structural biology professor at Scripps Research in La Jolla, CA.

“Our study provides critical insights for further improvement of HIV subunit trimer vaccines for future rounds of the iterative vaccine design process,” Ward and colleagues write. Despite more than 30 years of effort, the world still lacks an effective vaccine against acquired immunodeficiency syndrome (AIDS). Given the rapid success of the coronavirus vaccines, it may seem perplexing, but the reasons are many. The coronavirus infects cells in the airways and elsewhere. But HIV, short for “Human Immunodeficiency Virus,” infects the very immune cells needed to generate an immune response. That’s just the beginning of the challenge.

Compared to HIV, the coronavirus is slower to change and relatively stable. HIV has proven a master of disguise, able to cloak itself in a changing coating of protective sugar molecules stolen from its host, to make it appear friendly. Plus, it churns out mutated versions at an astonishingly rapid rate, staying one step ahead of people’s immune responses.

“The HIV surface spike is a sugar-coated, shape-shifting nightmare for antibodies to latch onto and provide protection,” says Dennis Burton, PhD, chair of the Department of Immunology and Microbiology at Scripps Research, and co-author on the paper.

“HIV exists in literally hundreds of thousands of different variants of concern compared to the handful for coronavirus,” Burton notes. To outfox HIV’s changeability, scientists have developed techniques to “rationally design,” or engineer, vaccine particles intended to prompt the formation of antibodies that broadly neutralize many subtypes of HIV.

Much like the current array of pandemic coronavirus vaccines, these HIV vaccine prototypes consist of a fragment of the actual virus, the surface spike known as the envelope glycoprotein (Env), which is found on the virus exterior.

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SCIENTISTS FIND BIOMARKERS IN PLATELETS FOR DEPRESSION, ANTIDEPRESSANT RESPONSE

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A new study has found biomarkers for depression in platelets that track the extent of the disorder.

Published in a new proof of concept study, researchers led by Mark Rasenick, University of Illinois Chicago distinguished professor of physiology and biophysics and psychiatry, have identified a biomarker in human platelets that tracks the extent of depression.

The research builds off of previous studies by several investigators that have shown in humans and animal models that depression is consistent with decreased adenylyl cyclase — a small molecule inside the cell that is made in response to neurotransmitters such as serotonin and epinephrine.

“When you are depressed, adenylyl cyclase is low. The reason adenylyl cyclase is attenuated is that the intermediary protein that allows the neurotransmitter to make the adenylyl cyclase, Gs alpha, is stuck in a cholesterol-rich matrix of the membrane — a lipid raft — where they don’t work very well,” Rasenick said.

The new study has identified the cellular biomarker for translocation of Gs alpha from lipid rafts. The biomarker can be identified through a blood test.

“What we have developed is a test that can not only indicate the presence of depression but it can also indicate therapeutic response with a single biomarker, and that is something that has not existed to date,” said Rasenick, who is also a research career scientist at Jesse Brown VA Medical Centre.

The researchers hypothesized that they will be able to use this blood test to determine if antidepressant therapies are working, perhaps as soon as one week after beginning treatment. Previous research has shown that when patients showed improvement in their depression symptoms, the Gs alpha was out of the lipid raft. However, in patients who took antidepressants but showed no improvement in their symptoms, the Gs alpha was still stuck in the raft — meaning simply having antidepressants in the bloodstream was not good enough to improve symptoms.

A blood test may be able to show whether or not the Gs alpha was out of the lipid raft

after one week.

“Because platelets turn over in one week, you would see a change in people who were going to get better. You’d be able to see the biomarker that should presage successful treatment,” Rasenick said.

Currently, patients and their physicians have to wait several weeks, sometimes months, to determine if antidepressants are working, and when it is determined they aren’t working, different therapies are tried.

“About 30 per cent of people don’t get better — their depression doesn’t resolve. Perhaps, failure begets failure and both doctors and patients make the assumption that nothing is going to work,” Rasenick said.

“Most depression is diagnosed in primary care doctor’s offices where they don’t have sophisticated screening. With this test, a doctor could say, ‘Gee, they look like they are depressed, but their blood doesn’t tell us they are. So, maybe we need to re-examine this,” he added.

Working with his company, Pax Neuroscience, Rasenick aims to develop the screening test after further research.

The Study has been published in the ‘Molecular Psychiatry Journal ‘.

A small molecule inside the cell that is made in response to neurotransmitters such as serotonin and epinephrine.

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Study finds long-term exposure to air pollution may increase virus risk

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Long term exposure to ambient air pollution may heighten the risk of COVID-19 infection, suggests recent research.

The association was strongest for particulate matter, with an average annual raise of 1 ug/m3 linked to a 5 per cent increase in the infection rate. This equates to an extra 294 cases/100,000 people a year, according to the findings, which focus on the inhabitants of one Northern Italian city.

While further research is needed to confirm cause and effect, the findings should reinforce efforts to cut air pollution, say the researchers.

Northern Italy has been hit hard by the coronavirus pandemic, with Lombardy the worst affected region in terms of both cases and deaths. Several reasons have been suggested for this, including different testing strategies and demographics. But estimates from the European Union Environmental Agency show that most of the 3.9 million Europeans residing in areas where air pollution exceeds European limits live in Northern Italy.

Recent research has implicated airborne pollution as a risk factor for COVID-19 infection, but study design flaws and data capture only up to mid-2020 have limited the findings, say the researchers.

To get around these issues, they looked at long term exposure to airborne pollutants and patterns of COVID-19 infection from the start of the pandemic to March 2021 among the residents of Varese, the eighth-largest city in Lombardy.

Among the 81,543 residents as of 31 December 2017, more than 97 per cent were

successfully linked to the 2018 annual average exposure levels for the main air pollutants, based on home address.

Regional COVID-19 infection data and information on hospital discharge and outpatient drug prescriptions were gathered for 62,848 adults yet to be infected with SARS-CoV-2, the virus responsible for COVID-19 at the end of 2019 until the end of March 2021.

Official figures show that only 3.5 per cent of the population in the entire region were fully vaccinated by the end of March 2021.

Estimates of annual and seasonal average levels of five airborne pollutants were

available for 2018 over an area more than 40 km wide: particulate matter (PM2.5, PM10); nitrogen dioxide (NO2); nitric oxide (NO); and ozone (O3).

The average PM2.5 and NO2 values were 12.5 and 20.1 ug/m3, respectively. The

corresponding population-weighted average annual exposures in Italy for the same year were 15.5 and 20.1 ug/m3, respectively.

Some 4408 new COVID-19 cases, which were registered between 25 February 2020 and March 13, 2021, were included in the study. This equates to a rate of 6005 cases/100,000 population/year. The population density wasn’t associated with a heightened risk of infection. But living in a residential care home was associated with a more than 10-fold heightened risk of the infection. Drug treatment for diabetes, high blood pressure, and obstructive airway diseases, as well as a history of stroke, were also associated with, respectively, a 17 per cent, 12 per cent, 17 per cent, and 29 per cent, heightened risk. After accounting for age, gender, and care home residency, plus concurrent long term conditions, averages, both PM2.5 and PM10 were significantly associated with an increased COVID-19 infection rate.

Every 1 ug/m3 increase in long term exposure to PM2.5 was associated with a 5 per cent increase in the number of new cases of COVID-19 infection, equivalent to 294 extra cases per 100,000 of the population/year.

Applying seasonal rather than annual averages yielded similar results, and these findings were confirmed in further analyses that excluded care home residents and further adjusted for local levels of deprivation and use of public transport. Similar findings were observed for PM10, NO2 and NO.

The observed associations were even more noticeable among older age groups,

indicating a stronger effect of pollutants on the COVID-19 infection rate among 55-64 and 65-74-year-olds, suggest the researchers.

This is an observational study, and as such, can’t establish cause. And although the researchers considered various potentially influential factors, they weren’t able to account for mobility, social interaction, humidity, temperature and certain underlying conditions, such as mental ill-health and kidney disease.

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BOOSTER DOSE NEUTRALISES COVID-19 OMICRON VARIANT, SAYS EU RESEARCH

Aim of study was to characterise efficacy of therapeutic antibodies and scientists concluded that many mutations in spike protein of variant enabled it to largely evade immune response

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An international team of researchers recently studied the sensitivity of Omicron to antibodies compared with the currently dominant Delta variant.

The new COVID-19 Omicron variant is more transmissible than the Delta variant. However, its biological characteristics are still relatively unknown.

In South Africa, the Omicron variant replaced the other viruses within a few weeks and led to a sharp increase in the number of cases diagnosed. Analyses in various countries indicate that the doubling time for cases is approximately 2 to 4 days. Omicron has been detected in dozens of countries, including France, and became dominant by the end of 2021.

In a new study supported by the European Union’s Health Emergency Preparedness and Response Authority (HERA), scientists from the Institut Pasteur and the Vaccine Research Institute, in collaboration with KU Leuven (Leuven, Belgium), Orleans Regional Hospital, Hospital Europeen Georges Pompidou (AP-HP) and Inserm, studied the sensitivity of Omicron to antibodies compared with the currently dominant Delta variant.

The aim of the study was to characterize the efficacy of therapeutic antibodies, as well as antibodies developed by individuals previously infected with SARS-CoV-2 or vaccinated, in neutralizing this new variant.

The scientists from KU Leuven isolated the Omicron variant of SARS-CoV-2 from a nasal sample of a 32-year-old woman who developed moderate COVID-19 a few days after returning from Egypt. The isolated virus was immediately sent to scientists at the Institut Pasteur, where therapeutic monoclonal antibodies and serum samples from people who had been vaccinated or previously exposed to SARS-CoV-2 were used to study the sensitivity of the Omicron variant.

The scientists used rapid neutralization assays, developed by the Institut Pasteur’s Virus and Immunity Unit, on the isolated sample of the Omicron virus. This collaborative multidisciplinary effort also involved the Institut Pasteur’s virologists and specialists in the analysis of viral evolution and protein structure, together with teams from Orleans Regional Hospital and Hospital Europeen Georges Pompidou in Paris.

The scientists began by testing nine monoclonal antibodies used in clinical practice or currently in preclinical development. Six antibodies lost all antiviral activity, and the other three were 3 to 80 times less effective against Omicron than against Delta.

The antibodies Bamlanivimab/Etesevimab (a combination developed by Lilly), Casirivimab/Imdevimab (a combination developed by Roche and known as Ronapreve), and Regdanvimab (developed by Celtrion) no longer had any antiviral effect against Omicron. The Tixagevimab/Cilgavimab combination (developed by AstraZeneca under the name Evusheld) was 80 times less effective against Omicron than against Delta.

“We demonstrated that this highly transmissible variant has acquired significant resistance to antibodies. Most of the therapeutic monoclonal antibodies currently available against SARS-CoV-2 are inactive,” commented Olivier Schwartz, co-last author of the study and Head of the Virus and Immunity Unit at the Institut Pasteur.

The scientists observed that the blood of patients previously infected with COVID-19, collected up to 12 months after symptoms, and that of individuals who had received two doses of the vaccine, taken five months after vaccination, barely neutralized the Omicron variant. But the sera of individuals who had received a booster dose of Pfizer, analyzed one month after vaccination, remained effective against Omicron.

Five to 31 times more antibodies were nevertheless required to neutralize Omicron, compared with Delta, in cell culture assays. These results help shed light on the continued efficacy of vaccines in protecting against severe forms of the disease.

“We now need to study the length of protection of the booster dose. The vaccines probably become less effective in offering protection against contracting the virus, but they should continue to protect against severe forms,” explained Olivier Schwartz.

“This study shows that the Omicron variant hampers the effectiveness of vaccines and monoclonal antibodies, but it also demonstrates the ability of European scientists to work together to identify challenges and potential solutions. While KU Leuven was able to describe the first case of Omicron infection in Europe using the Belgian genome surveillance system, our collaboration with the Institut Pasteur in Paris enabled us to carry out this study in record time,” commented Emmanuel Andre, co-last author of the study, a Professor of Medicine at KU Leuven (Katholieke Universiteit Leuven) and Head of the National Reference Laboratory and the genome surveillance network for COVID-19 in Belgium.

“There is still a great deal of work to do, but thanks to the support of the European Union’s Health Emergency Preparedness and Response Authority (HERA), we have clearly now reached a point where scientists from the best centres can work in synergy and move towards a better understanding and more effective management of the pandemic,” added Emmanuel.

The scientists concluded that the many mutations in the spike protein of the Omicron variant enabled it to largely evade the immune response. Ongoing research is being conducted to determine why this variant is more transmissible from one individual to the next and to analyze the long-term effectiveness of a booster dose.

The Study about this variant has been published in the ‘Nature Journal ‘

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INNER LANGUAGE DECODED

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A research team from the University of Geneva (UNIGE) and the Hopitaux Universitaires de Geneve (HUG) has succeeded in identifying certain signals produced by our brain when we speak to ourselves.

Findings were published in the journal Nature Communications. When human beings speak, different areas of their brain must be activated. However, the function of these regions can be seriously impaired after damage to the nervous system. For example, amyotrophic lateral sclerosis (or Charcot’s disease) can completely paralyze the muscles used to speak.

In other cases, following a stroke, for example, areas of the brain responsible for language can be affected: this is called aphasia. However, in many of those cases, the ability of patients to imagine words and sentences remains partly functional.

Decoding our internal speech is therefore of great interest to neuroscience researchers. But the task is far from easy, as Timothee Proix, the scientist in the Department of Basic Neuroscience at the UNIGE Faculty of Medicine, explains “Several studies have been conducted on the decoding of spoken language, but much less on the decoding of imagined speech. This is because, in the latter case, the associated neural signals are weak and variable compared to explicit speech. They are therefore difficult to decode by learning algorithms.”

That is, through computer programmes.

When a person speaks aloud, he or she produces sounds that are emitted at certain precise moments. Researchers can thus relate these tangible elements to the brain regions involved. In the case of imagined speech, the process is much less easy.

Scientists have no obvious information on the sequencing and tempo of the words or sentences formulated internally by the individual. The areas recruited in the brain are also less numerous and less active.

In order to perceive the neural signals of this very particular type of speech, the UNIGE team used a panel of thirteen hospitalized patients, in collaboration with two American hospitals. They collected data through electrodes implanted directly into patients’ brains in order to assess their epileptic disorders.

“We asked these people to say words and then to imagine them. Each time, we reviewed several frequency bands of brain activity known to be involved in language”, explains Anne-Lise Giraud, a professor in the Department of Basic Neuroscience at the UNIGE Faculty of Medicine, and newly appointed director of the Institut de l’Audition in Paris.

The researchers observed several types of frequencies produced by different brain areas when these patients spoke, either orally or internally.

“First of all, the oscillations called theta (4-8Hz), which correspond to the average rhythm of syllable elocution. Then the gamma frequencies (25-35Hz), observed in the areas of the brain where speech sounds are formed. Thirdly, beta waves (12-18Hz) related to the cognitively more efficient regions solicited, for example, to anticipate and predict the evolution of a conversation. Finally, the high frequencies (80-150Hz) that are observed when a person speaks out” explains Pierre Megevand, assistant professor in the Department of Clinical Neurosciences at the Faculty of Medicine of the UNIGE and associate physician at the HUG.

Thanks to these observations, the scientists were able to show that the low frequencies and the coupling between certain frequencies (beta and gamma in particular) contain essential information for the decoding of imagined speech.

Their research also reveals that the temporal cortex is an important area for the eventual decoding.

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Detection of ADHD more accurately: Study

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A new study has identified a new neurological marker for attention deficit disorder with or without hyperactivity. The research has been published in the ‘Biological Psychiatry Cognitive Neuroscience and Neuroimaging Journal’. Supported by the national research centre Synapsy, neuroscientists from the University of Geneva (UNIGE), the Centre for Biomedical Imaging (CIBM), and the University Hospital of Geneva (HUG) focused their attention on a new electroencephalographic approach called microstates to identify ADHD’s neurological signatures.

The microstates technique is used to look at the combined spatial and temporal aspects of cerebral activity. Using this technique, the research team discovered that a certain cerebral activity state associated with sleep and attention lasted longer among people with ADHD. The results provided evidence of a more robust ADHD biomarker and thus contributed towards helping psychiatry become a more precise medical discipline.

ADHD affects five per cent of adults, making it one of the most common psychological disorders. Current clinical diagnosis is based only on questionnaires that focus mainly on the inattention and impulsivity symptoms. However, neuroscientists speculate that ADHD’s causes, while still not well known, have a biological and genetic basis, suggesting that there may exist biomarkers that could help in its diagnosis. This was the scope of this new study supported by Synapsy, a research centre that has combined psychiatry and the neurosciences over the past twelve years to understand the neural basis of different psychological disorders in the hope of creating better means for diagnosing and treating them.

The study of the human brain is a difficult endeavour because we cannot directly access the brain to look at its cellular and molecular mechanisms. Hence, non-invasive investigative methods such as brain scans or electroencephalograms (EEG) are used. The latter test uses a network of electrode sensors placed on the subject’s scalp to measure the electrical fields generated by large-scale neural networks.

Recent studies have revealed abnormal EEG activity among patients affected by ADHD, suggesting that abnormal cerebral development may be the cause of ADHD. Unfortunately, the data vary too much from one study to another, making them unreliable markers for ADHD. “These variations are due either to the wide heterogeneity of ADHD’s causes or to the fact that traditional EEG analyses are not a good tool for looking into the matter because they do not take into account the Spatio-temporal aspects of cerebral states,” said Tomas Ros, a researcher at the Department of Psychiatry and Neuroscience at the UNIGE Faculty of Medicine.

Brain activity fluctuated successively from one state to another while at rest, manifesting different spatial configurations in the EEG’s electrical field. Neuroscientists speak most often of five “micro” states or main configurations, lettered from A to E.

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THIRD JAB? SENDING THE WRONG MESSAGE

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Vaccine

Omicron ( B1.1.529) quickly evolved to become a VoC within a few months’ time, spreading from S Africa to several nations worldwide[1]. The Technical Advisory Group on SARS-CoV-2 Virus Evolution (TAG-VE) monitoring the evolution of SARS-CoV-2 was convened to assess this variant after it was first reported to WHO from South Africa on 24 November 2021 from a specimen collected on 9 November 2021. The detection of B1.1.529 quickly coincided with a surge in COVID19 cases establishing it as the dominant variant. By the time travel advisories and other restrictions could kick in, Omicron already spread to 89 countries (as of 18th Dec 2021) infecting millions. According to the Institute for Health Metrics and Evaluation (IHME), Washington, omicron infections are set to surge in the next two to three months and may infect 1-2 billion people globally. What makes B1.1.529 special is the sheer number of mutations it accumulated (32 vs 12) as compared to the delta(B1.617.2), plus the rapidness it is spreading with an estimated Ro of 2.69 (vs 1.69 for the delta variant). For a populous country like India with over 8 lakh active cases[2], and a positivity of ~10-15%, the stakes are higher. The healthcare system that is already stretched beyond its capacity has seen a further dent with several HCW exposed and quarantined. Amidst the rising cases, the administration has to enforce lockdown, containment zones, and travel restrictions which may, in turn, affect the economy. However, it seems during this crisis, the public is getting influenced by a different set of narratives, derived from an overall short term observation, poor understanding of the full nature & scale of this variant, inadequate testing, surveillance, genome sequencing, as well as overlooking the long term health consequences of Omicron on adults as well as in children and pregnant women. This lack of our knowledge is giving rise to numerous misleading statements[3] even by the professionals, labeling Omicron to be a mild, benign variant, a variant of least concern, a variant that needs nearly no hospitalization or is associated with very low mortality. Taken to the public domain, this may create callousness and a sense of anarchy in following COVID-appropriate behavior like social distancing, double masking, or getting tested and vaccinated. This also falsely justifies hosting super-spreader events like religious and political rallies, ignoring the law and order, and downsizing the potential risk. We need to accept from all our past experiences that our understanding of the overall COVID pandemic is still very naïve and almost nil for this new variant. Still, a vast majority of the PCR/NAAT-based detection is not targeted to B1.1.529. SGTF(S Gene Target failure) is rarely used in diagnostic labs. With India’s sequencing agency, The Indian SARS-CoV-2 Genomics Consortium(INSACOG), sequencing a minuscule 2-3% of all positive cases, we are still in an ocean of uncertainties to comment on the real number of genuine Omicron cases[4]. Going by the average consensus worldwide, even if 60-80% is Omicron, that still implies that Delta and other variants are out there and may retaliate any time. Moreover we don’t know if B1.1.529 is just a transient quasi-species on its evolutionary trajectory in the process of evolving to a more virulent form. We also don’t know if Omicron will make us permissive for co-infection by another variants that are perhaps mutating at some corner of the world. The rapid spread of B1.1.529 with its extremely high transmissibility could in theory wipe out COVID-specific memory B/T cells, that many of us might be banking on, making them ineffective and futile. Worst, if it blunts the effect of the COVID-19 vaccine, acting as a “decoy virus” exhausting the pool of effector immune cells before another lethal variant steps in. With all these possibilities, labeling omicron as a harmless variant and taking the guard off is the last thing one should ever do. Further, the decision for a booster dose needs some serious thoughts following the philosophy that “more is not always the best”. Serology testing has shown a lesser efficiency in vaccine-induced neutralization against the new variant. Under these conditions, there is no credible evidence to show that a 3rd jab will make things all right. We need to consider that sometimes a higher dose of antibodies produced may in fact facilitate virus infection by the process of ADE(antibody-dependent enhancement)[5]. Though well observed in Dengue virus infection and not yet in SARS-CoV2, the probability how-so-ever small still remains. We have already seen a massive breakthrough re-infection amongst those fully vaccinated making it apparent that the vaccines are not capable enough to prevent new infection or virus transmission. Whether adding a booster dose to ramp the antibody level will do any benefit is highly uncertain and should be only considered based on solid science and rigorous clinical trials, rather than speculation. Also drawing parallels between Ab titers with disease protection can not only be misleading but also erroneous[6]. For a country as large and populous as India with just 64% fully vaccinated with a double dose (as of December 30th, 2021), demand for a 3rd booster dose is highly ambitious. Making the right choices and sending the right messages, more so in pandemic times might hold the key to overcoming the ongoing crisis. Sending the wrong message may do more harm than the virus itself.

Subhradip Karmakar, Additional Professor, All India Institute of Medical Sciences.

References:

1. https://www.who.int/news/item/26-11-2021-classification-of-omicron-(b.1.1.529)-sars-cov-2-variant-of-concern

2. India COVID cases . URL : https://www.mohfw.gov.in/

3. https://indianexpress.com/article/opinion/columns/its-dangerous-to-take-omicron-lightly-7710469/

4. https://scroll.in/article/1013438/lack-of-genome-sequencing-capacity-hampers-indias-efforts-to-track-the-spread-of-omicron

5. Narayan R, Tripathi S. Intrinsic ADE: The Dark Side of Antibody Dependent Enhancement During Dengue Infection. Front Cell Infect Microbiol. 2020 Oct 2;10:580096. doi: 10.3389/fcimb.2020.580096. PMID: 33123500; PMCID: PMC7573563.

6. Lisboa Bastos M, Tavaziva G, Abidi SK, Campbell JR, Haraoui LP, Johnston JC, Lan Z, Law S, MacLean E, Trajman A, Menzies D, Benedetti A, Ahmad Khan F. Diagnostic accuracy of serological tests for covid-19: systematic review and meta-analysis. BMJ. 2020 Jul 1;370:m2516. doi: 10.1136/bmj.m2516. PMID: 32611558; PMCID: PMC7327913.

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