Rare genetic disease: researchers discover new treatment for ADCY5-related dyskinesia

The movement disorder ADCY5-related dyskinesia can be treated with the asthma drug theophylline. This has been shown in a recent study by Martin Luther University Halle-Wittenberg (MLU), University Medicine Halle and University of Leipzig Medical Center. In the journal PLOS ONE, the researchers describe the case of a child with this disease whose symptoms improved significantly with the drug. ADCY5-related dyskinesia is an extremely rare disorder that causes dyskinesia and uncontrolled movements in affected individuals. Currently, there is no cure for this disease.

ADCY5-related dyskinesia is caused by defects in the ADCY5 gene. "Just one error in the genetic code of this gene can have devastating consequences," says Professor Andrea Sinz from the Institute of Pharmacy at MLU. In the case of ADCY5-related dyskinesia, the genetic defect causes a specific enzyme in the cells to become overactive. This enzyme is involved in the production of the second messenger "cAMP".

In those affected, too much "cAMP" tends to lead to uncontrolled movements, dyskinesia, and many other symptoms, such as speech deficiencies, starting in early infancy. The disease is considered very rare. According to estimates by the US National Institutes of Health, between one and 300 people are living with the disease in the United States; however, more precise numbers are not available. "Rare diseases like ADCY5-related dyskinesia are often not recognized and accurately diagnosed," says Sinz. The symptoms are easily confused with other medical conditions.

Could a Naturally Occurring Amino Acid Lead Us to a Cure for COVID-19?

An amino acid called 5-aminolevulinic acid (ALA) might be key to reduce the expression of ACE2, a cell membrane receptor that SARS-CoV-2 uses to infect cells. New insights gained by scientists at Tokyo Tech have clarified the relationship between ACE2, ALA, and the production of heme, which could pave the way to anti-viral drugs to cure COVID-19.

After more than two years since its discovery, six million deaths, and half a billion reported cases, there is still no effective cure for COVID-19. Even though vaccines have lowered the impact of outbreaks, patients that contract the disease can only receive supportive care while they wait for their own body to clear the infection.

A promising COVID-19 treatment strategy that has been gaining traction lately is targeting angiotensin-converting enzyme 2 (ACE2). This is a receptor found on the cell membrane that allows entry of the virus into the cell due to its high affinity for SARS-CoV-2’s spike protein. The idea is that reducing the levels of ACE2 on the membrane of cells could be a way to prevent the virus from entering them and replicating, thereby lowering its infectious capabilities.

Pseudomonas aeruginosa Bacteria produce a molecule that paralyzes immune system cells

Human endothelial cells use the molecules cadherin (green) and actin (purple) to form a flexible barrier around blood vessels. After adding the isolated LecB, their localization in the cell changes significantly: in the right half of the image, cadherin is no longer on the outside of the cell, but near the nucleus (blue).
Image Credit: Yubing Guo / Universities of Freiburg and Strasbourg

Bacteria of the species Pseudomonas aeruginosa are antibiotic-resistant hospital germs that can enter blood, lungs and other tissues through wounds and cause life-threatening infections. In a joint project, researchers from the Universities of Freiburg and Strasbourg in France have discovered a mechanism that likely contributes to the severity of P. aeruginosa infections. At the same time, it could be a target for future treatments. The results recently appeared in the journal EMBO Reports.

Many bacterial species use sugar-binding molecules called lectins to attach to and invade host cells. Lectins can also influence the immune response to bacterial infections. However, these functions have hardly been researched so far. A research consortium led by Prof. Dr. Winfried Römer from the Cluster of Excellence CIBSS - Centre for Integrative Biological Signaling Studies at the University of Freiburg and Prof. Dr. Christopher G. Mueller from the IBMC - Institute of Molecular and Cell Biology at the CNRS/University of Strasbourg has investigated the effect of the lectin LecB from P. aeruginosa on the immune system. It found that isolated LecB can render immune cells ineffective: The cells are then no longer able to migrate through the body and trigger an immune response. The administration of a substance directed against LecB prevented this effect and led to the immune cells being able to move unhindered again.

Heart failure places a great strain on healthcare

Anna Norhammar, adjunct professor at KI.
Photo Credit: Ulf Sirborn

Patients with heart failure often suffer from co-morbidities, which places a great strain on the healthcare services, a multinational study published in Heart reports. The researchers, who are based at Karolinska Institutet, identify an urgent need to improve risk management of the disease.

Up to 64 million people around the world have heart failure a figure that is expected to rise as populations age and diagnostic methods improve.

According to the new study, there are no multinational studies describing heart failure patients and the consequences of the disease.   

“Given that we know that the incidence of heart failure increases with population age, a modern, broad view of what the heart failure population looks like, involving risks and costs, is important for all forms of care planning,” says Anna Norhammar, adjunct professor at the Cardiology Unit, Department of Medicine (Solna), Karolinska Institutet.

Extracts from two wild plants inhibit COVID-19 virus

 Emory University graduate student Caitlin Risener, first author of the study, gathers tall goldenrod in South Georgia.
Photo Credit: Tharanga Samarakoon

Two common wild plants contain extracts that inhibit the ability of the virus that causes COVID-19 to infect living cells, an Emory University study finds. Scientific Reports published the results — the first major screening of botanical extracts to search for potency against the SARS-CoV-2 virus.

In laboratory dish tests, extracts from the flowers of tall goldenrod (Solidago altissima) and the rhizomes of the eagle fern (Pteridium aquilinum) each blocked SARS-CoV-2 from entering human cells.

The active compounds are only present in miniscule quantities in the plants. It would be ineffective, and potentially dangerous, for people to attempt to treat themselves with them, the researchers stress. In fact, the eagle fern is known to be toxic, they warn.

“It’s very early in the process, but we’re working to identify, isolate and scale up the molecules from the extracts that showed activity against the virus,” says Cassandra Quave, senior author of the study and associate professor in Emory School of Medicine’s Department of Dermatology and the Center for the Study of Human Health. “Once we have isolated the active ingredients, we plan to further test for their safety and for their long-range potential as medicines against COVID-19.”

Single drug injection wards off COVID-19 hospitalizations

A single injection of PEG-lambda interferon proved to be effective against all variants of the coronavirus tested by researchers at Stanford Medicine.
Image Credit: Gerd Altmann

In an international, multicenter, pivotal Phase 3 trial, a single under-the-skin injection of a biological drug given to patients within seven days of the onset of COVID-19 symptoms cut the likelihood they needed to be hospitalized in half. Patients treated within three days of showing symptoms fared even better. Among unvaccinated patients who were treated soon after symptom onset, hospitalization likelihood plummeted markedly.

The drug, pegylated lambda-interferon, or PEG-lambda, proved effective against all COVID-19 viral variants tested, including omicron. Side effects were no greater than those reported by placebo recipients.

A report on the success of the randomized, double-blind, placebo-controlled trial of nearly 2,000 newly infected COVID-19 patients was published online Feb. 9 in the New England Journal of Medicine.

PEG-lambda is a synthetic version of lambda-interferon, a naturally occurring protein that infected cells secrete as a first line of defense against viral infection.

Pharmacy Researchers Develop Treatment for Glioblastoma

Dr. Shipra Malik, left, and associate professor of pharmaceutics Dr. Raman Bahal pose for a photo in a lab inside the Pharmacy/Biology Building on Jan. 20, 2023.
Photo Credit: Sydney Herdle/UConn Photo

A team of researchers, including those at the University of Connecticut, has developed a nanoparticle-based treatment that targets multiple culprits in glioblastoma, a particularly aggressive and deadly form of brain cancer.

The results, a collaboration between UConn and Yale University, were published today in Science Advances.

The new treatment uses bioadhesive nanoparticles that adhere to the site of the tumor and then slowly release the synthesized peptide nucleic acids that they’re carrying. These peptide nucleic acids target certain microRNAs – that is, short strands of RNA that play a role in gene expression. Specifically, they’re directed at a type of overexpressed microRNA known as “oncomiRs” that lead to the proliferation of cancer cells and growth of the tumor.  When the peptide nucleic acids attach to the oncomiRs, they stop their tumor-promoting activity.

Antibody possible treatment for severe fatty liver disease

Micrograph of non-alcoholic fatty liver disease (NAFLD). Masson's trichrome & Verhoeff stain. The liver has a prominent (centrilobular) macrovesicular steatosis (white/clear round/oval spaces) and mild fibrosis (green). The hepatocytes stain red.  Macrovesicular steatosis is lipid accumulation that is so large it distorts the cell's nucleus.
Image Credit: Nephron CC BY-SA 3.0

There is currently no drug for treating non-alcoholic fatty liver disease, which affects many people with type 2 diabetes and which can result in other serious liver diseases. A study led by researchers from Karolinska Institutet has now identified a drug candidate for the treatment of fatty liver. The preclinical study, published in the Journal of Hepatology, indicates that an antibody that blocks the protein VEGF-B presents a possible therapeutic option for fatty liver disease.

“Fatty liver is associated with several serious and sometimes fatal diseases,” says the study’s first author Annelie Falkevall, researcher at the Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Sweden. “With the therapeutic principle that we’ve developed, it might be possible to prevent fatty liver and hopefully lower the risk of liver failure and terminal liver cancer.”

For decades, obesity and overweight have been a common global disease that, amongst other problems, has caused a sharp rise in the incidence of type 2 diabetes. According to the Swedish Diabetes Association, there are 500,000 cases of diabetes in Sweden alone, of which 85 to 90 percent are type 2.

Common heart medicine is linked to a reduced risk of committing violent crimes

Yasmina Molero.
Photo Credit: Niklas Faye-Wevle Samuelson

Beta blockers, commonly used to treat heart disease and high blood pressure, can be linked to a reduced risk of committing violent crimes. It shows a new registry study from Karolinska Institutet and the University of Oxford published in the journal PLOS Medicine.

Beta blockers lower blood pressure by blocking the effect of hormones like adrenaline. The medicine is used to treat a variety of conditions including high blood pressure, cardiovascular events, heart failure and anxiety. It has also been suggested to work for clinical depression and aggression, but some studies have found a link to increased suicidal tendencies and the results are contradictory.

In the current study, the researchers investigated the relationship between beta blockers and hospitalization for mental illness, suicidal tendencies, suicide and reports of violent crime. They studied 1.4 million individuals in Sweden and compared periods with and without beta blockers in the same individual over an eight-year period (2006-2013). In this way, the researchers were able to control factors that can affect relationships, such as genetics or disease history.

Periods of medication were associated with a 13 percent lower risk of being charged with violent crime. Since it is an observational study, conclusions about causation should be interpreted with caution.

One way to deal with aggression

- If the results are confirmed in other studies, including randomized controlled trials, beta blocks may be considered as a way to manage aggression in individuals with psychiatric diagnoses, say Yasmina Molero, researchers at Department of Clinical Neuroscience and Department of Medical Epidemiology and Biostatistics at Karolinska Institutet.

Use of beta-blockers was also linked to eight percent lower risk of hospitalization due to mental illness and eight percent increased risk of being treated for suicidal tendencies or dying in suicide. However, these relationships were inconsistent.

- The risk of hospitalization and suicidal tendencies varied depending on psychiatric diagnosis and previous mental health problems, but also on the severity and type of heart problems that the beta blockers were used to treat. This indicates that there are no links between beta blockers and these outcomes, says Yasmina Molero.

Heart problems are associated with depression

Previous research has linked serious heart events to an increased risk of depression and suicide. This may indicate that the mental disorders and other disabilities associated with serious heart problems, rather than the treatment with beta blockers, increase the risk of serious mental illness, according to the researchers.

Funding: The study was funded by the Wellcome Trust, Forte, the American Foundation for Suicide Prevention and the Karolinska Institutet's funds. Co-author Henrik Larsson has received grants from Shire Pharmaceuticals, Medice Speaker Fees, Shire / Takeda Pharmaceuticals and Evolan Pharma as well as sponsorship for a conference on adhd from Shire / Takeda Pharmaceuticals, all outside the current study.

Published in journal: PLOS Medicine

Source/Credit: Karolinska Institutet

Reference Number: ns013123_02

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Marburg vaccine shows promising results in first-in-human study

Colorized scanning electron micrograph of Marburg virus particles (blue) both budding and attached to the surface of infected VERO E6 cells (orange).
Image Credit: National Institute of Allergy and Infectious Diseases

A newly published paper in The Lancet shows that an experimental vaccine against Marburg virus (MARV) was safe and induced an immune response in a small, first-in-human clinical trial. The vaccine, developed by researchers at the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, could someday be an important tool to respond to Marburg virus outbreaks.

This first-in-human, Phase 1 study tested an experimental MARV vaccine candidate, known as cAd3-Marburg, which was developed at NIAID’s Vaccine Research Center (VRC). This vaccine uses a modified chimpanzee adenovirus called cAd3, which can no longer replicate or infect cells, and displays a glycoprotein found on the surface of MARV to induce immune responses against the virus. The cAd3 vaccine platform demonstrated a good safety profile in prior clinical trials when used in investigational Ebola virus and Sudan virus vaccines developed by the VRC.

Researchers revisit potent drug as promising treatment for acute leukemia

Photo Credit: Louis Reed

The two-pronged attack of a “forgotten drug” simultaneously targets two cancer-causing pathways of leukemia to stop the disease in its tracks

A team of researchers from the Cancer Science Institute of Singapore (CSI Singapore) at the National University of Singapore, led by Associate Professor Takaomi Sanda and Dr Lim Fang Qi, has breathed new life into an existing drug — combatting a type of blood cancer called T-cell acute lymphoblastic leukemia, or T-ALL.

The drug, called PIK-75, was initially discovered over a decade ago but was dismissed in favor of newer ones. Now, it has made a comeback that deems it unmissable — the researchers established that the drug could block not just one but two crucial cancer-causing pathways of T-ALL, enabling them to develop new treatments that could effectively stem the disease.

Scientists Suggest New Approach to Targeted Treatment of Bacterial Infections

Photo Source: Ural Federal University

It is based on the nanosystem with polyoxometalate

Chemists from the Ural Federal University have proposed a new approach to targeted treatment of affected areas of the human body, in particular, bacterial infections. It is based on a nanosystem, the core of which is polyoxometalate (containing molybdenum and iron). A broad-spectrum antibiotic, tetracycline, is attached to the surface of the polyoxometalate. This approach makes it possible to fight bacteria more effectively by targeting them. The results of the study are published in the journal Inorganics.

"The polyoxometalate ion is a charged nanoparticle that can be used as a base. It is very small - 2.5 nanometers. This allows it to easily penetrate cells and the walls of blood vessels. Drugs and additional substances (vector molecules) can be "planted" on it to help the system reach a specific affected organ. In this case, the drug is distributed less throughout the rest of the body. This reduces side effects, especially of highly toxic drugs," explains Margarita Tonkushina, a Researcher at the Section of Chemical Material Science and the Laboratory of Functional Design of Nanoclusters of Polyoxometalates at UrFU.

Mucosal antibodies in the airways provide durable protection against SARS-CoV-2

Charlotte Thålin, M.D. and associate professor at the Department of Clinical Sciences, Danderyd Hospital
Photo Credit: Ludvig Kostyal

Researchers hope that a nasal vaccine may generate mucosal immune responses that protect against SARS-CoV-2 infection.

High levels of mucosal IgA antibodies in the airways protect against SARS-CoV-2 infection for at least eight months. Omicron infection generates durable mucosal antibodies, reducing the risk of re-infection. These are the findings of a study published in The Lancet Infectious Diseases by researchers at Karolinska Institutet and Danderyd Hospital in Sweden. The results raise further hope for the feasibility of future nasal vaccine platforms to protect against infection.

“Antibodies in the blood protect from severe disease, but if we aim to limit infection, viral transmission and the emergence of new SARS-CoV-2 variants, we need to reinforce our immunity at the mucosal surface, which is the viral point of entry”, says Charlotte Thålin, M.D. and associate professor at the Department of Clinical Sciences, Danderyd Hospital, Karolinska Institutet who led the study. “This is not achieved by currently employed intramuscularly-delivered vaccines. But the hope is that a nasal vaccine may generate mucosal immune responses similar to those seen after infection, and thereby block the transmission chain”.

Ludwig Cancer Research study uncovers novel aspect of tumor evolution and potential targets for therapy

 Ping-Chih Ho, Ludwig Lausanne Associate Member
Photo Credit: Ludwig Cancer Research

A Ludwig Cancer Research study has discovered that the immune system’s surveillance of cancer can itself induce metabolic adaptations in the cells of early-stage tumors that simultaneously promote their growth and equip them to suppress lethal immune responses.

Led by Ludwig Lausanne Associate Member Ping-Chih Ho and published in Cell Metabolism, the study details the precise mechanism by which this “immunometabolic editing” of emergent tumors occurs in mouse models of the skin cancer melanoma and identifies a novel biochemical signaling cascade and proteins that orchestrate its effects. Aside from illuminating a previously unknown dimension of tumor evolution, the findings hold significant promise for improving the efficacy of cancer immunotherapy.

“We have uncovered dozens of metabolic enzymes that contribute to immune evasion in melanoma tumors,” said Ho. “These enzymes, as well as some of the individual components of the signaling pathway we’ve identified, represent a rich trove of potential drug targets to undermine the defenses erected by immunometabolic editing. Such drugs could make tumors vulnerable to immune clearance and could also be used in combination with checkpoint blockade and other immunotherapies to overcome the resistance most cancers have to such treatments.”

Developing antibiotics that target multiple-drug-resistant bacteria

The sphaerimicin analogs (SPMs) inhibit the activity of MraY, and hence the replication of bacteria, with different degrees of effectiveness. The potency of the analog increases as the IC50 decrease Illustration Credit: Takeshi Nakaya, et al. Nature Communications. December 20, 2022

Researchers have designed and synthesized analogs of a new antibiotic that is effective against multidrug-resistant bacteria, opening a new front in the fight against these infections.

Antibiotics are vital drugs in the treatment of a number of bacterial diseases. However, due to continuing overuse and misuse, the number of bacteria strains that are resistant to multiple antibiotics is increasing, affecting millions of people worldwide. The development of new antibacterial compounds that target multiple drug resistant bacteria is also an active field of research so that this growing issue can be controlled.

A team led by Professor Satoshi Ichikawa at Hokkaido University has been working on the development of new antibacterial. Their most recent research, published in the journal Nature Communications, details the development of a highly effective antibacterial compound that is effective against the most common multidrug-resistant bacteria.

Studies find Omicron related hospitalizations lower in severity than Delta and Pfizer-BioNTech COVID vaccine remains effective in preventing hospitalizations

Photo Credit: Fernando Zhiminaicela

Adult hospitalizations from Omicron-related SARS-CoV-2 (COVID-19) were less severe than Delta and the Pfizer-BioNTech vaccine (also known as Comirnaty and BNT162b2*) remains effective in preventing not only hospitalization, but severe patient outcomes associated with COVID-19, two new research studies have found.

The University of Bristol-led research, funded and conducted in collaboration with Pfizer Inc., as part of AvonCAP, is published in The Lancet Regional Health – Europe.

AvonCAP records adults who are admitted to Bristol’s two hospital Trusts – North Bristol NHS Trust (NBT) and University Hospitals Bristol and Weston NHS Foundation Trust (UHBW) with possible respiratory infection.

In the first paper ‘Severity of Omicron (B.1.1.529) and Delta (B.1.617.2) SARS-CoV-2 infection among hospitalized adults: a prospective cohort study in Bristol, United Kingdom’ researchers assessed whether Delta SARS-CoV-2 infection resulted in worse patient outcomes than Omicron SARS-CoV-2 infection, in hospitalized patients

The study aimed to provide more detailed data on patient outcomes, such as the need for respiratory support.

Scientists Have Created New Substance to Treat Neurological Disorders

Scientists used a set of 1,2,3-triazole derivatives and modeled the structure of the putative inhibitor.
 Photo Credit: Andrey Fomin

The international team of scientists, including chemists from the Ural Federal University, has developed a substance that may become the basis for drugs that suppress or alleviate a number of neurological disorders. These include, for example, psychosis, schizophrenia, Parkinson's and Huntington's diseases, etc. The scientists reported the development and first results of the study in the Journal of Biomolecular Structure and Dynamics. The study was supported by a grant from the Ministry of Science and Higher Education of the Russian Federation (Project No. 075-15-2020-777).

"We found that the enzyme Phosphodiesterase 10A, which is produced in the body, is directly linked to neurological disorders. If you inhibit this enzyme, you can significantly slow down or even suppress the disease. For this purpose, we used a set of derivatives of 1,2,3-triazole, a pharmacophore whose fragments are contained in many drugs, and modeled the structure of the putative TP-10 inhibitor. We hypothesize that it would have a positive effect on conditions associated with brain dysfunction by reducing the activity of the Phosphodiesterase 10A enzyme. Other inhibitors developed by foreign companies still have no reliable antipsychotic efficacy so far," notes Dhananjay Bhattacherjee, senior researcher at the Department of Organic and Biomolecular Chemistry at UrFU.

Scientists invent pioneering technique to construct rare molecules

Bahamaolide A is a polyketide natural product with potent antifungal activity, which was isolated from bacteria cultured from a sediment sample collected at North Cat Cay in the Bahamas and has now been synthesized in the chemical laboratory for the first time.
Image Credit: University of Bristol and Wikimedia Commons

Scientists have created a much faster way to make certain complex molecules, which are widely used by pharmaceuticals for antibiotics and anti-fungal medicines.

The first-of-its-kind discovery by chemists at the University of Bristol has the potential to speed up the production of such drugs, making them cheaper and more accessible.

The breakthrough, published in Nature Chemistry, marks the culmination of a five-year research project which has finally cracked how to reconstruct in a laboratory a particularly complex molecule, from the family of molecules known as polyketides.

Lead author Sheenagh Aiken, a PhD student at the university’s School of Chemistry when the work was completed, said: “It’s an exciting discovery, which could bring important benefits for the pharmaceutical industry and public health.

Experimental COVID-19 Vaccine Offers Long-Term Protection Against Severe Disease

A study involving rhesus macaques at the California National Primate Research Center shows that COVID-19 vaccines given to infant animals protect against lung disease one year after vaccination.
 Photo Credit: CNPRC

Two-dose vaccines provide protection against lung disease in rhesus macaques one year after they were vaccinated as infants, a new study shows. The work, published in Science Translational Medicine Dec. 1, is a follow-up to a 2021 studying showing that the Moderna mRNA vaccine and a protein-based vaccine candidate containing an adjuvant, a substance that enhances immune responses, elicited durable neutralizing antibody responses to SARS-CoV-2 during infancy in preclinical research.

The co-senior authors of the paper are Kristina De Paris, professor of microbiology and immunology at the University of North Carolina at Chapel Hill; Sallie Permar, professor and chair of the Department of Pediatrics at Weill Cornell Medicine; and Koen K.A. Van Rompay, leader of the Infectious Disease Unit at the California National Primate Research at the University of California, Davis. Co-first authors are Emma C. Milligan at the Children’s Research Institute, UNC School of Medicine; and Katherine Olstad at the CNPRC.

To evaluate SARS-CoV-2 infant vaccination, the researchers immunized two groups of eight infant rhesus macaques at the CNPRC at 2 months of age and again four weeks later. Each animal received one of two vaccine types: a preclinical version of the Moderna mRNA vaccine or a vaccine combining a protein developed by the Vaccine Research Center of the National Institute of Allergy and Infectious Diseases (NIAID), with a potent adjuvant formulation. Consisting of 3M’s molecular adjuvant 3M-052 formulated in a squalene emulsion by the Access to Advanced Health Institute (AAHI), the adjuvant formulation stimulates immune responses by engaging receptors on immune cells.

Blood thinning drug to treat recovery from severe COVID-19 is not effective

The HEAL-COVID trial (Helping to Alleviate the Longer-term consequences of COVID-19) is funded by the National Institute for Health and Care Research (NIHR) and the Cambridge NIHR Biomedical Research Centre. To date, more than a thousand NHS patients hospitalized with COVID have taken part in HEAL-COVID, a platform trial that is aiming to find treatments to reduce the number who die or are readmitted following their time in hospital.

In these first results from HEAL-COVID, it’s been shown that prescribing the oral anticoagulant Apixaban does not stop COVID patients from later dying or being readmitted to hospital over the following year (Apixaban 29.1%, versus standard care 30.8%).

As well as not being beneficial, anticoagulant therapy has known serious side effects, and these were experienced by participants in the trial with a small number of the 402 participants receiving Apixaban having major bleeding that required them to discontinue the treatment.

There was also no benefit from Apixaban in terms of the number of days alive and out of hospital at day 60 after randomization (Apixaban 59 days, versus standard care 59 days).

Following these results, the trial will continue to test another drug called Atorvastatin, a widely used lipid lowering drug (‘a statin’) that acts on other mechanisms of disease that are thought to be important in COVID.