OHDSI has established an international network of researchers and observational health databases with a central coordinating center housed at the Department of Biomedical Informatics at Columbia University.

In patients with rheumatoid arthritis, HCQ treatment in the short term (30 days) was found to not carry excess risk of complications associated with its use, but HCQ treatment in the long term had a 65% relative increase in cardiovascular-related mortality, compared to sulfasalazine.

HCQ + AZM had a cardiovascular mortality risk that was more than twice (2.19) as high as the comparative treatment even in the short term based on findings from more than 320,000 users of that combination therapy. This treatment also produced a 15-20% increased rate of angina/chest pain and heart failure.

This study, first published on MedRxiv, has already made significant impacts in the healthcare community. On April 23, the European Medicines Agency (EMA) cited the study in a warning about the risk of serious side effects with chloroquine and hydroxychloroquine. In July, the EMA again highlighted the study, among other efforts within the OHDSI community, in its eighth revision of The European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP) Guide on Methodological Standards in Pharmacoepidemiology.

This is the first published study to be generated from the OHDSI COVID Study-a-thon, a global effort in March to set the foundation for OHDSI efforts to design and execute network observational studies around characterization, patient-level prediction and population-level effect estimation to inform decision-making around the global pandemic. Multiple studies, several of which are highlighted later, have been posted to MedRxiv and are currently under peer review.

HCQ, a drug commonly used in the treatment of malaria, lupus and rheumatoid arthritis (RA), gained early attention during the pandemic as a potential COVID-19 treatment. The short-term (<30 days) safety profile did not identify excess risk in any of 16 severe adverse events as compared to a similar RA drug, sulfasalazine (SSZ). Long-term HCQ therapy was associated with a 65% increase in cardiovascular mortality as compared to SSZ.

“Hydroxychloroquine, both alone and in combination with azithromycin, gained strong consideration as a potential COVID treatment without a large-scale study of its overall safety profile,” said Daniel Prieto-Alhambra, PhD, co-senior author on this study. “We had access to an unprecedented amount of data on this drug, and we were relieved to find no worrying side effects in the short-term use of hydroxychloroquine. However, when prescribed in combination with azithromycin, it may induce heart failure and cardiovascular mortality and we would urge caution in using the two together.”

This study examined more than 950,000 HCQ users through deidentified electronic health records and administrative claims data over a 20-year period. Records were collected from 14 different databases spanning six nations (Germany, Japan, Netherlands, Spain, United Kingdom, United States) and then mapped to the OMOP Common Data Model to generate this large-scale analysis.

“At medical school we were taught to ‘first do no harm’ and to me, our study focuses on this core belief of modern medicine,” said Jennifer Lane, MD, who served as co-lead author on this study along with Jamie Weaver. “OHDSI has the power to investigate this question in a very thorough way and to go through rigorous steps. We are looking at patients from the general population, which is why it is so important to look at data from multiple countries. There are reasons why you may get bias from one data source, but if we find a signal in the Netherlands, and we find it in Spain, and we find it in the U.S., then we know we have something.”

The study was developed and executed by the OHDSI (Observational Health Data Sciences and Informatics) community, a multi-stakeholder, interdisciplinary collaborative to bring out the value of health data through large-scale analytics. All solutions are open-source, and links to the study protocol, code and results are posted at the bottom of this release.

“It required a global effort to generate this level of reproducible, reliable real-world evidence to inform decision-making around COVID treatment,” said Patrick Ryan, PhD, co-senior author on this study. “Our community collaborated for years to develop the high-level analytics which set the course for these studies. Standardizing data for nearly 1,000,000 patients on hydroxychloroquine provides confidence in these findings, and we are pleased to see that this study has already helped make a positive clinical impact as treatment options continue to be evaluated.”

To allay these doubts, Padmanabha Prasanna Simha, from the Indian Space Research Organisation, and Prasanna Simha Mohan Rao, from the Sri Jayadeva Institute of Cardiovascular Sciences and Research, experimentally visualized the flow fields of coughs under various common mouth covering scenarios. They present their findings in the journal Physics of Fluids, from AIP Publishing.

“If a person can reduce the extent of how much they contaminate the environment by mitigating the spread, it’s a far better situation for other healthy individuals who may enter places that have such contaminated areas,” Simha said.

Density and temperature are intricately related, and coughs tend to be warmer than their surrounding area. Tapping into this connection, Simha and Rao utilized a technique called schlieren imaging, which visualizes changes in density, to capture pictures of voluntary coughs from five test subjects. By tracking the motion of a cough over successive images, the team estimated velocity and spread of the expelled droplets.

Unsurprisingly, they found N95 masks to be the most effective at reducing the horizontal spread of a cough. The N95 masks reduced a cough’s initial velocity by up to a factor of 10 and limit its spread to between 0.1 and 0.25 meters.

An uncovered cough, in contrast, can travel up to 3 meters, but even a simple disposable mask can bring this all the way down to 0.5 meters.

“Even if a mask does not filter out all the particles, if we can prevent clouds of such particles from traveling very far, it’s better than not doing anything,” said Simha. “In situations where sophisticated masks are not available, any mask is better than no mask at all for the general public in slowing the spread of infection.”

Some of the other comparisons, however, were striking.

For example, using an elbow to cover up a cough is typically considered a good alternative in a pinch, which is contradictory to what the pair found. Unless covered by a sleeve, a bare arm cannot form the proper seal against the nose necessary to obstruct airflow. A cough is then able to leak through any openings and propagate in many directions.

Simha and Rao hope their findings will put to rest the argument that regular cloth masks are ineffective, but they emphasize that masks must continue to be used in conjunction with social distancing.

“Adequate distancing is something that must not be ignored, since masks are not foolproof,” Simha said.

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The findings could help explain how the brain, which rarely produces new cells, is able to cope with the accumulation of cell damage over time and prevent excess cell loss during aging. They may also help scientists answer questions about human age-related brain diseases.

Most cells have two copies of each chromosome, one from each parent. This provides each cell with two complete copies of DNA, referred to as the genome. But some cells accumulate extra copies of chromosomes, although how and why they do this is not entirely clear. Some scientists have suggested that excess chromosomes might lead to age-related brain diseases.

“The brain of the fruit fly Drosophila melanogaster is an ideal model for studying age-related changes in the brain because the fly has a relatively short lifespan, its brain cells rarely multiply, and we have excellent tools for manipulating fly genetics,” says lead author Shyama Nandakumar, a doctoral student in the department of Molecular, Cellular, and Developmental Biology at the University of Michigan, Ann Arbor, US.

In the study, Nandakumar and colleagues examined adult fly brain cells and found that some accumulate extra copies of their genome, especially in parts of the brain responsible for vision — the region of the brain which shows more DNA damage with age.

Next, they subjected fly brain cells to oxidative stress or ultraviolet radiation, which damage DNA and can cause cell death. They found that this exposure increased the production of extra copies of chromosomes in the cells, and the cells were less likely to die as a result of the damage. “These data suggest that cells with extra copies of the genome are more resistant to cell death and may serve a beneficial or protective role in the aging brain,” Nandakumar explains.

Previous studies have found that patients with early stages of Alzheimer’s disease have extra chromosomes in their brain cells than people of the same age who do not have the condition. This has led scientists to question whether accumulating extra chromosomes leads to brain cell death and brain disease.

“Our study suggests that the production of extra copies of chromosomes might actually be a normal response to the accumulation of age-related damage in flies and may even help protect against cell death,” concludes senior author Laura Buttitta, Associate Professor of Molecular, Cellular and Developmental Biology at the University of Michigan. “Further studies are now needed to determine if this is also true in humans.”

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Antivitamins are substances that inhibit the biological function of a genuine vitamin. Some antivitamins have a similar chemical structure to those of the actual vitamin whose action they block or restrict. For this study, Professor Kai Tittmann’s team from the Göttingen Center for Molecular Biosciences at the University of Göttingen worked together with Professor Bert de Groot’s group from the Max Planck Institute for Biophysical Chemistry Göttingen and Professor Tadgh Begley from Texas A&M University (USA). Together they investigated the mechanism of action at the atomic level of a naturally occurring antivitamin of vitamin B1. Some bacteria are able to produce a toxic form of this vital vitamin B1 to kill competing bacteria. This particular antivitamin has only a single atom in addition to the natural vitamin in a seemingly unimportant place and the exciting research question was why the action of the vitamin was still prevented or “poisoned.”

Tittmann’s team used high-resolution protein crystallography to investigate how the antivitamin inhibits an important protein from the central metabolism of bacteria. The researchers found that the “dance of the protons,” which can normally be observed in functioning proteins, almost completely ceases to function and the protein no longer works. “Just one extra atom in the antivitamin acts like a grain of sand in a complex gear system by blocking its finely tuned mechanics,” explains Tittmann. It is interesting to note that human proteins are able to cope relatively well with the antivitamin and continue working. The chemist de Groot and his team used computer simulations to find out why this is so. “The human proteins either do not bind to the antivitamin at all or in such a way that they are not ‘poisoned’,” says the Max Planck researcher. The difference between the effects of the antivitamin on bacteria and on human proteins opens up the possibility of using it as an antibiotic in the future and thus creating new therapeutic alternatives.

The research project was funded by the German Research Foundation (DFG).

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