COVID-19 creates conditions for emergence of 'superfungus' in Brazil

FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO

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IMAGE: FLUORESCENCE MICROSCOPY IMAGE ILLUSTRATING MORPHOLOGY OF C. AURIS. view more 

CREDIT: JOÃO NÓBREGA ALMEIDA JÚNIOR/UNIFESP

Fully occupied intensive care units (ICUs). Physically and mentally exhausted health workers. Chaotically overcrowded hospitals. These and similar problems posed by the COVID-19 pandemic in Brazil have created ideal conditions for the emergence of Candida auris, a microorganism some are calling a "superfungus" because of the speed with which it has developed drug resistance.

The first two cases were confirmed in December 2020 at a hospital in Salvador (state of Bahia, Northeast Brazil), and are described in the Journal of Fungi by a group of researchers led by Arnaldo Colombo, head of the Special Mycology Laboratory at the Federal University of São Paulo (UNIFESP). The study was supported by São Paulo Research Foundation - FAPESP.

"Nine other C. auris patients have since been diagnosed at the same hospital, some colonized [with the fungus in their organism but not doing harm] and others infected," Colombo told. "No other cases have been reported in Brazil, but there are grounds for concern. We're monitoring the evolutionary characteristics of C. auris isolates from patients at the hospital in Salvador, and we've already found samples with reduced sensitivity to fluconazole and echinocandins. The latter belong to the main class of drugs used to treat invasive candidiasis."

Except for C. auris, fungi of the genus Candida are part of the human gut microbiota and cause problems only when there are imbalances in the organism, Colombo explained. These include infections such as vaginal yeast infection and thrush (oral candidiasis), often caused by C. albicans.

In some cases, however, the fungus enters the bloodstream and causes a systemic infection known as candidemia, the most common form of invasive candidiasis, similar to bacterial sepsis. Invasion of the bloodstream and the immune system's exacerbated response to the pathogen can cause damage to several organs and even lead to death. According to scientific evidence, mortality among candidemia patients infected by C. auris can reach 60%.

"The species quickly becomes resistant to multiple drugs and isn't very sensitive to the disinfectants used by hospitals and clinics," Colombo said. "As a result, it's able to persist in hospitals, where it colonizes health workers and ends up infecting patients with severe COVID-19 and other long-stay critical patients."

Several factors make patients infected by SARS-CoV-2 ideal targets for C. auris, including long hospital stays, urinary and central venous catheters (allowing invasion of the bloodstream), and steroids and antibiotics (which disrupt the gut microbiota).

"The virus can damage the intestinal mucosa of severe COVID-19 patients [facilitating invasion of the bloodstream by pathogens] so that the patient becomes vulnerable to candidemia," Colombo said.

Several countries have reported the emergence of C. auris during the COVID-19 pandemic, he added, making the need to intensify control of hospital-acquired infections throughout Brazil even more urgent. Rational use of antimicrobial drugs in ICUs is equally important. Since the start of the pandemic, azithromycin and other antibiotics have been more widely prescribed, mostly without a genuine justification.

Monitoring

C. auris was first isolated in Japan in 2009 but the scientific community paid it little attention until some years later when outbreaks of candidemia caused by the superfungus occurred in Asia and Europe. In 2016, an article by the UNIFESP group in the Journal of Infection reported the arrival of the species in the Americas via Venezuela. It was soon detected in Colombia, Panama and Chile.

"In 2017 we participated in a task force convened by the Health Ministry and ANVISA [Brazil's health surveillance authority] and wrote a technical standard [Risk Notice 01/2017] warning health services that precautionary measures should be taken to monitor the possible arrival of C. auris in Brazil, which was confirmed only at the end of last year," Colombo said.

Since then, the UNIFESP team has been monitoring the emergence of novel fungal pathogens in bloodstream infections documented by medical centers across Brazil, without detecting C. auris until now.

Five clades or lineages of C. auris have so far been described in the world. According to Colombo, the clade isolated in Salvador resembles the Asian original more closely than the variant detected in Venezuela and other South American countries, suggesting a second independent arrival of the superfungus on the continent.

"Alternatively, there may be a local environmental source, since none of the Brazilian patients infected by the fungus traveled abroad or had infected relatives," Colombo said.

Every month since December, the researchers have received samples of the clade isolated at the hospital in Salvador for testing of its sensitivity to antifungal drugs in their laboratory.

"In these tests, we expose the cultured microorganism to progressive concentrations of antifungals in order to determine the lowest dose that can inactivate it. In the case of C. auris present in samples recently isolated in Salvador, for example, the dose has to be four to five times larger than the dose used to inactivate the isolate cultured in December 2020," Colombo said.

In partnership with Dutch colleagues, the UNIFESP group is conducting a genetic sequencing study to see if the gene that confers drug resistance on C. auris has mutated during the period.

"The mechanism that enables the species to develop drug resistance isn't enzymatic degradation, as in so many bacteria that are resistant to antibiotics," Colombo said. "The fungus develops structural modifications in the proteins to which the drug binds to inhibit cell wall synthesis [glucan synthase in the case of echinocandins], which is key to its survival. We're seeing this phenomenon happen here in Brazil."

In addition to redoubled care with hygiene, surveillance efforts to detect suspected pathogens should be stepped up, he added. Confirming the presence of C. auris in a sample is no trivial task, requiring specific equipment. The most widely used technique is matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry, fairly commonplace in microbiology laboratories but not always available in hospitals in Brazil.

"If the analysis is conducted using conventional automated methods, C. auris can be confused with other species, such as C. haemulonii or C. lusitaniae. Ideally, any strain of Candida that displays drug resistance should be sent for analysis to a reference laboratory," Colombo said.

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About São Paulo Research Foundation (FAPESP)

The São Paulo Research Foundation (FAPESP) is a public institution with the mission of supporting scientific research in all fields of knowledge by awarding scholarships, fellowships and grants to investigators linked with higher education and research institutions in the State of São Paulo, Brazil. FAPESP is aware that the very best research can only be done by working with the best researchers internationally. Therefore, it has established partnerships with funding agencies, higher education, private companies, and research organizations in other countries known for the quality of their research and has been encouraging scientists funded by its grants to further develop their international collaboration. You can learn more about FAPESP at http://www.fapesp.br/en and visit FAPESP news agency at http://www.agencia.fapesp.br/en to keep updated with the latest scientific breakthroughs FAPESP helps achieve through its many programs, awards and research centers. You may also subscribe to FAPESP news agency at http://agencia.fapesp.br/subscribe.

 

Data and safety review board reports how it monitored the COVID-19 vaccine trials

Responsibility for the safety, integrity and scientific validity of the trials fell to 12 experts of the COVID-19 Vaccine Data and Safety Monitoring Board, who now have taken the unusual step of publishing details of their review process

UNIVERSITY OF ALABAMA AT BIRMINGHAM

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IMAGE: RICH WHITLEY view more 

CREDIT: UAB

BIRMINGHAM, Ala. - Clinical evaluation of three COVID-19 vaccine candidates in 2020-21 during a worldwide pandemic that killed or sickened millions was unprecedented in terms of urgency and scope. Responsibility for the safety, integrity and scientific validity of the trials in the United States fell to 12 experts of the federally appointed COVID-19 Vaccine Data and Safety Monitoring Board, or COVID-19 DSMB, who in turn report to an oversight group.

This COVID-19 DSMB team -- which included co-contributing author Richard Whitley, M.D., distinguished professor of pediatrics in the University of Alabama at Birmingham School of Medicine -- has now taken the unusual step of publishing details of their review process in The Journal of Infectious Diseases.

Their goal, they say, is to assure the public of the board's independence and lack of interference from external actors, while they operated under exceptional conditions. Challenges the board faced included:

• The remarkable scale and pace of the trials.
• The frequency of safety events among a combined enrollment of more than 100,000 people, many of whom were older adults or persons with comorbidities that put them at independent risk of serious health events.
• The need to monitor a portfolio of related trials rather than a single trial, and the need to harmonize these studies.
• The politicized setting in which the trials have taken place, including a United States presidential election.

Despite these challenges, they say that the COVID-19 Vaccine DSMB also "can serve as a model for future situations in which there is an urgent need for coordinated development of multiple therapeutic or preventive interventions to address rapidly evolving public health threats."

The story began in May 2020, as the federal government launched Operation Warp Speed to accelerate COVID-19 vaccine development. The operation included funding for multiple large randomized trials to assess the safety and efficacy of candidate vaccines and agreements to purchase hundreds of millions of doses to assure timely manufacture of ample quantities of vaccine.

To ensure rigorous, independent and unbiased scientific and ethical oversight of the vaccine field trials, the National Institute of Allergy and Infectious Diseases, or NIAID, empaneled the COVID-19 Vaccine DSMB. The board has 11 members from the United States, Brazil, South Africa and the United Kingdom, including experts in infectious disease, vaccinology, immunology, biostatistics, pharmacoepidemiology, public health and bioethics, as well as a biostatistician, who is a full-time NIAID employee and serves as executive secretary.

The DSMB's Journal of Infectious Diseases article details their study review process as they reviewed three formal interim efficacy analyses of trials for vaccine makers Moderna, Janssen and AstraZeneca. The board currently is monitoring the Moderna, Janssen, AstraZeneca and Novavax trials. The trial of the Pfizer/BioNTech vaccine, which was not federally funded, has a separate DSMB.

The DSMB reports that it has met by videoconference more than 25 times, generally for two to three hours at a time. As needed, the board holds ad hoc meetings to address emerging safety concerns. If accrual or event milestones were met between scheduled meetings, the board met to review interim analyses.

The board focused on trial conduct, safety and vaccine efficacy. This included a close look at accrual of trial participants, including the numbers and proportions of people in relevant subgroups like age, sex, race, ethnicity and people with risk factors that predispose them to severe COVID-19.

"The DSMB's role in overseeing a portfolio of multiple trials," the board writes, "has facilitated its ability to perform safety monitoring across all trials. For example, when concerns first surfaced about thromboembolic events associated with AstraZeneca's vaccine in Europe, the DSMB was able to review relevant categories of adverse events across its portfolio of trials to look for broader patterns associated with SARS-CoV-2 vaccines as a class."

Participant safety was a central responsibility for the board, which devoted much attention at each meeting to review interim safety metrics. Given the large number of participants in the trials, the board also received regular reports of individual adverse safety events between meetings and determined what further information or actions in response might be needed.

Among the political challenges the board faced was what Science magazine called its "extraordinary rebuke" last March, when the board said the company had used potentially misleading and outdated data in its initial analysis.

The highly politicized atmosphere also included an August 2020 tweet by then-President Donald Trump that the United States Food and Drug Administration "deep state" was delaying COVID-19 vaccines, and his September suggestion that a vaccine for COVID-19 could be ready by Election Day. Another political challenge came when then-FDA Director Stephen Hahn said he was prepared to authorize a vaccine before Phase 3 trials were complete.

Yet politics did not affect the board's work. In its report, the COVID-19 Vaccine DSMB concluded that "Operation Warp Speed is an unprecedented effort to develop safe and effective vaccines that will help end the COVID-19 pandemic.

"Conducting clinical trials under these circumstances requires the utmost attention to participant safety and to data integrity, so that the public and the medical community will ultimately have trust in the vaccines and the process used to develop them. Although (the board) operates behind the scenes, by virtue of its access to unblinded interim data, its charge to recommend changes to ongoing studies based on these data, and its ability to examine emerging data across multiple parallel trials, the COVID-19 Vaccine DSMB is uniquely positioned to ensure that these goals are met."

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Co-authors with corresponding author Steven Joffe, M.D., University of Pennsylvania, and Whitley, of the report "Data and safety monitoring of COVID-19 vaccine clinical trials" are the other board members and the executive secretary. They are Abdel Babiker, University College London, United Kingdom; Susan S. Ellenberg, University of Pennsylvania; Alan Fix, Center for Vaccine Innovation and Access, PATH, Washington, D.C.; Marie R. Griffin, Vanderbilt School of Medicine, Nashville, Tennessee; Sally Hunsberger, NIAID, Rockville, Maryland; Jorge Kalil, Universidade de São Paulo, São Paulo, Brazil; Myron M. Levine, University of Maryland School of Medicine, Baltimore, Maryland; Malegapuru W. Makgoba, Office of Health Standards and Compliance, Pretoria, Republic of South Africa; Reneé H. Moore, Emory University, Atlanta, Georgia; and Anastasios A. Tsiatis, North Carolina State University, Raleigh, North Carolina.

Support for operations of the COVID-19 Vaccine DSMB came from NIAID.

 

Researchers develop more reliable rapid tests for COVID-19

Tests use innovative techniques that improve accuracy rivaling gold standard PCR test

UNIVERSITY OF MARYLAND SCHOOL OF MEDICINE

Research News

 

Researchers at the University of Maryland School of Medicine (UMSOM) have developed two rapid diagnostic tests for COVID-19 that are nearly as accurate as the gold-standard test currently used in laboratories. Unlike the gold standard test, which extracts RNA and uses it to amplify the DNA of the virus, these new tests can detect the presence of the virus in as little as five minutes using different methods.

One test is a COVID-19 molecular diagnostic test, called Antisense, that uses electrochemical sensing to detect the presence of the virus. The other uses a simple assay of gold nanoparticles to detect a color change when the virus is present. Both tests were developed by Dipanjan Pan, PhD, Professor of Diagnostic Radiology and Nuclear Medicine and Pediatrics at UMSOM and his research team. Dr. Pan has a joint appointment at the University of Maryland Baltimore County (UMBC).

"These tests detect the presence of the virus within 5 to 10 minutes and rely on simple processes that can be performed with little lab training," said Dr. Pan. They do not require the extraction of the virus's RNA - which is both complicated and time consuming.

They also are more reliable than the rapid antigen tests currently on the market, which detect the virus only in those with significantly high viral levels. "These two newer tests are extremely sensitive and can detect the presence of the virus, even in those with low levels of the virus," Dr. Pan said.

Dr. Pan's team included UMSOM research fellow Maha Alafeef, UMSOM research associate Parikshit Moitra, PhD, and research fellow Ketan Dighe, from UMBC.

Last month, the U.S. Food and Drug Administration (FDA) registered the laboratory of Dr. Pan as an approved laboratory development site for the Antisense test. The move paves the way for Dr. Pan's laboratory to begin conducting the test at the university, in research settings, as it undergoes further development.

In February, RNA Disease Diagnostics, Inc. (RNADD) received an exclusive global license from UMB and UMBC to commercialize the test. Dr. Pan serves as an unpaid scientific advisor to the company.

This test detects the virus in a swab sample using an innovative technology called electrochemical sensing. It uses a unique dual-pronged molecular detection approach that integrates electrochemical sensing to rapidly detect the SARS-CoV-2 virus.

"The final prototype is like a glucometer, which patients with diabetes use at home to measure their blood glucose levels," said Dr. Pan, "and is just as easy for people to do themselves."

Dr. Pan and his colleagues, in collaboration with RNA Disease Diagnostics, are launching a study of NBA basketball players in New York City to compare the Antisense test to rapid COVID tests that the NBA is using to monitor COVID infections in its players.

"We would like to see whether our test can yield more reliable results compared to the existing platforms," he said. "Current antigen-based rapid COVID tests miss infections about 20 percent of the time and also have high rates of false positive results. Our Antisense test appears to be about 98 percent reliable, which is similar to the PCR test."

Similar to the Antisense test, the second rapid test also does not require the use of any advanced laboratory techniques, such as those commonly used to extract RNA, for analysis. It uses a simple assay containing plasmonic gold nanoparticles to detect a color change when the virus is present. In April, Dr. Pan and his colleagues published a stepwise protocol in the journal Nature Protocols, explaining how the nano-amplified colorimetric test works and how it can be used.

Once a nasal swab or saliva sample is obtained from a patient, the nucleic acid (bits of genetic material) in the sample is amplified via a simple process that takes about 10 minutes. The test uses a highly specific molecule attached to the gold nanoparticles to detect a particular protein. This protein is part of the genetic sequence that is unique to the novel coronavirus. When the biosensor binds to the virus's gene sequence, the gold nanoparticles respond by turning the liquid reagent from purple to blue.

"Innovations in COVID-19 testing remain incredibly important even as the epidemic appears to be waning in this country," said E. Albert Reece, MD, PhD, MBA, Executive Vice President for Medical Affairs, UM Baltimore, and the John Z. and Akiko K. Bowers Distinguished Professor and Dean, University of Maryland School of Medicine. "As we continue to monitor infections in unvaccinated segments of our population and the potential spread of new variants, there will be a vital need for inexpensive rapid tests to ensure that we continue to maintain low infection rates."

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About the University of Maryland School of Medicine

Now in its third century, the University of Maryland School of Medicine was chartered in 1807 as the first public medical school in the United States. It continues today as one of the fastest growing, top-tier biomedical research enterprises in the world -- with 45 academic departments, centers, institutes, and programs; and a faculty of more than 3,000 physicians, scientists, and allied health professionals, including members of the National Academy of Medicine and the National Academy of Sciences, and a distinguished two-time winner of the Albert E. Lasker Award in Medical Research. With an operating budget of more than $1.2 billion, the School of Medicine works closely in partnership with the University of Maryland Medical Center and Medical System to provide research-intensive, academic and clinically based care for nearly 2 million patients each year. The School of Medicine has more than $563 million in extramural funding, with most of its academic departments highly ranked among all medical schools in the nation in research funding. As one of the seven professional schools that make up the University of Maryland, Baltimore campus, the School of Medicine has a total population of nearly 9,000 faculty and staff, including 2,500 student trainees, residents, and fellows. The combined School of Medicine and Medical System ("University of Maryland Medicine") has an annual budget of nearly $6 billion and an economic impact more than $15 billion on the state and local community. The School of Medicine, which ranks as the 8th highest among public medical schools in research productivity, is an innovator in translational medicine, with 600 active patents and 24 start-up companies. The School of Medicine works locally, nationally, and globally, with research and treatment facilities in 36 countries around the world. Visit medschool.umaryland.edu

Common cold combats COVID-19

YALE UNIVERSITY

Research News

 

Exposure to the rhinovirus, the most frequent cause of the common cold, can protect against infection by the virus which causes COVID-19, Yale researchers have found.

In a new study, the researchers found that the common respiratory virus jump-starts the activity of interferon-stimulated genes, early-response molecules in the immune system which can halt replication of the SARS-CoV-2 virus within airway tissues infected with the cold.

Triggering these defenses early in the course of COVID-19 infection holds promise to prevent or treat the infection, said Ellen Foxman, assistant professor of laboratory medicine and immunobiology at the Yale School of Medicine and senior author of the study. One way to do this is by treating patients with interferons, an immune system protein which is also available as a drug.

"But it all depends upon the timing," Foxman said.

The results were published June 15th in the Journal of Experimental Medicine.

Previous work showed that at the later stages of COVID-19, high interferon levels correlate with worse disease and may fuel overactive immune responses. But recent genetic studies show that interferon-stimulated genes can also be protective in cases of COVID-19 infection.

Foxman's lab wanted to study this defense system early in the course of COVID-19 infection.

Since earlier studies by Foxman's lab showed that common cold viruses may protect against influenza, they decided to study whether rhinoviruses would have the same beneficial impact against the COVID-19 virus. For the study, her team infected lab-grown human airway tissue with SARS-CoV-2 and found that for the first three days, viral load in the tissue doubled about every six hours. However, replication of the COVID-19 virus was completely stopped in tissue which had been exposed to rhinovirus. If antiviral defenses were blocked, the SARS-CoV-2 could replicate in airway tissue previously exposed to rhinovirus.

The same defenses slowed down SARS-CoV-2 infection even without rhinovirus, but only if the infectious dose was low, suggesting that the viral load at the time of exposure makes a difference in whether the body can effectively fight the infection.

The researchers also studied nasal swab samples from patients diagnosed close to the start of infection. They found evidence of rapid growth of SARS-CoV-2 in the first few days of infection, followed by activation of the body's defenses. According to their findings, the virus typically increased rapidly for the first few days of infection, before host defenses kicked in, doubling about every six hours as seen in the lab; in some patients the virus grew even faster.

"There appears to be a viral sweet spot at the beginning of COVID-19, during which the virus replicates exponentially before it triggers a strong defense response," Foxman said.

Interferon treatment holds promise but it could be tricky, she said, because it would be mostly effective in the days immediately after infection, when many people exhibit no symptoms. In theory, interferon treatment could be used prophylactically in people at high risk who have been in close contact with others diagnosed with COVID-19. Trials of interferon in COVID-19 are underway, and so far show a possible benefit early in infection, but not when given later.

These findings may help explain why at times of year when colds are common, rates of infections with other viruses such as influenza tend to be lower, Foxman said. There are concerns that as social distancing measures ease, common cold and flu viruses -- which have been dormant over the past year -- will come back in greater force. Interference among respiratory viruses could be a mitigating factor, creating an "upper limit" on the degree to which respiratory viruses co-circulate, she said.

"There are hidden interactions between viruses that we don't quite understand, and these findings are a piece of the puzzle we are just now looking at," Foxman said.

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Nagarjuna R. Cheemarla, a postdoctoral associate in Foxman's lab, was first author of the study, which was carried out by a team of Yale scientists in the Departments of Laboratory Medicine, Immunobiology, and Genetics.

Other Yale authors included Timothy Watkins, Valia Mihaylova, Bao Wang, Marie Landry, Dejian Zhao, and Guilin Wang.

Sequencing of wastewater can help monitor SARS-COV-2 variants

AMERICAN SOCIETY FOR MICROBIOLOGY

Research News

 

Washington, D.C. - June 15, 2021 - Viral genome sequencing of wastewater can provide an early warning system of emerging SARS-CoV-2 variants that is independent of investigations of identified clinical cases, according to a new study published in mSystems, an open-access journal of the American Society for Microbiology. In the study, researchers describe the detection and quantification of variant B.1.1.7, first identified in southeast England, in sewage samples from London, United Kingdom before widespread transmission of this variant was obvious from clinical cases.

"Wastewater sampling and environmental surveillance gives you a quick and accurate picture of what is happening with the coronavirus in the human population. Most people infected but not showing symptoms are not getting tested for the virus. Wastewater sampling gives you information on all people, including asymptomatic individuals, so it better reflects the circulation of the virus among humans," said study principal investigator Javier Martin, Ph.D., a biologist in the Division of Virology, National Institute for Biological Standards and Control, South Mimms, Potters Bar, Hertfordshire, United Kingdom "Environmental sampling and viral genome sequencing provide a less biased picture of virus circulating patterns among humans, how different variants predominate with time and how changes in strain predominance occurs."

In the new study, to evaluate the value of environmental surveillance for SARS-CoV-2 detection, researchers analyzed sewage samples collected in London between January 14, 2020 and January 26, 2021 for the presence of SARS-CoV-2. They had to distinguish the SARS-CoV-2 genetic signal from the billions of bacteria and viruses people excrete every day. "When we received a sample, we concentrated it using standard methods, and then we used PCR amplification and next generation sequencing targeting different regions of the genome to detect different genetic signatures characteristic of the different known variants," said Dr. Martin.

The researchers first detected variant B.1.1.7 in a sample from early November 2020, a few weeks before it was first noticed through clinical surveillance, and found that the frequency of B.1.1.7 mutations detected in sewage rapidly increased to >95% in January 2021, in accordance with increasing SARS-CoV-2 infections associated with B.1.1.7 viruses.

"Here, we show how environmental surveillance for SARS-CoV-2 can be used to help us understand virus transmission patterns and provide an early warning of variants becoming prevalent in the population," said Dr. Martin. "We will continue monitoring for the different variants focusing on those with potential high transmissibility and/or immune-evading properties. Our results contribute to a better epidemic control and future changes in vaccine design if necessary."

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Microscopic CCTV reveals secrets of malaria invasion

WALTER AND ELIZA HALL INSTITUTE

Research News

VIDEO: LATTICE LIGHT SHEET MICROSCOPY HAS BEEN USED TO REVEAL THE DETAILS OF HOW MALARIA PARASITES INVADE RED BLOOD CELLS - A KEY STEP IN THE DEADLY DISEASE. view more 

CREDIT: WEHI, AUSTRALIA

State-of-the-art video microscopy has enabled researchers at WEHI, Australia, to see the molecular details of how malaria parasites invade red blood cells - a key step in the disease.

The researchers used a custom-built lattice light sheet microscope - the first in Australia - to capture high-resolution videos of individual parasites invading red blood cells, and visualise the molecular and cellular changes that occur throughout this process. The research has provided critical new information about malaria parasite biology that may have applications for the development of much-needed new antimalarial medicines.

The research, which was published today in Nature Communications, was led by Ms Cindy Evelyn, Dr Niall Geoghegan, Dr Lachlan Whitehead, Professor Alan Cowman and Dr Kelly Rogers.

At a glance

• An advanced microscopy platform, called lattice light sheet microscopy, has been used to obtain detailed, real-time videos of the malaria parasite invading red blood cells.
• The research has revealed key steps in the parasite invasion process, which is a critical point of the malaria life-cycle and underpins many symptoms of malaria.
• The team's discoveries could advance the development of much-needed new antimalarial medicines.

Focusing on a deadly parasite

Malaria is a mosquito-borne disease that kills around 400,000 people globally each year. Many of the serious symptoms of malaria occur because of the invasion and growth of the Plasmodium parasite in an infected person's red blood cells, said Dr Rogers, who is the head of WEHI's Centre for Dynamic Imaging.

"Understanding in better detail exactly how the parasite invades red blood cells may reveal new ways to stop this stage of the parasite life cycle, potentially leading to much-needed new therapies," she said.

"We used microscopy - specifically a state-of-the-art approach, lattice light sheet microscopy (LLSM) - to follow the intricate cellular and molecular changes that occur when the malaria parasite invades red blood cells. We captured the first ever high-resolution, real time and dynamic views of the parasite in action."

Ms Evelyn, who began the research as an Honours student, said the research revealed many previously unrecognised aspects of parasite invasion.

"The videos we recorded showed the 'push and pull' interactions as the parasite landed on the red blood cell, and then entered the cell in an enclosed chamber - called a vacuole - where it grew and multiplied.There has long been contention in the field about whether the vacuole is derived from the parasite or the host cell. Our research resolved this question, revealing it was created from the red blood cell's membrane," she said.

Most antimalarial therapies and vaccines target the initial binding of malaria to red blood cells.

"By visualising these processes in more detail, our research may contribute in several ways to the development of new antimalarial therapies. For example, now that we know that the parasite vacuole relies on components of the red blood cell membrane, it might be possible to target these components with medicines to disrupt the parasite life cycle. This host-directed approach could be one way to bypass the malaria parasite's propensity to rapidly develop drug resistance," Dr Rogers said.

"LLSM may also have applications for observing the specific steps of parasite invasion that are blocked by potential new drugs - an area we are now very interested in pursuing."

New views of cells

LLSM is an advanced imaging technology that enables researchers to visualise cells and organs in unprecedented detail and in real time. Dr Geoghegan said LLSM had changed how cells could be studied.

"In the past, the choice of microscope for an experiment had to be a compromise between capturing a lower resolution video, which revealed dynamic processes like shape changes or movement, and capturing much higher-definition still images, which provided much more detail about how the cells and molecules are functioning," he said.

"LLSM allows us to obtain high-resolution videos of cells, which has been a game-changer for many fields of biological research.

We custom built a LLSM at WEHI - the first version of this technology in Australia. This groundbreaking microscopy has enabled us to progress multiple areas of research, including this malaria study. To achieve this, we brought together a multidisciplinary team with expertise in physics, engineering and biology - and the results of this current study have vindicated our approach."

The research was supported by the Australian National Health and Medical Research Council, an EMBO Long Term Fellowship, a Sir Henry Wellcome Fellowship and the Victorian Government.

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Over half of cardiovascular disease deaths worldwide occur in Asia

Paper urges identifying epidemiological features of CVD in Asian countries to combat epidemic

AMERICAN COLLEGE OF CARDIOLOGY

Research News

 

The number of people dying from cardiovascular disease (CVD) in Asia is increasing rapidly, with over half of all CVD deaths globally in 2019 occurring in Asian countries, according to a state-of-the-art review paper published in the inaugural issue of JACC: Asia. The data demonstrates an urgent need to understand the burdens and epidemiological features of CVD in Asian countries to develop localized CVD prevention strategies to combat the epidemic.

From 1990 to 2019, the number of CVD deaths in Asia rose from 5.6 million to 10.8 million. Nearly 39% of these CVD deaths were premature, meaning they occurred in a person less than 70 years old, which was significantly higher than premature CVD deaths in the U.S. (23%). Most CVD deaths were due to ischemic heart disease (IHD) or stroke. According to the researchers, increasing CVD epidemics in Asia are due to demographic changes, socioeconomics, living environments, lifestyles, prevalence of CVD risk factors and capacities to prevent and treat CVD.

In this paper, authors reviewed data on CVD epidemiology in Asian countries from multiple sources and identified five epidemiological features in Asia: continuously increasing CVD mortality rate; geographic differences in CVD mortality; regional differences in the dominant CVD subtype; countries that are in different transition stages of the CVD epidemic; and the increasing epidemics and massive burdens of key modifiable CVD risk factors in most countries with inadequate capacities for management.

"Timely information on the burdens and epidemiological features of CVD in Asian countries is crucial to understanding the challenges and orienting the development of reasonable policies strategies and actions to combat the CVD epidemic," said Dong Zhao, MD, PhD, professor of preventive cardiology at the Beijing Institute of Heart, Lung and Blood Vessel Diseases at Beijing Anzhen Hospital, Capital Medical University, and a deputy editor of JACC: Asia.

From 1990-2019, the proportion of CVD deaths among total deaths in Asia increased from 23% to 35%, and crude CVD mortality rates grew in both men and women. The rising crude CVD mortality rates indicate the increasing burden of CVD in Asian populations.

There were significant geographic differences in crude CVD mortality rates among Asian countries in 2019. The highest CVD mortality rate in Asia was in Georgia (810.7 per 100,000 population) and the lowest was in Qatar (39.1 per 100,000 population), representing a 20-fold difference.

While IHD and stroke are the most common causes of CVD in Asia, epidemics of these two types of CVD varied substantially between Asian regions and countries. IHD was the most dominant cause of CVD deaths in Central, Western and Southern Asia, whereas deaths from stroke were more common than IHD deaths in Eastern and Southeastern Asia. In China, the dominant subtype of CVD deaths has shifted from stroke to IHD. According to the authors, the underlying cause of the differences in the dominant CVD subtypes among Asian regions or countries is still not well understood.

The paper also compared the characteristics of CVD spectrums (the distributions of relevant disease categories in total deaths) in low-, middle- and high-income (or developed) Asian countries since countries at different stages of economic development may feature different transition stages of the CVD epidemic.

"It is critical to recognize the characteristics of different transition stages of the CVD epidemic in different Asian countries in order to guide the identification of priority issues in public health, resource allocation and research in these countries," Zhao said.

Most Asian countries are in the second stage of the rapidly increasing CVD epidemic. In these countries like China, CVD mortality rates are relatively high, with the proportion of CVD deaths among total deaths generally greater than 40%. Characteristics of CVD epidemics in high-income or developed countries feature the third stage of the epidemiological transition, with lower proportions of CVD deaths. In Japan and South Korea, the proportions of CVD deaths among total deaths decreased from 34.9% and 36.2% in 1990, to 26.6% and 24.3% in 2019, respectively.

According to the researchers, the increasing prevalence of CVD risk factors is a major modifiable cause of the rising CVD epidemics in Asia. These risk factors include dietary, smoking, dyslipidemia, diabetes and hypertension, among many others.

"The information summarized in this review provides a complete picture of CVD epidemiology in Asia, highlighting specific requirements for the development of localized CVD prevention strategies and research, and may illuminate not only the current but also future challenges faced by different Asian countries," Zhao said.

###

The paper published in the inaugural, June issue of JACC: Asia, the first region-specific cardiovascular journal with original peer-reviewed content. Other manuscripts published in the June issue include the following:

• Impact of Age and Sex on Subclinical Coronary Atherosclerosis in a Healthy Asian Population;
• Inter-Ethnic Difference in Cardiovascular Disease: Impact on Therapies and Outcomes; and more.

Learn more about JACC: Asia at http://www.jacc.org/jacc-asia.

For an embargoed copy of any of the papers in JACC: Asia, contact Dana Kauffman at dkauffman@acc.org.

The American College of Cardiology envisions a world where innovation and knowledge optimize cardiovascular care and outcomes. As the professional home for the entire cardiovascular care team, the mission of the College and its 54,000 members is to transform cardiovascular care and to improve heart health. The ACC bestows credentials upon cardiovascular professionals who meet stringent qualifications and leads in the formation of health policy, standards and guidelines. The College also provides professional medical education, disseminates cardiovascular research through its world-renowned JACC Journals, operates national registries to measure and improve care, and offers cardiovascular accreditation to hospitals and institutions. For more, visit acc.org.

The Journal of the American College of Cardiology ranks among the top cardiovascular journals in the world for its scientific impact. JACC is the flagship for a family of journals--JACC: Cardiovascular Interventions, JACC: Cardiovascular Imaging, JACC: Heart Failure, JACC: Clinical Electrophysiology, JACC: Basic to Translational Science, JACC: Case Reports, JACC: CardioOncology and JACC: Asia--that prides themselves in publishing the top peer-reviewed research on all aspects of cardiovascular disease. Learn more at JACC.org.

 OF MICE AND MEN

Research papers that omit 'mice' from titles receive misleading media coverage

Study suggests relationship between how scientists communicate findings and how journalists report research to public

PLOS

Research News

 

IMAGE: OMITTING MICE FROM THE PAPER'S TITLE: ARE SCIENTISTS IGNORING A RELEVANT CAVEAT? view more 

CREDIT: IMAGE BY SIBYA FROM PIXABAY

There is increasing scrutiny around how science is communicated to the public, but what is the relationship between how scientists report their findings and how media reports it to the public? A study published in PLOS Biology by Marcia Triunfol at Humane Society International, in Washington, DC and Fabio Gouveia at Oswaldo Cruz Foundation in Rio de Janeiro, Brazil suggests that when authors of scientific papers omit the basic fact that a study was conducted in mice (and not in humans) from the article title, journalists reporting on the paper tend to do the same.

Alzheimer's Disease is an exclusively human condition that does not occur naturally in other species, but around 200 rodent models have been developed to study it. News stories frequently lead with headlines omitting that Alzheimer's Disease research findings are based on research using mice, not humans.

To test the hypothesis that how scientists report their research plays a role in the news reporting, the researchers analyzed 623 scientific papers published in 2018 and 2019 that used mice either as models or as the biological source for experimental studies in Alzheimer's Disease research. They then divided the papers into two groups; those that declared in their titles that mice were the study's main species, and those that omitted mice from the paper's title. The authors analyzed whether there was any difference between these groups regarding the number of news stories each paper generated.

The researchers found an association between articles' titles and news stories' headlines, suggesting that journalists tend to follow authors' decision to omit the species studied in the paper's title. They also found that papers not mentioning mice in their titles receive more press coverage and are significantly more highly tweeted than papers that do. The study had several limitations, including that the articles analyzed only included open access publications. Additionally, findings cannot be extended to other fields before a careful analysis is done.

According to the authors, "To our knowledge, this is the first study to present scientific evidence that the way science is reported by scientists plays a role in how journalists report science news. News stories' headlines that omit mice as the main study subject may mislead the public regarding the actual state of affairs in Alzheimer's Disease research while raising false hopes for patients and their families".

Dr. Triunfol notes, "We need to remember that most people only read the headlines of news stories. Thus, if the headline omits that the Alzheimer's study was done in mice, most keep the impression that the study findings apply to humans, which is not true. We now know that virtually all findings obtained in animal studies in Alzheimer's Disease do not replicate to humans".

Dr. Triunfol adds, "In a follow up study we will investigate why scientists choose to omit mice from their studies' titles. In this article we raised some hypothesis".

###

Research article

Peer-reviewed; Observational study; Studies

In your coverage please use these URLs to provide access to the freely available articles in PLOS Biology: http://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3001260

Citation: Triunfol M, Gouveia FC (2021) What's not in the news headlines or titles of Alzheimer disease articles? #InMice. PLoS Biol 19(6): e3001260. https://doi.org/10.1371/journal.pbio.3001260

Funding: The authors received no specific funding for this work.

Competing Interests: The authors have declared that no competing interests exist.

Alzheimer disease research results over-hyped if science papers omit mice from the title

Scientists call for accurate reporting of animal studies to avoid misleading the public with exaggerated news headlines

HUMANE SOCIETY INTERNATIONAL

Research News

 

A study of media coverage of 623 scientific papers on Alzheimer disease research conducted in mice reveals that the news media are more likely to write a story about alleged breakthroughs or medical research findings if research authors omit mice from their studies' titles. On the other hand, papers that acknowledge mice in their titles result in limited media coverage.

In addition, the study titled "What's not in the news headlines or titles of Alzheimer disease articles? #In mice" conducted by Dr Marcia Triunfol of Humane Society International and Dr Fabio Gouveia of the Oswaldo Cruz Foundation in Brazil, and published in PLoS Biology, found that the resulting media coverage generated by papers with "missing mice" titles is also more likely to omit mice from their headlines.

This is of concern because scientific findings obtained from animal experiments should be reported with caution due to their limited relevance to human health. The biology and physiology of mice and other animals differ significantly to that of humans, such that research results obtained in animals often fail to be replicated in people. Despite that, the scientific value of articles downplaying that they relied on animal models is actually inflated by their disproportionate media exposure, raising concerns that the public and patients are being misled.

Dr Triunfol, one of the study's authors and Humane Society International's scientific advisor, says: "There are around 200 animal models to study Alzheimer disease, and yet the vast majority of potential treatments discovered through experiments on mice are ineffective when tested in humans. Despite this significant flaw in the animal models, we show that articles glossing over the fact that the results were obtained using animals are given increased visibility and therefore implied credibility by the media. The reporting of animal research needs to be addressed with far greater caution and more prominent disclaimers in mainstream media to ensure the public understands that the results of animal experiments may have little to no relevance to human patients."

The study's authors looked at research published in 2018 and 2019 in open-access journals and indexed in PubMed. Of the 623 papers reviewed, 405 added 'mice' in the titles but 218 made no mention of mice, despite the fact that in both groups mice were the main research subjects. Using Altmetric Explorer, a web-based platform that allows users to browse a report on digital attention data for research papers, Dr. Gouveia reported that he and Dr. Triunfol found that "when authors omit mice from the paper's title, writers of news stories reporting on these papers tend to follow suit. What we see is that in most cases their headlines do not mention mice either."

The study also shows that papers that omit mice from their titles generate twice the number of social media tweets compared to papers that do mention mice in the title (18.8 tweets against 9.7 tweets, on average).

Some examples of media stories based on mouse results but without mentioning mice in their headlines are "Common nutrient supplementation may hold the answers to combating Alzheimer's disease", "How flashing lights could treat Alzheimer's disease" and "How Exercise Might 'Clean' the Alzheimer's Brain," among many others. Such headlines risk giving the impression that these findings apply to people with Alzheimer disease, when in reality they apply to mice only, until/unless new scientific evidence is produced. The problem of "missing mice" in the media is so common, that in March 2019 @justsaysinmice burst onto Twitter (now with 70.5K followers) with the aim of drawing attention to headline news stories in which mice -- the subject of the breakthrough -- go unacknowledged.

Drs Triunfol and Gouveia call for implementation of editorial policies, such as the ARRIVE guidelines (an internationally accepted checklist of recommendations to improve the reporting of research involving animals), to require that titles of experimental articles identify the species and/or tissue sources used in the research, if not derived from humans. By improving the quality of scientific reporting, we can improve the accuracy of science media news and encourage greater transparency concerning the true state of affairs in Alzheimer disease research.

###

Analysis: Chile's transition to democracy slow, incomplete, fueled by social movements

CARNEGIE MELLON UNIVERSITY

Research News

 

A new article analyzes Chile's transition in 1990 from dictatorship to democracy, the nature of democracy between 1990 and 2019, and the appearance of several social movements geared to expanding this democracy. The article, by researchers at Carnegie Mellon University (CMU), appears in The Latin Americanist, a publication of the Southeastern Council of Latin American Studies.

"Our goal is to locate the October 2019 protest movement in the context of Chile's very slow and incomplete transition to democracy, as well as amid social movements that have consistently challenged the economic system and the democracy of elites that emerged after the end of the dictatorship in 1989," explains Silvia Borzutzky, teaching professor of political science and international relations at CMU's Heinz College, who cowrote the article.

The article presents a range of expert viewpoints on Chilean history, as well as the authors' analysis of how Chile's political and economic system and previous social movements culminated in what they call "a social explosion" in October 2019.

In its origins and performance, Chile's political system became illegitimate and provided the space for the emergence of several social movements, the authors argue. These included the movement of the Mapuche people to maintain autonomy and ownership of ancestral lands; the feminist movement, which focused on advancing women's rights, reducing poverty and maternal mortality, and strengthening laws on gendered violence; three different student movements; and a movement that sought changes in pension systems.

About 15 years after the end of the dictatorship, a new generation of Chileans began to see the government's inability to address educational issues, pensions, public transportation, and indigenous and women's rights. They took to the streets to demand change, and their movements became an almost permanent fixture of Chile's political landscape, the authors argue.

Although then-President Bachelet tried in 2006 to move from an elitist democracy to a democracy by commissions to expand participation, her failure created more dissatisfaction over lack of representation, dissatisfaction with politics, and persistent inequality, the authors suggest. Despite a stable economy, the political system fractured and remained largely incapable of meeting socioeconomic demands.

The authors cite these grievances and government-initiated violence to explain the massive protests in October 2019, known as the October 18 movement, but point out that other factors were also at play. By December 28, 2019, 27 people had died, nearly 2,500 were injured, and 2,840 were arrested, according to a United Nations investigation.

The article concludes by analyzing the demands made by the protesters and the government's responses to the October 18 movement. The authors also address the role of the COVID-19 pandemic, which delayed a referendum on a new constitution. Although the cycle of protests appears to have been tamed by the promise of a new constitution, the authors note that dissatisfaction could spur new protests at any time.

"The October 18 movement is both a continuation of and the culmination of many previous protests and actions," says Sarah Perry, a 2021 Master of Public Policy and Management graduate from CMU's Heinz College, who coauthored the article. "Because the country experienced a deficit of democratic values, these social movements were able to find their place, and to demand specific rights and benefits; they highlight the illegitimate nature of the political and economic systems in Chile."

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A push for a shift in the value system that defines "impact" and "success"

PLOS

Research News

 

Discussions of a broken value system are ubiquitous in science, especially after the COVID-19 pandemic served to expose inequality globally. However, according to the authors of an article publishing 15th June 2021 in the open access journal PLOS Biology, science itself is not "broken," but it was built on deeply-entrenched, systemic sexist and racist values, which perpetuate biases through the continued focus on citation rates and impact factors.

The author maintain that while equity within science has advanced thanks to the tireless efforts of generations of systemically marginalized groups, the system remains outdated, colonialist, and patriarchal. It overemphasizes contributions of males, and downplays the breadth of an individuals' meaningful scientific impacts outside of scientific literature - especially the contributions of women and other marginalized groups.

To write this article, a group of 24 women from across the world came together to explore long-standing problems associated with narrow definitions of success and impact in science. Co-lead author Dr. Sarah Davies, an Assistant Professor of Biology, says "As scientists, we should let the data speak for themselves - citations and impact metrics have been repeatedly shown to be sexist and racist, yet we still use them. It is high time we shift to a system that appreciates the varied avenues of impact in science and valuing mentorship and advocating for diversity will be key components of this change".

The paper calls for the global scientific community - especially those in positions of power and privilege - to reject all forms of implicit and systematic biases, especially when they have been thoroughly studied and documented - as is the case with citation and publication biases.

The authors advocate for dismantling the current biased value system by expanding measures of success beyond citations, in order to appreciate the multifaceted nature of scientific impact. Specifically, they call for a paradigm shift to scientific values based on multidimensional mentorship that incorporate diverse measures of success and impact and promote mentee wellbeing.

Dr. Sangeeta Mangubhai, a Fijian scientist with the Wildlife Conservation Society explains: "We propose building a new academic model that values the recruitment and retention of diverse scientists through fostering safe and healthy work environments. This new model calls for the rebuilding of the outdated value system to advance science through principles of justice, equity, diversity, and inclusion."

These authors join the call to action of all members of the scientific community - particularly those in positions of power - to re-evaluate how we define impact, and invest resources to accelerate change toward a more equitable, inclusive, and just system.

###

Research article

Peer reviewed; Observational study; People

In your coverage please use these URLs to provide access to the freely available articles in PLOS Biology: http://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3001282

Citation: Davies SW, Putnam HM, Ainsworth T, Baum JK, Bove CB, Crosby SC, et al. (2021) Promoting inclusive metrics of success and impact to dismantle a discriminatory reward system in science. PLoS Biol 19(6): e3001282. https://doi.org/10.1371/journal.pbio.3001282

Funding: The authors received no specific no specific funding for this work.

Competing Interests: The authors received no specific no specific funding for this work.