Body

Sepsis is estimated to cause 11 million deaths every year in the world. Its treatment is based on the use of antibiotics and organ support measures, but many times it fails due to unsuccessful attempts at modulating the immune response. Sepsis is a complication that occurs from a generalized infection and is characterized by a dysregulated immune response that entails a high risk of death. Surviving a severe infection requires the activation of mechanisms both of resistance, which reduce the number of infectious agents, and of disease tolerance, which control the damage caused by the immune response and the infectious agents that triggered it. Around one fourth of sepsis patients dies even if the infectious agent is eradicated completely.

The team of researchers led by Luís Ferreira Moita, principal investigator at Instituto Gulbenkian de Ciência (IGC), proposed to identify disease tolerance mechanisms focusing on the role of mitochondria in such processes. Most organisms have defence mechanisms against homeostasis perturbations (physiological mechanisms that allow organisms to respond to constant internal and environmental changes), which are essential to the initiation of the immune response. One of the main triggers relates to the activation of danger signals as soon as internal structures of the cell start failing. These structures are necessary to the normal functioning of cells and include, among others, the mitochondria, known for their essential role in cell metabolism, namely related to energy production, and that now have roles that extend far beyond that.

The research developed at the IGC selected a group of medical drugs known for their abilities to interfere with basic cell functions. Among them, it was observed that doxycycline, an antibiotic belonging to the family of the tetracyclines, confers an increase in mice survival upon sepsis, independently of its effects in the control of bacterial burden. Previous studies performed by others revealed that doxycycline blocks the functioning of a part of cells - the mitochondrial ribosome, which is responsible for protein production in these cellular structures. "We discovered that it is this inhibition of protein production in the mitochondria of the infected organism that explains the observed increase in survival of mice with sepsis, and it is independent of the antibacterial properties of this antibiotic", explains Luís Ferreira Moita.

For several decades, it has been known that some families of antibiotics provide benefits that go beyond their important antibacterial properties, but so far remain unexplained. "The results we obtained highlight that, in the case of doxycycline, these benefits reach the lungs, where there is a decrease in cell damage and the activation of tissue repair mechanisms. Additionally, in the liver, the stress response is activated together with metabolic changes that promote tissue repair" states Henrique Colaço, also author of the study.

This study stresses the need for a better understanding of the physiology of disease tolerance in vertebrates and opens new possibilities for therapies against infections and diseases like sepsis, based on the increase of disease tolerance mechanisms and not just their control.

Numerous studies over the last few weeks have pointed out that the effects of the Corona pandemic on people's mental health can be enormous and affect large parts of the population. In spring, Prof. Tatjana Schnell from the Existential Psychology Lab at the Department of Psychology at the University of Innsbruck, Austria, together with her colleague Henning Krampe from the Departement of Anaesthesiology at Charité - Universitätsmedizin Berlin, Germany, launched a comprehensive quantitative study. First results of this study have now been published in the journal Frontiers in Psychiatry. Between 10 April and 28 May, a total of 1538 German-speaking persons, mainly from Austria and Germany, completed online questionnaires about their living conditions, their perception of the pandemic situation (COVID-19 Stress) and various characteristics of mental health, with a main focus on meaning in life and self-control. For 20 years, the psychologist Tatjana Schnell has been studying meaning in life on various levels and examining its effects on the stability of mental health. "In the current study, we looked at the way meaning in life affected people during the period of restrictive lockdown and immediately afterwards. Did people with a strong sense of meaning in their lives cope better with the situation?," says Schnell. "Our second major focus was on self-control: how well were people able to restrict their needs and adapt to the exceptional situation," she says about the study's objectives. In general, Schnell and Krampe found that older people showed higher resilience. The data suggested that older participants had to struggle with significantly fewer negative psychological consequences than the younger: "Meaningfulness tends to increase with age; older people are often better able to adopt metaperspectives and thus benefit more from their life experience in terms of their psychological stability," the researchers conclude.

Values during lockdown better than afterwards

The first results of this study, which have now been published, clearly show that general mental distress was significantly increased during the first months of the pandemic. "People who had a strong sense of meaning in their lives, however, reported less severe mental distress overall. The ability of self-control - which is an important resource in terms of compliance with restrictions - was also beneficial to mental well-being. Both meaningfulness and self-control acted as a kind of buffer: they weakened the connection between COVID-19 stress and mental distress," Schnell explains. The scientists were also interested in the development over several months: "The problems were apparently less severe during the strict lockdown than afterwards. The ease of restrictions did not lead to an improvement of the psychological situation - in fact the opposite was true. Schnell and Krampe can only assume what the reason for this is: "Of course, one source of concern is economic losses. In addition, our data indicate a possible connection with the ambiguity of the situation: During the strict initial restrictions, the situation was clear to everyone. There were explicit guidelines and everyone was in the same boat, so to speak. This atmosphere has probably had a positive effect for many people". In the weeks following the lockdown, Schnell und Krampe registered both increasing crises of meaning and more severe psychological distress as well as a diminished sense of meaning in life and a deficiency in self-control. "We assume that self-control declined shortly after the lockdown - and seems to have continued declining, as we can observe in society - because the restrictions' purpose is less clear: In Austria and Germany, the measures have worked so well that the situation has not (yet) escalated, which leads one to question their meaning - the so-called prevention paradox. In addition, in recent months, communication by the authorities has become less explicit and comprehensible. But if the meaningfulness of the measures is not apparent, it is difficult for many people to maintain self-control in the long term," Tatjana Schnell points out.

Here Schnell and Krampe appeal once again to those responsible in politics: "If you want to achieve acceptance throughout society, you should act in a participatory manner. This implies that policy-making takes different perspectives into account, i.e. not only medicine and economics but also social sciences and the humanities. Moreover, democratic participation also means the active involvement of minorities and key interest groups. When this is successful, then self-control has less to do with obedience or resistance, but is a possible result of an informed personal decision".

Traumatic brain injury is a major cause of disability and can have major consequences for patients and their loved ones. Patients can suffer a range of physical, cognitive, behavioural and emotional problems.

People who fall and hit their head, or who are in traffic accidents or suffer other head injuries, often undergo an MRI if doctors suspect a brain injury. But it can be difficult to predict from an MRI exactly what kinds of issues, if any, will arise from the trauma.

Now, researchers hope that research on newer and more advanced MRI methods will benefit this patient group even better than today. However, progress to date has been limited by relatively small studies and has lacked standards for sharing and analysing this data across research centres.

"A major challenge in the research is to figure out which injury characteristics and which changes in the brain caused by the injury can predict how patients will recover and what follow-up they need. A big part of the challenge is that individual patients are so different," says Alexander Olsen. He is an associate professor at the Norwegian University of Science and Technology's (NTNU) Department of Psychology and a neuropsychologist at St Olavs Hospital.

The goal of the researchers is to combine and analyse large data sets on brain imaging from around the world to see if they can find connections that aren't discernible in single studies from individual centres.

The main ENIGMA project is based at the University of Southern California, and Olsen is co- leader of a subgroup focused on moderate to severe brain injuries with Frank Hillary from Penn State University.

The brain contains roughly 300 billion brain cells that decode 100 trillion messages to enable us to think and act.

"By pooling our resources, in terms of data, computational power and intellectual expertise, we'll be able to tackle some of the big unanswered questions in our field, such as how sex impacts outcome, whether there are subtypes within the broader patient population, or how to handle lesions in neuroimaging data," said Emily Dennis, who is co-principal investigator for ENIGMA's main group on brain injuries. This main brain injury group is made up of 170 researchers from 13 countries.

"Lots of brilliant scientists around the world have been working on these questions, and made a lot of progress, but this has been limited by the size of our individual samples," she said.

Part of the challenge here is that people's brains are so very different, as different as individual fingerprints, says Erin Bigler, a professor emeritus at Brigham Young University and adjunct professor in neurology and psychiatry at the University of Utah. Bigler has been involved with traumatic brain injury research for 50 years with more than 200 published papers on the subject.

"Traumatic brain injury is often referred to as the most complex disorder affecting the most complex organ," he said.

Add to that the fact that the brain contains roughly 300 billion brain cells that decode 100 trillion messages to enable us to think and act, and it's easy to see why researchers need lots of data from lots of different brains and brain injuries, Bigler said.

"Very large sample sizes are essential, otherwise it would be impossible to embrace all of this variability," he said.

To start, the ENIGMA project will apply different types of advanced analysis methods to MRI data already collected in collaboration with researchers from the United States, Europe, Australia, the Middle East, South Africa and South America.

MRI images today can tell clinicians the size of the injury and the kind of injury it is. But Olsen's research group is working with research-based MRI methods that use more advanced algorithms and statistics.

"We're working to develop better and more standardized ways of summarizing and making sense of the MRI data, and we hope to contribute to breakthroughs in research that will benefit patients," Olsen says.

The heterogeneity in methods and ways of analysing, along with the heterogeneity of the patient group, has made this kind of standardization impossible so far. Making progress in methods development can only happen through an international collaborative project of this magnitude that includes several thousand datasets.

Another advantage of this effort to combine data that might otherwise seem impossible to combine-- what researchers call "data harmonization" -- is that it can enable researchers to use old data that has been already collected, says Penn State's Hillary.

"Data aggregation is vital in imaging and genetics research, where data sets and statistical power in any one lab are small, but combining data from labs around the world offers new possibilities to understand brain disorders and may accelerate science," he said.

"Our effort is getting a 'second life' from data that have already been collected," Dennis added.

The knowledge and analysis methods that are developed will be shared openly with all interested researchers. Where the individual research groups approve it, arrangements will also be made for the enormous datasets to be open access.

The working group NTNU Open Data at the NTNU University Library will look into how to facilitate data sharing among researchers in a good and appropriate way.

"Our ultimate goal for sharing the MRI data we collect is to make it public and available wherever possible. There are important reasons why not everything can be open access, but we want the data to be shared in a responsible way as openly and freely as possible according to the laws and practices in the various places," Olsen says.

Olsen notes that it is a challenge to share all data openly. Researchers can still perform analyses where data is not shared, but include the results of analyses carried out locally at each site in meta-analyses. The next step, however, is to carry out mega-analyses.

"Mega-analyses would require sharing the data, and different parts of the world have differing practices for what's legal. A whole separate part of our work involves studying and creating solutions for access so that it will be easier for researchers to navigate that landscape. This is where NTNU Open and others come in with their expertise," Olsen says.

As things stand today, no one can be identified only from an MRI image of the brain. But Olsen believes that in this type of research we have to consider the theoretical possibility of this happening sometime in the future.

"You have to balance the risk with the possible benefits for patients and research," he says.

KNOXVILLE, Tenn. -- In the tropics and subtropics, families and communities frequently rely on bushmeat for food security as well as basic income. So, while the harvest and trade of wildlife are illegal in many locales, the practice is commonplace, and with it comes the potential for transmission of a zoonotic disease among human populations.

Even before the emergence of COVID-19, public health experts have been on alert for more information about the attitudes and practices of those who trade in and consume bushmeat. Depending on the wildlife species involved--baboons, bats, hippopotamus, various monkeys, and more--hunting, preparing and consuming bushmeat can carry with it the potential to contract and spread diseases such as the widely feared Ebola virus or the more widespread, and perhaps more economically devastating, bacterial infections caused by Escherichia coli (E. coli), Salmonella, Staphylococcus and others. The scientists theorize that if we can help bushmeat traders and consumers keep themselves safe, perhaps we can keep their communities safe, too.

To do that, you have to understand the practitioners.

A recent paper published in the journal PLOS ONE outlines how researchers with the University of Tennessee College of Veterinary Medicine and Department of Forestry, Wildlife and Fisheries, measured the attitudes, practices and zoonoses awareness among community members associated with the bushmeat trade in northern Uganda. The authors, BreeAnna Dell and Marcy Souza, both DVMs and public health experts, along with Adam Willcox, a research associate professor who specializes in the human dimensions associated with natural resources, interviewed 292 women from the region who cook for their households and 180 self-identified hunters from 21 villages bordering Uganda's Murchison Falls National Park. The scientists were working to gain insights into bushmeat preferences, opportunities for pathogen transmission and awareness of common wildlife-associated zoonoses.

Among their findings, they report that both hunters and, traditionally, the women who cook the meat consider primates to be the most likely wildlife species to carry diseases that humans can catch. Among common zoonotic pathogens, both groups believe that pathogens causing stomach ache or diarrhea and monkeypox can be transmitted by wildlife. Neither the women who cook nor the hunters report being frequently injured during cooking, butchering or hunting, and few report taking precautions while handling bushmeat.

"Based on responses to our questions about diseases that wildlife carry, almost all respondents were aware that there is a real and present risk of disease spillover from wildlife to people," the authors conclude. Further, they write, "Epidemics in recent years may contribute to this knowledge, but for hunters this awareness does not appear to influence or motivate any precautionary behaviors during the harvest of wildlife, as virtually no respondents reported taking precautions." In fact, financial gain was the hunters' primary motivation.

In an unexpected twist, the survey results reveal that the majority of women who cook believe that hunters and dealers never or rarely disguise primate meat as another kind of meat in the marketing process. However, the majority of hunters report that they usually disguise primate meat as another kind of meat. The women overwhelmingly report they prefer to avoid purchasing primate meat. "Primates, rodents, and bats have long been investigated as important groups in zoonotic spillover events," says Dell. "While rodents and bats demonstrate high species diversity within their groups that contributes to their high microbial diversity, primates are closely related to humans and are believed to share many pathogens with humans, facilitating transmission. These findings raise concerns, as the ability of cooks to know and assess the risks of handing primate meat is subverted through the disguise of these species in the market."

These data, and more outlined in the paper including perceptions of disease prevalence and transmission as well as hunting and marketing practices, help clarify where hunters and cooks are most susceptible to injury and exposure to infectious agents.

"Expanding our knowledge of awareness, perceptions and risks enables us to identify opportunities to mitigate infections and injury risk and promote safe handling practices," comments Dell. What's more, Souza says advancing the knowledge of community practices may assist public health officials as they work to help communities and individuals mitigate their own disease risk.

Willcox adds that the data may ultimately lead to the development of more successful and appropriate conservation tactics for wildlife species in general and specifically in Uganda's Murchison Falls National Park.

BOSTON -- Researchers have validated a new radiolabeled molecule that can be used with imaging tests to accurately detect and characterize brain injury. The team, led by investigators at Massachusetts General Hospital (MGH), recently received clearance from the U.S. Food and Drug Administration (FDA) to initiate a first-in-human study with the strategy.

As described in the Journal of Cerebral Blood Flow & Metabolism, the novel tracer, called [18F]3F4AP, is designed to bind to potassium channels and is radiolabeled so it can be visualized through positron emission tomography (PET) imaging. Potassium channels in the brain's neurons become exposed when the neurons become demyelinated, or lose their protective coating (called myelin), which occurs with a variety of neurodegenerative conditions.

"Because potassium channels increase in expression and accessibility upon demyelination, this tracer holds promise for imaging multiple sclerosis and other diseases such as traumatic brain and spinal cord injuries, stroke and Alzheimer's disease," said co-senior author Pedro Brugarolas, PhD, an investigator in MGH's Gordon Center for Medical Imaging and an assistant professor in the Department of Radiology at Harvard Medical School.

When tested in monkeys, [18F]3F4AP exhibited excellent properties for brain imaging, including high penetration into the brain, fast washout or clearance, and excellent reproducibility when tested multiple times, researchers say. Furthermore, "the tracer showed unusually high resistance to metabolic degradation and minimal binding to blood proteins--properties that are difficult to come by and are highly beneficial in PET imaging," said lead author Nicolas Guehl, PhD, an investigator in the Department of Radiology at MGH and an instructor in radiology at Harvard Medical School (HMS).

Also, the tracer generated a high signal in the right frontal cortex of a monkey that the researchers later learned had sustained a minor brain injury several years before being transferred to them. "The tracer detected the brain lesion better than other PET tracers commonly used for brain imaging and better than magnetic resonance imaging, the standard imaging modality used to detect demyelination," said co-senior author Marc Normandin, PhD, assistant director of MGH's Gordon Center for Medical Imaging and assistant professor at HMS.

The team is now poised to test the work in patients with clearance from the FDA. "There are many tracers developed and tested in animals that never make it to humans, so this is an important achievement," said Daniel Yokell, PharmD, associate director for Radiopharmacy and Regulatory Affairs at the Gordon PET Core at MGH, who prepared the FDA Investigational New Drug application that was authorized.

Testing in humans will likely begin imminently. "We are thrilled to have the MGH Gordon PET Core be the first site to produce [18F]3F4AP for clinical investigations and explore its role in many promising applications," said co-author Georges El Fakhri, PhD, director of MGH's Gordon Center for Medical Imaging and the Nathaniel and Diana Alpert Professor of Radiology at HMS.

DALLAS - Oct. 22, 2020 - Two new UT Southwestern studies published today report some surprising findings: Only half of practicing physicians are registered to vote, and the most common obstacle faced by resident physicians is the lack of time to vote. The researchers say finding ways to increase voter participation among doctors is critical as the nation tackles health care issues.

"Our government leaders have an important role in shaping health policy that directly affects our patients," says Hussain Lalani, M.D., M.P.H., a UTSW resident in internal medicine and first author of both studies. "How can we have physicians, who care for patients and see the challenges our health care system faces firsthand, be more engaged in the voting process? To do that, we have to understand the barriers they face."

In one study, published in JAMA Internal Medicine, the researchers examined data for more than 112,000 physicians registered to vote in Texas, California, and New York. Researchers found this group's voting rate was 14 percent lower than the general population. In addition, half of eligible physicians in these three populous states were not registered to vote.

The largest specialty in the group was primary care. Forty percent of the physicians were baby boomers and 36 percent were Generation Xers. Sixty-six percent were male.

"There's always been a minority of physicians involved as advocates or elected officials. Now, more people are becoming interested in getting involved in health policy. Voting is a fundamental way of being engaged," says Arthur Hong, M.D., assistant professor of population and data sciences in the department of internal medicine and an author of both studies. "Doctors who were already registered actually voted more often than the general population."

In the second study, published in the Journal of General Internal Medicine, researchers surveyed 175 resident physicians across eight of the largest specialties at UT Southwestern. The most common specialty was internal medicine, the mean age was 29, and 52 percent were male.

Residents were asked to rate four barriers to voting: voter registration, logistical hurdles, time, and psychological factors. Of the four, the most common was time, followed by psychological barriers, such as the perception that their vote would not make a difference. Registration was not an issue, as 96 percent were registered to vote.

"Physician burnout is not necessarily just about the length of your shifts. It's also how much control you have in your work life," says Rija Siddiqui, M.D., a UTSW resident in psychiatry and author of the second study. "Physicians in training often work in socioeconomically disadvantaged areas with low resources."

Both Lalani and Siddiqui say there is an ongoing cultural shift within health care to prioritize civic engagement. They have been involved in Dallas-area efforts to make it easier for physicians to vote, such as holding voter registration drives at Parkland Memorial Hospital and helping resident physicians get engaged in the process. Ninety-nine percent of the internal medicine residents at UT Southwestern are now registered to vote after a resident-led initiative.

More extensive research on physicians and voting is lacking. The last known study in this field, "Do Doctors Vote?" was published in 2006 in the Journal of General Internal Medicine. Researchers at the University of Pennsylvania looked at two U.S. Census surveys from 1996-2002 and found that physicians vote less often than the general population.

New questions are at the forefront as a study published in the Journal of Clinical Microbiology from nine children's hospitals finds that most asymptomatic children who tested positive for COVID-19 had relatively low levels of the virus compared to symptomatic children. The authors caution that the reason for this finding is unclear and more questions need to be answered. Were the asymptomatic children generally tested later in their disease, and were their viral loads potentially higher closer to the beginning of their infections? If tested early in disease, would asymptomatic children have viral loads as high as symptomatic children? Or do asymptomatic children typically not carry as much virus as children with symptoms? If so, how would lower viral loads impact the risk of transmission? These questions are essential to further clarify the public health impact of pediatric COVID-19.

"While these findings provide some reassurance about the safety of asymptomatically infected children attending school, these unanswered questions suggest that risk mitigation measures in daycares, schools and the community remain critical to reduce the spread of COVID-19. Children must continue to wear masks, maintain social distance and wash their hands frequently," said first author Larry Kociolek, MD, pediatric infectious diseases expert at Ann & Robert H. Lurie Children's Hospital of Chicago and Assistant Professor of Pediatrics at Northwestern University Feinberg School of Medicine. "At this stage, we can't predict which children are likely to carry more or less virus, because in every age group we tested, there were some asymptomatic kids with a higher viral load. However, even the groups of asymptomatic kids with highest viral load in our study still had lower viral loads than the children with symptoms."

The study included 339 asymptomatic and 478 symptomatic children (ages 0-17 years) matched by age groups. All children in the study screened positive for COVID-19 using PCR tests at nine children's hospitals across the United States and Canada. To be able to combine PCR data from the different assays used at the nine institutions, the team adjusted cycle threshold (Ct) values by centering each value around the institutional median Ct value from symptomatic children tested with that assay, and also converted them to estimated viral loads (copies/mL). It is the first large and comprehensive investigation into SARS-CoV-2 viral loads in asymptomatic children.

The analysis demonstrated that asymptomatic children with diabetes and/or recent contact with a COVID-19 case, as well as those tested for surveillance purposes (rather than for pre-procedure or pre-admission purposes), had significantly higher estimated risk of being in the quartile with the highest viral burden. The authors note that the finding that patients more likely to have recent infections (contact/surveillance) were more likely to have higher viral loads suggests that timing of infection relative to diagnostic testing impacted the viral loads in the asymptomatic kids in the study. However, they also note that even in the asymptomatic surveillance sub-cohort with highest viral loads, median viral loads were still significantly lower than in the symptomatic cohort.

"We now need to know what the peak viral loads are in asymptomatic kids with COVID-19," said principal investigator and senior author Nira Pollock, MD, PhD, Associate Medical Director of the Infectious Diseases Diagnostic Laboratory at Boston Children's Hospital and Associate Professor of Pathology and Medicine at Harvard Medical School. "Did the timing of testing just miss the peak in many of the asymptomatic kids in this study, or do asymptomatic kids actually have lower peak viral loads than symptomatic kids?"

The authors also point out that the levels of the virus they found in the asymptomatic children were mostly lower than the levels that the available rapid antigen tests are able to detect.

"It is important to recognize that rapid antigen tests are less sensitive than the PCR tests used in hospitals, and that many of the asymptomatic kids in our study likely would have tested negative using the rapid tests based on our understanding of the limits of detection of those tests," said Dr. Pollock. "Our findings should raise caution about using low sensitivity tests for asymptomatic screening programs in pediatric populations. Overall, we want to encourage more studies to better understand the viral loads in asymptomatic kids--particularly peak viral loads early in infection."

Boston - A medication frequently used to treat diabetic macular edema, which is the most common cause of blindness in people with diabetes, is less effective when used to treat the condition in Black patients, new study results show. Led by researchers at Boston Medical Center, the study demonstrated that Black patients were significantly less likely than white patients to show short-term visual improvement after both a single injection and a series of three injections with the drug bevacizumab (Avastin), the most common treatment in the U.S. for diabetic macular edema. Published in the American Journal of Ophthalmology, the results underscore the need to increase diversity in participation in clinical trials for the treatment of diabetic macular edema in order to develop treatments that are effective for all patients.

This is the first study looking at race as a factor in the treatment of diabetic macular edema, a condition that results from fluid build-up around the macula, producing blurry and distorted vision. Diabetic macular edema is caused by diabetic retinopathy, a complication of diabetes that is the leading cause of blindness among working-age adults in the U.S. Of the approximately 7.7 million Americans who have diabetic retinopathy, it is estimated that 775,000 of those individuals also have diabetic macular edema, which is the leading cause of vision loss for those with diabetes.

The three medications that are most commonly used to treat diabetic macular edema - aflibercept, bevacizumab, and ranibizumab - were initially developed to treat age related macular degeneration (AMD), which is the number one cause of blindness in older patients and a condition that primarily affects white individuals. After these medications were found to be effective for AMD, they were then studied for the treatment of diabetic eye disease, which disproportionately affects Black patients.

"The results from our study show a gap in treatment for Black individuals with diabetic macular edema, despite the fact that they are more heavily impacted by this disease," said Manju Subramanian, MD, an ophthalmologic surgeon at Boston Medical Center and the study's senior and corresponding author. "When clinical research trials don't include enough diversity, it will not provide comprehensive data about the efficacy across different racial and ethnic groups, which as we can see, results in disparities in care."

For this study, the researchers focused on bevacizumab (Avastin), given that it is a first-line treatment for diabetic macular edema. They used data from electronic medical records of patients treated for the condition at Boston Medical Center - 314 received one injection of the medication, and 151 received the series of three injections of the same medication. After the first injection, 26.71 percent of Black patients compared to 39.39 percent of Hispanic and 50 percent of White patients experienced improved visual acuity. For those who received three injections, 33.82 percent of Black patients compared to 54.76 percent of Hispanic patients and 58.54 percent of white patients experienced improvements in their visual acuity.

According to the U. S. Department of Health and Human Services Office of Minority Health, African American and Black adults are 60 percent more likely to have been diagnosed with diabetes than white, non-Hispanic adults. Evidence points to a variety of factors that play a role in the increased diabetes incidence in Black Americans, including biological risk factors, lower access to health care, and socioeconomic status.

"Black individuals represent 13.4 percent of the US population but carry at least twice the prevalence of diabetic macular edema compared to white individuals, and should be represented in future research accordingly," said Subramanian, also an associate professor of ophthalmology at Boston University School of Medicine.

An international team of researchers has identified a direct molecular link between meat and dairy diets and the development of antibodies in the blood that increase the chances of developing cancer. This connection may explain the high incidence of cancer among those who consume large amounts of dairy products and red meat, similar to the link between high cholesterol and an increased risk of heart disease.

The study was led by Dr. Vered Padler-Karavani of the Department of Cell Research and Immunology at the Shmunis School of Biomedicine and Cancer Research at Tel Aviv University's George S. Wise Faculty of Life Sciences. The results of the research were published on September 23, 2020, in BMC Medicine.

Neu5Gc is a sugar molecule found in the tissues of mammals but not in poultry or fish. Humans develop antibodies to Neu5Gc in infancy, when they are first exposed to dairy and meat products. While it is known that these antibodies increase the risk of cancer, especially colorectal cancer, no direct link had been found between the antibodies and meat and dairy consumption.

For the study, the researchers used samples from NutriNet-Santé, an extensive national nutritional survey conducted in France. Salam Bashir, a PhD student in Dr. Padler-Karavani's lab, together with other team members measured the amount of Neu5Gc sugar in a variety of dairy and meat foods common in the French diet and calculated the daily Neu5Gc intake of 19,621 adults aged 18 and over, who reported all of their food intake online over a period of several days.

The research team then took a representative sample of 120 participants and tested the levels of the anti-Neu5Gc antibodies in their blood.

Based on these findings and the quantification of Neu5Gc sugar in various food products from France, Dr. Padler-Karavani and her team created an index called the Gcemic index. This index ranks foods whose excessive consumption can lead to an increase in the antibodies - and possibly to an increase in the risk of cancer.

"We found a significant correlation between high consumption of Neu5Gc from red meat and cheeses and increased development of those antibodies that heighten the risk of cancer," Dr. Padler-Karavani says. "For years there have been efforts to find such a connection, but no one did. Here, for the first time, we were able to find a molecular link thanks to the accuracy of the methods used to measure the antibodies in the blood and the detailed data from the French diet questionnaires."

Dr. Padler-Karavani adds that this combination of methods allowed the researchers to predict that those who eat a lot of red meat and cheese will develop high levels and a different variety of the antibodies, and therefore may be at higher risk for cancer - especially colorectal cancer, but other cancers as well.

The coronavirus, responsible for the COVID-19 pandemic, has one official name--SARS-CoV-2. But according to virologists, mutations lead to hundreds of genetically-distinct versions of the virus. Scientists at Children's Hospital Los Angeles have used these viral signatures to reveal transmission patterns, which show the effectiveness of early safety measure policies.

Scientists at Children's Hospital Los Angeles gathered an extensive pool of genomic data--information about the virus's genetic makeup--to examine transmission patterns throughout the United States since the outbreak of the pandemic. Their peer-reviewed genomic epidemiology study, which includes the largest group of U.S. samples to date, reveals that early rigorous travel restrictions and other measures to control viral transmission, especially the ones implemented in the states of Washington and California, significantly limited spread of this deadly virus. Tracking viral mutation signatures is critical to understanding how the virus behaves and mutates. This information is used by scientists and public health officials to develop effective strategies to limit the spread of COVID-19 during a second wave this fall.

Viral Mutations as Clues for Epidemiologists

When a virus replicates, it makes copies of its genetic material. Mutations--mistakes in the copying process--occur routinely. The errors become embedded in the genome of the virus and pass along as it replicates. This means that a particular virus will evolve its own unique signature as it collects these genetic mis-copies. Each new version of the virus, identifiable by its unique combination of genetic mutations accumulated sequentially and over time, is known as a haplotype.

According to virologists and geneticists at Children's Hospital Los Angeles, SARS-CoV-2 mutates about every two weeks. Some mutations may strengthen the virus or make the disease more severe. Other mutations weaken the virus, which may cause that haplotype to die out. The vast majority of mutations are not significant and don't markedly affect the virus or the disease it causes. Nevertheless, these haplotypes are very useful to scientists for tracking the spread of the pandemic.

Each sample of SARS-CoV-2 is like a map of where it has been.

"By looking at the sequences, you can learn a lot about the virus and how it spreads," says Xiaowu Gai, PhD, Director of Bioinformatics in the Center for Personalized Medicine at CHLA. He explains that while it's common to refer to the virus, it isn't really one single entity.

"The virus that infects a patient in California will be different from the virus that infects a patient in Iowa because of how rapidly it mutates," he says. "If samples from patients this far away from each other don't differ, we can infer that there has been travel between the two states."

Studying the Genome to Understand Disease Spread

"Fighting a pandemic requires a highly interdisciplinary team of people," says Dr. Gai. "The world needs clinicians, virologists, pathologists and data scientists. We are so fortunate to have such a team at Children's Hospital Los Angeles that have worked hard and so well together since the beginning."

Actually, the team began their work before the beginning, when SARS-CoV-2 hadn't yet made it to the United States.

Back in February, Jennifer Dien Bard, PhD, could tell a pandemic was imminent. As the Director of the Clinical Microbiology and Virology Laboratory, she recognized the importance of testing and how gathering genomic information can contribute to understanding and battling a disease.

"If we underestimate mutation rate and don't know how the virus is behaving, any vaccine that is developed could be less effective," she says. As soon as possible, the team established the SARS-CoV-2 whole genome sequencing assay. "It's a test that reads out the entire gene library of the virus in each patient sample," says Dr. Dien Bard. "This gives us a lot of information fast."

Fast, in a race against a pandemic, is key.

"In those early days of the pandemic, we sprang into action," says Dr. Gai. "We wanted to develop tools to understand the transmission pattern because it makes a huge impact on how we should be dealing with the virus and the disease."

After the genomic test was developed, Dr. Gai and Dr. Dien Bard worked with Senior Research Associate Lishuang Shen, testing dozens of samples using their assay. But in order to understand how the virus spreads state to state and globally, the researchers needed many more samples from locations other than California. The team turned to the global scientific community and accessed sequence data from over 6,000 U.S. samples. From this data set, the team was able to identify hundreds of SARS-CoV-2 haplotypes.

Dr. Gai stresses that public data sharing is incredibly beneficial to studies like these. "Institutions all around the globe have been contributing SARS-CoV-2 sequence data," he says. "The scientific community has done something very important in sharing all of this information."

Clear patterns emerged from the data. Some haplotypes were found in only one state. These unique, state-specific variants provide evidence that the virus has not spread to neighboring states. Two states - Washington and California - had the highest number of unique haplotypes.

"What we've identified with this study is that the states who implemented travel restrictions and safer-at-home orders early during the pandemic were very effective in reducing spread," says Dr. Gai. "Otherwise, similar mutation signatures would be found everywhere."

Orders to stay at home, wear masks, and cancel travel have impacted viral spread. "California was one of the few states to implement these measures early on," says Dr. Dien Bard, "and I think that certainly helped."

The global COVID-19 pandemic is far from over. But data like these will give the scientific community better tools to understand the virus, which is a critical step in containing it.

"Epidemiological studies can teach us a lot about the virus," says Dr. Gai. "We will need to continue to follow safety measures--because our data show that they work."

BOSTON - A young woman who had been hospitalized for three months straight due to debilitating, recurrent infections with no apparent underlying cause was finally able to go home thanks to a Massachusetts General Hospital (MGH) team who put their heads together, discovered a root of the problem, and developed a novel treatment strategy just for her.

Eight months after she had received an autologous bone marrow transplant at age 20, the patient developed a central line-associated bloodstream infection, which was followed by a string of bacterial and fungal infections of a type typically seen in patients with compromised immune systems.

"She had a hospitalist who was very caring and wanted to see her do well but had reached a limit in clinical care and management. Nothing was working for her," says investigator Michael K. Mansour, MD, PhD, of the Division of Infectious Diseases and Department of Medicine at MGH, and assistant professor of Medicine at Harvard Medical School.

Mansour and the other members of the multidisciplinary team that finally cracked the case describe their novel investigative and therapeutic approaches in an article published online in The Journal of Allergy and Clinical Immunology: In Practice.

In addition to Ryan Thompson, MD, and Priscilla Parris, NP, from the complex care hospitalist service, the team collaborating on the young woman's care included Mark Pasternack, MD, of the Pediatric Infectious Disease Unit, and Joceyln Farmer, MD, PhD, and Rebecca Saff, MD, PhD, of the Allergy and Clinical Immunology Unit.

After standard immune testing failed to demonstrate an explanation for these repeated infections, "they reached out to me, because my research is focused on one specific immune cell: the neutrophil. It's the most common immune cell in our blood," Mansour says. "They asked me if we could run some experiments on her neutrophils to try to understand whether they were defective, and, in collaboration with Daniel Irimia, MD, PhD, and Alex Hopke, PhD, from the MGH BioMEMS Resource Center, that in fact was what this team found."

After obtaining permission from the patient and the institutional review board (IRB), Natalie Alexander, a research technician in the Mansour Laboratory, isolated neutrophils from the patient's blood and discovered that her cells, which when healthy are key to healing wounds and fighting infections, were working poorly compared to those of similar neutrophils from a healthy person.

The investigators then treated the isolated neutrophils with growth factors and FDA-approved cytokines to see whether they could stimulate neutrophils to mount a stronger defense against fungal and bacterial invaders. They found that the treatment restored neutrophil function, improving control of pathogens in a dish.

Finally, after receiving the patient's consent and the IRB's approval, the team began treating the patient with twice-weekly injections of a type of growth factor called granulocyte-colony stimulating factor (G-CSF). G-CSF is typically given to patients with neutrophil deficiency from immune disorders, as well as patients whose neutrophils have been depleted from chemotherapy.

"She was able to go home for the first time in months, spend time with her family and see her dogs. It was a really special moment," Mansour says.

The patient has remained on G-CSF therapy without serious side effects, and although she still gets bloodstream infections, the overall frequency and severity of those infections have lessened since she was started on the growth factor. The cause of her underlying neutrophil deficiency is still under investigation.

Mansour says that the case illustrates how clinicians and researchers working in different medical specialties can pool their intellectual resources and experience to tackle highly challenging medical cases and improve the lives of others, one patient at a time.

"It embodies the entire spirit of the hospital: we all came together, we put her safety and her current condition at the forefront, we applied cutting-edge research and found something - it's a rare moment when we can do that and have it result in a wonderful outcome," he says.

University of Alberta scientists have identified the mechanism of action behind a new type of precision cancer drug for blood cancers that is set for human trials, according to research published today in Nature Communications.

The research team led by Luc Berthiaume, cell biology professor in the Faculty of Medicine & Dentistry, spent four years working to understand how the compound PCLX-001 targets enzymes that perform myristoylation, a cellular process in which the fatty acid myristate modifies proteins so they can move to membranes and become part of the cell signalling system.

"The enzymes that transfer myristate onto proteins are overexpressed in some cancer cells, meaning there's more of those enzymes, so they have long been thought of as a logical target for cancer treatment," said Berthiaume, who is also chief scientific officer and co-founder of Pacylex Pharmaceuticals, the U of A spinoff company developing the drug.

"Until now no one has done a thorough analysis of this hypothesis," Berthiaume said. "We actually found that several types of cancer cells have fewer of these enzymes, making them seemingly easier to kill with our lead drug."

To demonstrate this, the researchers tested the drug against 300 different cancer cell types. They reported that blood cancer cells including lymphomas and leukemia, which have fewer of the enzymes, are extremely sensitive to the drug. It also killed other types of cancer cells when given at a higher concentration.

The team found that the drug stopped B-cell lymphoma tumour survival signals, killed B-cell tumour cells in both test-tube and animal experiments, and left non-cancerous cells unharmed, Berthiaume said.

Having completed the necessary biosafety studies, Pacylex plans to initiate Phase 1 trials of PCLX-001 in lymphoma, leukemia, breast and colon cancer patients at the Cross Cancer Institute in Edmonton, the B.C. Cancer Centre in Vancouver and Princess Margaret Cancer Centre in Toronto later this year, Berthiaume said.

"We think PCLX-001 is a compound with a large therapeutic window that can kill the cancer cells at a much lower concentration than what is needed to kill normal cells," he said. "That is the holy grail of cancer therapies."
"Because of the highly selective nature of our drug, it's often referred to as a precision medicine, and we anticipate minimal side-effects," he said.

A team of researchers in the US and Australia have developed a way of testing potential drugs for children's cancers so as to take account of the wide genetic diversity of these diseases.

In new research to be presented at the 32th EORTC-NCI-AACR [1] Symposium on Molecular Targets and Cancer Therapeutics, which is taking place online, Professor Peter Houghton, director of the Greehey Children's Cancer Research Institute (San Antonio, USA), said that instead of conventional testing designs, which use multiple mice as models for rare children's cancers, analysis had revealed that it was possible to evaluate them on a single mouse.

Conventional testing is able to test only a few cancers at a time; however, these new findings mean that single mouse testing can be used to evaluate the action of more anti-cancer drugs against more tumours and more genetic variants of the same cancer in order to represent the clinical diseases more accurately. This could help to accelerate the development of better treatments for children's cancers.

Prof Houghton said: "Over the past decade, genetic studies have shown that cancers in children that were once considered homogenous in nature are in reality quite heterogenous, and may represent different 'diseases' that would respond differently to treatments. More importantly, such differences may be exploited therapeutically. Conventional drug testing in mice can identify active drugs but is restricted by the number of cancer mouse models that can be used due to resource constraints."

New drugs, or re-purposing of existing drugs, have to be tested in animal models of diseases before being evaluated in humans. This involves taking a sample of a particular tumour and grafting it into mice that have had their immune systems disabled to see how it responds to the treatment, known as patient-derived xenografts. In this study, patient-derived xenografts from 90 acute lymphoblastic leukaemias and 50 solid tumours in children were used to evaluate small molecule drugs and antibody drug conjugates (ADCs) - drugs that combine monoclonal antibodies with anti-cancer agents and are designed to target and kill tumour cells while sparing healthy cells.

Prof Houghton's centre is part of a group of laboratories, each focused on particular childhood cancers, that are part of the Pediatric Preclinical Testing Consortium (PPTC), funded by the US National Cancer Institute (NCI) to test new anti-cancer drugs.

He said: "One of the limitations of this testing programme is that when using conventional testing, which involves ten mice per treatment group, only a limited number of tumour models can be used and these do not necessarily reflect the genetic or epigenetic diversity of the clinical disease. We retrospectively analysed data from the PPTP and asked a simple question, 'would we have obtained the same results if we had used one mouse per treatment rather than ten mice?'.

"The results for response were similar to conventional testing. Our analysis of more than 2,100 drug/tumour model studies showed that 78% of single mouse tests correctly recapitulated the average response from testing according to the conventional experiment design with around 95% agreement. Basically, we could have generated exactly the same data using one mouse instead of ten." [2]

In the study presented to the Symposium, the researchers prospectively investigated conventional testing and single mouse testing for three drugs in acute lymphoblastic leukaemias (topotecan, birinapant and eltanexor), and for two ADCs in solid tumours (trastuzumab-deruxtecan and mCD276-PBD).

"In the single mouse testing, each mouse carries a different patient-derived tumour xenograft: you can think of each mouse as an individual 'patient'," said Prof Houghton. "For leukaemias, Richard Lock's group at the Children's Cancer Institute in Australia, a consortium member, used 80 to 90 different patient-derived leukaemia xenograft models and for solid tumours between 31 to 34 models. While the conventional approach gave us statistically significant results in the few models tested, the single mouse testing allowed for identification of subgroups of tumours that have exceptional response to particular drugs.

"Results from conventional testing and single mouse testing were essentially identical in 47 studies where both approaches used the same tumour model. In the leukaemia study we used 90 mice, whereas to attain the same information using conventional testing would have required 1,800 mice. For the solid tumours, it was 34 mice as opposed to 680 mice.

"In practical terms this means we could save resources and use fewer animals. However, of greater importance is that, with the same allocation of resources, we could increase the number of animal tumour models within a particular type of cancer by up to 20-fold to see how the drugs performed in different genetic or epigenetic variants of that disease.

"Single mouse testing may be particularly valuable for identifying responsive tumour types and biological markers that are associated with tumour response, including which different cancer therapies different tumour types may respond to. This could speed up the development of new and better therapies for childhood cancers. For example, for trastuzumab-deruxtecan, reported here, five of the most responsive models are extracranial rhabdoid tumours of infants."

He concluded: "The study also contributes to the shift in how we undertake preclinical testing, and will facilitate testing of molecularly targeted agents relevant to paediatric cancer, as mandated by the Research to Accelerate Cures and Equity for Children Act (RACE for Children Act). This act requires the US Food and Drug Administration to develop a list of molecular targets and molecular targets of new drugs and biologics in development. If agents are determined to be substantially relevant to the growth and progression of paediatric cancer, this may trigger the requirement to investigate them further in children. This will require approaches to preclinical testing that incorporate models accurately representing the genetic and epigenetic heterogeneity of children's cancers. Single mouse testing addresses this issue and the NCI has now embraced the approach."

Professor Emiliano Calvo is co-chair of the EORTC-NCI-AACR Symposium on behalf of the EORTC; he is Director of START Madrid Group in Madrid, Spain, and Director of Clinical Research at the START Madrid-Centro Integral Oncológico Clara Campal hospital in Madrid and he was not involved in the research. He commented: "These findings suggest that single mouse testing is a valid way to identify anti-cancer drugs that may show activity in a broad range of tumours or only in a small sub-set of tumours. This approach is particularly important for children's cancers. As childhood cancer is a rare but diverse set of diseases, it can take longer for the research community to identify drugs or new biological targets against which anti-cancer therapies can be aimed. Anything that can speed up the testing of treatments is to be welcomed and this study raises awareness in the research community that single mouse testing is not only accurate but also provides us with far greater power to identify genetic biomarkers associated with tumour response."

Vaccines are being hailed as the solution to the covid-19 pandemic, but the vaccine trials currently underway are not designed to tell us if they will save lives, reports Peter Doshi, Associate Editor at The BMJ today.

Several covid-19 vaccine trials are now in their most advanced (phase 3) stage, but what will it mean exactly when a vaccine is declared "effective"?

Many may assume that successful phase 3 studies will mean we have a proven way of keeping people from getting very sick and dying from covid-19. And a robust way to interrupt viral transmission.

Yet the current phase 3 trials are not actually set up to prove either, says Doshi.

"None of the trials currently underway are designed to detect a reduction in any serious outcome such as hospitalisations, intensive care use, or deaths. Nor are the vaccines being studied to determine whether they can interrupt transmission of the virus," he writes.

He explains that all ongoing phase 3 trials for which details have been released are evaluating mild, not severe, disease - and they will be able to report final results once around 150 participants develop symptoms.

In Pfizer and Moderna's trials, for example, individuals with only a cough and positive lab test would bring those trials one event closer to their completion.

Yet Doshi argues that vaccine manufacturers have done little to dispel the notion that severe covid-19 was what was being assessed.

Moderna, for example, called hospitalisations a "key secondary endpoint" in statements to the media. But Tal Zaks, Chief Medical Officer at Moderna, told The BMJ that their trial lacks adequate statistical power to assess that endpoint.

Part of the reason may be numbers, says Doshi. Because most people with symptomatic covid-19 infections experience only mild symptoms, even trials involving 30,000 or more patients would turn up relatively few cases of severe disease.

"Hospitalisations and deaths from covid-19 are simply too uncommon in the population being studied for an effective vaccine to demonstrate statistically significant differences in a trial of 30,000 people," he adds. "The same is true regarding whether it can save lives or prevent transmission: the trials are not designed to find out."

Zaks confirms that Moderna's trial will not demonstrate prevention of hospitalisation because the size and duration of the trial would need to be vastly increased to collect the necessary data. "Neither of these I think are acceptable in the current public need for knowing expeditiously that a vaccine works," he told The BMJ.

Moderna's trial is designed to find out if the vaccine can prevent covid-19 disease, says Zaks. Like Pfizer and Johnson and Johnson, Moderna has designed its study to detect a relative risk reduction of at least 30% in participants developing lab-confirmed covid-19, consistent with FDA and international guidance.

Zaks also points to influenza vaccines, saying they protect against severe disease better than mild disease. "To Moderna, it's the same for covid-19: if their vaccine is shown to reduce symptomatic covid-19, they will feel confident it also protects against serious outcomes," Doshi writes.

But Doshi raises another important issue - that few or perhaps none of the current vaccine trials appear to be designed to find out whether there is a benefit in the elderly, despite their obvious vulnerability to covid-19.

If the frail elderly are not enrolled into vaccine trials in sufficient numbers to determine whether there is a reduction in cases in this population, "there can be little basis for assuming any benefit against hospitalisation or mortality," he warns.

Doshi says that we still have time to advocate for changes to ensure the ongoing trials address the questions that most need answering.

For example, why children, immunocompromised people, and pregnant women have largely been excluded; whether the right primary endpoint has been chosen; whether safety is being adequately evaluated; and whether gaps in our understanding of how our immune system responds to covid-19 are being addressed.

"The covid-19 vaccine trials may not have been designed with our input, but it is not too late to have our say and adjust their course. With stakes this high, we need all eyes on deck," he argues.

BOSTON - The drug tocilizumab (Actemra) does not reduce the need for breathing assistance with mechanical ventilation or prevent death in moderately ill hospitalized patients with COVID-19, according to a new study led by researchers at Massachusetts General Hospital (MGH). The study, published in the New England Journal of Medicine (NEJM), casts doubt on earlier research suggesting that tocilizumab, which is commonly prescribed for rheumatoid arthritis (RA) and other conditions, might be an effective treatment for patients with worsening cases of COVID-19.

About 15 percent of patients with COVID-19 develop severe cases. These patients typically develop pneumonia, which reduces oxygen levels in the blood and requires hospitalization. Evidence has suggested that this life-threatening condition may be caused by a so-called "cytokine storm," in which the immune system unleashes an abnormally high volume of inflammatory cells--which are normally protective--that damages the lungs and requires treatment with supplemental oxygen.

"Inflammatory markers in the peripheral blood are elevated at sky-high levels," says MGH rheumatologist John H. Stone, MD, MPH, who was the principal investigator of the NEJM study. COVID-19 patients with elevated levels of a cytokine called interleukin-6 (IL-6) have a greater need for supplemental oxygen delivered with mechanical ventilation and greater risk of dying.

The drug tocilizumab blocks IL-6. Stone previously conducted clinical trials that led to the approval of tocilizumab for treating another inflammatory condition: giant cell arteritis. Several previous studies suggested that tocilizumab may benefit COVID-19 patients, though none were randomized, double-blind, placebo-controlled ("gold standard") trials needed to confirm that hypothesis. The NEJM study, led by MGH researchers and conducted during the height of the pandemic by a group of seven hospitals, was called the Boston Area COVID-19 Consortium (BACC) Bay Tocilizumab Trial.

The study included 243 hospitalized patients with moderately severe cases of COVID-19 who had high levels of inflammation and at least two of the following symptoms: pneumonia, low blood-oxygen levels and fever. Two-thirds of the participants received an infusion of tocilizumab, while the remaining patients were given a placebo in addition to standard care. Most of the patients involved were receiving supplemental oxygen through a nasal tube or cannula. The primary goal of the study was to find out whether tocilizumab prevented recipients from eventually requiring breathing assistance delivered by a ventilator through a tube inserted in the mouth (intubation) or dying.

The study found that patients treated with tocilizumab were just as likely as those given placebo infusions to eventually require intubation or die over a four-week period. Likewise, the conditions of patients in both groups improved or worsened at the same rate.

"We demonstrated very clearly that, for patients with the disease severity we studied, the use of IL-6 receptor blockade is not warranted," says Stone, noting that other studies of tocilizumab administered to patients already intubated have also found no benefit. It's possible that the drug might help COVID-19 patients whose disease severity falls somewhere between that of the patients included in the BACC Bay Trial and those who already require mechanical ventilation, says Stone. Studies addressing this question are under way.