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A recent study outlines a range of privacy concerns related to the programs that users interact with when using Amazon's voice-activated assistant, Alexa. Issues range from misleading privacy policies to the ability of third-parties to change the code of their programs after receiving Amazon approval.

"When people use Alexa to play games or seek information, they often think they're interacting only with Amazon," says Anupam Das, co-author of the paper and an assistant professor of computer science at North Carolina State University. "But a lot of the applications they are interacting with were created by third parties, and we've identified several flaws in the current vetting process that could allow those third parties to gain access to users' personal or private information."

At issue are the programs that run on Alexa, allowing users to do everything from listen to music to order groceries. These programs, which are roughly equivalent to the apps on a smartphone, are called skills. Amazon has sold more than 100 million Alexa devices (and possibly twice that many), and there are more than 100,000 skills for users to choose from. Because the majority of these skills are created by third-party developers, and Alexa is used in homes, researchers wanted to learn more about potential security and privacy concerns.

With that goal in mind, the researchers used an automated program to collect 90,194 unique skills found in seven different skill stores. The research team also developed an automated review process that provided a detailed analysis of each skill.

One problem the researchers noted was that the skill stores display the developer responsible for publishing the skill. This is a problem because Amazon does not verify that the name is correct. In other words, a developer can claim to be anyone. This would make it easy for an attacker to register under the name of a more trustworthy organization. That, in turn, could fool users into thinking the skill was published by the trustworthy organization, facilitating phishing attacks.

The researchers also found that Amazon allows multiple skills to use the same invocation phrase.

"This is problematic because, if you think you are activating one skill, but are actually activating another, this creates the risk that you will share information with a developer that you did not intend to share information with," Das says. "For example, some skills require linking to a third-party account, such as an email, banking, or social media account. This could pose a significant privacy or security risk to users."

In addition, the researchers demonstrated that developers can change the code on the back end of skills after the skill has been placed in stores. Specifically, the researchers published a skill and then modified the code to request additional information from users after the skill was approved by Amazon.

"We were not engaged in malicious behavior, but our demonstration shows that there aren't enough controls in place to prevent this vulnerability from being abused," Das says.

Amazon does have some privacy protections in place, including explicit requirements related to eight types of personal data - including location data, full names and phone numbers. One of those requirements is that any skills requesting this data must have a publicly available privacy policy in place explaining why the skill wants that data and how the skill will use the data.

But the researchers found that 23.3% of 1,146 skills that requested access to privacy-sensitive data either didn't have privacy policies or their privacy policies were misleading or incomplete. For example, some requested private information even thought their privacy policies stated they were not requesting private information.

The researchers also outline a host of recommendations for how to make Alexa more secure and empower users to make more informed decisions about their privacy. For example, the researchers encourage Amazon to validate the identity of skill developers and to use visual or audio cues to let users know when they are using skills that were not developed by Amazon itself.

"This release isn't long enough to talk about all of the problems or all of the recommendations we outline in the paper," Das says. "There is a lot of room for future work in this field. For example, we're interested in what users' expectations are in terms of system security and privacy when they interact with Alexa."

Forager ants do it, vampire bats do it, guppies do it, and mandrills do it. Long before humans learned about and started "social distancing due to COVID-19," animals in nature intuitively practiced social distancing when one of their own became sick.

In a new review published in Science, Dana Hawley, a professor of biological sciences in the Virginia Tech College of Science and colleagues from the University of Texas at Austin, University of Bristol, University of Texas at San Antonio, and University of Connecticut have highlighted just a few of the many non-human species that practice social distancing, as well as lessons learned from their methods to stop the spread of bacterial, viral, and parasitic infections.

"Looking at non-human animals can tell us something about what we have to do as a society to make it such that individuals can behave in ways when they are sick that protect both themselves and society as a whole", said Hawley, who is an affiliated faculty member of the Global Change Center and the Center for Emerging, Zoonotic, and Arthropod-Borne Pathogens, which are both housed within the Fralin Life Sciences Institute.

"Staying home and limiting interactions with others is an intuitive behavioral response when we feel sick -- and one that we see across many types of animals in nature -- but humans often suppress this instinct, at great potential cost to ourselves and our communities, because of pressures to continue working or attending classes even while sick", added Hawley.

We all have had that experience of feeling sick. You may feel lethargic and just can't seem to muster the energy to get out of bed or hang out with friends. Although you may not know it, you are practicing a form of social distancing. Since you are not actively trying to avoid people and just rolling with the punches of general malaise, Hawley and co-authors refer to this as "passive social distancing." Of course, this has been observed in non-human species as well.

Vampire bats, who feed solely on the blood of other animals, have been well studied because they are highly social, compared to their fruit- and insect-eating bat relatives. Since blood is not nutritional and difficult to find most days, the bats form strong social bonds by sharing food and grooming -- or licking and cleaning each other's fur.

To learn more about their "sickness behavior," or how their behavior changes in response to infection, researchers inject the bats with a small piece of cell membrane from a gram-negative bacteria known as lipopolysaccharide. The harmless substance triggers an immune response and their sickness behaviors, such as decreased activity and decreased grooming, without actually exposing them to a pathogen.

"Passive social distancing in vampire bats is a 'byproduct' of sickness behavior," said Sebastian Stockmaier, who led the review while a Ph.D. student at the University of Texas at Austin, where he is still affiliated. "For instance, sick vampire bats might be more lethargic so that they can divert energy to a costly immune response. We have seen that this lethargy reduces contact with others and that sick vampire bats groom each other less."

Mandrills also exhibit grooming behaviors in order to maintain their social bonds, as well as their hygiene. However, these highly social primates are strategic about their social distancing behaviors. Because their grooming behaviors are important to keep their standing in society, they avoid contagious group mates, while occasionally increasing their risk of infection by continuing to groom their infected close relatives.

On the other hand, many types of ants practice a form of active social distancing. Over the course of evolution, some ant species have adapted to abandon their tight knit-groups when they are feeling sick. In these cases, the infected individual's self sacrifice is seen as an act of public good to protect the rest of the colony and carry forth the genes that will keep the closely related colony thriving in the future.

But there are other cases where the healthy animals go out of their way to exclude sick members from the group or by avoiding contact with them altogether.

Bees are another group of social insects whose main goal is to do everything for the greater good of the hive and their queen. So when infected bees are detected within the hive, healthy bees have no choice but to exclude the infected bees -- by aggressively kicking them out of the hive.

In other species, the healthy individuals are the ones to leave the group to protect themselves from disease, but often at great cost. To reduce their risk of catching or transmitting a virus, healthy Caribbean spiny lobsters abandon their den when they detect an infected group member in it. Not only does this result in the loss of protection within the group and their den, but they are also exposing themselves to deadly predators in the open ocean. But for them, it is worth this risk to avoid a highly lethal virus.

Although not all cases are this severe, reducing one's own social interactions will always incur consequences of some kind, including loss of warmth or having more difficulty finding food.

Unfortunately, humans have gotten all too familiar with the costs and benefits of social distancing since the inception of the COVID-19 pandemic. But Hawley says that there are actually many ways in which we have altered our behavior in the midst of disease, without even realizing it.

"COVID-19 has really highlighted the many ways that we use behavior to deal with disease," said Hawley. "I think that we have all unconsciously used these types of behaviors throughout our lives, and it is only just now coming into focus how important that these behaviors are in protecting ourselves from getting sick.

"If you are sitting on an airplane and somebody next to you is coughing, you may be less likely to want to talk to them, or you may lean over to one side of your seat. There are so many ways that we are altering our behavior to minimize disease risk and we do it all the time without thinking because it is evolutionarily ingrained in us."

As new mutants of the SARS-Cov-2 virus arise, humans will have to continue to wear masks to protect themselves and others and social distance. Unlike animals in nature, humans have developed technology like Zoom to create social connections and bridges while they are physically distancing themselves from others. Hawley also explored virtual technology as a means of compensating for costs of social distancing in humans in a review published in The Royal Society Proceedings B.

Whether you are a forager ant, a Caribbean spiny lobster, or a human, it is clear that social distancing is a behavior that both benefits us as individuals and the community that connects us with one another. Therefore, we must take care of ourselves and others by practicing a behavior that is more apparent, and more imperative, now than ever before: active social distancing.

Cervical cancer is a serious global health threat which kills more than 300,000 women every year. It's a disease that disproportionately affects women in low- and middle-income countries in equatorial Africa, Latin America and Southeast Asia, yet it is a preventable disease and decades of research have produced the tools needed to eliminate it.

Recognizing this urgent public health issue, the editorial team of Preventive Medicine, led by Editor-in-Chief Dr. Eduardo Franco, Director, Division of Cancer Epidemiology and Chair, Gerald Bronfman Department of Oncology at McGill University, is publishing a special issue titled "From Science to Action to Impact: Eliminating Cervical Cancer," which outlines the required courses of action to eliminate cervical cancer.

The journal's publication coincides with International HPV Awareness Day on March 4 and is dedicated to the more than half a million women who are struck by cervical cancer every year. Its publication follows the official launch last November of the World Health Organization (WHO) strategy to accelerate the elimination of cervical cancer. The strategy outlines targets for all countries to achieve by the year 2030: 90 percent human papillomavirus (HPV) vaccination coverage to prevent the infections that cause cervical cancer, 70 percent screening coverage, and 90 percent access to treatment for women identified with cervical disease.

Dr. Anna Giuliano and Dr. Linda Niccolai, two giants in the field of cervical cancer prevention research, served as guest editors for the issue. Dr. Giuliano, Director of the Center for Immunization and Infection Research in Cancer and Professor in the Department of Cancer Epidemiology at the Moffitt Cancer Center, and Dr. Niccolai, Professor of Epidemiology, Yale School of Public Health, Director of the Connecticut Emerging Infections Program, and member of Yale Cancer Center, assembled an outstanding group of international scientists and practitioners who contributed papers on basic science, clinical medicine, public health practice and mathematical modeling, all focused on the targeted action needed in each of these realms to achieve cervical cancer elimination.

"In the history of medicine, we never dared to conjugate the verb 'eliminate' with respect to cancer," says Dr. Franco. "The toll in human suffering for a disease that is preventable makes the elimination of cervical cancer a moral goal that we have an ethical obligation to achieve. HPV vaccination can prevent the vast majority of cervical cancers and molecular HPV testing is a great technology to detect the remaining precancerous lesions that are not prevented. These two preventive strategies must be deployed on a global scale."

In their editorial, Drs. Giuliano and Niccolai emphasize that in addition to public health and clinical resources for research and health care, there is a critical need for government officials to take a strong stand. "We have all the tools we need for cervical cancer elimination: vaccination, screening and treatment, for both primary and secondary prevention," says Dr. Niccolai. "What we need now is the commitment of political, medical and public health officials to make this happen." Dr. Giuliano further explains, "The articles in this issue were selected to encapsulate the knowledge we have and effort needed to reach global cervical cancer elimination. Our intent was to inspire action globally among scientists, health care providers, policy leaders and communities to accelerate progress toward this attainable goal."

The COVID-19 pandemic has created both challenges and opportunities regarding global efforts to conduct HPV screening and vaccination. "The pandemic has taught us how to be agile and creative, and how to work toward health promotion under the most difficult of circumstances. It has forced us to reimagine how we deliver health care including preventive services," says Dr. Niccolai. "It has also highlighted for the public the powerful potential of vaccines to protect our health."

"We are delighted to place Preventive Medicine, a respected journal that has an international readership in public health, to the service of this great cause," says Dr. Franco, who has served as Editor-in Chief since 2013. "Drs. Giuliano and Niccolai have done an outstanding job. This special issue of the journal presents a technically feasible and realistic roadmap for facing the great challenge of eliminating cervical cancer."

Amsterdam, March 4, 2021 - Cervical cancer is a serious global health threat which kills more than 300,000 women every year. It's a disease that disproportionately affects women in low- and middle-income countries in equatorial Africa, Latin America and Southeast Asia, yet it is a preventable disease and decades of research have produced the tools needed to eliminate it.

Recognizing this urgent public health issue, the editorial team of Preventive Medicine, led by Editor-in-Chief Dr. Eduardo Franco, Director, Division of Cancer Epidemiology and Chair, Gerald Bronfman Department of Oncology at McGill University, is publishing a special issue titled "From Science to Action to Impact: Eliminating Cervical Cancer," which outlines the required courses of action to eliminate cervical cancer.

The journal's publication coincides with International HPV Awareness Day on March 4 and is dedicated to the more than half a million women who are struck by cervical cancer every year. Its publication follows the official launch last November of the World Health Organization (WHO) strategy to accelerate the elimination of cervical cancer. The strategy outlines targets for all countries to achieve by the year 2030: 90 percent human papillomavirus (HPV) vaccination coverage to prevent the infections that cause cervical cancer; 70 percent screening coverage; and 90 percent access to treatment for women identified with cervical disease.

Dr. Anna Giuliano and Dr. Linda Niccolai, two giants in the field of cervical cancer prevention research, served as guest editors for the issue. Dr. Giuliano, Director of the Center for Immunization and Infection Research in Cancer and Professor in the Department of Cancer Epidemiology at the Moffitt Cancer Center, and Dr. Niccolai, Professor of Epidemiology, Yale School of Public Health, Director of the Connecticut Emerging Infections Program, and member of Yale Cancer Center, assembled an outstanding group of international scientists and practitioners who contributed papers on basic science, clinical medicine, public health practice and mathematical modeling, all focused on the targeted action needed in each of these realms to achieve cervical cancer elimination.

"In the history of medicine, we never dared to conjugate the verb 'eliminate' with respect to cancer," says Dr. Franco. "The toll in human suffering for a disease that is preventable makes the elimination of cervical cancer a moral goal that we have an ethical obligation to achieve. HPV vaccination can prevent the vast majority of cervical cancers and molecular HPV testing is a great technology to detect the remaining precancerous lesions that are not prevented. These two preventive strategies must be deployed on a global scale."

In their editorial, Drs. Giuliano and Niccolai emphasize that in addition to public health and clinical resources for research and health care, there is a critical need for government officials to take a strong stand. "We have all the tools we need for cervical cancer elimination: vaccination, screening and treatment, for both primary and secondary prevention," says Dr. Niccolai. "What we need now is the commitment of political, medical and public health officials to make this happen."

Dr. Giuliano further explains, "The articles in this issue were selected to encapsulate the knowledge we have, and effort needed to reach global cervical cancer elimination. Our intent was to inspire action globally among scientists, health care providers, policy leaders and communities to accelerate progress toward this attainable goal."

The COVID-19 pandemic has created both challenges and opportunities regarding global efforts to conduct HPV screening and vaccination. "The pandemic has taught us how to be agile and creative, and how to work toward health promotion under the most difficult of circumstances. It has forced us to reimagine how we deliver health care including preventive services," says Dr. Niccolai. "It has also highlighted for the public the powerful potential of vaccines to protect our health."

"We are delighted to place Preventive Medicine, a respected journal that has an international readership in public health, to the service of this great cause," says Dr. Franco, who has served as Editor-in Chief since 2013. "Drs. Giuliano and Niccolai have done an outstanding job. This special issue of the journal presents a technically feasible and realistic roadmap for facing the great challenge of eliminating cervical cancer."

WASHINGTON (March 4, 2021)--Over the next month, 209 U.S. counties in the United States will need to implement crisis workforce strategies to deal with potentially dangerous shortfalls of intensive care unit doctors, according to a new analysis published today. The analysis draws on data from a just launched county-level hospital workforce estimator, one that takes into account the strain on staffing due to the COVID-19 pandemic.

"The shortages could occur just as public health officials warn that variants of the coronavirus are spreading in the United States and could trigger a sharp rise in the number of Americans infected," Clese Erikson, the principal investigator on the project and deputy director of the Health Equity Workforce Research Center at the George Washington University, said. "Our new online estimator will help county and local public health officials project shortages in the near future and take steps to help keep staffing at safe levels."

The analysis shows that ICU doctors in those 209 counties will be taking care of more than 24 severely ill patients at one time. Typically, an ICU doctor will care for half that number of patients or less at the same time--and, at 24 or higher, hospitals will have to quickly organize and train non-ICU providers to step in and help provide care.

Erikson and her team are part of the Fitzhugh Mullan Institute for Health Workforce Equity, which is based at the GW Milken Institute School of Public Health. To develop the new tool--the first to look at hospital workforce strain at the county level--they collaborated with Premier Inc., a healthcare improvement company, the National Association of County and City Health Officials (NACCHO) and IQVIA, a healthcare data and analytics organization.

"This new ability to drill down to the county level is important for local leaders," Erikson said. A previous Mullan Institute tool estimated the hospital workforce shortages at the state level.

An analysis using data from the County Hospital Workforce Estimator estimates that 7% of all U.S. counties will experience significant strains in their hospital workforce due to longstanding patterns of maldistribution and the added strain of the COVID-19 pandemic.

Additionally, the analysis suggests that 12 U.S. counties will need to put in place contingency strategies within the next month in order to cope with a surge in severely ill patients, including those with new variants of COVID-19.

Local leaders can use the tool to assess the need for additional public health measures, such as social distancing guidelines. Research shows that if 95% of the population wears a mask, future cases of COVID-19 are prevented and that can help avoid a crisis in the local hospital.

"The work of public health and health care are complementary. Even as vaccination programs scale-up, traditional public health measures are critical to reducing suffering and ensuring our healthcare infrastructure is not overwhelmed," Lori Freeman, chief executive officer of NACCHO, said. "This tool can help localities better understand the strain faced by the hospital workforce and adjust public health recommendations accordingly."

Past media reports have largely focused on the dangers of a surge in COVID-19 cases and a shortfall in ICU beds. However, workforce shortages can be a much more difficult problem to solve. Hospitals can create a new COVID-19 unit by taking over an underused floor or wing, but they have more difficulty finding trained doctors and others to fill in when health care workers get sick or must quarantine.

"Premier has been scaling up our predictive analytics capabilities throughout the pandemic to help healthcare providers predict COVID-19 cases, supply resources, and now, workforce levels so they can ensure safe patient care," Angela Lanning, informatics and technology services chief operating officer at Premier, said. "Our models are fueled by data from more than 4,000 hospitals and health systems across the U.S., and we're thrilled to contribute to tools like this that enable business intelligence that's immediately actionable and meaningful in the healthcare setting."

An innovative cell-based treatment for cancer has been found promising for the control of infections caused by fungi. A study published in the journal Cytotherapy reports that the use of CAR (chimeric antigen receptor) T-cells programmed to “recognize” Cryptococcus spp. fungi was effective in combating infection in vitro and in mice.

C. gattii and C. neoformans are present in soil with dead organic matter and places contaminated by the droppings of pigeons and other birds. They cause systemic mycoses in the human organism. They can infect the lungs and central nervous system, causing meningitis or meningoencephalitis. The symptoms vary according to the site of the infection, which can be fatal. Transmission occurs by inhalation of the fungi.

About 1 million cases of Cryptococcus infection are reported worldwide every year, according to the US Centers for Disease Control and Prevention (CDC). The mortality rate ranges from 20% to 70%, and 220,000 cases of cryptococcal meningitis occur annually, affecting mainly people living with HIV-AIDS.

To escape the host’s immune response, Cryptococcus covers itself in a capsule made up primarily of glucuronoxylomannan (GXM), a polysaccharide considered its main virulence factor. It is difficult for the human immune system, especially T CD4+ and T CD8+ cells, to recognize and prevent the infection.

In the study, the group redirected T CD8+ cells to target the GXM in the capsule via expression of a GXM-specific CAR, in order to have the cells recognize the pathogen directly and contain its growth.

“The findings show that GXMR-CAR T-cells can be redirected to recognize C. neoformans. Future studies will focus on determining the therapeutic efficacy of such cells in an animal model of cryptococcosis,” the authors conclude in the article.

The first author is Thiago Aparecido da Silva, a Brazilian researcher affiliated with the University of São Paulo’s Ribeirão Preto Medical School (FMRP-USP). In an interview given to Agência FAPESP, Silva explained that the infusion of GXMR-CAR T-cells not only contained the fungus’s growth but also reduced the number of so-called titan cells that make the infection more virulent. These are abnormally large yeast cells with a diameter of more than 45 micrometers.

Silva is a researcher in FMRP-USP’s Department of Cellular and Molecular Biology and Pathogenic Bioagents (Biocel) and is supported by FAPESP via a postdoctoral fellowship and a research internship abroad.

“This reduction in titan cells points to a good prognosis for new treatments for cryptococcosis,” Silva said. “CAR T-cells can be used to treat other fungal infections and can be associated with conventional drugs to reduce their side-effects. CAR T-cells can establish immune memory and protect the patient against reinfection by invasive fungi.”

Silva is now working on ways to optimize the protective response of CAR T-cells to fungal disease, including infections caused by Candida albicans and Histoplasma capsulatum, with support from FAPESP via a Young Investigator Grant.

Direct death of fungi

Researchers at MD Anderson Cancer Center in Texas (USA) who collaborate with Silva were the first to explore the direct death of fungi from redirected T CD8+ cells with a CAR targeting a carbohydrate found in the cell wall of Aspergillus fumigatus.

Interest in the use of CAR T-cells to treat cancer and other diseases has increased in several countries. In most studies involving the technique, the researchers targeted the antigen CD19 to contain multiplication of abnormal B-cells causing lymphoma or other kinds of severe disease (read more at: agencia.fapesp.br/31675).

CAR T-cell therapy in various forms has been approved since 2017 by the US Food and Drug Administration (FDA), especially to treat leukemia and lymphoma.

In Brazil, a group of researchers at the Center for Cell-Based Therapy (CTC), hosted by FMRP-USP, tested this innovative cancer treatment with reprogrammed cells from the patient for the first time in 2019. CTC is a Research, Innovation and Dissemination Center (RIDC) supported by FAPESP.

The technique was used to treat an advanced case of diffuse large B-cell lymphoma (DLBCL), a type of non-Hodgkin lymphoma (read more at: agencia.fapesp.br/31675). In February 2020, CDC launched a book with practical information on the production of CAR T-cells.

Target recognition

Silva and the other authors of the latest study raise the hypothesis that redirecting GXMR-CAR T-cells induces cytotoxic activity against fungi that express GXM in the cell wall. The study shows that modified human T-cells expressing GXMR-CAR were capable of binding to GXM in vitro and interacting with the yeast form of C. neoformans.

“The most critical part of the construction of a CAR is the target recognition portion, in which we use monoclonal antibodies that interact with Cryptococcus,” Silva said. “We use the DNA sequence that encodes the part of the antibody that recognizes the fungus and combine it with the DNA sequence that encodes the other portions of the CAR.”

With a relatively minor genetic change, a new treatment developed by researchers at the Georgia Institute of Technology and Emory University appears to stop replication of both flu viruses and the virus that causes Covid-19. Best of all, the treatment could be delivered to the lungs via a nebulizer, making it easy for patients to administer themselves at home.

The therapy is based on a type of CRISPR, which normally allows researchers to target and edit specific portions of the genetic code, to target RNA molecules. In this case, the team used mRNA technology to code for a protein called Cas13a that destroys parts of the RNA genetic code that viruses use to replicate in cells in the lungs. It was developed by researchers in Philip Santangelo's lab in the Wallace H. Coulter Department of Biomedical Engineering.

"In our drug, the only thing you have to change to go from one virus to another is the guide strand -- we only have to change one sequence of RNA. That's it," Santangelo said. "We went from flu to SARS-CoV-2, the virus that causes Covid-19. They're incredibly different viruses. And we were able to do that very, very rapidly by just changing a guide."

The guide strand is a map that basically tells the Cas13a protein where to attach to the viruses' RNA and begin to destroy it. Working with collaborators at the University of Georgia, Georgia State University, and Kennesaw State University, Santangelo's team tested its approach against flu in mice and SARS-CoV-2 in hamsters. In both cases, the sick animals recovered.

Their results are reported Feb. 3 in the journal Nature Biotechnology. It's the first study to show mRNA can be used to express the Cas13a protein and get it to work directly in lung tissue rather than in cells in a dish. It's also the first to demonstrate the Cas13a protein is effective at stopping replication of SARS-CoV-2.

What's more, the team's approach has the potential to work against 99% of flu strains that have circulated over the last century. It also appears it would be effective against the new highly contagious variants of the coronavirus that have begun to circulate.

The key to that broad effectiveness is the sequence of genes the researchers target.

"In flu, we're attacking the polymerase genes. Those are the enzymes that allow the virus to make more RNA and to replicate," said Santangelo, the study's corresponding author.

With help from a collaborator at the Centers for Disease Control and Prevention, they looked at the genetic sequences of prevalent flu strains over the last 100 years and found regions of RNA that are unchanged across nearly all of them.

"We went after those, because they're far better conserved," Santangelo said. "We let the biology dictate what our targets would be."

Likewise, in SARS-CoV-2, the sequences the researchers targeted so far remain unchanged in the new variants.

The approach means the treatment is flexible and adaptable as new viruses emerge, said Daryll Vanover, a research scientist in Santangelo's lab and the paper's second author.

"One of the first things that society and the CDC is going to get when a pandemic emerges is the genetic sequence. It's one of the first tools that the CDC and the surveillance teams are going to use to identify what kind of virus this is and to begin tracking it," Vanover said. "Once the CDC publishes those sequences -- that's all we need. We can immediately screen across the regions that we're interested in to target it and knock down the virus."

Vanover said that can result in lead candidates for clinical trials in a matter of weeks -- which is about how long it took them to scan the sequences, design their guide strands, and be ready for testing in this study.

"It's really quite plug-and-play," Santangelo said. "If you're talking about small tweaks versus large tweaks, it's a big bonus in terms of time. And in pandemics -- if we had had a vaccine in a month or two after the pandemic hit, think about what things would look like now. If we had a therapy a month after it hit, what would things look like now? It could make a huge difference, the impact on the economy, the impact on people."

The project was funded by the Defense Advanced Research Projects Agency's (DARPA) PReemptive Expression of Protective Alleles and Response Elements (PREPARE) program, with the goal of creating safe, effective, transient, and reversible gene modulators as medical countermeasures that could be adapted and delivered rapidly. That's why the team decided to try a nebulizer for delivering the treatment, Santangelo said.

"If you're really trying to think of something that's going to be a treatment that someone can actually give themselves in their own house, the nebulizer we used is not terribly different from one that you can go buy at a pharmacy," he said.

The team's approach also was sped along by their previous work on delivering mRNA to mucosal surfaces like those in the lungs. They knew there was a good chance they could tackle respiratory infections with that approach. They decided to use mRNA to code for the Cas13a protein because it's an inherently safe technique.

"The mRNA is transient. It doesn't get into the nucleus, doesn't affect your DNA," Santangelo said, "and for these CRISPR proteins, you really don't want them expressed for long periods of time."

He and Vanover said additional work remains -- especially understanding more about the specific mechanisms that make the treatment effective. It has produced no side effects in the animal models, but they want to take a deeper look at safety as they consider moving closer to a therapy for human patients.

"This project really gave us the opportunity to push our limits in the lab in terms of techniques, in terms of new strategy," said Chiara Zurla, the team's project manager and a co-author on the paper. "Especially with the pandemic, we feel an obligation to do as much as we can as well as we can. This first paper is a great example, but many will follow; we've done a lot of work, and we have a lot of promising results."

What The Study Did: This randomized clinical trials reports that among adults with mild COVID-19, a five-day course of ivermectin, compared with placebo, didn't significantly improve the time to resolution of symptoms. The findings don't support the use of ivermectin for treatment of mild COVID-19, although larger trials may be needed to understand the effects of ivermectin on other clinically relevant outcomes.

Authors: Eduardo López-Medina, M.D., M.Sc., of the Centro de Estudios en Infectología Pediátrica in  Cali, Colombia, is the corresponding author.

To access the embargoed study: Visit our For The Media website at this link https://media.jamanetwork.com/

(doi:10.1001/jama.2021.3071)

Editor's Note: The article includes conflict of interest and funding/support disclosures. Please see the article for additional information, including other authors, author contributions and affiliations, conflict of interest and financial disclosures, and funding and support.

What The Article Says: This Viewpoint proposes ways to maximize vaccine efficacy and allocation given the rise of coronavirus variants and authorization of a Johnson & Johnson vaccine, including reserving the latter for younger healthier populations, boosting it with a single-dose messenger RNA (mRNA) vaccination and single mRNA immunization of people with prior documented SARS-CoV-2 infection.

Authors: John P. Moore, Ph.D., of Weill Cornell Medicine in New York, is the corresponding author.

To access the embargoed study: Visit our For The Media website at this link https://media.jamanetwork.com/

(doi:10.1001/jama.2021.3465)

Editor's Note: The article includes an Editor's Note. Please see the article for additional information, including other authors, author contributions and affiliations, conflict of interest and financial disclosures, and funding and support.

NEW YORK, NY (March 4, 2021)--Inflammatory heart disease is a rare finding among professional athletes with mild or asymptomatic COVID-19 infection, a large-scale study has found.

The study, led by Columbia University Vagelos College of Physicians and Surgeons in collaboration with the major North American sports leagues and their respective players' associations, was published online today in JAMA Cardiology.

Athletes and COVID-19

Studies suggest that approximately 20% of patients hospitalized with severe COVID-19 develop some type of heart damage, but the impact of mild or asymptomatic infections on the heart is not known.

Viral infections can cause inflammatory heart disease--inflammation in the heart muscle (myocarditis) or the lining of the heart (pericarditis). The condition can trigger abnormal heart rhythms and accounts for approximately 5% of cases of sudden cardiac death in athletes. 

"Athletes have a unique risk because of demands on the heart from strenuous exercise, which can increase the risk of abnormal heart rhythms in those with underlying inflammatory heart disease," says David Engel, MD, associate professor of medicine at Columbia University Vagelos College of Physicians and Surgeons and senior author of the paper. 

Early in the COVID-19 pandemic, isolated reports of college and professional athletes who developed heart inflammation were widely publicized, causing alarm among medical professionals, sports leagues, and universities. 

In the spring of 2020, the American College of Cardiology (ACC) Sports and Exercise Cardiology section recommended that competitive athletes who test positive for SARS-CoV-2 undergo screening for inflammatory heart disease before returning to the field, court, or ice. The recommendations called for a specific screening protocol with blood tests, electrocardiography, and echocardiography. The guidelines were adopted and implemented across all of the major sports leagues, including Major League Baseball, Major League Soccer, the National Football League, the National Hockey League, and men's and women's National Basketball Associations. 

"While all of the major professional leagues had implemented COVID-19 testing programs and the ACC screening protocol, there was no data on how prevalent heart inflammation may be among athletes who tested positive for the coronavirus or how effective the screening program would be to allow athletes to safely return to sport after COVID-19," Engel says. "The leagues realized that if they pooled their screening data, we would soon have an answer."

Very Low Incidence of Heart Inflammation in Athletes with Mild COVID-19

The study included data from 789 professional athletes across the professional leagues who were screened for post-COVID-19 cardiac inflammation. None had severe COVID-19 symptoms, and approximately 40% had very mild or no symptoms.

Abnormal cardiac screening results raising concern for potential COVID-19-associated cardiac injury were found in 30 (3.8%) of the athletes. Further assessment with diagnostic cardiac MRI and cardiac stress tests ultimately found heart inflammation in only five of the athletes (0.6%). 

None of the athletes with inflammatory heart disease had a history of heart disease and all were restricted from athletic activities, in accordance with ACC guidelines.

"Our study shows that it is rare for professional athletes with mild COVID-19 to develop heart inflammation, but the risk is not zero," says Engel. "These findings give college and other athletic organizations some clinically relevant context to help them optimize their return-to-play screening protocols with a measure of confidence."

PHILADELPHIA (March 4, 2021) - Equitable implementation of COVID?19 vaccine delivery is a national and global priority, with a strong focus on reducing existing disparities and not creating new disparities. But while a framework has been recognized for equitable allocation of COVID?19 vaccine that acknowledges the rights and interests of sexual and gender minorities (SGM), it fails to identify strategies or data to achieve that goal.

A new study with support from researchers at the University of Pennsylvania School of Nursing (Penn Nursing) examined the prevalence of COVID testing and diagnosis and assessed COVID?19 vaccine acceptance among a large national sample of SGM. It showed that medical mistrust, social concern, and race were significantly associated with decreased COVID?19 vaccine acceptance by SGM participants. Results have been published in the article "COVID?19 Vaccine Acceptance Among an Online Sample of Sexual and Gender Minority Men and Transgender Women" in the journal Vaccines.

"Given that stigma and discrimination drive health inequities among SGM, which may result in increased risk of severe COVID?19 disease and influence COVID?19 vaccine acceptance, research examining COVID?19 vaccine acceptance among SGM is needed," says Daniel Teixeira da Silva, MD, National Clinician Scholar and Postdoctoral Fellow at the Penn Program for Sexuality, Technology and Action Research (PSTAR) and the lead investigator of the study.
The psychosocial and economic impact of the COVID?19 pandemic disproportionately affects SGM compared to cisgender heterosexual populations. Studies show that since the beginning of the COVID?19 pandemic, SGM have been more likely to experience job loss, income reduction, and decreased access to gender-affirming resources. While SGM populations are disproportionately vulnerable to poor COVID?19 outcomes, little has been known about COVID?19 vaccine acceptance among this group until this study.

The study showed that SGM who experienced medical mistrust were less likely to accept a COVID?19 vaccine. In addition, SGM participants in the study who identified as Black reported decreased COVID?19 vaccine acceptance. COVID?19 vaccine acceptance was greater among study participants who endorsed altruistic attitudes and were less concerned about COVID?19 social concerns.

"The confluence of disproportionate psychosocial and economic burdens with increased vulnerability to minority stressors among SGM may decrease COVID?19 vaccine uptake and further deepen health inequities," says José A. Bauermeister, PhD, MPH, Chair of the Department of Family and Community Health at Penn Nursing, one of the co-investigators of the study.

Healthcare provider recommendations have been found to be associated with increased COVID?19 acceptance. These results suggest that providers and public health efforts that approach medical mistrust with empathy and validation -- and which also address concerns about discrimination and support altruistic intentions -- may be more successful engaging SGM in COVID?19 vaccine uptake.

"As the planning of COVID?19 vaccine rollout efforts is conceptualized and designed, these data may inform equitable implementation strategies and prevent worsening health inequities among SGM populations," says Bauermeister.

The drug nusinersen is approved for the treatment of 5q spinal muscular atrophy (SMA). The German Institute for Quality and Efficiency in Health Care (IQWiG) has now examined in an early benefit assessment whether the drug offers an added benefit for patients in comparison with the appropriate comparator therapy.

According to the findings, there is an indication of a major added benefit in comparison with best supportive care (BSC) in children with early onset of disease (in the first six months of life). The drug manufacturer did not submit any relevant data for children with a later onset of disease, so that an added benefit in comparison with BSC is not proven here. For infants who are not yet symptomatic but are expected to have early onset of disease due to a certain genetic predisposition (no more than two SMN2 gene copies), a hint of a non-quantifiable added benefit of nusinersen in comparison with BSC can be derived from the study data.

5q spinal muscular atrophy - SMA

SMA leads to the progressive death of certain nerve cells in the spinal cord that are responsible for muscle movement. Without these nerve cells, the muscles receive no movement signal, remain unused and become weak. This impairs a child's motor development. The cause of 5q spinal muscular atrophy is a change in the genetic information on the "survival motor neuron" (SMN1) gene. It is located on the longer arm, the so-called q-arm, of the 5th chromosome - hence the abbreviation "5q". There are different forms of 5q spinal muscular atrophy:

The infantile form (SMA type 1) already begins in the first weeks of life. It has particularly serious consequences: children with this condition do not learn to sit on their own and, if left untreated, they usually die at the age of one to two years. This form accounts for about half of all children with the disease. The infantile form affects up to 10 out of 100 000 newborns in Germany.

The other forms of spinal muscular atrophy begin after the sixth month of life (SMA type 2, type 3 and type 4). The later the onset of the disease, the more motor skills a child can develop and the higher its life expectancy.

Assessment in three patient groups

In the therapeutic indication, children with early onset of disease (SMA type 1) can be distinguished from those with later onset (SMA type 2, type 3 and type 4). In addition, the group of pre-symptomatic children diagnosed during SMA newborn screening forms an important third patient group.

The derivation of the added benefit for children with early onset of disease (SMA type 1) is based on data from the ENDEAR study, a randomized controlled trial (RCT) in patients with genetic documentation of 5q SMA who were younger than six months of age at symptom onset, and who had no more than two SMN2 gene copies. The study overall provides an indication of a major added benefit. In order to achieve an advantage in overall survival, it is particularly crucial that children with early symptom onset (age: under 12 weeks) are treated with nusinersen. In order to achieve progress in symptoms (achievement of motor milestones and permanent ventilation), it is important that treatment with nusinersen is initiated as early as possible after symptom onset.

As the manufacturer did not provide any relevant data for the assessment of the added benefit of nusinersen in comparison with BSC in children with later onset of disease (type 2, type 3 and type 4), an added benefit for this patient group is not proven.

For pre-symptomatic children with 5q SMA, there are no RCTs of direct comparison between nusinersen and the appropriate comparator therapy BSC or a corresponding indirect comparison based on RCTs. However, under certain circumstances, a transfer of evidence from one population to another (without sufficient data) is possible. The IQWiG project team considered these circumstances to be present here and therefore transferred the added benefit from the ENDEAR study for children with early onset of disease to pre-symptomatic patients (each with two SMN2 gene copies). Due to the associated greater uncertainty of the assessment, there is no indication, but a hint of a non-quantifiable added benefit of nusinersen in comparison with BSC for this patient group.

Progress in the treatment of SMA

Beate Wieseler, Head of IQWiG's Drug Assessment Department, summarizes the results of the early benefit assessment: "Children with type 1 SMA develop more motor skills with nusinersen, do not need ventilation until later, and live longer. That's why it's good that SMA screening has recently become part of newborn screening in German statutory health insurance and is paid for by health insurance funds."

Besides nusinersen, a second drug, onasemnogene abeparvovec, was approved for the treatment of 5q SMA a year ago. Due to the limited informative value of the clinical data available so far, the therapeutic value of onasemnogene abeparvovec in comparison with nusinersen cannot yet be conclusively assessed. The Federal Joint Committee (G-BA) therefore obliged the manufacturer of onasemnogene abeparvovec to collect routine practice data in order to close the evidence gap. Beate Wieseler emphasizes: "It would be good if the routine practice data generated in this way allowed a fair comparison between nusinersen and onasemnogene abeparvovec."

Researchers at Baylor College of Medicine show that analysis of the proteomics, or all the protein data, from aggressive human cancers is a useful approach to identify potential novel therapeutic targets. They report in the journal Oncogene, the identification of "proteomic signatures" that are associated with clinical measures of aggressive disease for each of the seven cancer types studied. Some signatures were shared between different types of cancer and included cellular pathways of altered metabolism. Importantly, experimental results provided proof-of-concept that their proteomics analysis approach is a valuable strategy to identify potential therapeutic targets.

"There are two notable aspects of this study. One is that we explored the proteomic landscape of cancer looking for proteins that were expressed in association with aggressive forms of cancer," said co-corresponding author Dr. Chad Creighton, professor of medicine and co-director of Cancer Bioinformatics at the Dan L Duncan Comprehensive Cancer Center at Baylor. "We analyzed protein data that included tens of thousands of proteins from about 800 tumors including seven different cancer types - breast, colon, lung, renal, ovarian, uterine and pediatric glioma - made available by the Clinical Proteomic Tumor Analysis Consortium (CPTAC) mass-spectrometry-based proteomics datasets."

Computational analysis for the CPTAC datasets identified proteomic signatures associated with aggressive forms of cancer. These signatures pointed at altered cellular pathways that might be driving aggressive cancer behavior and could represent novel therapeutic targets. Each cancer type showed a distinctive proteomic signature for its aggressive form. Interestingly, some signatures were common to different types of cancer.

The other aspect of this study was to provide proof-of-concept that the proteomic analysis was a useful strategy to identify drivers of aggressive disease that could potentially be manipulated to control cancer growth.

"That's exactly what we were able to do with this new, very powerful dataset," said co-corresponding author Dr. Diana Monsivais, assistant professor of pathology and immunology at Baylor. "We focused on the uterine cancer data for which the computational analysis identified alterations in a number of proteins that were associated with aggressive cancer. We selected protein kinases, enzymes that would represent stronger candidates for therapeutics."

Of hundreds of initial candidates, the researchers selected four kinases for functional studies in uterine cancer cell lines. They found that the kinases not only were expressed in the uterine cancer cells lines, but also that manipulating the expression of some of the kinases reduced the survival or the ability to migrate for some uterine cancer cells. Cell migration is a property of cancer cells that allows them to spread cancer to other tissues.

This work is the result of a productive collaboration between two Baylor centers, the Dan L Duncan Comprehensive Cancer Center and the Center for Drug Discovery.

"Chad conducted this wonderful analysis on new CPTAC datasets and was interested in validating it in a human cancer. He approached us about performing functional studies to determine whether some proteins could translate to new targets for endometrial cancer," Monsivais said. "Our experiments provided proof-of-concept that proteomics analysis is a useful strategy not only to better understand what drives cancer, but to identify new ways to control it or eliminate it."

"Historically, researchers have only been generating transcriptomic data (the messenger RNA (mRNA) that is translated into protein). Looking at the protein data itself, which is made available by the CPTAC, enables researchers to extract a new layer of information from these cancers," Creighton said. "In this study, we compared mRNA and protein signatures and, although in many cases they overlapped, about half the proteins in the proteomic signatures were not included in the corresponding mRNA signature, suggesting the need to include both mRNA and protein data in cancer studies."

Parkinson's disease has always been considered a brain disorder. However, new research reveals a close link between the disease and certain immune cells in the blood.

Researchers from Aarhus University have taken the first step on a path which can lead to new ways of understanding and, in the long term, possibly treating this widespread disease that affects not only motor functions but also cognition and emotions.

"We know that Parkinson's disease is characterized by an inflammation in the brain, and that this is crucial for the progression of the disease. But in the study, our interest has been focused on the immune cells found outside the brain," explains Marina Romero-Ramos, who is associate professor at the Department of Biomedicine at Aarhus University.

The researchers have studied a group of patients suffering from REM Sleep Behaviour Disorder (RBD), a condition where the patients physically act vivid dreams with vocalizations and movements. If a patient e.g. dreams that they are running, their legs will move as if they were actually running. The sleep disorder is often discovered by a spouse as it results in violent movements at night, and the diagnosis is often indicative of something more. Patients with RBD have a high risk of developing Parkinson's - statistically approximately ninety per cent of them will be diagnosed with a parkinsonism related disorder over the course of 5-10 years.

The blood's immune system changes very early on

In Parkinson's disease, a protein called alpha-synuclein aggregates in the neurons in the brain, and this kills the cells. The same protein also aggregates in the brain of people with the RBD, and it is therefore regarded as an early form of Parkinson's disease. This has led the researchers from the Department of Biomedicine at Aarhus University - in collaboration with a group of neurologists and experts in nuclear medicine at Aarhus University Hospital, led by Dr. Nicola Pavese - to carry out scans of the brains of 15 patients with RBD and ten healthy people. The scan revealed that the patients with the sleep disorder had inflammation and a loss of neuronal activity in the brain. Although they did not present symptoms of Parkinson's, their neurons were already ill and the brain's immune cells were activated.

The groundbreaking discovery happened when Dr. Marina Romero-Ramos and her colleagues from Aarhus University analysed blood samples from these patients. It turned out that the inflammation in the brain, and the associated loss of brain cells, directly related to changes in some immune cells in the blood, the monocytes. When certain proteins increased on these immune cells, there was in parallel increased inflammation in the brain and a decrease on the neuronal activity. This is a key finding when it comes to understanding Parkinson's disease.

"We could see that the blood's immune system changes very early on - even before Parkinson's is diagnosed," says Marina Romero-Ramos.

"This is the first study to show that the body's immune system continuously communicates with the brain during the development of Parkinson's disease, and that changes in the body's immune system influence the condition of the neurons in the brain. In connection with Parkinson's, this presents us with new opportunities for studying the immune cells in the blood and finding new forms of treatment," she says.

This means that the researchers now hope to find and investigate ways to influence Parkinson's disease by treating the blood and not the brain. Previous experiments on mice and rats suggest that this is possible, even though there is still much research to be done, as Dr. Romero-Ramos explains.

"This opens up the possibility of being able to design immunotherapy that modulates cells in the blood, which subsequently would stop or delay the changes in the brain. For the patients, being able to enjoy more years with good quality of life will be very significant," she says.

"It also opens up opportunities for us to be able to find biomarkers in the blood that can tell us how someone's brain is doing. Blood tests can be done more often and cheaper than a brain scan."

Rare data from patients

The brain is a special type of tissue, and for many years researchers believed that the immune response in the brain was independent from the rest of the body. The study has now confirmed that the immune response in the brain and the body communicate with each other during RBD, and this is a discovery that the researchers could not have made without the help of the volunteers that took part in the study.

"We've had a unique combination of researchers at Aarhus University Hospital who take images of the brain, and researchers like me who analyse immune cells in the blood. It is very rare to get both analyses from a patient and it has only been possible because a group of people were willing to participate in the trial, which we're very grateful for. Participation involved two visits to the hospital for a brain scan, which itself isn't painful, but of course it requires time and patience," says Marina Romero-Ramos.

The data should be now evaluated and replicated by more labs, and hopefully new groups of patients will provide blood samples, brain scans and their patience for further testing.

"This lays the foundation. We can continue to build on the study, because we've now discovered that there is a change in the blood at a very early stage of Parkinson's disease, and that it's related to changes in the brain. We didn't have the data to truly say this before."

ARLINGTON HEIGHTS, IL (March 4, 2021) - Many new mothers with infants want very much to breastfeed as it is the gold standard for early nutrition. What to do when you find out your young child has a food allergy, and you are breastfeeding? A new study in Annals of Allergy, Asthma and Immunology, the scientific journal of the American College of Allergy, Asthma and Immunology (ACAAI), found that more than 28% of the women were given no guidance on whether they could eat the same food their breastfeeding child was allergic to.

“We found that guidance from healthcare practitioners for breastfeeding mothers in this situation was inconsistent,” says pediatrician and internist Hannah Wangberg, MD, ACAAI member and lead author of the study. “Of the 133 mothers who completed the survey, 47% were advised to continue breastfeeding without dietary restriction and 17% were advised to avoid eating the food(s) their child was allergic to while breastfeeding. A minority of the mothers (12%) reported their child experienced an allergic reaction to breast milk.”

When mothers in the survey were asked if they had received conflicting advice from their healthcare providers on what they should or should not eat while breastfeeding their food allergic child, more than 30% said they had received conflicting advice. The study authors point out that the survey did not specifically ask whether the child's allergist or primary care provider gave the advice. The study also makes clear that no mothers were encouraged to stop breastfeeding entirely.

According to allergist Jay Lieberman, MD, chair of the ACAAI Food Allergy Committee, "There is no uniform guidance I'm aware of on this topic, which is perhaps one reason for the confusion. That's in part because there is not a lot of good data available. That said, there is little evidence that if a mother eats a food that the child is allergic to, that this will lead to a reaction in the child."

Dr. Lieberman says he tells breastfeeding mothers to continue breastfeeding and eating whatever they want. However, if they feel more comfortable avoiding the child's allergen, that's fine as well, but to continue breastfeeding is ideal.

For the 89% of mothers that continued to breastfeed after their child's food allergy diagnosis, 46% continued to eat the food their child was allergic to on a regular basis (greater than once per week) and did not alter how they provided breast milk to their child. An additional 25% continued to eat the food their child was allergic to on an infrequent basis (less than once per week) without altering how they provided breast milk to their child.