Body

Researchers from the group of Hans Clevers (Hubrecht Institute) developed the first patient-derived organoid model for cervical cancer. They also modelled the healthy human cervix using organoids. In close collaboration with the UMC Utrecht, Princess Máxima Center for pediatric oncology and the Netherlands Cancer Institute, the researchers used the organoid-based platform to study sexually transmitted infections for a herpes virus. The model can potentially also be used to study the human papillomavirus (HPV), which is one of the main causes of cervical cancer. The results were published in Cell Stem Cell on the 13th of April.

Cervical cancer is a common gynecological malignancy, often caused by the human papillomavirus (HPV). However, good models to study human cervical tissues were lacking. Reason enough for the group of Hans Clevers to develop an organoid-based model for the healthy cervix and associated malignancies including cervical cancer. The project was conducted in close collaboration with researchers from the UMC Utrecht, the Princess Máxima Center for pediatric oncology and the Netherlands Cancer Institute.

Mini organs

The researchers obtained human cervical tissue from either healthy patients or patients with different types of cervical cancer. From these tissues they grew organoids; tiny 3D structures of about half a millimeter in size that closely mimic organ function. The organoids derived from healthy tissue closely resemble the tissue architecture and gene expression profiles of the actual human cervix. Therefore, the organoids hold great promise for studying what happens when a virus infects the human cervix. Kadi Lõhmussaar, first author on the paper, explains: "For our study, we used a herpes virus - herpes simplex virus-1 (HSV-1) - to demonstrate the potential of the model for research into sexually transmitted infections."

Prospectively, the model could also be applied to study the human papillomavirus (HPV) and how that virus causes cancer. "Cervical cancer is often caused by HPV-infection, but research into this virus was complicated as the virus is difficult to culture in the lab. Our new model might be able to overcome this obstacle," says Lõhmussaar.

Tumoroids

The organoids grown from cancerous tissue - also called tumoroids - closely resemble actual tumors. They show mutation- and gene expression profiles that are typical for cancer and they carry similar morphological abnormalities. The researchers also found that the tumoroids respond differently to common chemotherapeutics, paving way to the era of precision medicine. "Hopefully in the future, we can predict which chemotherapy will work best for specific patients based on results obtained in the tumoroids."

Biobanks

The organoids can be derived via patients' Pap-brush material. The study shows that the tiny bit of tissue obtained from this procedure is sufficient for starting an organoid culture. This opens up the possibility to not only look at fixed cells under the microscope, but also do in-depth analyses of the living cells that might be on their way to become cancerous. Additionally, given that the Pap-brush is non-invasive for patients, the new organoid model provides the research community with a relatively easy access to the tissue of interest and a new model system. Lõhmussaar: "This will hopefully facilitate a rapid generation of additional organoid-based cervical cancer biobanks worldwide. That would offer new means for advancing research into cervical biology and associated diseases."

Below please find link(s) to new coronavirus-related content published today in Annals of Internal Medicine. All coronavirus-related content published in Annals of Internal Medicine is free to the public. A complete collection is available at https://annals.org/aim/pages/coronavirus-content.

Much can be learned by following original placebo recipients after they receive the COVID-19 vaccine
Proposed approach would allow researchers to estimate durability of vaccine efficacy and whether the vaccine eventually becomes harmful to some
Free full text: https://www.acpjournals.org/doi/10.7326/M20-8149

Authors from the National Institutes of Health (NIH) and colleagues suggest ways in which we could learn by continuing to follow vaccine trial participants who originally received placebo. They mathematically demonstrate that long-term placebo-controlled vaccine efficacy can be estimated even after the placebo group has been vaccinated. While less precise than estimates from a standard trial where the placebo group remains unvaccinated, this proposed approach permits assessment of the durability of vaccine efficacy and whether the vaccine eventually becomes harmful to some. A report is published today in Annals of Internal Medicine.

The authors explain that deferred vaccination, if done open-label, may lead to riskier behavior in the unblinded original vaccine group, confounding estimates of long-term vaccine efficacy. Hence, deferred vaccination via blinded crossover, where the vaccine group receives placebo and vice versa, is the preferred way to assess vaccine durability and potential delayed harm. Deferred vaccination allows placebo recipients timely access to the vaccine when it would no longer be proper to maintain them on placebo, yet still allows important insights about immunologic and clinical effectiveness over time.

April 13th, 2021, Washington, D.C. - The severe health and economic impacts of the COVID-19 pandemic have disrupted food systems and upended livelihoods. Yet pandemic responses have demonstrated the power of well-crafted policies to blunt the impact of major shocks while laying the groundwork for stronger, more resilient food systems, according to the 2021 Global Food Policy Report, released today by the International Food Policy Research Institute (IFPRI). The report provides lessons drawn from the current crisis that can help us transform food systems to reduce the impact of the ongoing pandemic, better prepare for future shocks, and address longstanding weaknesses and inequalities.

"We have known for a while now that there are major problems with our food systems, that they are unequal and unsustainable," said Johan Swinnen, director general of IFPRI. "This crisis has revealed these problems in a way that none of us can ignore, but it has also demonstrated that we have effective ways to address these problems."

The report draws on evidence from low- and middle-income countries (LMICs) across the globe to analyze both the impacts of and the policy responses to the crisis, with a particular focus on vulnerable groups, who have suffered disproportionately. The report details how livelihoods, food security, and nutrition have been affected; how and why impacts have varied across regions and countries; and what our food systems and food supply chains need to look like to better absorb such shocks in the coming years.

Unsurprisingly, the report finds that COVID-19 and restrictions on social interactions and business operations have disproportionately affected marginalized people in LMICs, driving up poverty -- by as much as 20%, according to IFPRI estimates -- and malnutrition. Supply chain disruptions have also taken a toll on dietary quality and diversity, leading to increased nutritional deficiencies, particularly among vulnerable groups. IFPRI projections suggest that the declines in food security and proper nutrition from the pandemic could cause an additional 6.7 million children to experience wasting in 2020 alone.

“There is no better time than now to seize the moment to start doing something about our food systems,” said Agnes Kalibata, secretary general special envoy to the 2021 Food Systems Summit, at a launch event for the report. “This report is a huge tool for unlocking the evidence and actions that can help us move forward.”

Among vulnerable populations, women, for example, have faced disproportionate burdens throughout the crisis, and national policy responses have largely failed to adopt gender-sensitive approaches that could narrow the gender gap. Although women make up 39% of the global workforce, they account for 54% of the jobs lost during the pandemic. The report suggests future efforts to respond to shocks include complimentary programming to increase gender equity and protections for other vulnerable groups, including refugees and displaced people.

The report also highlights key lessons from the pandemic about food systems. In general, demand-side effects, due to job losses and falling incomes, had a stronger impact on food security than supply disruptions. Food value chains, despite many disruptions, proved to be fairly resilient, albeit with variations across commodities and regions; and policies declaring agrifood workers and services as essential helped to cushion disruptions. Research findings show that food systems transitioning from traditional to modern, characterized by longer but often fragmented supply chains, proved to be most vulnerable.

Many countries invested heavily in social protection measures to help stem rising poverty and food insecurity, increasing benefits or expanding them to new recipients. Programs built on robust existing systems were the most successful, but the scale of growth in programs across the globe showed that widespread political will can rapidly grow such pro-poor programming.

"In many low- and middle-income countries, the impacts of COVID-19 have been lower than expected during most of 2020, and evolving policy responses have, in many cases, helped to mitigate damages," said John McDermott, director of the CGIAR Research Program on Agriculture for Nutrition and Health.

He cautioned that the pandemic is evolving quickly, however, with Africa, South Asia, and Latin America experiencing new waves of disease and vaccine delivery delays expected for many LMICs. "While we don't expect returns to strict early lockdowns in most LMICs, we are still in the middle of this crisis and do not yet know how things will play out going forward."

Learning from what has and hasn't worked can play a major role in curtailing the impacts of the ongoing pandemic and meeting the 2030 Sustainable Development Agenda. Major shocks like COVID-19 that disrupt food, health, and economic systems are likely to increase due to climate change and global interconnectivity, making transforming these systems imperative. The report suggests three avenues for increased resilience: limiting the frequency and magnitude of shocks; investing in early warning systems to anticipate shocks; and building capacity to adapt to and absorb shocks when they happen.

The report notes the important role of private sector innovation in times of crisis, which requires an enabling policy environment, as well as physical and digital infrastructure. Better digital infrastructure is imperative not only for a business environment that fosters innovation, but also to bridge the "digital divide" that leaves the world's most vulnerable underserved and more exposed to the impacts of crises.

COVID-19 has presented the opportunity for making these and other changes that will transform the world's food systems. Doing so, the report's contributors stress, will require multifaceted, evidence-based approaches as well as cooperation and collaboration within and across sectors and borders.

"The pandemic has shifted the political equilibrium of what is possible - showing that we have the will and capacity to make big changes to transform food systems for the better. We need to seize this opportunity at every level of policy and throughout food systems so we are better prepared to deal with the next major shock and able to transform food systems toward more inclusion, more sustainability and better health," said Swinnen.

New research led by a professor at NUI Galway is set to change how doctors treat some patients with high blood pressure - a condition that affects more than one in four men and one in five women.

The study by researchers at NUI Galway, Johns Hopkins University and Harvard Medical School found no evidence that diastolic blood pressure - the bottom reading on a blood pressure test - can be harmful to patients when reduced to levels that were previously considered to be too low.

Lead researcher Bill McEvoy, Professor of Preventive Cardiology at NUI Galway and a Consultant Cardiologist at University Hospital Galway, said the findings have the potential to immediately influence the clinical care of patients.

Professor McEvoy said: "We now have detailed research based on genetics that provides doctors with much-needed clarity on how to treat patients who have a pattern of high systolic values - the top reading for blood pressure - but low values for the diastolic, or bottom, reading.

"This type of blood pressure pattern is often seen in older adults. Old studies using less reliable research methods suggested that the risk for a heart attack began to increase when diastolic blood pressure was below 70 or above 90. Therefore, it was presumed there was a sweet-spot for the diastolic reading."

High blood pressure is a major cause of premature death worldwide, with more than 1 billion people having the condition. It is linked with brain, kidney and other diseases, but it is best known as a risk factor for heart attack. More recently, high blood pressure has emerged as one of the major underlying conditions that increase the risk of poor outcomes for people who become infected with Covid-19.

Professor McEvoy and the international research team analysed genetic and survival data from more than 47,000 patients worldwide. The study, published in the prestigious medical journal Circulation, showed:

There appears to be no lower limit of normal for diastolic blood pressure and no evidence in this genetic analysis that diastolic blood pressure can be too low.

There was no genetic evidence of increased risk of heart disease when a patient's diastolic blood pressure reading is as low as 50.

The authors also confirmed that values of the top, systolic, blood pressure reading above 120 increased the risk of heart disease and stroke.

Blood pressure medications reduce both systolic and diastolic values.

Professor McEvoy added: "Because doctors often focus on keeping the bottom blood pressure reading in the 70-90 range, they may have been undertreating some adults with persistently high systolic blood pressure.

"The findings of this study free up doctors to treat the systolic value when it is elevated and to not worry about the diastolic blood pressure falling too low.

"My advice now to GPs is to treat their patients with high blood pressure to a systolic level of between 100-130mmHg, where possible and without side effects, and to not worry about the diastolic blood pressure value."
Dr Joe Gallagher, Irish College of General Practioners' Lead, National Heart Programme, said: "This data helps remove uncertainty about how to treat people who have an elevated systolic blood pressure but low diastolic blood pressure. This is a common clinical problem which causes much debate. It will help impact clinical practice internationally and shows the importance of Irish researchers in clinical research."

The research team used new technologies to take into account genetic information that is unbiased, which was not the case with prior observational studies. They assessed data from 47,407 patients in five groups with a median age of 60.

Cancer patients from the UK were 1.5 times more likely to die following a diagnosis with COVID-19 than cancer patients from European countries.

This is the finding of a study of over 1000 patients - 924 from European countries and 468 from the UK - during the first wave of the COVID-19 pandemic. The research team, led by Imperial College London, say the study highlights the need for UK cancer patients to be prioritised for vaccination.

The study tracked data between 27 February to 10 September 2020, across 27 centres in six countries: Italy, Spain, France, Belgium, Germany and the UK.

The results, published in the European Journal of Cancer, showed that 30 days after a COVID-19 diagnosis, 40.38 per cent of UK cancer patients had died, versus 26.5 per cent of European patients.

Six months after a COVID-19 diagnosis, 47.64 per cent of UK cancer patients had died, compared to 33.33 per cent of European patients.

Dr David Pinato, lead author of the study from Imperial's Department of Surgery and Cancer, said: "This is the first study showing UK cancer patients were more likely to die following a COVID-19 diagnosis compared to European patients. We knew the UK had one of the highest deaths rates from COVID-19. However, in addition to this, prior to COVID-19 the UK already lagged behind European nations in terms of cancer care, with the UK having lower survival rates from many cancers compared to many other EU nations. We need to now prioritise cancer patients in the UK, as this study suggests they are extremely vulnerable - more so than in many other countries."

The study also found that UK patients were less likely to be receiving cancer treatment at the time of COVID-19 diagnosis, compared to European patients. This was most likely due to guidance from the UK National Institute for Health and Care Excellence, say the team, which recommended pausing cancer treatment during the first UK wave of COVID-19, due to concerns cancer treatment would increase risk of COVID-19.

However, the study found pausing cancer treatment did not affect risk of death following COVID-19 diagnosis.

The study also found equal proportions between the UK and EU of complicated COVID-19 cases, rates of intensive care admission and use of ventilation. In addition to this, UK cancer patients were less likely to receive anti-COVID-19 therapies including corticosteroids, anti-virals and interleukin-6 antagonists. There were also similar rates of admission to intensive care units.

The study team added that UK cancer patients tended to be more frail than European cancer patients, which may have led to the increased death rates following a COVID-19 diagnosis.

Dr Alessio Cortellini, co-author of the paper from the Department of Surgery and Cancer, added: "UK cancer patients tended to be older than European patients, were more likely to be male, and have other conditions such as obesity or diabetes. All of these may have contributed to the increased mortality rate, and show why cancer patients should be prioritised for COVID-19 vaccination."

Artificial intelligence could be one of the keys for limiting the spread of infection in future pandemics. In a new study, researchers at the University of Gothenburg have investigated how machine learning can be used to find effective testing methods during epidemic outbreaks, thereby helping to better control the outbreaks.

In the study, the researchers developed a method to improve testing strategies during epidemic outbreaks and with relatively limited information be able to predict which individuals offer the best potential for testing.

"This can be a first step towards society gaining better control of future major outbreaks and reduce the need to shutdown society," says Laura Natali, a doctoral student in physics at the University of Gothenburg and the lead author of the published study.

Machine learning is a type of artificial intelligence and can be described as a mathematical model where computers are trained to learn to see connections and solve problems using different data sets. The researchers used machine learning in a simulation of an epidemic outbreak, where information about the first confirmed cases was used to estimate infections in the rest of the population. Data about the infected individual's network of contacts and other information was used: who they have been in close contact with, where and for how long.

"In the study, the outbreak can quickly be brought under control when the method is used, while random testing leads to uncontrolled spread of the outbreak with many more infected individuals. Under real world conditions, information can be added, such as demographic data, age and health-related conditions, which can improve the method's effectiveness even more. The same method can also be used to prevent reinfections in the population if immunity after the disease is only temporary."

She emphasises that the study is a simulation and that testing with real data is needed to improve the method even more. Therefore, it is too early to use it in the ongoing coronavirus pandemic. At the same time, she sees the research as a first step in being able to implement more targeted initiatives to reduce the spread of infections, since the machine learning-based testing strategy automatically adapts to the specific characteristics of diseases. As an example, she mentions the potential to easily predict if a specific age group should be tested or if a limited geographic area is a risk zone, such as a school, a community or a specific neighbourhood.

"When a large outbreak has begun, it is important to quickly and effectively identify infectious individuals. In random testing, there is a significant risk failing to achieve this, but with a more goal-oriented testing strategy we can find more infected individuals and thereby also gain the necessary information to decrease the spread of infection. We show that machine learning can be used to develop this type of testing strategy," she says.

There are few previous studies that have examined how machine learning can be used in cases of pandemics, particularly with a clear focus on finding the best testing strategies.

"We show that it is possible to use relatively simple and limited information to make predictions of who would be most beneficial to test. This allows better use of available testing resources."

COLUMBUS, Ohio ¬- New data published by researchers at The Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC - James) suggests that an oral drug currently used in the clinical setting to treat neuromuscular diseases could also help prevent a common form of skin cancer caused by damage from ultraviolet-B (UVB) radiation from the sun.

While this data was gathered from preclinical studies, senior author Sujit Basu, MD, PhD, says preliminary results in animal models are very promising and worthy of immediate further investigation through phase I human studies.

Basu and his colleagues reported their initial findings online ahead of print April 12 in Cancer Prevention Research, a journal of the American Association for Cancer Research.

According to the American Cancer Society, more than 5.4 million basal and squamous cell skin cancers are diagnosed annually in the United States. The disease typically recurs throughout a person's lifetime, and advanced disease can lead to physical disfiguration. These cancers are linked to the sun's damaging rays, and despite increased public awareness on sun safety precautions, rates of the disease have been increasing for many years.

Previous peer-reviewed, published studies have shown that dopamine receptors play a role in the development of cancerous tumors; however, their role in precancerous lesions is unknown.

In this new study, OSUCCC - James researchers report data showing that the neurotransmitter/neurohormone dopamine, by activating its D2 receptors, can stop the development and progression of certain UVB-induced precancerous squamous skin cancers. Researchers also describe the molecular sequence of events that leads to cancer suppression.

"Cancer control experts have been stressing the importance of reducing exposure to the sun and practicing sun-safe habits for many years, but scientific data shows us that cumulative damage of UV rays ultimately leads to skin cancer for many people. Finding better ways to prevent these cancers from developing is critical to reduce the global burden of this disease," says Basu, a researcher with the OSUCCC - James Translational Therapeutics Research Program and a professor of pathology at The Ohio State University College of Medicine.

"Our study suggests that a commonly used drug that activates specific dopamine receptors could help reduce squamous cell skin cancer recurrence and possibly even prevent the disease entirely. This is especially exciting because this is a drug that is already readily used in clinical settings and is relatively inexpensive. We are excited to continue momentum in this area of research," adds Basu.

The OSUCCC - James is working on plans to begin further testing in a phase I experimental clinical trial in the coming months.

Studies show wearing masks and social distancing can contain the spread of the COVID-19 virus, but their combined effectiveness is not precisely known.

In Chaos, by AIP Publishing, researchers at New York University Tandon School of Engineering and Politecnico di Torino in Italy developed a network model to study the effects of these two measures on the spread of airborne diseases like COVID-19. The model shows viral outbreaks can be prevented if at least 60% of a population complies with both measures.

"Neither social distancing nor mask wearing alone are likely sufficient to halt the spread of COVID-19, unless almost the entire population adheres to the single measure," author Maurizio Porfiri said. "But if a significant fraction of the population adheres to both measures, viral spreading can be prevented without mass vaccination."

A network model encompasses nodes, or data points, and edges, or links between nodes. Such models are used in applications ranging from marketing to tracking bird migration. In the researchers' model, based on a susceptible, exposed, infected, or removed (recovered or has died) framework, each node represents a person's health status. The edges represent potential contacts between pairs of individuals.

The model accounts for activity variability, meaning a few highly active nodes are responsible for much of the network's contacts. This mirrors the validated assumption that most people have few interactions and only a few interact with many others. Scenarios involving social distancing without mask wearing and vice versa were also tested by setting up the measures as separate variables.

The model drew on cell phone mobility data and Facebook surveys obtained from the Institute for Health Metrics and Evaluation at the University of Washington. The data showed people who wear masks are also those who tend to reduce their mobility. Based on this premise, nodes were split into individuals who regularly wear masks and socially distance and those whose behavior remains largely unchanged by an epidemic or pandemic.
Using data collected by The New York Times to gauge the model's effectiveness, the researchers analyzed the cumulative cases per capita in all 50 states and the District of Columbia between July 14, 2020, when the Centers for Disease Control and Prevention officially recommended mask-wearing, through Dec. 10.

In addition to showing the effects of combining mask wearing and social distancing, the model shows the critical need of widespread adherence to public health measures.

"U.S. States suffering the most from the largest number of infections last fall were also those where people complied less with public health guidelines, thereby falling well above the epidemic threshold predicted by our model," Porfiri said.

The article, "How adherence to public health measures shapes epidemic spreading: a temporal network model," is authored by Brandon M Behring, Alessandro Rizzo, and Maurizio Porfiri. The article will appear in Chaos on Month Date, 2021 (DOI: 10.1063/5.0041993). After that date, it can be accessed at https://aip.scitation.org/doi/10.1063/5.0041993.

PLYMOUTH MEETING, PA [April 13, 2021] -- The April 2021 issue of JNCCN--Journal of the National Comprehensive Cancer Network publishes new research from Memorial Sloan Kettering Cancer Center (MSK) and Gustave Roussy Institute, which suggests that baseline brain imaging should be considered in most patients with metastatic kidney cancer. The researchers studied 1,689 patients with metastatic renal cell carcinoma (mRCC) who had been considered for clinical trial participation at either of the two institutions between 2001 and 2019 and had undergone brain imaging in this context, without clinical suspicion for brain involvement. The researchers discovered 4% had asymptomatic brain metastases in this setting. This group was found to have a low median 1-year overall survival rate (48%), and median overall survival (10.3 months).

"With 4% overall incidence in this cohort, one might conclude that baseline brain imaging should be considered in all patients with metastatic kidney cancer, particularly those with multiorgan involvement and/or pulmonary metastases" said lead MSK researcher Ritesh R. Kotecha, MD, who also worked with investigators from Gustave Roussy, a leading academic cancer center located just outside Paris, France.

"Brain imaging is routinely obtained for kidney cancer patients with symptoms that suggest central nervous system (CNS) metastases, but none of the patients with brain metastases included here were symptomatic," added senior researcher Martin H. Voss, MD, also with MSK. "In current practice chest, abdomen, and pelvis are routinely imaged from the time that metastatic disease is first detected yet many oncologists do not image the brain."

The researchers found 86% of the patients with asymptomatic brain metastases harbored metastatic disease in 2 or more additional organ systems, most-commonly the lung, followed by liver and bone.

"The retrospective study by Kotecha, et. al. demonstrates that incidental brain metastases occur in a clinically significant percentage of patients with newly diagnosed metastatic renal cell carcinoma," commented Eric Jonasch, MD, Professor, Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, who was not involved in this research.

Dr. Jonasch, who is Vice-Chair of the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) Panel for Kidney Cancer, continued: "The findings in this study are important for two reasons. First, they show that the overall prognosis of patients with brain metastases is consistently worse than the broader population of patients with metastatic renal cell carcinoma. We need to develop a deeper scientific understanding of why this patient population has a worse outcome, and we need to include them in future clinical trials. Second, they underscore the utility for MRI imaging of all patients with metastatic renal cell carcinoma both at initial diagnosis, and at regular intervals, to detect occult brain metastases, since specific treatment strategies are required for this patient population."

The researchers acknowledged that their data cannot provide input as to how frequently brain surveillance should be repeated, and called for additional study.

Biomedical scientists are increasingly using deconvolution methods, those used to computationally analyze the composition of complex mixtures of cells. One of their challenges is to select one method that is appropriate for their experimental conditions among nearly 50 available.

To help with method selection, researchers at Baylor College of Medicine and the Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital have extensively evaluated 11 deconvolution methods that are based on RNA-sequencing (RNA-seq) data analysis, determining each method's individual strengths and weaknesses in a variety of scenarios. From these analyses, the researchers derived guidelines that scientists can use to determine the deconvolution method that optimally fits their needs. The study appears in the journal Genome Biology.

"A great deal of work in biomedical research involves analyzing heterogeneous biological tissues to gain insight into the contribution of individual cells in, for instance, cancer growth or brain development," said corresponding author Dr. Zhandong Liu, associate professor of pediatrics-neurology at Baylor and director of the Bioinformatics Core of the Jan and Dan Duncan Neurological Research Institute.

Analyzing complex cellular mixtures is a difficult task. Researchers can conduct such analyses with laboratory techniques that physically separate and/or identify cellular components, but this method is time consuming and expensive.

Alternatively, researchers can use deconvolution methods that computationally extract information about individual cells in a mixture by analyzing large datasets derived from the bulk, such as RNA sequencing data.

For example, some researchers studying stem cells, a rare type of cell, might be interested in the percentage of these cells in the total blood cell population. They could conduct RNA-seq analysis of the bulk of cells and then apply a deconvolution method to determine the percentage of stem cells in the mixture. But, what method should they use?

In another example, if a scientist were interested only in the relative proportions of different cell types in a mixture, then one method would be best for deconvolution. But if the scientist wanted to find out the actual percentage of each cell type, then that deconvolution method would not be the best for that job, but another one that works better at providing that kind of answer. How can a scientist know which method works best in each situation?

"Our lab is one of many that developed deconvolution methods early on, contributing to the nearly 50 deconvolution methods currently out there to do this type of job," said first author Haijing Jin, a graduate student in Baylor's graduate program of quantitative and computational biosciences working in the Liu lab. "The methods are based on different mathematical models and/or different assumptions to try to solve deconvolution problems, which involve basically how to go from a bulk heterogeneous tissue to profiles of individual cells."

Because of this growing interest in deconvolution and the abundance of methods available, Liu and Jin felt that it was time to establish a guideline or benchmark to understand the strengths and the weaknesses of each method.

Running thousands of scenarios

The team studied 11 methods. They selected them according to the quality of the programing, the number of citations in the scientific literature and their popularity in the field.

"One of the challenges we faced was how to best test the strengths and weaknesses of each method in many possible scenarios," Jin said.

The researchers decided to use a computational or in silico approach that enabled them to simulate the thousands of scenarios necessary to test all the methods.

"All these scenarios represented real-life experimental situations in cell research, cancer research or developmental biology. We simulated each one of them so we could identify the best deconvolution method for each scenario for people who are interested in applying these methods to their experiments," Jin said.

"That's the value of this work," Liu said. "We are providing a benchmark study on various deconvolution methods and guidance for people working on different topics in biology to facilitate the analysis of their experimental results."

A gene therapy protects eye cells in mice with a rare disorder that causes vision loss, especially when used in combination with other gene therapies, shows a study published today in eLife.

The findings suggest that this therapy, whether used alone or in combination with other gene therapies that boost eye health, may offer a new approach to preserving vision in people with retinitis pigmentosa or other conditions that cause vision loss.

Retinitis pigmentosa is a slowly progressive disease, which begins with the loss of night vision due to genetic lesions that affect rod photoreceptors - cells in the eyes that sense light when it is low. These photoreceptors die because of their intrinsic genetic defects. This then impacts cone photoreceptors, the eye cells that detect light during the day, which leads to the eventual loss of daylight vision. One theory about why cones die concerns the loss of nutrient supply, especially glucose.

Scientists have developed a few targeted gene therapies to help individuals with certain mutations that affect the photoreceptors, but no treatments are currently available that would be effective for a broad set of families with the disease. "A gene therapy that would preserve photoreceptors in people with retinitis pigmentosa regardless of their specific genetic mutation would help many more patients," says lead author Yunlu Xue, Postdoctoral Fellow at senior author Constance Cepko's lab, Harvard Medical School, Boston, US.

To find a widely effective gene therapy for the disease, Xue and colleagues screened 20 potential therapies in mouse models with the same genetic deficits as humans with retinitis pigmentosa. The team chose the therapies based on the effects they have on sugar metabolism.

Their experiments showed that using a virus carrier to deliver a gene called Txnip was the most effective approach in treating the condition across three different mouse models. A version of Txnip called C247S worked especially well, as it helped the cone photoreceptors switch to using alternative energy sources and improved mitochondria health in the cells.

The team then showed that giving the mice gene therapies that reduced oxidative stress and inflammation, along with Txnip gene therapy, provided additional protection for the cells. Further studies are now needed to confirm whether this approach would help preserve vision in people with retinitis pigmentosa.

"The immediate next step is to test Txnip for safety in animals beyond mice, before moving on to a clinical trial in humans," explains senior author and Howard Hughes Institute Investigator Constance Cepko, the Bullard Professor of Genetics and Neuroscience at Harvard Medical School. "If it ultimately proves safe in people, then we would hope to see it become an effective approach for treating those with retinitis pigmentosa and other forms of progressive vision loss, such as age-related macular degeneration."

Violent blows or jolts to the head can cause traumatic brain injury (TBI), and there are currently about five million people in the U.S. living with some form of chronic impairment after suffering a TBI. Even in a mild form, TBI can lead to lifelong nerve cell deterioration associated with a wide array of neuropsychiatric conditions. Tragically, there are no medicines to protect nerve cells after injury. Behind aging and genetics, TBI is the third leading cause of Alzheimer's disease (AD), yet the link between these two conditions is not understood.

In a new study, published online today in Cell, researchers have discovered a new way to prevent brain nerve cells from deteriorating after injury, which also revealed a potential mechanistic link between TBI and AD. Their discovery also yielded a new blood biomarker of nerve cell degeneration after injury, which is significant because there is an urgent need for mechanism-based blood biomarkers that can diagnose TBI and stage its severity.

Prior to this study, it had been previously reported that a small protein in nerve cells, called tau, was modified by a chemical process called acetylation in the post-mortem brains of AD patients. But how this modification came about, as well as its role in the disease process, was not understood.

"Normally, tau functions in nerve cells to maintain the appropriate structure of the axon, which is the nerve cell extension required for nerve cells to communicate with one another," said Andrew A. Pieper, MD, PhD, senior author on the study, Harrington Discovery Institute (HDI) Investigator and Director of the HDI Neurotherapeutics Center at University Hospitals (UH), Morley-Mather Chair in Neuropsychiatry at UH, Director of the Translational Therapeutics Core of the Cleveland Alzheimer's Disease Research Center, and VA Geriatric Research, Educational and Clinical Care (GRECC) Investigator. "Given the relationship between AD and TBI, we wondered whether elevated acetylated-tau (ac-tau) might also occur in TBI, and if so, then whether this could provide an experimental platform to study its potential role in nerve cell deterioration."

Dr. Pieper's lab discovered that ac-tau increased rapidly in multiple forms of TBI in mice and rats, and persisted chronically when nerve cell degeneration was untreated. They also showed that the increased ac-tau in human AD brain was further exacerbated when the AD patient also had a prior history of TBI.

"Our research showed that after ac-tau rises, a specific structure at the junction of the nerve cell body and its axon, called the axon initial segment, breaks down," explained Min-Kyoo Shin, PhD, co-first author of the study. "As a result, tau is no longer appropriately sequestered in axons. This leads to axonal degeneration, followed by neurologic impairment."

The team tested therapeutic interventions after TBI at each of the three nodal points in the new signaling pathway that they identified as leading to increased nerve cell ac-tau after injury. Using known medicines or experimental drugs, they saw that all three points provided effective therapeutic opportunity.

Strikingly, they found that two FDA-approved medicines of the NSAID class (anti-inflammatory medicines commonly used as pain relievers), salsalate and diflunisal, were potently neuroprotective after TBI in mice. Relative to all other NSAIDs and distinct from their anti-inflammatory property, these two medicines inhibit the acetyltransferase enzyme in nerve cells that adds the acetyl group onto tau protein after brain injury.

Next, they examined more than seven million patient records and learned that usage of either salsalate or diflunisal was associated with decreased incidence of both AD and clinically diagnosed TBI, compared to usage of aspirin in other patients for the same time period. The protective effect was stronger in diflunisal and salsalate, which correlates with diflunisal's superior potency in inhibiting the acetyltransferase enzyme, relative to salsalate. The NSAID aspirin was used as a comparison group because it does not inhibit the acetyltransferase.

Lastly, because the tau protein freely diffuses from the brain into the blood, the researchers examined whether ac-tau might also be elevated in the blood after TBI. In mice, they found that blood levels of ac-tau correspond tightly with brain levels, and that blood levels return to normal when mice are treated with therapeutics that lower brain ac-tau and thereby protect nerve cells. Importantly, they also found that ac-tau was significantly increased in the blood of human TBI patients.

"This work has a number of potential clinical implications," explained Edwin Vázquez-Rosa, PhD, co-first author on the study. "First, it shows that the medicines salsalate and diflunisal provide previously unidentified neuroprotective activity by this new mechanism, and that in the course of being prescribed these medicine for traditional indications patients appear to also be relatively protected from developing neurodegenerative conditions. Accordingly, these medicines may also help protect TBI patients from developing AD. Finally, our work provides a new blood biomarker of neurodegeneration in the brain after TBI that could be harnessed to stage severity and progression of nerve cell deterioration after injury."

Robert A. Bonomo, MD, Associate Chief of Staff at VA Northeast Ohio Healthcare System and professor at Case Western Reserve School of Medicine added, "Many of our patients suffer from TBI or AD. These important findings will have a tremendous, long-term impact on our Veteran population."

Next steps in the research involve further investigation of the applicability of ac-tau as a biomarker in neurodegenerative disease and the potential utility of diflunisal or salsalate as neuroprotective medicines for people, as well as deeper study of the mechanisms by which ac-tau causes nerve cell deterioration.

AMES, Iowa - Narratives are a powerful tool that can help explain complex issues, but they can also serve as sources of misinformation, which presents a challenge as public health agencies work to educate people about COVID-19 vaccine.

In a paper published by the Proceedings of the National Academy of Sciences, author Michael Dahlstrom, a professor and director of Iowa State University's Greenlee School of Journalism and Mass Communication, examined how narratives or storytelling can help counter misinformation and provide a connection between science and the human experience. Dahlstrom says simply presenting the facts, without some connection, may not help people make informed decisions.

"If the person doesn't have the context, background or experience to connect facts in accurate ways, you're basically giving them puzzle pieces that might not fit together and then expecting them to make a clear picture," he said. "In science, which is often complicated, it can be helpful to present the facts and show how they connect, so people see the broader landscape in an accurate way to make a decision."

That's important because narratives often have a disproportionate influence on attitudes and behaviors, when contrasted with scientific information. This is true whether the narrative is about vaccines, climate change or any other topic. Dahlstrom says we are hardwired to make sense of the world around us, and stories are the primary structure we use to make those connections.

For example, a story about how the COVID-19 vaccine is allowing families to reconnect after months apart is more persuasive and compelling than explaining how the vaccine works and its efficacy, Dahlstrom said. However, he cautions that stories won't always have an impact. On controversial issues, there will be people on both extremes who align with stories that confirm what they believe and attack stories counter to their beliefs.

As Dahlstrom explained in the paper, research has shown that audiences have a difficult time identifying errors in narratives and will generally accept those errors as fact. Even when people know a story is misleading or incorrect, they still tend to believe it, rather than disregard. That is why presenting an equally compelling narrative may be more effective than trying to counter that misinformation with facts alone.

"Narratives can be the cause and remedy of scientific misinformation. It really depends on how the narrator incorporates science in the message. Taking the facts and connecting them in a way that show human experiences add up over time," Dahlstrom said. "The connections built by stories tend to embed themselves into the connections you've already made in your head. They are then deeply connected to other experiences, which is why they're powerful."

Dahlstrom says one final takeaway is that stories or narratives are not anti-science, which is often the perception of scientists. It's how the author crafts the story or uses the narrative that is often the problem.

PITTSBURGH, April 13, 2021 - What can vaccine proponents, clinicians and public health communicators learn from "anti-vaxxers?" A lot, according to new guidance for pro-vaccination social media events written by University of Pittsburgh health scientists.

The five-part guidelines, published today in the journal Vaccine, arose from an analysis of a grassroots pro-vaccination campaign organized last year by popular physician and social media personality Zubin Damania, M.D., colloquially known as "ZDoggMD." Unexpectedly, more than three-quarters of the tweets associated with the event were opposing vaccination, researchers found.

"While at first it felt a little defeating that the event was co-opted to spread anti-vaccination messages, we learned some really constructive lessons," said lead author Beth Hoffman, M.P.H., a doctoral student at Pitt's Graduate School of Public Health. "I expect our guidelines will prove valuable now as health professionals work to address COVID-19 vaccine hesitancy and misinformation, as well as in the development of future health communication campaigns to promote vaccines."

Following two separate instances in November 2019 and January 2020 where vaccination antagonists launched social media attacks, as well as harassed and personally threatened clinicians who had posted positively on social media about vaccination, ZDoggMD called on all health care professionals and vaccine advocates to speak up in support of vaccines using the hashtag #DoctorsSpeakUp on March 5, 2020. The event was supported by Shots Heard Round the World, a project of Public Good Projects (PGP), a public health nonprofit responsible for some of the nation's most successful health campaigns. Shots Heard was created in 2019 following a coordinated online attack against pediatrics practice Kids Plus Pediatrics.

Hoffman and her team turned to Twitter to collect all publicly available tweets with the #DoctorsSpeakUp hashtag posted on March 5, 2020--a total of 106,275 tweets, of which 19,332 were original.

The team then analyzed a random sampling of original tweets, examining the type of account they came from (organization, health care professional, parent or both), whether they had pro- or anti-vaccine attitudes, and whether the tweet gave a personal narrative or made statements about research or science, or both.

The researchers found that 78.9% of the tweets were anti-vaccine, despite the event being organized as a pro-vaccination campaign. Only 5.4% came from "bots," or automated accounts, which is lower than previous studies looking at bots that tweet about vaccines.

"The high level of anti-vaccine tweets and the low use of bots suggest this was a highly coordinated response by anti-vaccine antagonists," said senior author Jaime Sidani, Ph.D., M.P.H., assistant professor of general internal medicine at Pitt. "This was not a coincidental convergence of people with anti-vaccine sentiment, nor was it an attack orchestrated by a few people or organizations deploying bots."

After further examining the tactics the anti-vaccine movement used in co-opting the #DoctorsSpeakUp hashtag and event, Hoffman's team developed guidelines for future pro-vaccine media events:

Use best practices for risk communication, which include sharing personal narratives and citing scientific research.

Leverage partnerships to create a broad coalition of vaccine advocates.

Maximize inclusivity; for example, the #DoctorsSpeakUp hashtag didn't represent the full complement of pro-vaccine advocates, which include nurses and parents, among others.

Share a list of suggested tweets with stakeholders and potential participants prior to the event.

Train event participants on responding to messages clearly and with compassion.

"Health professionals are highly trusted, but if they're interacting only inside the four walls of an exam room, then they may not be providing their patients with health information when and where they need it," said co-author Todd Wolynn, M.D., pediatrician and chief executive officer of Kids Plus Pediatrics and founder of the Shots Heard Round the World project to aid health professionals targeted for their vaccine advocacy.

"True anti-vaccine antagonists are a very small group, but very effective communicators. About 20% of the general population can be described as vaccine hesitant--and many turn to social media with questions," he said. "It's critical that clinicians meet these people where they are, on social media, and learn how to use it effectively to counter anti-vaxxers and inoculate the public against misinformation."

With a grant from the Richard King Mellon Foundation, the Pitt team is expanding upon this work to investigate COVID-19 vaccine misinformation by analyzing how people are connected on Twitter and what messages are being shared. The goal is to guide the creation and dissemination of effective educational messaging about the COVID-19 vaccines that can be shared through multiple platforms--social media, television, in-person discussions--to help people who may be hesitant to receive a vaccine make fact-based decisions.

A recent study indicates that a U.S. ban on the use of tanning beds among minors would prevent thousands of cases of melanoma in adolescents and would save millions of dollars in healthcare costs. The findings are published early online in CANCER, a peer-reviewed journal of the American Cancer Society.

Indoor tanning has been linked to an increased risk of melanoma, with the highest risk in those who start using tanning beds at a young age. Unfortunately, the use of tanning beds is a common practice among U.S. adolescents.

Despite the risk of indoor tanning, only a handful of countries have implemented policies to ban tanning beds. Such bans have the potential to save lives and treatment-related costs but come with costs of policy implementation and enforcement, as well as lost revenue to the tanning industry.

To consider both the benefits and costs of a ban, investigators modeled the life course of the U.S. population aged between 14 and 17 years and compared two situations: ban versus no ban.

The team's simulations revealed that fully adhering to a ban would prevent 15,101 melanoma cases and 3,299 melanoma recurrences among 17.1 million minors, saving $61 in direct and indirect healthcare costs per minor. When including intervention costs and economic losses to the tanning bed industry, banning still saved $12 per minor and a total of $205.4 million over the lifetimes of 17.1 million minors.

"A ban on tanning bed use in minors is not universal in Canada and the U.S. In Brazil and Australia there is a total ban not just in minors, while in Austria, Belgium, France, Germany, Portugal, Spain, and the United Kingdom, national bans exist for those under the age of 18," said lead author Antoine Eskander, MD, ScM, FRCSC, of the University of Toronto and Sunnybrook Health Sciences Centre.

"This work demonstrates the societal implications of a ban in North America and points to the value of this policy, which should be considered by state, provincial, and national/federal governments," added co-senior author David Goldstein, MD, MSc, FRCSC, of the University of Toronto and Princess Margaret Cancer Centre.