Body

New Rochelle, NY, January 15, 2021--The biodistribution of adeno-associated virus (AAV) gene transfer vectors can be measured in nonhuman primates using a new method. The method quantifies whole-body and organ-specific AAV capsids from 1 to 72 hours after administration. Study design and results are presented in the peer-reviewed journal Human Gene Therapy. Click here to read the full-text article free on the Human Gene Therapy website through February 15, 2021.

AAV capsids were labeled with I-124 and delivered using two routes of administration: intravenous and directly into the cerebrospinal fluid (CSF). Biodistribution was measured by quantitative positron emission tomography (PET) at 1, 24, 48, and 72 hours after AAV administration. Two AAV vectors - AAVrsh.10 and AAV9 - were compared.

"Following intravenous administration, both vectors behaved in a similar fashion, distributed primarily to the liver and to a lesser extent heart. Neither were detected at significant levels in the brain. Both vectors administered intravenously also distribute to the vertebrae," state Ronald Crystal, Weill Cornell Medical College, and coauthors. About 50% dispersed throughout the body, in part in skeletal muscle.

Following administration into the CSF, the labeled capsid had a half-life of approximately 10 hours, suggesting the possibility of slow diffusion into the brain.

In animals with pre-existing immunity, compared to naïve animals, there was a 10-fold increase in biodistribution to the spleen.

"PET imaging is a powerful tool to track biodistribution, which is a critical property affecting the safety and efficacy of gene therapy," according to Editor-in-Chief of Human Gene Therapy Terence R. Flotte, MD, Celia and Isaac Haidak Professor of Medical Education and Dean, Provost, and Executive Deputy Chancellor, University of Massachusetts Medical School.

HAMILTON, ON, Jan. 15, 2021 -- A team of neuroscientists and engineers at McMaster University has created a nasal spray to deliver antipsychotic medication directly to the brain instead of having it pass through the body.

The leap in efficiency means patients with schizophrenia, bipolar disorder and other conditions could see their doses of powerful antipsychotic medications cut by as much as three quarters, which is expected to spare them from sometimes-debilitating side effects while also significantly reducing the frequency of required treatment.

The new method delivers medication in a spray that reaches the brain directly through the nose, offering patients greater ease of use and the promise of improved quality of life, including more reliable, effective treatment.

Ram Mishra, a Professor in the Department of Psychiatry and Behavioural Neurosciences and Co-Director of McMaster's School of Biomedical Engineering, and Todd Hoare, a Canada Research Chair and Professor of Chemical Engineering, describe their research in a newly published article in the Journal of Controlled Release.

They and their co-authors Michael Majcher, Ali Babar, Andrew Lofts, and Fahed Abuhijleh have proven the concept of their new delivery mechanism in rats, using PAOPA, a drug commonly prescribed to treat schizophrenia.

A problem for patients using antipsychotic medications, Mishra explains, is that taking them orally or by injection means the drugs must pass through the body before they reach the brain through the blood. To be sure enough oral or injected medication reaches the brain, a patient must take much more than the brain will ultimately receive, leading to sometimes serious adverse side effects, including weight gain, diabetes, drug-induced movement disorders and organ damage over the long term.

When delivered through the nose, the spray medication can enter the brain directly via the olfactory nerve.

"The trick here is to administer the drug through the back door to the brain, since the front door is sealed so tightly," Mishra says. "This way we can bypass the blood-brain barrier. By delivering the drug directly to the target, we can avoid side effects below the brain."

Mishra and collaborator Rodney Johnson of the University of Minnesota had previously created a water-soluble form of the medication, which was used in the current research. The new form they created was easier to manipulate, but they still lacked an effective vehicle for getting it to the brain. A particular issue was that drugs delivered via the nose are typically cleared from the body quickly, requiring frequent re-administration.

Hoare, in the meantime, had been working with an industrial partner to develop the use microscopic nanoparticles of corn starch for agricultural applications.

The two scientists, who work across campus from one another, came together after researchers in their labs met at an internal McMaster conference. Two of the researchers, Babar and Lofts, worked on the project in both labs.

The engineering team was able to bind the drug to the corn starch nanoparticles that, when sprayed together with a natural polymer derived from crabs, could penetrate deep into the nasal cavity and form a thin gel in the mucus lining, slowly releasing a controlled dose of the drug, which remains effective for treating schizophrenia symptoms over three days.

"The cornstarch nanoparticles we were using for an industrial application were the perfect vehicle," Hoare says. "They are naturally derived, they break down over time into simple sugars, and we need to do very little chemistry on them to make this technology work, so they are great candidates for biological uses like this."

The gradual release means patients would only need to take their medication every few days instead of every day or, in some cases, every few hours.

There is currently no cure for osteoarthritis, but a group of scientists believe they've discovered a method through which a simple knee injection could potentially stop the disease's effects. These researchers showed that they could target a specific protein pathway in mice, put it into overdrive and halt cartilage degeneration over time. Building on that finding, they were able to show that treating mice with surgery-inducedknee cartilage degeneration through the same pathway via the state of the art of nanomedicine could dramatically reduce the cartilage degeneration and knee pain. These findings were published in Science Translational Medicine.

"Our lab is one of the few in the world studying epidermal growth factor receptor (EGFR) signaling in cartilage and, from the beginning, we have found that EGFR deficiency or inactivation accelerates osteoarthritis progression in mice," said Ling Qin, PhD, an associate professor of Orthopaedic Surgery. "Thus, we proposed that its activation could be used to treat osteoarthritis, and in this study, we've proven for the first time that over-activating it inside the knee blocks the progression of osteoarthritis."

Qin explained that tests from the other labs that do work with EGFR have drawn "confusing and controversial" results. But Qin's lab has consistently found the ties between osteoarthritis and EGFR deficiencies, which formed the bedrock of their hypothesis.

The researchers compared typical mice with those that had a molecule that bound to EGFR, called a ligand, that was over-overexpressed in chondrocytes, the building blocks of cartilage. This overexpression drives the over-activation of EGFR signaling in knee cartilage. When examining them, the mice with overexpressed HBEGF (the EGFR ligand) were found to consistently have enlarged cartilage, meaning that it wasn't wearing away like the mice who had normal EGFR activity. Moreover, when these mice aged to adulthood, their cartilage was resistant to degeneration and other hallmarks of osteoarthritis, even if their knee's meniscus was damaged.

To further prove that the over-activated EGFR was the reason for the mice's resiliency, the researchers found that gefitinib treatments, which are designed to block EFGR function, took away the protection against cartilage degeneration.

With all of this knowledge gained, the researchers turned an eye toward potential clinical treatment solutions. In a new series of tests they created nanotherapeutics by attaching a potent EGFR ligand, transforming growth factor-alpha, onto synthetic nanoparticles, to inject into mice who already had cartilage damage in their knees.

"Free EGFR ligands have a short half-life and cannot be retained inside of a joint capsule due to their small size," explained Zhiliang Cheng, PhD, a research associate professor in Penn Engineering and another of the co-corresponding authors on the paper. "Nanoparticles help to protect them from degradation, restrict them within the joint, reduce off-target toxicity, and carry them deep inside dense cartilage to reach chondrocytes."

When mice were injected with these nanotherapeutics, the researchers saw that they slowed cartilage degeneration and bone hardening, as well as eased knee pain. There also were no major side effects seen in the mice who were treated.

"While many of the technical aspects of this application still need to be worked out, the ability to stop or slow the course of osteoarthritis with an injection rather than surgery would dramatically change how we feel and function as we age and after injury," said one of the study's co- authors, Jaimo Ahn, MD, PhD, a former faculty member at Penn Medicine now chief of orthopaedic trauma and associate chair of orthopaedic surgery at the University of Michigan.

The treatment is likely some time away for human patients, but the nanoparticles used have already been clinically tested and deemed safe, which makes it easier to quickly translate to clinical use.

"There is a great unmet medical need for a disease-modifying osteoarthritis drug," Qin said. "In the future, we will optimize the drug design and test it in large animals before proceeding to clinical trials. We hope our research could lead to a novel drug that will improve the health and well-being of the more than 27 million osteoarthritis patients in the United States."

MADISON, Wis. -- The demand for COVID-19 vaccines continues to outpace supply, forcing public health officials to decide who should be first in line for a shot, even among those in the same pool of eligible vaccine recipients.

To assist these efforts, researchers at the University of Wisconsin School of Medicine and Public Health and UW Health have developed a tool that incorporates a person's age and socioeconomic status to prioritize vaccine distribution among people who otherwise share similar risks due to their jobs. The tool helps identify those who are at greater risk of severe complications or death from COVID-19.

UW Health has implemented the prioritization algorithm to equitably provide limited doses to frontline health care workers. Other organizations can also access the freely available tool to guide their own vaccine distribution plans.

While the UW-Madison tool was designed with the first phase of eligible recipients in mind, it could be used as vaccine distribution expands to larger populations. As the eligible population increases, the gap between initial supply and demand could grow, making such prioritization tools even more helpful.

"Knowing we're going to have limited vaccine for some time, we wanted to develop an algorithm to equitably distribute vaccinations within these risk groups," says Grace Flood, the director of clinical analytics and reporting in the Office of Population Health at UW Health, who helped lead development of the tool along with the Health Innovation Program within SMPH.

In addition to age, the algorithm uses the Social Vulnerability Index to measure a person's susceptibility to severe COVID-19 based on where they live. The Centers for Disease Control and Prevention developed the SVI metric to help emergency responders identify which neighborhoods and towns will require the most support following natural disasters or public health emergencies.

The SVI incorporates 15 measures in four categories: socioeconomic status, housing composition and disability, minority status and language, and housing and transportation. Race and ethnicity have been closely correlated with higher COVID-19-related hospitalizations and mortality.

Flood and her team incorporated the SVI in accordance with a report by the National Academies of Sciences, Engineering and Medicine that recommended using the index to fairly distribute vaccines. Because Wisconsin publishes data about COVID-19 deaths at the census-tract level, "we were able to determine the relationship for risk of mortality between age and SVI," says Flood. This relationship allowed the researchers to verify that age and SVI combined provide an accurate estimate of an individual's risk.

Since age and SVI are readily available pieces of information about an individual and each contributes to COVID-19 risk, an algorithm that incorporates both elements may serve as one of the best ways to distribute vaccines until supply catches up to demand, says Flood.

The researchers have published their algorithm in the Annals of Family Medicine COVID-19 collection and made it available for download on the project's website.

PHILADELPHIA - Our biological or circadian clock synchronizes all our bodily processes to the natural rhythms of light and dark. It's no wonder then that disrupting the clock can wreak havoc on our body. In fact, studies have shown that when circadian rhythms are disturbed through sleep deprivation, jet lag, or shift work, there is an increased incidence of some cancers including prostate cancer, which is the second leading cause of cancer death for men in the U.S. With an urgent need to develop novel therapeutic targets for prostate cancer, researchers at the Sidney Kimmel Cancer - Jefferson Health (SKCC) explored the circadian clock and found an unexpected role for the clock gene CRY-1 in cancer progression. The study was published on January 15th in Nature Communications.

"When we analyzed human cancer data, the circadian factor CRY-1 was found to increase in late stage prostate cancers, and is strongly associated with poor outcomes," explains Karen Knudsen, MBA PhD, executive vice president of oncology services for Jefferson Health and enterprise director of SKCC, and senior author of the study. "However, the role CRY-1 in human cancers has not been explored."

A common therapy for prostate cancer involves suppressing the male hormone androgen and/or the androgen receptor, as prostate tumors require androgens to develop and progress to advanced disease. With their collaborators in the U.S. and Europe, the researchers found that CRY-1 is induced by the androgen receptor in prostate tumor tissue obtained from patients, thus explaining in part the high levels of CRY-1 observed in human disease.

"This was a clear indication of CRY-1's link to prostate cancer," says Ayesha Shafi, PhD, a postdoctoral researcher in Dr. Knudsen's lab and first author of the study. "As we looked further into the role of CRY1, we unexpectedly found that the circadian factor was altering the way that cancer cells repair DNA."

Cancer treatments aim to damage the DNA in cancer cells and cause defects in repair mechanisms; eventually the cells self-destruct when the damage is severe. The researchers probed CRY-1's possible role in DNA repair in cultured cells, animal models and tissue harvested from prostate cancer patients. They first induced DNA damage by exposing cancer cells to radiation and found that CRY-1 levels became elevated, indicating that it was responding to this type of damage. They also found that CRY-1 directly regulates the availability of factors essential for the DNA repair process, and alters the means by which cancer cells respond to DNA damage. The findings suggest that CRY-1 may offer a protective effect against damaging therapies.

"The fact that CRY-1 is elevated in late-stage prostate cancer may explain why androgen-targeting treatments become ineffective at those later stages," says Dr. Shafi. "It also tells us that if a tumor has high levels of CRY-1, DNA repair targeting treatments may be less effective for them."

"Not only have we outlined a role for CRY-1 outside of its canonical function in circadian rhythms, Dr. Shafi's findings are the first to reveal the means by which CRY1 contributes to aggressive disease," adds Dr. Knudsen. "It's notable that the pro-tumor functions of CRY1 may be viable targets to treat prostate cancer, and this is a direction that Dr. Shafi's future work will explore."

Looking ahead, the team plans to explore how best to target and block CRY-1 and what other existing therapies may work synergistically to hinder DNA repair in prostate cancer cells. They also plan to study more circadian rhythm genes and determine how circadian disruption may affect cancer treatment.

"It's been shown that circadian disruptions can affect efficacy of treatment, but also that aligning treatment with the body's natural rhythms or giving therapy at certain times of the day can be beneficial," explains Dr. Knudsen. "Our findings open up a multitude of important research questions exploring the link between the circadian clock and cancer."

Researchers have developed a DNA test to quickly identify secondary infections in COVID-19 patients, who have double the risk of developing pneumonia while on ventilation than non-COVID-19 patients.

For patients with the most severe forms of COVID-19, mechanical ventilation is often the only way to keep them alive, as doctors use anti-inflammatory therapies to treat their inflamed lungs. However, these patients are susceptible to further infections from bacteria and fungi that they may acquire while in hospital - so called 'ventilator-associated pneumonia'.

Now, a team of scientists and doctors at the University of Cambridge and Cambridge University Hospitals NHS Foundation Trust, led by Professor Gordon Dougan, Dr Vilas Navapurkar and Dr Andrew Conway Morris, have developed a simple DNA test to quickly identify these infections and target antibiotic treatment as needed.

The test, developed at Addenbrooke's hospital in collaboration with Public Health England, gives doctors the information they need to start treatment within hours rather than days, fine-tuning treatment as required and reducing the inappropriate use of antibiotics. This approach, based on higher throughput DNA testing, is being rolled out at Cambridge University Hospitals and offers a route towards better treatments for infection more generally. The results are reported in the journal Critical Care.

Patients who need mechanical ventilation are at significant risk of developing secondary pneumonia while they are in intensive care. These infections are often caused by antibiotic-resistant bacteria, and are hard to diagnose and need targeted treatment.

"Early on in the pandemic we noticed that COVID-19 patients appeared to be particularly at risk of developing secondary pneumonia, and started using a rapid diagnostic test that we had developed for just such a situation," said co-author Dr Andrew Conway Morris from Cambridge's Department of Medicine and an intensive care consultant. "Using this test, we found that patients with COVID-19 were twice as likely to develop secondary pneumonia as other patients in the same intensive care unit."

COVID-19 patients are thought to be at increased risk of infection for several reasons. Due to the amount of lung damage, these severe COVID-19 cases tend to spend more time on a ventilator than patients without COVID-19. In addition, many of these patients also have a poorly-regulated immune system, where the immune cells damage the organs, but also have impaired anti-microbial functions, increasing the risk of infection.

Normally, confirming a pneumonia diagnosis is challenging, as bacterial samples from patients need to be cultured and grown in a lab, which is time-consuming. The Cambridge test takes an alternative approach by detecting the DNA of different pathogens, which allows for faster and more accurate testing.

The test uses multiple polymerase chain reaction (PCR) which detects the DNA of the bacteria and can be done in around four hours, meaning there is no need to wait for the bacteria to grow. "Often, patients have already started to receive antobiotics before the bacteria have had time to grow in the lab," said Morris. "This means that results from cultures are often negative, whereas PCR doesn't need viable bacteria to detect - making this a more accurate test."

The test - which was developed with Dr Martin Curran, a specialist in PCR diagnostics from Public Health England's Cambridge laboratory - runs multiple PCR reactions in parallel, and can simultaneously pick up 52 different pathogens, which often infect the lungs of patients in intensive care. At the same time, it can also test for antibiotic resistance.

"We found that although patients with COVID-19 were more likely to develop secondary pneumonia, the bacteria that caused these infections were similar to those in ICU patients without COVID-19," said lead author Mailis Maes, also from the Department of Medicine. "This means that standard antibiotic protocols can be applied to COVID-19 patients."

This is one of the first times that this technology has been used in routine clinical practice and has now been approved by the hospital. The researchers anticipate that similar approaches would benefit patients if used more broadly.

PULLMAN, Wash. - Scientists have identified the presence of a non-tobacco plant in ancient Maya drug containers for the first time.

The Washington State University researchers detected Mexican marigold (Tagetes lucida) in residues taken from 14 miniature Maya ceramic vessels.

Originally buried more than 1,000 years ago on Mexico's Yucatán peninsula, the vessels also contain chemical traces present in two types of dried and cured tobacco, Nicotiana tabacum and N. rustica. The research team, led by anthropology postdoc Mario Zimmermann, thinks the Mexican marigold was mixed with the tobacco to make smoking more enjoyable.

The discovery of the vessels' contents paints a clearer picture of ancient Maya drug use practices. The research, which was published today in Scientific Reports, also paves the way for future studies investigating other types of psychoactive and non-psychoactive plants that were smoked, chewed, or snuffed among the Maya and other pre-Colombian societies.

"While it has been established that tobacco was commonly used throughout the Americas before and after contact, evidence of other plants used for medicinal or religious purposes has remained largely unexplored," Zimmermann said. "The analysis methods developed in collaboration between the Department of Anthropology and the Institute of Biological Chemistry give us the ability to investigate drug use in the ancient world like never before."

Zimmermann and colleagues' work was made possible by NSF-funded research which led to a new metabolomics-based analysis method that can detect thousands of plant compounds or metabolites in residue collected from containers, pipes, bowls and other archaeological artifacts. The compounds can then be used to identify which plants were consumed.

Previously, the identification of ancient plant residues relied on the detection of a limited number of biomarkers, such as nicotine, anabasine, cotinine and caffeine.

"The issue with this is that while the presence of a biomarker like nicotine shows tobacco was smoked, it doesn't tell you what else was consumed or stored in the artifact," said David Gang, a professor in WSU's Institute of Biological Chemistry and a co-author of the study. "Our approach not only tells you, yes, you found the plant you're interested in, but it also can tell you what else was being consumed."

Zimmermann helped unearth two of the ceremonial vessels that were used for the analysis in the spring of 2012. At the time, he was working on a dig directed by the National Institute of Anthropology and History of Mexico on the outskirts of Mérida where a contractor had uncovered evidence of a Maya archeological site while clearing lands for a new housing complex.

Zimmermann and a team of archeologists used GPS equipment to divide the area into a checkerboard-like grid. They then hacked their way through dense jungle searching for small mounds and other telltale signs of ancient buildings where the remains of important people such as shamans are sometimes found.

"When you find something really interesting like an intact container it gives you a sense of joy," Zimmermann said. "Normally, you are lucky if you find a jade bead. There are literally tons of pottery sherds but complete vessels are scarce and offer a lot of interesting research potential."

Zimmermann said the WSU research team is currently in negotiations with several institutions in Mexico to get access to more ancient containers from the region that they can analyze for plant residues. Another project they are currently pursuing is looking at organic residues preserved in the dental plaque of ancient human remains.

"We are expanding frontiers in archaeological science so that we can better investigate the deep time relationships people have had with a wide range of psychoactive plants, which were (and continue to be) consumed by humans all over the world," said Shannon Tushingham, a professor of Anthropology at WSU and a co-author of the study. "There are many ingenious ways in which people manage, use, manipulate and prepare native plants and plant mixtures, and archaeologists are only beginning to scratch the surface of how ancient these practices were."

An innovative new study is set to examine if changing our mealtimes to earlier or later in the day could reduce the risk of developing Type 2 diabetes.

Led by Dr Denise Robertson, Professor Jonathan Johnston and post graduate researcher Shantel Lynch from the University of Surrey, the study, outlined in the journal Nutrition Bulletin, will investigate if changing the time we eat during the day could reduce risk factors such as obesity and cholesterol levels that are typically associated with the development of Type 2 diabetes. The team of researchers will also for the first time investigate, via a series of interviews with participants and their friends and family, the impact of such changes on home life, work/social commitments and whether co-habitants of those who make such modifications are influenced to alter their own meal timings/eating habits as a result.

During the unique 10-week study, 51 participants aged between 18- 65 years old who have been identified as having an increased/moderate/high risk of developing Type 2 diabetes will be split into three groups. The first, a control group, will be asked to make no changes to their eating habits; the second group will be required to restrict their eating times during the day to between 7am- 3pm; and the third group will limit their eating time to between 12-8pm.

Participants will regularly attend the Surrey Clinical Investigations Unit to monitor their blood pressure, waist and hip circumferences and provide blood and urine samples. A registered dietitian will also use specialist eye-tracking equipment to analyse participants' eye gaze direction to identify and monitor any changes to food preferences over the course of the intervention. Previous research has shown that eye gaze direction is a strong signal of attention and preference behaviours.

Researchers will examine in detail results gathered from such visits to determine if changing the time meals are consumed to earlier or later in the day could reduce risk factors associated with Type 2 diabetes.

Senior scientist of the study Dr Denise Robertson, Reader in Nutritional Physiology at the University of Surrey, said: "Type 2 diabetes is a growing problem in the UK, with over three million people diagnosed and 12.3 million people at potential risk of developing the condition, which can increase the likelihood of developing serious problems with our eyes, heart and nervous system.

"Public health initiatives are often rolled out with a focus on prevention, but these have had limited success. We need to adopt different approaches in preventing this condition. A simple solution to this could be altering when we eat our meals, lessening the risk factors associated with the development of Type 2 diabetes."

PGR student and registered dietitian Shantel Lynch said: "Treating Type 2 diabetes and its associated complications places a tremendous strain on the NHS. To ease such strain there needs to be more of a focus on prevention and tackling the areas, which are often lifestyle choices, that lead to the development of the condition.

"The possible benefits of altering mealtimes, such as weight loss, have become increasingly topical in nutrition-related research. However, there are still many unanswered questions and we hope to contribute to this field of research while finding out whether time-restricted feeding may help to reduce the risk of developing long-term illnesses like Type 2 diabetes, and how feasible it is to follow this diet in real life."

Jonathan Johnston, Professor of Chronobiology and Integrative Physiology at the University of Surrey, said: "Changing our mealtimes limits our energy intake to a set number of hours in the day, which leads to an extension of the daily fast that generally happens overnight. This study will help us understand what time of day is optimal to eat to reduce our chances of developing Type 2 diabetes.

"We will also for the first time be investigating the impact of time-restricted feeding on individuals' work, social and home life to understand the obstacles people encounter in adapting to new mealtimes, which may affect their ability to stick to the schedule."

Leesburg, VA, January 14, 2021--According to ARRS' American Journal of Roentgenology (AJR), new suspicious findings occurred in 5.5% of breast MRI examinations performed to monitor response to neoadjuvant therapy; none of these new lesions were malignant.

"Our findings suggest that new lesions that arise in the setting of neoadjuvant therapy are highly unlikely to represent a new site of malignancy, particularly if the index malignancy shows treatment response," wrote Donna A. Eckstein and colleagues in the department of radiology and biomedical imaging at the University of California, San Francisco.

Based on a presentation at the ARRS 2019 Annual Meeting, Honolulu, HI, the researchers' retrospective review pinpointed all breast MRI examinations performed to assess response to neoadjuvant therapy between 2010 and 2018. Cases with new suspicious lesions assessed as BI-RADS 4 or 5 and found after the initiation of neoadjuvant treatment were included. Meanwhile, exclusion criteria were cases with no pretreatment MRI, cases in which the suspicious lesion was present on the baseline MRI but remained suspicious, and cases with insufficient follow-up. Pathologic examination determined malignant outcomes, whereas benignity was established by pathologic examination, follow-up imaging, or both.

A total of 419 breast MRI examinations in 297 women (mean patient age, 45 years; range, 32-65 years) were performed to assess response to neoadjuvant treatment. After exclusions, 23 MRI examinations (5.5%) with new suspicious findings distinct from the site of known malignancy comprised the final study cohort. Of these 23 lesions, 13 new suspicious findings (56.5%) were contralateral to the known malignancy, nine (39.1%) were ipsilateral, and one (4.3%) involved the bilateral breasts. Lesion types included mass (16, 69.6%), nonmass enhancement (5, 21.7%), and focus (2, 8.7%).

Noting that, currently, there are no guidelines for the management of new suspicious imaging findings identified on MRI during the course of neoadjuvant systemic breast cancer treatment, "results in this small cohort suggest that these new findings are highly likely to be benign, particularly in the setting of response to therapy, which may potentially obviate biopsies in these patients in the future," wrote Eckstein et al.

"However," the authors of this AJR article concluded, "larger studies across different facilities are needed to confirm whether biopsy may be safely averted in this scenario."

Making people stand in front of a scanner to have their body temperature read can result in a large number of false negatives, allowing people with Covid-19 to pass through airports and hospitals undetected.

A new study argues that taking temperature readings of a person's fingertip and eye would give a significantly better and more reliable reading and help identify those with fever.

The study, co-led by human physiologist and an expert in temperature regulation, Professor Mike Tipton, is published in Experimental Physiology.

Professor Tipton, of the University of Portsmouth, said: "If scanners are not giving an accurate reading, we run the risk of falsely excluding people from places they may want, or need, to go, and we also risk allowing people with the virus to spread the undetected infection they have."

The study found four key factors:

Temperature alone isn't a good indicator of disease -- not all who have the virus have a fever and many who do, develop one only after admission to hospital;

Measuring skin temperature doesn't give an accurate estimation of deep body temperature (raised in a fever). A direct measure of deep body temperature is impractical;

A high temperature, even one taken from deep body, does not necessarily mean a person has Covid-19; and

Taking two temperature measurements, one of the finger, the other of the eye, is likely to be a better and more reliable indicator of a fever-induced increase in deep body temperature.

Professor Tipton said: "Using a surface temperature scanner to obtain a single surface temperature, usually the forehead, is an unreliable method to detect the fever associated with Covid-19. Too many factors make the measurement of a skin temperature a poor surrogate for deep body temperature; skin temperature can change independently of deep body temperature for lots of reasons. Even if such a single measure did reflect deep body temperature reliably, other things, such as exercise can raise deep body temperature.

"The pandemic has had a devastating global effect on all aspects of our lives, and unfortunately, it's unlikely to be the last pandemic we face. It's critical we develop a method of gauging if an individual has a fever that's accurate and fast."

The most common symptom of 55,924 confirmed cases of Covid-19 reported in China up to February 22, 2020 was fever, followed by other symptoms, including dry cough, sputum production, shortness of breath, muscle or joint pain, sore throat, headache chills, nausea or vomiting, nasal congestion, and diarrhoea.

However, the researchers say a significant proportion (at least 11 %) of those with Covid-19 do not have a fever, and that fewer than half those admitted to hospital with suspected Covid-19 had a fever. Although the majority of positive cases go on to develop a high temperature after being admitted to hospital, they were infectious before their temperature soared.

Professor Tipton said: "We think we can improve the identification of the presence of fever using the same kit but looking at the difference between eye and finger temperature - it's not perfect, but it is potentially better and more reliable."

The same scanners can easily be adapted to take these two measurements.

The new study argues that taking temperature readings of a person's fingertip and eye would give a significantly better and more reliable reading and help identify those with fever.

A change in deep body temperature is a critical factor in diagnosing disease with as little as a one degree increase indicating a potential disease.

The many methods of detecting deep body temperature, widely used in hospitals, are too expensive, invasive and time consuming to be widely used outside hospitals.

Professor Tipton said: "During the SARS epidemic, in 2003, there was a need for a fast, effective mass screening method and infrared thermography became and remains the cornerstone measurement, despite concerns over its reliability."

A 2005 study of 1,000 people comparing forehead temperature with three different infrared thermometers gave different temperatures, ranging from 31 °C to 35.6 °C. The infrared thermometers measurements alone varied by as much as 2 °C. In another study, more than 80 per cent of the 500 people tested using infrared, gave a false negative result.

Such differences in skin temperature could be due to a range of reasons, including whether the individual has recently exercised, has an infection, sunburn or recently drunk alcohol, how close an individual stands to a scanner, how warm or cool the air is, how much fat a person has on their body and even their blood pressure.
ENDS

Making people stand in front of a scanner to have their body temperature read can result in a large number of false negatives, allowing people with Covid-19 to pass through airports and hospitals undetected.

Leading experts in physiology have suggested instead that taking temperature readings of a person's fingertip and eye would give a significantly better and more reliable reading and help identify those with fever. The study is published in Experimental Physiology.

Professor Tipton, of the University of Portsmouth, said: "If scanners are not giving an accurate reading, we run the risk of falsely excluding people from places they may want, or need, to go, and we also risk allowing people with the virus to spread the undetected infection they have."

The study found four key factors:

Temperature alone isn't a good indicator of disease -- not all who have the virus have a fever and many who do, develop one only after admission to hospital;

Measuring skin temperature doesn't give an accurate estimation of deep body temperature (raised in a fever). A direct measure of deep body temperature is impractical;

A high temperature, even one taken from deep body, does not necessarily mean a person has Covid-19; and

Taking two temperature measurements, one of the finger, the other of the eye, is likely to be a better and more reliable indicator of a fever-induced increase in deep body temperature.

Professor Tipton said: "Using a surface temperature scanner to obtain a single surface temperature, usually the forehead, is an unreliable method to detect the fever associated with Covid-19. Too many factors make the measurement of a skin temperature a poor surrogate for deep body temperature; skin temperature can change independently of deep body temperature for lots of reasons. Even if such a single measure did reflect deep body temperature reliably, other things, such as exercise can raise deep body temperature.

"The pandemic has had a devastating global effect on all aspects of our lives, and unfortunately, it's unlikely to be the last pandemic we face. It's critical we develop a method of gauging if an individual has a fever that's accurate and fast."

The most common symptom of 55,924 confirmed cases of Covid-19 reported in China up to February 22, 2020 was fever, followed by other symptoms, including dry cough, sputum production, shortness of breath, muscle or joint pain, sore throat, headache chills, nausea or vomiting, nasal congestion, and diarrhoea.

However, the researchers say a significant proportion (at least 11 %) of those with Covid-19 do not have a fever, and that fewer than half those admitted to hospital with suspected Covid-19 had a fever. Although the majority of positive cases go on to develop a high temperature after being admitted to hospital, they were infectious before their temperature soared.

Professor Tipton said: "We think we can improve the identification of the presence of fever using the same kit but looking at the difference between eye and finger temperature - it's not perfect, but it is potentially better and more reliable."

The same scanners can easily be adapted to take these two measurements.

The new study argues that taking temperature readings of a person's fingertip and eye would give a significantly better and more reliable reading and help identify those with fever.

A change in deep body temperature is a critical factor in diagnosing disease with as little as a one degree increase indicating a potential disease.

The many methods of detecting deep body temperature, widely used in hospitals, are too expensive, invasive and time consuming to be widely used outside hospitals.

Professor Tipton said: "During the SARS epidemic, in 2003, there was a need for a fast, effective mass screening method and infrared thermography became and remains the cornerstone measurement, despite concerns over its reliability."

A 2005 study of 1,000 people comparing forehead temperature with three different infrared thermometers gave different temperatures, ranging from 31 °C to 35.6 °C. The infrared thermometers measurements alone varied by as much as 2 °C. In another study, more than 80 per cent of the 500 people tested using infrared, gave a false negative result.

Such differences in skin temperature could be due to a range of reasons, including whether the individual has recently exercised, has an infection, sunburn or recently drunk alcohol, how close an individual stands to a scanner, how warm or cool the air is, how much fat a person has on their body and even their blood pressure.

Philadelphia, January 14, 2021--Based on preclinical studies of an investigational drug to treat peripheral nerve tumors, researchers at Children's Hospital of Philadelphia (CHOP) as part of the Neurofibromatosis Clinical Trials Consortium have shown that the drug, cabozantinib, reduces tumor volume and pain in patients with the genetic disorder neurofibromatosis type 1 (NF1). The results of the Phase 2 clinical trial, co-chaired by Michael J. Fisher, MD at CHOP, were published recently in Nature Medicine.

"This is the second class of drugs to demonstrate a very promising response rate for NF1 patients with these tumors," said first author Fisher, Chief of the Section of Neuro-Oncology and Director of the Neurofibromatosis Program at CHOP, and Group Chair for the NF Clinical Trials Consortium, which includes 25 sites developing innovative biologically-based clinical trials for complications of NF. "Collectively, the data presented in this study illustrate a true bench-to-bedside approach, coordinating translational and clinical efforts to advance targeted therapies for a rare disease like NF1."

NF1 is a rare tumor predisposition syndrome, affecting approximately 1 in 3000 people worldwide. The condition involves the proliferation of tumors throughout the central and peripheral nervous system. One of the most prevalent type of tumors in NF1 are plexiform neurofibromas (PN), multicellular tumors composed of tumorigenic Schwann cells, fibroblasts, perineural cells, macrophages, mast cells, and secreted collagen. The tumors arise within nerves, affect up to half of patients with NF1, grow rapidly during childhood, and can lead to motor and sensory dysfunction, pain, and disfigurement. When the tumors impinge on vital structures like the airway or the spinal cord, they can be life-threatening, and although the tumors are not malignant, they can become so over time.

Because chemotherapy and radiation are ineffective at treating these tumors, surgery is the current standard of care. However, given that the tumors can be intertwined with nerves and other vital structures, surgery is often not possible. Recent studies have shown that a MEK inhibitor called selumetinib can be an effective treatment in some children with NF1-related PNs, but not all patients respond to this treatment, so there is a need for more treatment options.

Based on preclinical studies of cabozantinib, a tyrosine kinase inhibitor that targets both the tumorigenic Schwann cells in PNs as well as the complex tumor microenvironment, the researchers enrolled patients in a single arm, multicenter Phase 2 clinical trial. Twenty-three patients between the ages of 16 and 34 enrolled in the trial; twenty-one were evaluable for drug toxicity and 19 were evaluable for their response to the treatment. Of the 19 patients studied for response, eight (42%) had a partial response, defined as having greater than a 20% decrease in tumor volume, and 11 had stable disease after 12 rounds of treatment. No patient had disease progression while participating in the trial. The eight patients who had a partial response to treatment also reported a significant reduction in tumor pain intensity and pain interference in daily life.

Patients enrolled in the trial reported several adverse events, including diarrhea, nausea, asymptomatic hypothyroidism, fatigue, and palmar plantar erythrodysesthesia, a condition that causes redness, swelling, and pain on the palms of the hands and/or the soles of the feet. However, none of the side effects were reported as being severe.

Based on the benefit of cabozantinib demonstrated in this study, the NF Clinical Trials Consortium opened a pediatric cohort as well, enrolling patients ages 3 to 15. Enrollment is complete, and the study is ongoing.

"It's incredibly exciting that we now have two classes of drugs that result in tumor responses, given that we had no promising agents only a few years ago," Dr. Fisher said. "However, despite this excitement, neither cabozantinib nor MEK inhibitors shrink all tumors or make them go away completely. Therefore, we are building on these results as well as ongoing laboratory studies and are planning future exploration of combination therapies, so that we can further improve outcomes for these patients with these debilitating and life-threatening tumors."

A novel new study suggests that the behavior public officials are now mandating or recommending unequivocally to slow the spread of surging COVID-19--wearing a face covering--should come with a caveat. If not accompanied by proper public education, the practice could lead to more infections.

The finding is part of an unique study, just published in JMIR Public Health and Surveillance, that was conducted by a team of health economists and public health faculty at the University of Vermont's Larner College of Medicine in partnership with public health officials for the state of Vermont.

The study combines survey data gathered from adults living in northwestern Vermont with test results that showed whether a subset of them had contracted COVID-19, a dual research approach that few COVID studies have employed. By correlating the two data sets, researchers were able to determine what behaviors and circumstances increased respondents' risk of becoming sick.

The key risk factor driving transmission of the disease, the study found, was the number of daily contacts participants had with other adults and seniors.

That had relevance for two other findings.

Those who wore masks had more of these daily contacts compared with those who didn't, and a higher proportion contracted the virus as a result.

Basic human psychology could be at work, said Eline van den Broek-Altenburg, an assistant professor and vice chair for Population Health Science in the Department of Radiology at the Larner College of Medicine and the study's principal investigator.

"When you wear a mask, you may have a deceptive sense of being protected and have more interactions with other people," she said.

The public health implications are clear. "Messaging that people need to wear a mask is essential, but insufficient," she said. "It should go hand in hand with education that masks don't give you a free pass to see as many people as you want. You still need to strictly limit your contacts."

Public education messaging should make clear how to wear a mask safely to limit infection, van den Broek-Altenburg added.

The study also found that participants' living environment determined how many contacts they had and affected their probability of becoming infected. A higher proportion of those living in apartments were infected with the virus compared with those who lived in single family homes.

"If you live in an apartment, you're going to see more people on a daily basis than if you live in a single family home, so you need to be as vigilant about social distancing," van den Broek-Altenburg said.

The study controlled for profession to prevent essential workers, who by definition have more contacts and are usually required to wear masks, from skewing the results.

"It's generally known that essential workers are at higher risk, and our study bore that out," van den Broek-Altenburg said. "We wanted to see what else predicted that people were going to get sick," she said.

Reported cases in Chittenden County, Vermont only one-fifth of likely total

The study provides the first estimate of unreported cases in Vermont's Chittenden County, where most study participants live. The survey found that 2.2 percent of the survey group had contracted the virus, suggesting that an estimated 3,621 Chittenden County residents were likely to have become ill, compared with just 662 reported cases, just 18%.

That figure translates to a hospitalization rate of 1.2% and adjusted infection fatality rate of 0.55%.

This finding is important for policy-makers, van den Broek-Altenburg said, in and out of Vermont.

"If you know how many people are sick or have been sick, you're much better equipped to make precise predictions of will happen in the future and fashion the appropriate policies," she said.

It also shows the importance of serologic and PCR testing of the general population, she said.

"If you only test symptomatic patients, you'll never be able to find out how many people have already had the virus. With our random sample study we were able to show that Vermont has so far only tested less than one-fifth of the people who have likely had the virus. To capture the larger population, random samples of the population are needed so we can also capture asymptomatic patients, which appears to be the majority of COVID-19 cases."

The study, among other things, is a proof of concept, van den Broek-Altenburg said.

"I hope it leads to other, larger studies that combine survey data with widespread testing. This approach is essential to both understanding the dynamics of this pandemic and planning our response to futures ones."

Ten of the 454 survey respondents who took the serologic test had antibodies for Covid-19, and one tested positive for the virus. Given the small number, researchers simplified their models and were able to reach a high confidence level in the two key findings.

"We tested our models and found that the results were robust through several different model specifications," van den Broek-Altenburg said.

To create the study group, the researchers sent a survey to 12,000 randomly selected people between the ages 18 and 70 who had at least one primary care visit at the University of Vermont Medical Center, which services primarily northwestern Vermont, in the past three years.

New research from CU Cancer Center member Jing Hong Wang, MD, PhD, and recent University of Colorado Immunology program graduate Rachel Woolaver, PhD, may help researchers develop more effective personalized immunotherapy for cancer patients.

Working within Wang's specialty of cancer immunology and head and neck squamous cell carcinomas (HNSCCs), the researchers worked to establish a mouse model that would help them understand why some hosts' immune systems reject tumors easily, while others have a harder time doing so. Their research was published last week in the Journal for ImmunoTherapy of Cancer.

"It's particularly interesting now because the field of cancer treatment has really been going in the direction of immunotherapy, where you give drugs that can reactivate the immune system and get it to kill the tumors on its own," Woolaver says.

That's in contrast to chemotherapy and radiation, which can kill other cells along with tumor cells. "We're just trying to figure out how can we contribute to the field of understanding what causes heterogeneity (differences) in anti-tumor immune responses," she says.

Wang, Woolaver and other cancer researchers on the Anschutz Medical Campus started the research by transplanting HNSCC tumors into genetically identical mice. Theoretically, their response to the cancer would be identical, but it turned out that 25% of the mice spontaneously rejected the tumor. The researchers started looking more closely at both the mice and the tumor cells to try to understand what was causing the mice to kill the cancer on their own.

What they discovered is that it all depended on the types of the immune cells known as CD8 T cells that were present in the mouse. Even identical twins have different T cells due to the random DNA recombination event generating these T cells, Wang explains, so the genetically identical mice had different arrays of the T cells as well. The mice's response to cancer depended on how their specific T cells matched up with the set of mutated proteins known as neoantigens that were present in the tumor they were fighting.

"Each of your T cells has a different receptor, and each T cell will be specific to a neoantigen," Woolaver says. "If you have T cells that are specific to all of them or majority of them, you're going to be able to get rid of your tumor and have a good anti-tumor immune response."

What the researchers showed in the publication, Wang explains, is that the mice that spontaneously rejected tumors had vastly different T cell receptors from those that succumbed to tumor development.

For the next phase of their research, Wang and her team members plan to study how to enable a cancer patient to develop a more diverse T cell response so they have a better chance of successfully fighting off a tumor.

"Because patient tumors are very heterogenous from each other, it's very difficult to study them," Woolaver says. "In our paper, we characterize a new model of tumor heterogeneity that has a lot of interesting immunological aspects that we can study to try to help improve the immune response to cancer."

Wang adds that the research can be important in developing new types of immunotherapy.

"I don't think it's well recognized in the field that intrinsic differences in the immune system can make an impact," Wang says. "Most people just focus on 'Why are all the T cells not activated,' or 'The T cells are exhausted,' or something like that. But maybe a patient doesn't have the right T cells from the beginning. If they don't have the right T cells that can recognize neoantigens, how can they have the effective anti-tumor immune response?"

The COVID-19 pandemic, which claimed more than 336,000 lives in the United States in 2020, has significantly affected life expectancy, USC and Princeton researchers have found.

The researchers project that, due to the pandemic deaths last year, life expectancy at birth for Americans will shorten by 1.13 years to 77.48 years, according to their study published Thursday in the Proceedings of the National Academy of Sciences.

That is the largest single-year decline in life expectancy in at least 40 years and is the lowest life expectancy estimated since 2003.

The declines in life expectancy are likely even starker among minority populations. For Blacks, the researchers project their life expectancy would shorten by 2.10 years to 72.78 years, and for Latinos, by 3.05 years to 78.77 years.

Whites are also impacted, but their projected decline is much smaller -- 0.68 years -- to a life expectancy of 77.84 years.

Overall, the gap in life expectancy between Blacks and whites is projected to widen by 40%, from 3.6 to more than 5 years -- further evidence of the disease's disparate impact on disadvantaged populations.

"Our study analyzes the effect of this exceptional number of deaths on life expectancy for the entire nation, as well as the consequences for marginalized groups," said study author Theresa Andrasfay, a postdoctoral fellow at the USC Leonard Davis School of Gerontology. "The COVID-19 pandemic's disproportionate effect on the life expectancy of Black and Latino Americans likely has to do with their greater exposure through their workplace or extended family contacts, in addition to receiving poorer health care, leading to more infections and worse outcomes."

COVID-19 appears to have eliminated many of the gains made in closing the Black-white life expectancy gap since 2006. Latinos, who have consistently experienced lower mortality than whites -- a phenomenon known as the "Latino paradox" -- would see their more than three-year survival advantage over whites reduced to less than one year.

"The huge decline in life expectancy for Latinos is especially shocking given that Latinos have lower rates than the white and Black populations of most chronic conditions that are risk factors for COVID-19," said study co-author Noreen Goldman, the Hughes-Rogers Professor of Demography and Public Affairs at the Princeton School of Public and International Affairs. "The generally good health of Latinos prior to the pandemic, which should have protected them from COVID-19, has laid bare the risks associated with social and economic disadvantage."

The study's authors estimated life expectancy at birth and at age 65 for 2020 for the total U.S. population and by race and ethnicity. They used four scenarios of deaths -- one in which the COVID-19 pandemic had not occurred and three others that include COVID-19 mortality projections by the Institute for Health Metrics and Evaluation, an independent global health research center at the University of Washington.

"The bigger reductions in life expectancy for the Black and Latino populations result in part from a disproportionate number of deaths at younger ages for these groups," Goldman said. "These findings underscore the need for protective behaviors and programs to reduce potential viral exposure among younger individuals who may not perceive themselves to be at high risk."

Life expectancy as an indicator of population health

Of the analyzed deaths for which race and ethnicity have been reported to the National Center for Health Statistics, 21% were Black and 22% Latino. Black and Latino Americans have experienced a disproportionate burden of coronavirus infections and deaths, reflecting persistent structural inequalities that heighten risk of exposure to and death from COVID-19.

The researchers say life expectancy is an important indicator of a population's health and an informative tool for examining the impact of COVID-19 on survival.

In the decades before the COVID-19 pandemic, annual improvements in U.S. life expectancy had been small but overall life expectancy had rarely declined. An exception was the annual reduction of 0.1 year for three consecutive years -- 2015, 2016, and 2017 -- which were attributed in part to increases in so-called "deaths of despair" among middle-aged whites related to drug overdoses, including opioids, as well as alcohol-related liver disease and suicide.

The projected pandemic-related drop in life expectancy is about 10 times as large as the declines seen in recent years.

The last major pandemic to significantly reduce life expectancy in a short period of time was the 1918 influenza pandemic, which research indicates reduced life expectancy by an extraordinary 7-12 years.

As of Wednesday, more than 10 million Americans had received their first COVID-19 vaccination dose, according to the U.S. Centers for Disease Control and Prevention. But the vaccines may not be enough to immediately reverse the impact of the disease on U.S. life expectancy.

"While the arrival of effective vaccines is hopeful, the U.S. is currently experiencing more daily COVID-19 deaths than at any other point in the pandemic," Andrasfay said. "Because of that, and because we expect there will be long-term health and economic effects that may result in worse mortality for many years to come, we expect there will be lingering effects on life expectancy in 2021."

"That said," she added, "no cohort may ever experience a reduction in life expectancy of the magnitude attributed to COVID-19 in 2020."

The study authors say they are now studying occupational exposures to COVID-19 by race and ethnicity to further comprehend its disproportionate impact.