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Washington, DC - July 24, 2020 - Researchers have shown that there is a low risk for healthy people to acquire Candida auris during travel. The research is presented at ASM Microbe Online, the annual meeting of the American Society for Microbiology.

Candida auris is an emerging, multidrug-resistant, fungus associated with high mortality rates. It can also survive for long periods of time on common surfaces such as linens and doors, leading to significant outbreaks in healthcare settings. Due to these characteristics, the Centers for Disease Control and Prevention (CDC) has identified this organism as an urgent health threat and has created screening protocols to identify and track its spread.

Little is known about the transmission of C. auris, specifically how it has spread globally, but international travel has been implicated as a potential mode of acquisition and transmission.

The researchers looked at a cohort of healthy U.S. international travelers to determine if they were likely to acquire C. auris during travel. Using a culture-based screening method, they found no C. auris acquisition in 94 U.S. subjects returning from international travel.

"This suggests that healthy travelers are not at high risk for C. auris acquisition during international travel and that they are likely not a significant reservoir for global transmission," said Margaret Becker, a research technician at Massachusetts General Hospital in the department of pathology.

The subjects evaluated in the study were from Massachusetts, predominately from the Boston area, and were enrolled at the travel clinic located at Massachusetts General Hospital. During their trips, 3 travelers visited a healthcare faculty and none of the cohort was hospitalized.

While the researchers acknowledge that both the small sample size and the lack of hospital exposure were limitations of the study, "the success of implementing the screening protocol opens up the possibility of developing a detection system that could be used for high-risk populations in the future, such as individuals that receive medical care overseas," said Becker.

Margaret Becker and Barbara Belford processed all the subject samples. Margaret Becker set up and validated the protocol and Elizabeth Oliver enrolled the subjects and followed up with them to retrieve epidemiological data and trip updates. Edward Ryan, Regina LaRocque and Sarah Turbett directed the study. This work was supported by the US Centers for Disease Control and Prevention [Grant Number U01CK000490]. The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.

ASM Microbe Online brings you the dynamic, cutting-edge science of ASM Microbe 2020, the annual meeting of the American Society for Microbiology. Explore the latest research in the microbial sciences with ePosters, hear from experts in the field during live keynotes and access track-related content with a curated selection of on-demand sessions.

An experimental messenger RNA (mRNA)-based vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) elicits protective immune responses in mice and non-human primates, researchers report on July 23rd in the journal Cell. Two injections of the vaccine were sufficient to induce robust immunity, completely preventing SARS-CoV-2 infection in mice.

"The robust protection observed in the present studies and the clear immune correlates of protection pave the path forward for future COVID-19 vaccine development in humans," says senior study author Cheng-Feng Qin of the Beijing Institute of Microbiology and Epidemiology.

mRNA-based vaccines are attractive options for protecting against SARS-CoV-2 because they can be rapidly designed and manufactured at a large scale within weeks. Moreover, preclinical studies have demonstrated that mRNA-based vaccines induce potent and broadly protective immune responses against various pathogens with an acceptable safety profile.

In the Cell study, Qin and his colleagues developed a vaccine consisting of mRNA that encodes the receptor-binding domain (RBD) of the spike (S) protein, which is located on the surface of SARS-CoV-2. The vaccine, named ARCoV, is encapsulated in lipid nanoparticles, which improves delivery into tissues.

Targeting RBD rather than the entire S protein may represent a safer option, potentially triggering the production of fewer non-neutralizing antibodies. These antibodies could enhance viral entry into cells and viral replication through a process called antibody-dependent enhancement of infection, which has been previously reported for the related virus SARS-CoV--the causative agent of the SARS outbreak in 2002 to 2003.

The researchers injected ARCoV into the muscle tissue of 16 mice and provided a booster shot two weeks later. The vaccine elicited the production of high levels of neutralizing antibodies, which protect host cells by preventing the virus from interacting with them. These antibodies were cross-reactive, offering broad protection against three different strains of SARS-CoV-2. In addition, the vaccine increased the number of T cells in the spleen.

Mice that received two doses of ARCoV and were exposed to SARS-CoV-2 35 days later showed no signs of viral RNA in the lungs or trachea and no lung damage or inflammation. Results from 20 cynomolgus monkeys showed that two ARCoV doses induced a virus-specific T cell response and the production of neutralizing antibodies at levels that far exceed those seen in most recovered COVID-19 patients. Moreover, none of the vaccinated animals experienced adverse effects.

To assess the thermal stability of ARCoV, the researchers stored the vaccine at various temperatures for one, four, or seven days, injected it into mice, and visualized its tissue distribution. The results showed that the vaccine was effectively delivered to tissues, achieving the same high level of expression after being stored at room temperature for one week, without any signs of decreased activity. "A ready-to-use and thermostable vaccine like ARCoV is highly desirable to eliminate the need for cold-chain transportation," Qin says.

The researchers are currently evaluating the long-term stability of ARCoV. "In addition, the duration of neutralization antibody induced by ARCoV is yet to be determined, as experience from other human coronaviruses has indicated the possibility of re-infection due to waning of the antibody response," Qin says. "Future studies are needed to evaluate the long-term immune response in animal models and the effectiveness of ARCoV in humans."

Osaka, Japan - Cancer diagnosis requires a lengthy process of multiple analyses of tissue biopsies, impeding the quick and early detection of cancers. In a new study, researchers from Osaka University developed a novel imaging system that uses near-infrared light to be less invasive and more time efficient than the conventional approach.

Histopathological analysis, or the investigation of tissue biopsies, is the cornerstone of cancer diagnosis. First, multiple specimens from different tissue locations are biopsied. These specimens are then sent to a pathologist, who will stain the tissues for molecules of interest to determine whether cancerous cells are present. Although an established process, it can be particularly invasive, as a sufficient number of biopsies from multiple locations within the same organ are necessary to increase the chances of catching the potential cancer—which is not always possible for certain organs like the lungs, pancreas and uterus. Suspected cervical cancer is even a contraindication for biopsy acquisition. Another major downside of this process is the slow turnaround time, owing to the complexity of tissue acquisition, histopathological preparation, evaluation and preparation of the report.

"Time is of the essence when it comes to cancer," says corresponding author of the study Masaru Ishii. "The goal of our study was to develop a novel technique that can provide a cancer diagnosis in real-time using the obtained tissues only, without further histopathological preparation."

To achieve their goal, the researchers focused on cervical cancer, the fourth most common type of cancer in women. They obtained biopsies from healthy patients and patients with cervical cancer, and imaged them right away with their imaging system that uses near-infrared light to scan the tissues. An additional feature of this imaging system is its ability to not only scan tissues in two dimensions, as it is done conventionally, but also in three dimensions, thus obtaining a full picture of the tissues. The researchers found that the nuclei, compartments within cells that contain the DNA, had an irregular shape in cancerous tissue. By leveraging this finding and analyzing it using a machine learning algorithm, the researchers were able to set up a quantitative approach to classify tissues into normal and cancerous based on nuclear shape. Going a step further, the researchers developed an additional classification algorithm that takes the amount of connective tissue in the biopsies into account when deciding whether the tissue is healthy or diseased.

But did this imaging system improve the diagnosis of cervical cancer? To verify the accuracy of the imaging results, the researchers sent the specimen to pathologists who then did a conventional histopathological analysis of the biopsies and found a significant overlap between both approaches. Employing both newly developed classification algorithms even enabled the differentiation between invasive cancer and so-called cervical intraepithelial neoplasia, a precursor to invasive cancer detected by collecting cervical cells with Pap smears. Taken together, this novel imaging method enabled tissues to be visualized in three-dimensions and to be analyzed for cancer without extensive tissue preparation.

"These are striking results that show how the combination of our technique with image analysis using artificial intelligence enables the less-invasive, quick and quantitative detection of cervical cancer compared to the conventional approach," says Ishii. "Our imaging system could help develop novel medical devices as an improved approach for the diagnosis of cancers."

As several Neandertal genomes of high quality are now available researchers can identify genetic changes that were present in many or all Neandertals, investigate their physiological effects and look into their consequences when they occur in people today. Looking into one gene that carries such changes, Hugo Zeberg, Svante Pääbo and colleagues found that some people, especially from central and south America but also in Europe, have inherited a Neandertal variant of a gene that encodes an ion channel that initiates the sensation of pain.

By using data from a huge population study in the UK, the authors show that people in the UK who carry the Neandertal variant of the ion channel experience more pain. "The biggest factor for how much pain people report is their age. But carrying the Neandertal variant of the ion channel makes you experience more pain similar to if you were eight years older", says lead author Hugo Zeberg, a researcher at the Max Planck Institute for Evolutionary Anthropology and Karolinska Institutet. "The Neandertal variant of the ion channel carries three amino acid differences to the common, 'modern' variant", explains Zeberg. "While single amino acid substitutions do not affect the function of the ion channel, the full Neandertal variant carrying three amino acid substitutions leads to heightened pain sensitivity in present-day people."

On a molecular level, the Neandertal ion channel is more easily activated which may explain why people who inherited it have a lowered pain threshold. "Whether Neandertals experienced more pain is difficult to say because pain is also modulated both in the spinal cord and in the brain", says Pääbo. "But this work shows that their threshold for initiating pain impulses was lower than in most present-day humans."

Optical tweezers are a device which uses a laser beam to move micron-sized objects such as living cells, proteins, and molecules. In 2018, the American physicist Arthur Eshkin received the Nobel Prize for this technology. Before this, it was impossible to move such objects since any attempt to grab it led to destruction. Optical tweezers do not disturb the internal structure of the object.

"Optical tweezer is a media name for optical traps. Their general principle of operation is as follows: the lens focuses the laser light, and the particles in the focusing field, according to the laws of physics, begin to move towards the maximum intensity of the light field. Thus, this allows capturing and moving particles. Previously, we have proposed to use microparticles made of a dielectric material, for example, quartz instead of lenses to increase the degree of localization of the optical field in the focusing area in these optical traps, operating in the reflection mode," Igor Minin project manager, professor of the TPU Division for Electronic Engineering, says.

Interacting with such a particle, the light is focused in the form of a photon jet in the direction opposite to the radiation incidence. Due to its properties, it is this photon jet that acts as a trap or tweezers.

"To form a classical photonic jet, there is a necessary condition such as the ratio of the refractive indices of a particle and a medium must be less than two. If it is higher, then the jet will not form. Previously, it was believed that it is impossible to increase the refractive index and at the same time form a photon jet. We jointly with a team from the Institute of Atmospheric Optics theoretically have demonstrated that it is possible," Igor Minin says.

To achieve this, the joint research team formed a jet in the reflection mode.

"There are two modes: refraction and reflection. In the former case, a jet is formed when light passes through a dielectric particle. In the latter case, we put a flat mirror behind the particle, and the focal point moves to the mirror. As a result, we have double-focusing when the light is focused through a particle on a mirror, which reflects it back to the same particle that forms a photonic jet. Using this mode, we managed to form a jet from a dielectric particle with the ratio of a particle and a medium higher than two. This increases the capture area at times," the scientist underlines.

Currently, the group is preparing experiments to confirm the simulation results in practice.

What is the incidence of viral hepatitis caused by blood transfusions before and after Sweden introduced screening of blood in the early 1990s? In an article published in Eurosurveillance ahead of World Hepatitis Day on 28 July, the authors also try to estimate how many people of those who were infected with hepatitis B and C through blood transfusion still live with undiagnosed hepatitis.

Transmission of viral hepatitis via blood transfusion or through the use of plasma-derived products is rare in Europe nowadays due to effective blood safety programmes which include exclusion criteria for donors and blood screening for hepatitis B (HBV) and C (HCV). Large numbers of infected blood donors and recipients of blood transfusions have been identified since screening was implemented around the year 1990.

The Swedish public health agency estimated in 2015 that between 35 000 - 45 000 people in Sweden are living with diagnosed HCV. A similar estimate for HBV does not exist for Sweden.

Dahl et al performed a retrospective cohort study based on different nationwide data sources covering Sweden's transfusion experience from 1968 to 2012 and nationwide notified infections. The aim was to estimate the past and present burden of transfusion transmission of all types of viral hepatitis and to find undiagnosed infections with hepatitis C virus (HCV).

A total of 1 146 307 transfused patients were included in the analysis of HCV transmission for the study. Some 12 000 patients had received at least one transfusion from a donor in one of the strata that were identified as substantial and statistically significant risk increases, namely patients transfused before 1992 with units from a donor with a subsequent HCV diagnosis.

Based on this, the data analysis by Dahl et al identified 1 180 transfused patients and 44 blood donors who they consider at a high risk of being infected with HCV and who are still alive, living in Sweden and had not yet been diagnosed with HCV infection at the end of follow-up in 2017.

No signs of HBV transmission via blood transfusion since 1992

"For hepatitis C, we found ongoing transmission in Sweden before the anti-HCV blood screening was fully implemented in 1992. After that, transmission of HCV decreased to undetectable levels. Our study did not show any signs of hepatitis B transmission through transfusions after 1992", says Gustaf Edgren, associate Professor of epidemiology at the Swedish Karolinska Institutet. "Those people, that we have identified as still undiagnosed with hepatitis C should be tested and offered treatment."

The study showed only one possible case of transmission of hepatitis A after blood transfusion in Sweden. And even though no HEV transmission related to transfusion was identified in this study, an earlier study found that one in 7 896 Swedish plasma donations were positive for HEV RNA, which indicates that this transmission route probably also happens in Sweden.

The study was based on notified infections only, which limits its sensitivity as it depends on the extent to which infections had been diagnosed in Sweden. Which, in turn can also depend on whether the hepatitis infection is symptomatic.

WHAT:
Kidney transplantation from deceased donors with HIV to people living with both HIV and end-stage kidney disease is feasible and safe, investigators supported by the National Institutes of Health have found. Their study demonstrates that the pool of available kidneys for people with HIV can be expanded by including donors with HIV, making more kidneys available for all who are awaiting a transplant.

The new findings build on research from 2019, when scientists from the University of Cape Town and NIH reported that people living with HIV who received kidney transplants from deceased donors with HIV had high overall survival and kidney graft survival after five years.

People living with HIV have a growing prevalence of end-stage kidney disease and are nearly three times more likely to die while on kidney dialysis than people without HIV. Kidney transplantation extends the lives of people with HIV and end-stage kidney disease, but these individuals face a shortage of donors and limited access to donor kidneys. The HIV Organ Policy Equity (HOPE) Act, passed by the U.S. Congress and signed into law in 2013, allows organ transplants from donors with HIV to recipients with HIV in approved research studies in the United States. Experts concurred that kidney transplantation between people with HIV would expand the pool of available organs and save lives. Consequently, investigators sought to explore the safety of this innovative transplantation practice.

The multicenter study was conducted by the HOPE in Action team led by Christine M. Durand, M.D., associate professor of medicine, and Dorry Segev, M.D., professor of surgery at Johns Hopkins University in Baltimore. NIH's National Institute of Allergy and Infectious Diseases (NIAID) funded the study with additional support from the National Cancer Institute, also part of NIH.

Between March 2016 and July 2019, investigators at 14 clinical research sites enrolled 75 adults with end-stage kidney disease and HIV whose virus was reliably suppressed by anti-HIV therapy. Twenty-five participants received kidney transplants from deceased donors with HIV, and 50 participants received kidney transplants from deceased donors without HIV. The latter group included 22 donors who had false-positive HIV tests, another new organ source that has been an unexpected benefit of the HOPE Act.

All participants survived transplantation at a median follow-up of 1.4 years for recipients of HIV-positive kidneys and 1.8 years for recipients of HIV-negative kidneys. One year after transplantation, overall graft survival was excellent and comparable between recipients of HIV-positive kidneys (91%) and HIV-negative kidneys (92%). In addition, there were no differences in the rates of infections requiring hospitalization, serious adverse events (1.1 per person year) or HIV-related complications, which were rare.

Dr. Durand also is leading the HOPE in Action Multicenter Kidney Study, a large-scale, NIAID-sponsored clinical trial to further study the safety of kidney transplantation between people with HIV.

CHAMPAIGN, Ill. -- Researchers have confirmed that Heartland virus, an emerging pathogen with potentially dire consequences for those infected, is present in Lone Star ticks in two Illinois counties hundreds of miles apart. Lone Star ticks were first detected in Illinois in 1999, but had not been found to be infected with Heartland virus in the state.

The findings are reported in the journal Emerging Infectious Diseases.

In July 2018, a resident of Kankakee County was hospitalized after suffering several tick bites while camping on private property. Two months later and more than 250 miles to the south, a resident of Williamson County was hospitalized with many of the same symptoms: fever, diarrhea, headache, fatigue, decreased appetite and nausea. This patient also noticed tick bites after camping. The Centers for Diseases Control and Prevention confirmed that clinical samples from both patients tested positive for Heartland virus, which is spread by ticks. Both patients eventually recovered.

Tick-borne illnesses share symptoms with many other diseases and misdiagnoses sometimes occur, said Holly Tuten, a vector ecologist with the Illinois Natural History Survey who led the new research. INHS is a division of the Prairie Research Institute at the University of Illinois at Urbana-Champaign.

"Heartland virus won't show up on a standard diagnostic panel for tick-borne bacterial diseases," she said. "And with COVID-19 on the collective mind, a tick-borne viral infection could be overlooked, especially in cases where a tick bite was missed."

According to the CDC, there are no vaccines to prevent infection with the Heartland virus or medications to treat it. Most people infected with the virus end up hospitalized and a few have died.

To determine the source of the viral infections, health department officials in each county interviewed the patients to learn where they were when they were bit. This information allowed Tuten and her team to determine whether ticks in those areas carried the virus.

Previous research showed that the Lone Star tick, Amblyomma americanum, can carry and transmit the Heartland virus, so the researchers focused their efforts on collecting this species.

"Lone Star ticks are very aggressive ambush predators and many people don't realize this," Tuten said. "I've seen Lone Star ticks run across a forest floor to me."

The site in Kankakee County was a rural homestead with barnyard animals and a small amount of forest surrounded by cropland, Tuten said. The patient in Williamson County may have been exposed in a heavily wooded wildlife refuge or outside a suburban home with a few trees.

The researchers collected ticks in all three locales. They shipped their tick samples to the CDC Arboviral Diseases Branch in Fort Collins, Colorado, where the ticks were combined in batches of 10-30 for testing.

"A single batch of male Lone Star ticks from each county was found to be positive for the Heartland virus," Tuten said. "Infected Lone Star ticks had been found as far north as Missouri, so we expected to find the infections in ticks from Williamson County in the southern part of Illinois. But finding so many Lone Star ticks in Kankakee County, including some with the virus, really surprised us."

The detection of Heartland virus in adult Lone Star ticks a year after human infection suggests that the infected ticks may have overwintered in the area, Tuten said.

"We want to alert physicians and public health officials throughout Illinois that there is a fairly new pathogen out there that is a danger to public health," she said. "I don't want people to avoid the woods and parks. I just want them to be aware, so they can take concrete steps to reduce tick encounters and bites."

When drugs to kill microbes are ineffective, host-directed therapy uses the body's own immune system to deal with the infection. This approach is being tested in patients with COVID-19, and now a team of researchers at Trinity College Dublin has published a study showing how it might also work in the fight against tuberculosis (TB). The findings are published in the journal Frontiers in Immunology today (Thursday 23rd July 2020).

Although the bacteria that causes TB (called Mtb) has scourged humankind for millennia, we do not fully understand the complexities and interplay of the human immune response to this ancient bug. Worryingly, there are increasing numbers of people with antibiotic resistant TB, which is hard to treat and is becoming a global threat to public health.

Scientists at the Trinity Translational Medicine Institute (TTMI) at St. James's Hospital are dedicated to understanding the intricacies of the human immune response to Mtb with the aim of finding ways to target and promote the immune response to overcome the infection. Scientists already know that the human immune response can both under or over respond to the bacteria resulting in a difficulty to treat the disease. This complex immune response is analogous to driving with both the accelerator and the brakes fully engaged at the same time.

The research team led by Health Research Board Emerging Investigator, Dr Sharee Basdeo, and Professor Joseph Keane, Clinical Medicine, Trinity College has recently discovered a way to manipulate human immune responses to Mtb to tip the balance in favour of the patient. All changes in immune cell responses to an infection are governed by changes in what genes are active and 'open' for business. Because our DNA stretches out to nearly 2 meters but needs to fit inside every tiny cell in our body, it needs to be very tightly packed up. Its packaging, and how easy it is to open and close, very often dictates the activity of the genes. This is known as "epigenetics".

The research team used a drug approved for cancer treatment called suberoylanilide hydroxamic acid (SAHA for short, also known as Vorinostat). This drug is an epigenetic inhibitor, meaning it can block the machinery that closes up genes. Using this drug on human immune cells that are infected with the bacteria that causes TB, they discovered that SAHA releases the brakes on the immune system by stopping the production of an anti-inflammatory signal while at the same time promoting more appropriate pro-inflammatory signals that may help the patient to clear the infection. Importantly, the team discovered that this fine-tuning of the immune response early in the reaction to infection also benefits later immune responses, which may also aid in the design of future vaccine strategies.

Dr Donal Cox, Research Fellow, Clinical Medicine, Trinity College and senior author on the paper, suggests that this may be a new and exciting addition to our arsenal of antibiotic therapies. He said:

"Understanding and being able to manipulate the immune system is a crucial component of treating infectious diseases. Having host directed therapies targeting the human immune response will be key in addressing the likely pandemics that will arise in the future due to increasing antibiotic resistance, particularly TB."

"We would also like to thank and highlight the important contributions that patients made in this study by providing blood and lung cells without which this research would not be possible."

PREVALENCE OF CHRONIC KIDNEY DISEASE AMONG MEXICAN AMERICANS HAS DOUBLED IN RECENT YEARS
Media Contact: Michael E. Newman, mnewma25@jhmi.edu

A new study looking at nearly three decades of data from some 54,000 people has determined that the overall prevalence of chronic kidney disease (CKD) for several racial/ethnic and socioeconomic groups in the United States has stabilized in recent years, except Mexican Americans.

Results from the research, conducted by investigators from the U.S. Centers for Disease Control and Prevention (CDC) and three medical institutions -- including Deidra Crews, M.D., associate professor of medicine at the Johns Hopkins University School of Medicine -- were reported in the July 16, 2020, issue of JAMA Network Open.

Prevalence, as defined by the CDC, is "the proportion of persons in a population who have a particular disease or attribute at a specified point in time or over a specified period of time." The study team looked at CKD prevalence among adults age 20 or older from 1988 to 1994 and from 1999 to 2016 for four racial/ethnic groups (non-Hispanic white, non-Hispanic Black, Mexican American and other), three educational levels (less than high school, high school and more than high school) and three income levels (low, middle and high).

"We found that overall prevalence of CKD, as well as the rates for all of the groups except one -- Mexican Americans -- stayed significantly the same from 2005 through 2016," says Crews. "Among Mexican Americans during that period, the prevalence doubled, even when our analyses accounted for several potentially confounding variables, such as age and sex."

Crews says the finding is consistent with recent studies showing a worsening overall health status for the Mexican American population compared with non-Hispanic whites.

Another revelation from the study, Crews adds, is that although CKD prevalence rates stabilized between 2005 and 2016 for most of the racial/ethnic groups and socioeconomic levels analyzed, significant disparities in who gets CKD still remain across racial/ethnic groups and socioeconomic levels.

"To narrow the gaps and move closer to health equity, stronger efforts are needed to effectively correct these persistent disparities in kidney health," Crews says.

Data for the study came from the National Health and Nutrition Examination Survey (NHANES), a federal program to assess the health and nutritional status of adults and children in the United States over long periods of time. NHANES findings are used to determine the prevalence of major diseases and risk factors for those illnesses.

GENE THERAPY ALLEVIATES OBSTRUCTIVE SLEEP APNEA IN MICE
Media Contact: Vanessa McMains, vmcmain1@jhmi.edu

Floppy, untoned muscles in a person's tongue and airway can block airflow and result in obstructive sleep apnea -- a common disorder in which breathing repeatedly starts and stops during sleep, sometimes hundreds of times each night. Sleep apnea can cause daytime tiredness, increase the chance of accidents from falling asleep while driving, disrupt metabolism and if left untreated for years, lead to depression, high blood pressure, heart disease, stroke or death. Now, Johns Hopkins Medicine researchers have shown in mice that they can treat the condition and keep the airway open by using gene therapy to stimulate the nerve that contracts muscles in the tongue.

The researchers say their findings, published online on July 16, 2020, by the American Journal for Respiratory and Critical Care Medicine, ultimately may be translated into therapy for people at greatest risk of death from obstructive sleep apnea's impact, such as those with conditions like stroke or severe atherosclerotic heart disease.

"The tongue muscles that are partly responsible for obstructive sleep apnea have a direct line via a nerve to the area of the brain that controls them," says senior author Vsevolod Polotsky, M.D., Ph.D., director of sleep basic research and professor of medicine at the Johns Hopkins University School of Medicine. "Knowing this, we looked for a way to use this pathway in two directions: first, to travel to the control area with gene therapy to make it receptive to drug stimulation, and then once it's been activated, send a signal back to the tongue to make the problem muscles contract."

Obstructive sleep apnea affects 30% of adult men and 15% to 20% of women, says Polotsky. According to current medical practice, the gold standard for treating the condition is a continuous positive airway pressure (CPAP) machine that provides a steady flow of air to the user during sleep. "However," he adds, "only 50% of people adhere to the treatment, so our team has been investigating alternative therapies."

The tongue has eight pairs of muscles. One of these sets, the genioglossus, is stimulated by the hypoglossal nerve, which runs to it from the medulla, the lowest part of the brainstem. The medulla is connected to the spinal cord and controls involuntary functions, such as breathing and heartbeat. By implanting a pacemaker in the tongue, other researchers have shown that electrical pulses can make the hypoglossal nerve contract the genioglossus and prevent sleep apnea. The problem with this procedure, Polotsky says, is that it requires invasive surgery.

In their study, Polotsky and his team turned to a non-invasive method -- an innocuous virus -- to deliver laboratory-developed chemical receptors to the brains of obese mice. Once in place within the medulla, these receptors -- known as DREADDs (Designer Receptors Exclusively Activated by Designer Drugs) -- enable the brain cells in the medulla to accept a synthetic ("designer") drug. The artificial DREADD receptors remain in the medulla for months after a single tongue injection.

After Polotsky and his colleagues injected the drug under the skin of the obese mice, it traveled up the hypoglossal nerve to the waiting DREADDs and stimulated the brain cells, which in turn activated the nerve to send a return signal to contract the tongue's genioglossus muscles.

The researchers used magnetic resonance imaging on the sleeping mice to show that their airways opened after delivering the drug, but not in other mice injected with only saline. The researchers also measured six-fold higher electrical activity in the tongue muscles of the drug-treated mice, which indicated the tongue was contracting.

In upcoming mouse studies, the researchers plan to refine the virus delivery system to ensure it only gets DREADDs into the type of brain cells that control the hypoglossal nerve, rather than other nearby neurons. They also will look at the role that other tongue muscles may play in obstructive sleep apnea.

Based on these studies, human trials of DREADDs may follow.

"We believe that if this treatment works in humans, the drug to activate the receptors could be given orally every night and its effects will last about five to six hours," says research associate Thomaz Fleury Curado, Ph.D., who led the study. "Therefore, by the time a person gets up, talking and eating won't be a problem."

NATIONAL STUDY SHOWS KIDNEY TRANSPLANTATION BETWEEN PEOPLE WITH HIV IS SAFE AND SUCCESSFUL
Media Contact: Michael E. Newman, mnewma25@jhmi.edu

Kidney transplantation from deceased donors who had the human immunodeficiency virus (HIV) to people living with HIV and end-stage kidney disease is safe and consistently yields positive outcomes, according to researchers at Johns Hopkins Medicine and 13 other medical institutions. They say their finding could pave the way for more HIV-positive organs of all types -- not just kidneys -- being available for lifesaving transplants for people with HIV who need them.

The study was posted online on July 23, 2020, by the American Journal of Transplantation. It was performed under the authority of the HIV Organ Policy Equity (HOPE) Act, passed by Congress and signed into law in 2013. The act allows organ transplants from donors with HIV to recipients with HIV in approved U.S. research studies.

"This is an exciting culmination of 10 years of work: estimating the national impact of HIV-to-HIV transplants in 2011, helping write the HOPE Act in 2013, performing the first HIV-to-HIV transplants in the United States in 2016, and now collaborating across the country to demonstrate the safety of this procedure," says Dorry Segev, M.D. Ph.D., professor of surgery and epidemiology at the Johns Hopkins University School of Medicine and co-leader of the HOPE in Action study team. "Fully successful implementation of the HOPE Act could mean hundreds of additional transplants and hundreds of additional lives saved each year."

Between March 2016 and July 2019, the HOPE in Action team enrolled 75 adults with end-stage kidney disease and HIV whose virus was suppressed by anti-HIV therapy. Of the participants, 25 received kidneys from deceased donors with HIV and 50 received kidneys from deceased donors without HIV.

All participants survived transplantation, with median follow-up of 1.4 years for recipients of HIV-positive kidneys and 1.8 years for recipients of HIV-negative kidneys. At one year after transplantation, overall graft survival was excellent and comparable between HIV-positive kidneys (91%) and HIV-negative kidneys (92%). Additionally, there were no differences in hospitalizations due to infections, rates of serious adverse events or HIV-related complications, which were rare.

"People living with HIV face a higher risk of kidney failure than those without the virus, but their lack of access to suitable donor organs has previously meant many deaths while waiting for a transplant," says Christine Durand, M.D., associate professor of medicine at the Johns Hopkins University School of Medicine and co-leader of the HOPE in Action study team. "So it's a major step forward for our study to show that transplant outcomes using HIV-positive organs are comparable to HIV-negative ones."

In a 2011 study, also published in the American Journal of Transplantation, a team led by Brian Boyarsky, M.D., a surgical research fellow and assistant resident at the Johns Hopkins University School of Medicine, estimated that 300 to 500 people with HIV could become deceased organ donors every year, potentially providing as many as 1,000 transplants annually for recipients living with the virus.

The new study provides solid evidence that the increase to the organ donor pool predicted nearly a decade ago is possible.

The work was primarily funded by the National Institute of Allergy and Infectious Diseases with additional support from the National Cancer Institute.

Responding to a need to quickly develop billions of doses of lifesaving COVID-19 vaccines, a scientific team at The University of Texas at Austin has successfully redesigned a key protein from the coronavirus, and the modification could enable much faster and more stable production of vaccines worldwide.

The new findings are described in the journal Science.

Most coronavirus vaccine candidates train the human immune system to recognize a key protein on the surface of the SARS-CoV-2 virus called the spike protein in order to fight infection. Researchers designed a new version of this protein that, when expressed in cells, produces up to 10 times more protein than that of an earlier synthetic spike protein already in use in multiple COVID-19 vaccines. Along with colleagues at the National Institutes of Health, several members of the UT research team also designed the earlier version of the spike protein found in at least two COVID-19 vaccine candidates currently in U.S. clinical trials.

"Depending on the type of vaccine, this improved version of the protein could reduce the size of each dose or speed up vaccine production," said Jason McLellan, an associate professor in the Department of Molecular Biosciences and senior author of the paper. "Either way, it could mean more patients have access to vaccines faster."

Dubbed HexaPro, the new protein is also more stable than the team's earlier version of the spike protein, which should make it easier to store and transport. It also keeps its shape even under heat stress, during storage at room temperature and through multiple freeze-thaws. Such qualities are desirable in a robust vaccine.

The Bill & Melinda Gates Foundation have contributed to the development of the technology through a grant in the interest of making vaccines accessible to people in lower-income countries. Vaccine companies with different platform technologies will have the ability to test and further develop COVID vaccines that use HexaPro. McLellan has also indicated there is interest from partners in extending access to the technology to people in the developing world.

"Four billion people living in developing countries will need access to a vaccine, as all of us will," McLellan said.

HexaPro also could be used in COVID-19 antibody tests where it would act as a probe to identify the presence of antibodies in a patient's blood, indicating whether a person has previously been infected with the virus.

The paper's first author is Ching-Lin Hsieh, a postdoctoral researcher in McLellan's lab. Corresponding authors are McLellan; Ilya Finkelstein, an associate professor in the Department of Molecular Biosciences; and Jennifer Maynard, a professor in the Cockrell School of Engineering.

The team's original version of the spike protein forms the basis of vaccine candidates currently in human clinical trials, including Moderna's mRNA-1273 and Novavax's NVX-CoV2373.

For nucleic acid-based vaccines that use the patient's own cells to create the viral proteins that trigger an immune response, such as mRNA-1273, this improved spike protein might enable next-generation versions that require a much smaller dose to elicit the same immune response from a patient. For subunit vaccines that contain a version of the actual viral protein as an antigen, such as NVX-CoV2373, many more vaccine doses could be produced in the same time frame. Either way, from a production standpoint, this could mean accelerating access to lifesaving vaccines.

Drawing on their experience creating stabilized proteins as vaccines against MERS-CoV, the coronavirus that causes Middle East respiratory syndrome, and other viruses, the researchers identified 100 different modifications to the spike protein that they believed might lead to a more stable, more highly expressed version. Next they created 100 different versions of the protein by inserting the genetic blueprints for each version into a different culture of human cells. Of those 100 versions of the spike protein, 26 were more stable or had higher expression.

The researchers then took four of those beneficial modifications, plus two from their original stabilized spike protein, and combined them to create HexaPro. When they inserted the genetic blueprints for this version of the spike protein into a human cell culture, the cells produced 10 times as much protein than that of their original protein.

UNIVERSITY PARK, Pa. -- L-type calcium channel blockers (LCCBs) -- the most widely used drugs for treating hypertension -- may harm the heart as much as help it, according to a new study.

The research team, led by Penn State, found that in rats and human cells in vitro, LCCBs cause changes in blood vessels -- known as vascular remodeling -- that reduce blood flow and increase pressure. Examining epidemiological data, the team also found that LCCBs are associated with a greater risk for heart failure. The findings suggest that care should be taken when prescribing these drugs to patients, particularly older adults and those with advanced hypertension.

"In the United States, nearly half of all adults -- or just over a hundred million -- have hypertension, and its prevalence is increasing; worldwide, the condition is expected to affect 1.56 billion people by 2025," said Mohamed Trebak, professor of cellular and molecular physiology, Penn State. "L-type calcium channel blockers are one of the most widely prescribed drugs to treat hypertension, yet we have found that these drugs may cause the same type of damage they are intended to prevent."

Trebak explained that vascular smooth muscle cells (VSMCs) make up the walls of blood vessels, where they help the vessels to control blood flow by contracting and relaxing. This activity is regulated by the concentration of calcium within the cells. VSMCs contain numerous calcium-permeable channels to control this calcium concentration. Under conditions of hypertension, these channels allow too much calcium to enter VSMCs, which triggers the cells to undergo physiological changes, known as "remodeling," and to divide and proliferate. These remodeled, proliferative cells cause blood vessel walls to thicken and stiffen and blood pressure to rise.

"L-type calcium channel blockers were created to prevent this from happening," said Trebak. "Yet, we found that these drugs also simultaneously cause remodeling and proliferation of VSMCs through another mechanism."

To investigate the specific mechanisms by which LCCBs affect VSMCs, Trebak and his colleagues used optical, electrophysiological and molecular tools to examine smooth muscle cells in vitro and in rats.

The team found that calcium entry into VSMCs is mediated by stromal-interacting molecule (STIM) proteins activating ORAI calcium channels and that chronic exposure to LCCBs causes these STIM proteins to become overactive, which triggers VSMCs to proliferate. Their results appeared on July 8 in Proceedings of the National Academy of Sciences.

Additionally, the researchers examined epidemiological data from the Penn State clinical database and found that incidences of heart failure were significantly higher in hypertensive patients treated with LCCBs than in hypertensive patients treated with other types of hypertension medications.

"Treatment with LCCBs is clinically associated with elevated incidence of heart failure, which prompts a careful examination of the use of LCCBs during chronic hypertension where vascular remodeling is evident," said Trebak. "Extra care should be taken when hypertensive patients present with COVID-19, as LCCBs may exacerbate their vascular damage.

PHILADELPHIA -- Studies have shown that intrauterine devices (IUDs) that release progestins can help adult women with heavy menstrual bleeding, discomfort, and cramping, in addition to providing contraception. However, there are little data on whether they reduce these symptoms in younger women and adolescents, especially those with physical or intellectual disabilities. New research from the largest dataset studied to date, demonstrates that IUDs are an effective means of stopping periods or managing symptoms associated with periods in adolescents with disabilities.

"Young women with complex medical conditions, including physical, intellectual, and developmental disabilities, are often interested in menstrual management or suppression for many reasons," says Beth Schwartz, MD, Director of Pediatric and Adolescent Gynecology at Thomas Jefferson University and Nemours Children's Health System and Assistant Professor of Obstetrics & Gynecology and Pediatrics at Sidney Kimmel Medical College at Thomas Jefferson University. "This study describes how safe and effective this option is for young women and their families."

The results were reported in the journal Pediatrics, July 23rd, 2020.

For young women with intellectual or developmental disabilities, puberty and the onset of a menstrual cycle can be alarming and difficult to understand. "Many families seek support for this difficult transition," says Dr. Schwartz. "IUDs don't always come to mind for many pediatric providers. This data shows physicians that this treatment option can be immensely helpful and improve a young woman's quality of life."

Dr. Schwartz and colleagues at Cincinnati Children's Hospital Medical Center performed a retrospective chart review of all IUDs placed there over a 10-year period. The analysis included women ages 22 and under who had never had a baby, and who had a physical, intellectual or developmental disability. The study ultimately included 159 patients with disabilities in the analysis, whose mean age was 16 (range of 9-22 years) at IUD placement.

The results showed that 65% of young women and adolescents reported less bleeding one year after IUD placement, and only 7% had worsened bleeding. As many as 59% had no bleeding with the IUD placement, which is very high compared to the general population and to other menstrual management methods.

The researchers also found that 95% of women in the study kept their IUD after 1 year, and an estimated 73% still had it at 5 years, which is an indication of satisfaction with the treatment. "These rates are much higher than those reported in studies with adult women without disabilities and compared to other methods of contraception," says Dr. Schwartz. The side effects reported were also rare, at 5% or less.

"Women with disabilities and their families request help managing menarche for reasons of hygiene, mood issues, exacerbation of other medical issues, abnormal bleeding and pregnancy prevention," says Dr. Schwartz. "We hope this data will help reassure physicians that this is a viable option."

In a separate study, Dr. Schwartz also examined the use of IUDs in an adolescent population without disabilities but who were using them primarily for medical reasons, such as heavy bleeding or menstrual pain. In this group, which included 219 adolescents and young women, 80% reported reductions in volume of menstrual bleeding, and 76% reported reductions in pain. "These benefits are similar to what we see in the adult population," says Dr. Schwartz, "and suggest that IUDs could be a helpful tool in managing menstrual symptoms for young women whose lives are disrupted or negatively impacted by difficult cycles. These methods should not be reserved for adult women or only for birth control. In fact, the majority of patients in both studies had never been sexually active."

DUARTE, Calif. -- Experts at City of Hope and the Translational Genomics Research Institute (TGen) are using one of the world's most comprehensive genomic analysis tools to map out personalized treatment plans for metastatic kidney cancer patients.

While the physician-scientists are at the beginning of this long journey, they believe they're on the right path. They recently published a study in the Journal of Immunotherapy of Cancer that suggests mutations in the TERT gene predicts that a patient may not be receptive to immune checkpoint inhibitors such as nivolumab or pembrolizumab.

"The hope is to one day identify patients who will benefit from immunotherapy and those who will not. Eventually we may be able to distinguish which patient is better suited for other treatments, like targeted therapy," said Sumanta Pal, M.D., one of the study's senior authors and co-director of the Kidney Cancer Program at City of Hope, a world-renowned independent research and treatment center for cancer, diabetes and other life-threatening diseases. Examples of targeted therapy include vascular endothelial growth factor (VEGF) tyrosine kinase inhibitors like cabozantinib.

Nearly 74,000 new cases of kidney cancer will be diagnosed this year, and about 14,800 people will die from the disease, according to the American Cancer Society. Ironically, experts know patients who have certain genetic mutations are more susceptible to specific drugs, but most doctors are not genetically sequencing each kidney cancer patient's tumors, Pal said.

"It's a paradox: We don't use targeted therapy in a targeted fashion," he added. "At City of Hope, we have begun to provide comprehensive genome and exome sequencing for all patients with Stage 4 cancer, regardless of their cancer site."

City of Hope is on pace to be the only major cancer center in the United States to genetically profile the tumors of every single patient, regardless of cancer type. The goal is to enable patients to receive effective targeted therapies or to enroll people in innovative clinical trials as early as possible so that they can fight their disease.

In the study, Pal and his colleagues sent samples of 91 patients' tumors to TGen's clinical laboratory, Ashion Analytics, so that the specimens could be sequenced by GEM ExTra a leading-edge tool that features tumor-normal whole exome sequencing and tumor whole transcriptome sequencing. These are molecular-level analyses of each patient's entire protein-coding DNA and RNA.

"The goal was to identify genomic alterations that correlated with therapy response," said Sara Byron, Ph.D., assistant professor in TGen's Integrated Cancer Genomics Division and co-senior author of the study. "We wanted to use this 'real-world evidence' to explore potential molecular and genomic features associated with response." (Ashion Analytics recently announced that Medicare has approved coverage of GEM ExTra, potentially providing 44 million more patients access to this test, which aims to match patients with the best available treatments for their disease.)

Kidney cancer treatment regimens involving either targeted therapy or immunotherapy have burgeoned since 2015. Because new treatments sprouted so rapidly, scientists have not yet discovered the ideal strategy to sequence regimens for optimal outcomes. Moreover, the current way treatment risk is assessed tends to be subjective with ingrained bias, the study reported. City of Hope and TGen are working to develop objective laboratory-based biomarkers for kidney cancer.

Only patients whose genomic profiling was performed prior to systemic treatment were included in the study. Patients received either targeted therapy known as VEGF tyrosine kinase inhibitors (sunitinib, cabozantib, lenvatinib/everolimus) or immunotherapy (nivolumab, ipilimumab, pembrolizumab). They were divided into those who received no clinical benefit, meaning their disease progressed, or those who received clinical benefit, meaning the disease shrunk or stabilized for more than six months. Some 19,396 genes and nucleic sequences were analyzed to tease out a therapeutic treatment plan that would have best suited each patient based on their specific tumor mutations. More research in larger sample sizes are needed, but the scientists are off to a good start.

"Stage 4 cancer is often considered incurable, but that doesn't always have to be the case," Pal said. "By sequencing all protein-coding DNA, that is by sequencing the whole exome, we may be able to identify new therapeutic targets, and that's a very exciting prospect."

A research group centered around Kobe University Graduate School of Medicine's Professor YAMADA Hideto and Associate Professor TANIMURA Kenji (Department of Obstetrics and Gynecology), and Professor ARASE Hisashi et al. of Osaka University's Research Institute for Microbial Diseases (RIMD) have revealed for the first time in the world the high frequency of a novel autoantibody in women suffering from recurrent pregnancy loss. Joint research by Kobe University and Osaka University in 2015 previously discovered that this autoantibody also causes diseases such as thrombosis.

It is expected that these results will contribute towards the illumination of the underlying mechanisms behind recurrent pregnancy loss, thrombosis and pregnancy complications such as hypertensive disorders; leading to the development of new treatment methods.

The findings were published online on June 25 in the American College of Rheumatology's journal 'Arthritis and Rheumatology'.

Main Points

Those with recurrent pregnancy loss (RPL) experience repeated miscarriages and stillbirths, making them unable to give birth to a healthy baby.

In Japan, approximately 1,400,000 women are believed to suffer from RPL. In more than half of cases the cause cannot be determined, making it difficult to prescribe a treatment method. This is a big problem, especially in light of Japan's low birthrate and aging population.

This study was based at Kobe University, which is putting a lot of effort into RPL research, and covered 227 patients in five university hospitals across the country. Approximately a quarter of these patients tested positive for the novel autoantibody (neo-self antibody). Furthermore, almost one fifth tested positive for the neo-self antibody among patients for whom common tests had been unable to determine the cause.

It is expected that these results can illuminate the underlying mechanisms behind RPL, thrombosis and hypertensive disorders of pregnancy, leading to the development of new treatment methods. Furthermore, it is hoped that these research results can be the key to solving the low birthrate and aging population issues.

Research Background

Recurrent pregnancy loss (RPL) is a disorder in which the sufferer is able to get pregnant yet experiences repeated miscarriages and stillbirths, making them unable to give birth to a healthy baby. There is believed to be an estimated 1,400,000 women with RPL in Japan. Given Japan's low birthrate and aging population, this is an important issue to overcome. However, at present the cause remains unknown in over half of patients, making it difficult to know how to cure RPL in many cases.

However, joint research conducted by RIMD's Professor Arase Hisashi and Kobe University's Associate Professor Tanimura Kenji discovered a completely new autoantibody that causes antiphospholipid syndrome. This syndrome can lead to the occurrence of thrombosis (in which blood clots can block up blood vessels in vital organs, endangering life such as by causing a stroke), miscarriages, and hypertensive disorders of pregnancy, which can endanger the lives of pregnant women. These findings were published as a thesis in the American Society of Hematology's journal 'Blood' in 2015.

RPL involving repeated miscarriages is also a clinical manifestation of antiphospholipid syndrome. As previously mentioned, the cause of RPL is unknown in over half of cases, however the association between this neo-self antibody and RPL had not been investigated. This research group hypothesized that the neo-self antibody could be connected to RPL in cases with unexplained causes.

With this in mind, blood samples were collected from RPL patients across five university hospitals (Kobe University, University of Toyama, Okayama University, The University of Tokyo, and Hyogo Medical University), and the samples were tested for neo-self antibodies at RIMD. For the first time in the world, the research group conducted this clinical study to illuminate the association between RPL and the neo-self antibody.

Research Findings

This study was led by Kobe University, which is putting a lot of effort into RPL research, and involved testing for neo-self antibodies with the consent of outpatient couples affected by RPL at five university hospitals nationwide. At the same time, a detailed examination into the cause of RPL in each case was carried out. This included testing for thyroid disorders, a chromosome analysis of each couple, and blood tests to investigate conditions that make blood clots form easily, such as the presence of antiphospholipid antibodies. Also, tests were carried out on the couples for genetic complexes that are associated with susceptibility to various diseases, such as Human Leukocyte Antigen (HLA) Class II. (For example, it is known that those with HLA-DR4 are prone to RPL).

The neo-self antibody testing method used in the study is a patented technology developed by this research group. This method involves producing cells where the complexes produced byβ2-glycoprotein I (a protein that is believed to be targeted by the antibody that causes antiphospholipid syndrome) and HLA Class II (the HLA type that increases susceptibility to antiphospholipid syndrome) are present on the cell surface. A reaction is then conducted between the complexes and the patient's blood to detect antibodies (neo-self antibodies), which bind to the complexes on the cell surface.

First of all, 208 women who did not have RPL and had previously given birth to healthy babies were tested for neo-self antibodies to establish normal levels. Subsequently, it was found that 52 (23%) out of 227 patients with RPL tested positive for the neo-self antibody.

The results of the tests carried out to determine the causes of RPL were evaluated. The neo-self antibody was the factor with the highest frequency compared to all other factors that were tested, including uterine issues (such as malformation and myomas), thyroid dysfunction, and chromosomal abnormalities in each partner. This indicts the possibility that this neo-self antibody is a major cause of RPL. Even after testing for common RPL causes, the cause could not be determined in around half of the patients (121 women). However, 24 (20%) of the 121 women with unexplained RPL were found to test positive for only the neo-self antibody (Figure 1). In particular, many who tested negative for antiphospholipid antibody criteria tested positive for the neo-self antibody (Figure 2).

When neo-self antibody positive women with RPL were compared with those RPL patients who tested negative, it was found that the frequency of those who had the HLA-DR4 gene, which predisposes the patient to RPL, was higher in neo-self antibody positive women than in negative women. Currently, it is unclear as to why those with HLA-DR4 are prone to RPL. It is hoped that this study's discoveries can serve as a key to understanding the reason.

By investigating the neo-self antibody, the researchers were able to illuminate the onset mechanism of RPL, in particular the onset mechanism of the disorder in some unexplained cases. This could lead to a solution for Japan's low birthrate and aging population issues.

Further Developments

This study has shown that the novel autoantibody (neo-self antibody) that was discovered by Associate Professor Tanimura and Professor Arase et al. is a major cause of RPL. Next, the researchers aim to generate a drug which inhibits neo-self antibodies or suppresses their production. In addition, it is hoped that research into neo-self antibodies will illuminate the onset mechanism for obstetrics patients with conditions, such as unexplained hypertensive disorders of pregnancy and fetal growth restriction, where the cause is unknown. This could lead to the development of treatment methods for these patients. Furthermore, it is possible that there is a neo-self antibody that triggers many common autoimmune disorders, such as rheumatism. Such a discovery could be revolutionary for both rheumatology and immunology.