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Rush University Medical Center has opened enrollment for a new clinical trial investigating whether the drug hydroxychloroquine is better than a placebo in preventing COVID-19 infection in healthy people working in health care settings. The Healthcare Worker Exposure Response & Outcomes of Hydroxychloroquine (HERO-HCQ) Trial will enroll 15,000 people from the HERO Registry, an online community of thousands of people working in health care, which supports this and future trials.

The study will randomize participants to receive either one month of hydroxychloroquine or one month of a placebo to examine whether the drug is effective in preventing COVID-19.

"The HERO Registry provides a virtual community of health care workers that can help us better understand their health outcomes and experiences, and prioritize unmet health care worker needs," said Dr. Yoona Rhee, assistant professor of infectious diseases and the primary investigator of the study at Rush University Medical Center.

The HERO-HCQ is the first trial to be offered from this registry.

"There is a lot of interest in testing this drug as a preventive agent for COVID-19, because it appeared to block SARS-CoV-2 (the virus that causes COVID-19) from entering cells in lab studies," said Susanna Naggie, principal investigator for the HERO-HCQ Trial and associate professor of medicine at the Duke University School of Medicine. "But like all medications, there are potential risks as well as benefits. Before we can make recommendations on using hydroxychloroquine to prevent COVID-19, we need solid evidence, and the HERO-HCQ trial will help provide this data to guide decision-making."

Researchers at Rush plan to recruit at least 375 people into the study. All people working in health care settings who provide care, supplies, or services to patients at Rush University Medical Center and Rush Oak Park Hospital -- such as nurses, therapists, physicians, emergency responders, food service workers, environmental services workers, interpreters and transporters -- are invited to first join the HERO Registry to determine their interest in the HERO-HCQ Trial. To participate in the study, when they sign up for the registry health care workers must answer "yes" to a question determining interest in being contacted about participation in a randomized clinical trial of hydroxychloroquine.

"Health care workers remain at risk of infection with the COVID-19 virus. High-quality studies of health care workers are imperative to understand whether preventive therapy can help reduce their risk of developing COVID-19," Rhee said. "The HERO-HCQ trial seeks to answer that question -- whether hydroxychloroquine can help prevent these health care workers from acquiring COVID-19."

Hydroxychloroquine is an oral prescription medication approved by the US Food and Drug Administration for the treatment of malaria and autoimmune diseases such as lupus and arthritis. Study participants will receive nasal swab tests for COVID-19 and blood tests to detect the presence of COVID-19 virus antibodies at the beginning of the study and after four weeks. Researchers also will collect information about participants' health and ask them to fill out quality-of-life surveys.

Unlike typical studies that take months to collect and analyze data, researchers will analyze data from the study every two weeks. "As soon as we have evidence of the effectiveness of the drug, the lead investigators will conclude the trial and make a recommendation based on whether it proves to be a beneficial preventative therapy," Rhee said.

Researchers at the Duke Clinical Research Institute designed and are coordinating the HERO-HCQ Trial. The study is being conducted through clinical research sites in PCORnet, the Patient-Centered Outcomes Research Institute, which is providing up to $50 million in funding.

CHICAGO --- A new review of neurological symptoms of COVID-19 patients in current scientific literature reveals the disease poses a global threat to the entire nervous system, reports a Northwestern Medicine study published this week in Annals of Neurology.

About half of hospitalized patients have neurological manifestations of COVID-19, which include headache, dizziness, decreased alertness, difficulty concentrating, disorders of smell and taste, seizures, strokes, weakness and muscle pain.

"It's important for the general public and physicians to be aware of this, because a SARS-COV-2 infection may present with neurologic symptoms initially, before any fever, cough or respiratory problems occur," said lead author of the review, Dr. Igor Koralnik, Northwestern Medicine chief of neuro-infectious diseases and global neurology and a professor of neurology at Northwestern University Feinberg School of Medicine.

The review describes the different neurological conditions that may occur in COVID-19 patients and how to diagnose them, as well as likely pathogenic mechanisms.

"This understanding is key to direct appropriate clinical management and treatment," Koralnik said.

The disease may affect the entire nervous system, including the brain, spinal cord and nerves as well as the muscles. There are many different ways COVID-19 can cause neurological dysfunction, he said. Because this disease may affect multiple organs (lung, kidney, heart), the brain may also suffer from lack of oxygenation or from clotting disorders that may lead to ischemic or hemorrhagic strokes. In addition, the virus may cause direct infection of the brain and meninges. Finally, the reaction of the immune system to the infection may cause inflammation that can damage the brain and nerves.

Koralnik and colleagues have formed a Neuro-COVID research team and started a retrospective analysis of all COVID-19 patients hospitalized at Northwestern Medicine to determine the frequency and type of neurological complications, as well as response to treatment.

Since knowledge about the long term outcome of neurologic manifestations of COVID-19 is limited, Koralnik also will follow some of those patients prospectively in his new outpatient Neuro-COVID clinic to determine if neurological problems are temporary or permanent. These studies will provide the foundation on how to diagnose, manage and treat the many neurologic manifestations of COVID-19, he said.

A study published in Molecular Psychiatry shows that patient-derived adult stem cells can be used to model major depressive disorder and test how a patient may respond to medication.

Using stem cells from adults with a clinical diagnosis of depression, the University of Illinois at Chicago researchers who conducted the study also found that fish oil, when tested in the model, created an antidepressant response.

UIC's Mark Rasenick, principal investigator of the study, says that the research provides a number of novel findings that can help scientists better understand how the brain works and why some people respond to drug treatment for depression, while others experience limited benefits from antidepressant medication.

"It was also exciting to find scientific evidence that fish oil -- an easy-to-get, natural product -- may be an effective treatment for depression," said Rasenick, UIC distinguished professor of physiology and biophysics and psychiatry at the College of Medicine.

Major depressive disorder, or depression, is the most common psychiatric disorder. Around one in six individuals will experience at least one depressive episode in their lifetime. However, antidepressant treatment fails in about one-third of patients.

In the study, the UIC researchers used skin cells from adults with depression that were converted into stem cells at Massachusetts General Hospital and then directed those stem cells to develop into nerve cells. The skin biopsies were taken from two types of patients: people who previously responded to antidepressant treatment and people who have previously been resistant to antidepressants.

When fish oil was tested, the models from treatment-sensitive and treatment-resistant patients both responded.

Rasenick says the response was similar to that seen from prescription antidepressants, but it was produced through a different mechanism.

"We saw that fish oil was acting, in part, on glial cells, not neurons," said Rasenick, who is also a research career scientist at Jesse Brown VA Medical Center and president and chief scientific officer at Pax Neuroscience, a UIC startup company. "For many years, scientists have paid scant attention to glia -- a type of brain cell that surrounds neurons -- but there is increasing evidence that glia may play a role in depression. Our study suggests that glia may also be important for antidepressant action.

"Our study also showed that a stem cell model can be used to study response to treatment and that fish oil as a treatment, or companion to treatment, for depression warrants further investigation," Rasenick said.

Scientists have developed a new gene therapy approach that offers tremendous promise for one day treating an eye disease that leads to blindness and affects thousands of people across the globe.

Researchers from Trinity College Dublin and University College London (UCL) teamed up to pool their expertise in genetics, virology and ophthalmology, beginning the journey towards a new treatment for a group of eye diseases collectively referred to as retinitis pigmentosa (RP). Their exciting results are published today in leading journal, Stem Cell Reports.

RP is a group of rare, genetic disorders that involve a breakdown and loss of cells in the retina, which is the light sensitive tissue that lines the back of the eye. Common early stage symptoms include difficulty seeing at night and a loss of side (peripheral) vision, with blindness often developing in time.

Scientists have known for some time that mutations in the gene 'RP2', which is responsible for making a protein essential for normal vision, are associated with RP diseases. However, there are currently no therapies to treat people living with a number of RP diseases.

The collaborative team behind the exciting new research used a modified common virus to deliver a normal, functioning copy of the RP2 gene into "mini retinas", which had been engineered from stem cells and which contained the defective version of the gene. The "mini retinas" developed in UCL simulated the RP2 disease in patients.

Subsequent analysis showed that these mini retinas had successfully taken up the functioning RP2 gene following the viral delivery and produced the essential protein associated with it.

Crucially, the treated mini retinas showed significant improvement - underlining that the approach had rescued them from RP.

Ciara Shortall, PhD Researcher in Trinity's School of Genetics and Microbiology, is one of the main authors of the published study.

Explaining the significance of the work, she said:
"For the last 30 years there has been a lot of buzz about gene therapies and their potential for treating a huge variety of debilitating diseases and disorders, but it is really only recently that science has overcome difficulties associated with such approaches and begun to bring potential therapies far closer.

"In relative terms it is now fairly easy to replace troublesome genes with functioning versions using non-harmful viruses, which is what we have done here. And while we are still some time and a lot of work away from an approved therapy it is hugely exciting to have begun a journey that could one day provide an effective treatment to rescue eyesight."

The Trinity team, led by Professor Jane Farrar, used their expertise in genetics and virus creation in the process, while the UCL team, led by Professor Michael Cheetham, took the lead in creating the mini retinas used to road-test the gene therapy.

Professor Cheetham said:
"It is an important development that we can now reproduce so many elements of inherited disease using these mini-retinas. It makes it possible for us to study in detail why people go blind and try to find ways to prevent blindness. It's exciting that the gene therapy seems to be so effective for this form of RP."

Ocular research in Trinity College Dublin is supported by the Health Research Board of Ireland, Science Foundation Ireland, Fighting Blindness Ireland and Health Research Charities Ireland.

- Urging the healthcare and regulatory community to use the terms as published for the different subtypes of MS and for describing disease activity, which is critical for selecting clinical trial participants

New York, NY - An international committee of multiple sclerosis (MS) experts has clarified their previously published descriptors of the different courses of MS and disease activity. MS subtypes are consensus definitions rather than pathologically defined phenotypes, and are easily misconstrued. The review was prompted in part by differences in specified indications for MS therapies recently approved by the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA). The goal of the review is to improve care and access to treatments, and to refine the selection of clinical trial participants so that trial outcomes can be better applied to clinical care.

The review, recently published in the journal Neurology(1), was an effort by the International Advisory Committee on Clinical Trials in MS (a body currently sponsored by the European Committee for Treatment and Research in MS and the US National Multiple Sclerosis Society). The work was led by Fred Lublin, MD, of the Corinne Goldsmith Dickinson Center for Multiple Sclerosis, Icahn School of Medicine at Mount Sinai in New York City.

"With this review, we're encouraging the healthcare and regulatory community to use the terms as described for the different subtypes of MS and for describing disease activity," noted Dr. Lublin. "It's critical not just for improving patient care, but also for selecting participants for clinical trials, so you are comparing apples to apples." Dr. Lublin was senior author of two previous papers defining MS subtypes that were published in 1996 and 2013 under the auspices of the committee.

The 2013 course descriptors paper(2) and current diagnostic criteria for MS define four subtypes: clinically isolated syndrome (single episode not meeting diagnostic criteria for MS), relapsing remitting MS, secondary progressive MS, and primary progressive MS. The paper recommended adding modifying terms to the subtypes to describe an individual's current disease state, such as "active" (shown by relapse or changes on MRI) and "progression" (shown by worsening of disability independent of relapse activity). Importantly, these subtypes must be framed in time. While the time period was not specified, it was recommended that an assessment be performed at least annually.

Subsequent to the 2013 paper, there has been confusion in the use of the terms activity, progression, and worsening, and they have been used without reference to timeframe. For example, indications for recent MS therapy approvals by the EMA have defined activity as either clinical relapse or imaging-detected inflammation, whereas the FDA defined activity only in terms of relapses. Neither agency specified a timeframe for the disease activity.

The current review reiterates the definition of "activity" as clinical relapses or imaging features of inflammatory activity, as evaluated annually or over some other interval as long as it is specified. The definition of "progression" is reiterated as clinical evidence of disability worsening, independent of relapses, in patients in a progressive phase, as evaluated annually or over some other interval as long as it is specified. Further, the more general term "worsening" refers to any increase in impairment or disability as the result of residual deficits caused by relapses, or increasing disability during progressive phases of MS.

"As part of its ongoing activities, the committee plans to continue to reevaluate and refine course descriptors, especially when new evidence-based methods enable pathological distinctions between MS phenotypes, said Professor Alan Thompson, Chair of the International Advisory Committee on Clinical Trials in MS and Dean of University College London's Faculty of Brain Sciences. "This would vastly improve prognosis, treatment choices, and the development of more selective therapies."

Scientists have developed a new test that can help identify people who are likely to develop hepatocellular carcinoma (HCC), the most common form of liver cancer. The approach uses a simple blood test to check for the patient's previous exposure to certain viruses.

A study of the new approach was led by researchers at the National Cancer Institute (NCI), part of the National Institutes of Health. The study also involved researchers from the National Institute of Diabetes and Digestive and Kidney Diseases and several academic centers. The findings were published June 10 in Cell.

"Together with existing screening tests, the new test could play an important role in screening people who are at risk for developing HCC. It could help doctors find and treat HCC early. The method is relatively simple and inexpensive, and it only requires a small blood sample," said the study's leader, Xin Wei Wang, Ph.D., co-leader of the NCI Center for Cancer Research (CCR) Liver Cancer Program.

Certain factors increase a person's chances of developing HCC, such as infection with hepatitis B or hepatitis C virus or cirrhosis of the liver. People who have risk factors are recommended to get screened for HCC every six months with an ultrasound with or without a blood test for alpha-fetoprotein.

But not everyone with risk factors for HCC will develop the disease. Although screening can lead to earlier detection, most patients are diagnosed when the cancer is advanced and often incurable. However, HCC that is caught early has a much better chance of being cured.

"We need a better way to identify people who have the highest risk for HCC and who should get screened more frequently," said Dr. Wang, who is also part of NCI's Translational Liver Cancer Consortium. Better early detection and surveillance approaches are particularly important because rates of HCC are rising in the United States.

"A main focus of the NCI CCR Liver Cancer Program is to develop new methods for early detection, diagnosis, and treatment, with the goal of improving outcomes for patients with HCC," said Tim Greten, M.D., co-leader of the Liver Cancer Program and a collaborator of the study.

Many screening tests detect features of cancer cells. But those features can change over time, and not all cancer cells in a tumor have the same characteristics. The NCI team took a different approach: detecting features of the cancer's environment rather than cancer cells themselves.

More research is providing evidence that cancer development is influenced by interactions between viruses and the immune system. The team reasoned that certain interactions between viruses and the immune system may raise the risk of developing HCC.

To explore that possibility, the scientists scanned people's blood for "footprints" left behind by past viral infections. Because these footprints are left in antibodies, proteins made by the immune system, they also reflect how the immune system reacted to the infection. The mixture of footprints each person has creates a unique pattern, which the researchers called a viral exposure signature.

The team checked for the footprints of more than 1,000 different viruses in blood samples from around 900 people, including 150 who had HCC. They identified a specific viral exposure signature that could accurately distinguish people with HCC from people with chronic liver disease and healthy volunteers. This signature contained footprints from 61 different viruses.

The researchers then tested the signature on blood samples from 173 people with chronic liver disease who were part of a 20-year study. During that time, 44 of the participants developed HCC. Using blood samples taken when the cancer was diagnosed, the signature correctly identified those who developed HCC (area under the curve, AUC=0.98). Importantly, the signature also worked when the researchers used blood samples taken at the beginning of the study, up to 10 years before diagnosis (AUC=0.91).

The signature appeared to be far more accurate than an alpha-fetoprotein test (AUC=0.91 vs. 0.62). An AUC of 0.5 indicates that a test is no better than chance in identifying disease, whereas an AUC of 1.0 represents a test with perfect accuracy.

The scientists are continuing to study their approach and plan to test it in clinical trials. They are collaborating with Katherine McGlynn, Ph.D., of NCI's Division of Cancer Epidemiology and Genetics to test the approach in a prospective surveillance study of people with risk factors for HCC.

It's possible that viral infections--even ones that don't cause cancer--may change the immune system in ways that influence the development of other cancers. For example, certain infections may lessen the immune system's ability to keep cancer cells in check. NCI scientists are testing the viral exposure signature in a study of prostate cancer, and others are considering applying the approach to a screening study for ovarian, esophageal, liver, and breast cancer in Africa.

Mass burials are common remnants of the many plague outbreaks that ravaged Medieval Europe. A number of these graveyards are well documented in historical sources, but the locations of most, and the victims they contain, have been lost to the pages of time. In Vilnius, Lithuania, one such cemetery was found in a typical way: accidental discovery during a routine city construction project.

A new study published in the journal Scientific Reports details the findings of genomic analyses on these medieval skeletons, with important implications for the history of syphilis in Europe.

Just another plague pit?

"Historical information on this Vilnius graveyard is unavailable, but the burial context, along with its location outside of the medieval city limits, pointed to plague, or some other major infectious disease outbreak," comments Rimantas Jankauskas, Professor of the Faculty of Medicine, Vilnius University. "To be certain, we needed confirmation through DNA analysis."

Kirsten Bos, a group leader for Molecular Palaeopathology at the Max Planck Institute for the Science of Human History (MPI-SHH) in Jena, Germany, is frequently contacted by archaeologists requesting such analyses.

"Plague was a common disease at the time, and the information we get from all the ancient DNA work can tell us a lot about how it was spreading," says Bos, a specialist in ancient pathogen DNA recovery who led the current study.

Working in Bos's team, doctoral candidate Karen Giffin took on DNA analysis of the putative plague victims and quickly identified the pathogen's DNA in the teeth of several individuals.

"I was happy to have identified them as victims of medieval plague," says Giffin, "but we wanted to see if the new techniques we were developing in molecular detection of pathogens could allow us to learn anything more about the health of this population."

More than just plague

"The typical method for pathogen detection in archaeological bone requires that you have some idea of what you're looking for," explains Alexander Herbig, group leader of Computational Pathogenomics at the MPI-SHH. "In this case we applied a relatively new hypothesis-free DNA screening approach to search for any other pathogens we might be able to identify at the molecular level."

This process unlocked a second secret of the 15th century graveyard. One of the four plague victims, a young woman, also showed a weak signal of something that seemed related to modern syphilis.

"It was impressive to find traces of such a disease in an historical skeleton because their molecular preservation in ancient bone is known to be problematic," comments Bos.

Diseases in the syphilis family, known as the treponemal diseases, are assumed to have had a long history with humans, though their inferred history in Europe is laden with controversy. The prevailing opinion holds that the first outbreak of syphilis in Europe coincided with Charles VIII's 1495 siege of Naples, where a debilitating disease erupted amongst his infantry and quickly spread around Europe. Since this outbreak happened just after the return of Columbus and his crew from their first trans-Atlantic voyage, most discussants believe syphilis was a newcomer to Europe that originated in the New World. But support is growing for a different theory. An increasing number of specialists in bone pathology believe they have properly identified examples of pre-1493 syphilis in Europe, which has ignited on-going debates about models of its evolution.

"We were able to reconstruct an impressively well-preserved genome that, to our surprise, fell within the diversity of modern yaws," comments Giffin. Yaws is a lesser-known treponemal disease primarily of the skin that affects both humans and other primates in warm, tropical environments. "Finding it in northern Europe in the mid-15th century was unexpected," she adds.

Yaws seems much younger than we thought

Since yaws infects both humans and non-human primates, some believe it to be a very old disease, having been with humans before the massive Pleistocene migrations that spread us around the globe.

"To our surprise, the yaws genome we reconstructed was just a few genetic steps away from the ancestor of all yaws varieties known in humans and non-human primates," says Bos. "Given the age of our medieval skeletons, it seems that all strains of yaws that we know today appeared on the scene only about 1000 years ago."

"This has important implications for the history of treponemal disease in Europe," Bos adds. "We can now confirm that yaws was circulating in medieval Europe, and given its similarity to syphilis and its recent emergence, it's possible that yaws contributed in some way to the famous late 15th to 16th century outbreak that we normally ascribe only to syphilis."

One possibility is that yaws emerged in either humans or other primates in West Africa within the last millennium and made its way to Europe in the mid-15th century. European presence in West Africa increased in the 15th century, as did the forced relocations of Africans to Europe through establishment of the transatlantic slave trade. These activities would have rapidly disseminated a new and highly contagious disease such as yaws.

"The enigma about the origin of syphilis is still open," says Bos, "but disease ecology in medieval Europe is clearly more complex than we think."

In conventional ultrasounds, variations in soft tissue structure distort ultrasound wavefronts. They blur the image and can hence prove detrimental to medical diagnosis. Researchers at the Institut Langevin (CNRS/ESPCI Paris-PSL)* have developed a new non-invasive ultrasound method that avoids such aberrations. In an article published in the journal PNAS** on 10 June 2020, the scientists showed how this method can subtly compensate for the distortions that a focused wave undergoes as it travels through the studied tissue, with an ideal resolution and contrast optimized for each pixel in the image. This approach can be extended to any type of wave, and can be controlled by a multi-sensor network. Applications range from biomedical diagnosis to optical microscopy, detection of cracks in industrial materials, and the monitoring of volcanoes and fault zones in geophysics.

This imaging method, known as matrix imaging, was also the subject of an article published recently in the journal Physical Review X***, as it can also help develop new approaches to imaging. This research was funded by an ERC Consolidator grant (no. 819261) as part of the European Union's Horizon 2020 Programme for Research and Innovation, and led to the filing of a patent by the CNRS, published in February 2020 (WO2020016250A1).

Men who regularly used a free web resource made significantly more health changes than men who did not, finds a new study from the University of British Columbia and Intensions Consulting.

The researchers compared differences in behaviour among 863 men who accessed DontChangeMuch.ca and a benchmark sample of 2,000 Canadian men who had not. They found 75 per cent of regular users of the site reported improving their eating habits, and 70 per cent said they were engaging in more sports or exercise.

In addition, 58 per cent said they recently made an effort to sit less and walk more, and almost half (46 per cent) lost weight. Forty-five per cent said they had cut back on alcohol consumption.

"Men are more likely to die from clogged arteries and heart disease and live an average of nine years of their lives in extremely poor health," says study lead author John Oliffe, a nursing professor who leads the men's health program at UBC. "Free e-health resources can help men access information and resources that they may otherwise be unable to, and the positive changes in their health can ripple out to benefit their families and society."

DontChangeMuch.ca was launched in 2014 by the Canadian Men's Health Foundation (CMHF) to start a men's health movement by engaging them in large numbers online. It provides exercise tips, health advice and other resources.

"We believe we have 'cracked the code' to engaging large numbers of men on-line which has been an elusive goal for health care," says Wayne Hartrick, founding president of the CMHF. "Because many men avoid healthy basics, like nutrition and activity and seeing the doctor regularly, men's poor health is costing Canada about $37 billion in lost productivity and health care costs. Now, for the first time, we have research that shows our humorous, guy-friendly 'don't change much' blend of a marketing-driven programming, based on unbiased, evidence-based research works."

"e-health sites like this are particularly relevant for men during the COVID-19 lockdown, and potentially into the future as an alternative to physical facilities. They can choose and freely use content that is relevant and timely for them, any time they want," said study co-author Nick Black, managing partner at Intensions Consulting.

"We have long recognized the huge, unnecessary burden of men's poor health. It is a missing piece of the family health puzzle so we need to change men's behaviours en masse," says study co-author Dr. Larry Goldenberg, a professor of urologic sciences at UBC and founding chair of CMHF. "Waiting until they show up at the doctor's office in crisis is not the way to go. Making early, positive changes improves their lives, their families' lives and reduces the strain on our healthcare systems."

"Men like it online, they like humour, they like being able to control what information they get, they like the anonymity," says Hartrick. "This is critically important because e-health can be scaled to engage many more men than in traditional health settings."

Peter Baker, director of the UK-based Global Action for Men's Health, a collaborative project that includes organizations like CMHF, says, "Many men's unhealthy and risky behaviours are a worldwide problem and new solutions are urgently needed. DontChangeMuch.ca confirms the global potential of digital technologies to nudge men towards healthier behaviours. An approach they can relate to can help to reduce unnecessary chronic disease, lessen suffering and early deaths, and cut the costs of treatment."

Patients who go into shock caused by sepsis (septic shock) are treated with the antihypotensive agent norepinephrine. Researchers from Radboud university medical center published results in today's American Journal of Respiratory and Critical Care Medicine revealing that its use is not without drawbacks: the drug disrupts the immune system and increases susceptibility to infections. This may have negative consequences for patients. Research into alternatives is therefore justified.

Sepsis is a life-threatening inflammatory response spreading throughout the body due to an infection. One in four patients with sepsis succumbs to it, and it is the number one cause of death across the globe. As such, sepsis was recently designated as a global health priority by the World Health Organization (WHO). Patients with sepsis have a severely dysregulated immune system, which impairs clearance of the infection and leaves the body susceptible to new infections with an increased risk of death. Severe sepsis also often leads to a dangerously low blood pressure called septic shock, which requires treatment with antihypotensive agents. Norepinephrine has been the primary agent of choice to increase blood pressure in this condition since the 1950s.

White blood cells

However, intensive care researchers Roel Stolk and Matthijs Kox have now shown that norepinephrine contributes to the dysregulation of the immune system and thereby impairs the ability to combat infections. They found the first indications in laboratory tests, by exposing white blood cells to norepinephrine in combination with bacterial and viral components to induce an inflammatory response. Norepinephrine proved to suppress the function of these immune cells.

Impaired defense against infections

The researchers then switched to an animal model. Roel Stolk, lead author of the study: "We replicated an infection in mice by injecting them with endotoxin, a bacterial cell-wall component. If mice were administered norepinephrine, their immune response was strongly suppressed."

Furthermore, in mice with an actual bacterial infection, infusion of norepinephrine led to increased bacterial growth in the spleen, liver, and blood, again indicating a weakened immune system. "We also studied the effect of vasopressin, an alternative antihypotensive agent, on white blood cells and mice," Stolk says. "Interestingly, in contrast to norepinephrine, this drug has no effects on the immune system or defense against infections."

Healthy volunteers

"Next, we wanted to know whether the effects of norepinephrine also apply to humans," said Matthijs Kox, head of the study. "We infused either norepinephrine, vasopressin, or a placebo in three groups of healthy volunteers. We then administered a low dose of endotoxin to these volunteers. Once again, we observed clear differences. Compared to the placebo group, blood concentrations of proinflammatory proteins decreased in the group that received norepinephrine, while levels of anti-inflammatory proteins increased. With vasopressin, we once again observed no effects on the immune response. Those results confirmed the previous data that norepinephrine suppresses the immune system."

Two hundred sepsis patients

Stolk and Kox also examined a group of nearly 200 patients with septic shock, all of whom were treated with norepinephrine. In these patients, they found that the balance between proinflammatory and anti-inflammatory proteins in the blood tipped towards the anti-inflammatory side in patients who were treated with higher dosages of norepinephrine. They also showed that these adverse effects of norepinephrine on the immune system were less pronounced in patients who used beta-blockers for their heart condition or blood pressure.

Further research

Based on this study, the researchers conclude that the use of antihypotensive agents in patients with sepsis should be reevaluated, preferably in a large group of patients. Kox: "Compare the effects of norepinephrine with those of vasopressin, for example, as we have shown the latter to have no adverse effects on the immune system. Further research is also required into the effects of beta-blockers in sepsis patients treated with norepinephrine. Both strategies could improve defense against infections in these patients, which may lead to improved treatment of this serious condition."

Inoperable malignant pleural mesothelioma, is a rare and aggressive cancer of the protective lining of the lungs, or pleura, often caused by exposure to asbestos. At the annual meeting of the American Society of Clinical Oncology (ASCO), held virtually from May 29-31, 2020, a researcher from the Johns Hopkins Kimmel Cancer Center presented findings from a multicenter study that evaluated the efficacy of an immunotherapy-plus-chemotherapy combination for the disease.

According to Patrick Forde, M.B.B.Ch., associate professor of oncology at the Johns Hopkins University School of Medicine, director of the Kimmel Center's thoracic cancer clinical research program and a Bloomberg~Kimmel Institute for Cancer Immunotherapy investigator, the study looked at 55 patients from 15 U.S. cancer centers who received the immunotherapy drug durvalumab in combination with two anticancer chemotherapies -- cisplatin and pemetrexed -- to create a novel first-line treatment.

Patients received six treatments of the combination therapy every three weeks, followed by treatment with durvalumab alone, for up to one year in total. The chemo-immunotherapy combination improved overall survival to 20.4 months from the historically expected survival of 12 months with chemotherapy alone. This is the first study to show survival times exceeding 20 months for patients with inoperable mesothelioma. The treatment was well-tolerated overall, with no unexpected side effects reported.

"Inflammation is key to the development of pleural mesothelioma and, as such, it represents a key target for immunotherapy. This, in addition to earlier studies that showed promising results using the same immunotherapy drug in previously treated cases, led us to study the combination," says Forde. "Because of the promising results, we are in the process of starting a phase 3 study to confirm the benefit of this approach." This study will begin accruing patients across the United States and Australia in late 2020.

The researchers studied tissue samples from patients who received the combination therapy and found that it prevented a protein called PD-L1 from forming a "protective armor" around cancer cells. The researchers say that's because immunotherapies known as checkpoint blockers, such as durvalumab, act against PD-L1 and therefore, disrupt a cancer cell's ability to avoid detection and destruction by immune cells.

Scientists have found a potential new way to promote blood clotting that could be used to help develop treatments for Von Willebrand Disease, the most common genetic bleeding disorder.

The study, led by researchers at RCSI University of Medicine and Health Sciences, is published in the Journal of Thrombosis and Haemostasis.

Patients with Von Willebrand Disease have a deficiency or dysfunction in a protein that plays a key role in clotting blood. The current treatment for the disease is to frequently inject patients with a drug that promotes the production of this protein or with concentrations of the protein itself.

Funded by the SFI-Pfizer Biotherapeutics Innovation Award Programme, researchers from RCSI and Pfizer tested a modified molecule that extends the life of the clotting protein within the body's circulation. Their study found that administering this modified molecule significantly increased the half-life fivefold compared to the unmodified protein in laboratory models.

"The current treatments for Von Willebrand Disease place a heavy burden on healthcare systems and for the patients themselves. Long-acting therapies for the disease have the potential to reduce this burden. While more preclinical testing is need, these are promising early results," said the study's lead author Dr Jamie O'Sullivan, a research lecturer within the Irish Centre for Vascular Biology at RCSI.

Von Willebrand Disease is an inherited bleeding disorder that affects up to 1% of the world's population. Awareness of the disease is limited since patients' bleeding symptoms can be mild. However, they can suffer from severe bleeding when there is a serious injury or need for surgery.

Research from the Department of Kinesiology at McMaster University has found that the practical advantages of high-intensity interval training (HIIT), or short bursts of all-out exercise, could be especially beneficial for people who have experienced spinal cord injuries (SCI).

While many studies have proven the benefits of HIIT for the able-bodied, much less is known about its impact - for better or worse -- on the SCI population.

In a comprehensive review published online in the journal Spinal Cord, researchers from McMaster, the USA and the UK have weighed the evidence regarding the overall health benefits, potential adverse effects and feasibility of interval training for people with SCI.

Researchers found HIIT and sprint interval training (SIT) improve cardiorespiratory fitness in people with SCI to a degree that appears to match longer bouts of moderate intensity exercise. Importantly, the population is generally able to tolerate both HIIT and SIT, and there have been very few reports of harm from this type of training, the researchers have found.

"This may be especially relevant in the in-patient rehabilitation environment, where newly injured people with SCI spend a number of weeks before being discharged to the community," says Audrey Hicks, a professor in the Department of Kinesiology and one of the lead authors of the study.

"During this time, the patient's days are extremely full, with physiotherapy, occupational therapy, functional training and exercise training, all with the goal of optimizing transition to the community," she says. "The time demands are enormous, so more efficient forms of exercise can be particularly attractive."

Spinal cord injuries typically lead to reduced physical activity, which in turn leads to other health problems such as a decline in fitness, muscle atrophy, increased body fat, and increased risk for heart disease and diabetes.

Hicks and her team have shown in a previous study that a program of SIT three times a week for five weeks is as effective in improving indices of cardiorespiratory fitness as traditional moderate intensity exercise and takes a fraction of the time to complete.

She says it is now to learn more about the feasibility and implementation of HIIT for people with spinal cord injuries because that form of training requires quick transitions between higher to lower intensity exercise, which poses challenges for those with limited mobility.

"It is important to encourage more research to be done to establish safe guidelines for its implementation in this population," says Hicks.

WASHINGTON--Eating a late dinner may contribute to weight gain and high blood sugar, according to a small study published in the Endocrine Society's Journal of Clinical Endocrinology & Metabolism.

Over 2.1 billion adults are estimated to have overweight or obesity which make health complications like diabetes and high blood pressure more likely. Some studies suggest that consuming calories later in the day is associated with obesity and metabolic syndrome.

"This study sheds new light on how eating a late dinner worsens glucose tolerance and reduces the amount of fat burned. The effect of late eating varies greatly between people and depends on their usual bedtime," said the study's corresponding author Jonathan C. Jun, M.D., of the Johns Hopkins University School of Medicine in Baltimore, M.d. "This shows that some people might be more vulnerable to late eating than others. If the metabolic effects we observed with a single meal keep occurring chronically, then late eating could lead to consequences such as diabetes or obesity."

The researchers studied 20 healthy volunteers (10 men and 10 women) to see how they metabolized dinner eaten at 10 p.m. compared to 6 p.m. The volunteers all went to bed at 11 p.m. The researchers found that blood sugar levels were higher, and the amount of ingested fat burned was lower with the later dinner, even when the same meal was provided at the two different times.

"On average, the peak glucose level after late dinner was about 18 percent higher, and the amount of fat burned overnight decreased by about 10 percent compared to eating an earlier dinner. The effects we have seen in healthy volunteers might be more pronounced in people with obesity or diabetes, who already have a compromised metabolism," said the study's first author Chenjuan Gu, M.D., Ph.D., of the Johns Hopkins University.

This is not the first study to show effects of late eating, but it is one of the most detailed. Participants wore activity trackers, had blood sampling every hour while staying in a lab, underwent sleep studies and body fat scans, and ate food that contained non-radioactive labels so that the rate of fat burning (oxidation) could be determined.

"We still need to do more experiments to see if these effects continue over time, and if they are caused more by behavior (such as sleeping soon after a meal) or by the body's circadian rhythms," Jun said.

Other authors include Nga Brereton, Amy Schweitzer, Daisy Duan, Luu V. Pham and Vsevolod Y. Polotsky of the Johns Hopkins University; and Matthew Cotter, Elisabet Børsheim and Robert R. Wolfe of the University of Arkansas for Medical Sciences in Little Rock, Ark.

Dopamine is a neurotransmitter involved in everything from higher cognitive functions to motor control, motivation, arousal, reinforcement, and sexual gratification, the receptors it acts on have been a longstanding target for treating disorders like Parkinson's disease, which is caused by the degeneration of dopamine-using neurons that control movement.

The problem is that for at least two decades, no-one has been able to "see" what a dopamine receptor looks like when it is activated by dopamine - at least not in high enough resolution to offer avenues for designing drugs that can target the receptors effectively.

In a major collaborative study published in Nature, scientists from the lab of Patrick Barth at EPFL, with colleagues at UTSW and UCSD have now worked out the high-resolution structure of an activated form of a dopamine receptor in a native lipid membrane environment. "The native receptor is so misbehaved and its active form so transient that attempts at observing the receptor structure 'in action' have failed so far," says Barth.

The way the scientists solved the problem was by combining state-of-the art computational allosteric and de novo protein design approaches developed by Barth's group allowing the researchers to engineer a highly stable but activated dopamine receptor whose structure they could then study and solve.

The EPFL team created a receptor with artificial building blocks such as activating switches and de novo binding sites, which replaced unstable, structurally disordered, and inactivating regions of the native receptor.

"This hybrid functional/de novo computational protein design approach is powerful, as it enabled us to create a receptor with considerably enhanced activity and stability while recapitulating key native functionalities such as dopamine-mediated intracellular signaling and binding," says Barth.

The success was also made possible by using high-end lipid reconstitution techniques and cryo-electron microscopy, overcoming obstacles in previous studies that attempted to determine the receptor's structure using X-ray crystallography and by keeping the receptor inside detergents.

The problem is that detergents are very poor mimics of the cell's lipid membranes where receptors like the dopamine one are naturally located. Also, detergents have a reputation of distorting and even inactivating receptors, which doesn't help when attempting to see what they look like in action. "This represents the first atomic-level membrane-receptor structure determined in a native lipid bilayer," says Barth.

"The breakthrough will enable improved drug discovery efforts against, for example, Parkinson disease," he adds. "But it also sets the stage for broadly applying functional and de novo protein design approaches to accelerate the structure determination of challenging protein targets and create proteins with novel functions for a broad range of therapeutic and biotechnological applications."