Body

When the SARS-nCoV-2 pandemic commenced in Wuhan, China at the end of 2019, there were few available clinical guidelines to deploy, let alone adapt and adopt to treat the surge of COVID-19 patients. Doctors in China, Italy, across Europe and the US began to observe deaths due to blood clots. The aim of this study is to first explain how clinical guidelines, on which bedside clinicians have grown accustomed, can be created in the midst of a pandemic through a scoping review of the evolving scientific literature of the pathophysiology of the COVID-19 hypercoagulable state. The second, following the evidence from the scoping review, is to create comprehensive VTE/PE Thromboprophylaxis Clinical Guidelines for COVID-19 patients. These clinical guidelines will enable all providers to have a basis to prevent blood clots from forming that have lead to death from heart attack, stroke and pulmonary embolism due to COVID-19.

Inappropriate use of antibiotics is an important driver of antimicrobial resistance, yet the extent of antibiotic prescribing in outpatient primary care settings across low- and middle-income countries (LMICs) is unknown. A study published in PLOS Medicine by Giorgia Sulis and Madhukar Pai at McGill University, Montreal, Canada and colleagues found that approximately 50% of patients at primary care clinics in LMICs received at least one antibiotic, possibly suggesting widespread overprescribing.

To assess the magnitude and patterns of antibiotic prescribing in primary care settings across LMICs, the researchers systematically reviewed over 10,000 published studies, focusing on 48 cross-sectional studies in their final analyses. Using available data from individual studies, they calculated the proportion of patients who received an antibiotic prescription from a LMIC healthcare facility and the proportion of all drug prescriptions containing any antibiotic. While the researchers were able to quantify widespread prescribing of antibiotics in primary care settings, most analysed studies did not evaluate the appropriateness of prescriptions. The authors also conducted a subgroup analysis of 16 studies that reported details on prescriptions and found that 60% of antibiotics were commonly used drugs with a low potential for selecting resistance.

According to the authors, "this is the first comprehensive analysis of antibiotic prescriptions in primary care in LMICs". More high-quality studies are needed to collect data on the types, clinical reasons for prescribing, and appropriateness of antibiotics prescribed. "The inappropriate use of antibiotics comes with serious risks to patients and communities in terms of toxicity, adverse events and selection of resistant microorganisms. For this reason, a better evaluation of the patterns of inappropriate antibiotic prescribing is critical", said Giorgia Sulis, an infectious diseases physician who led the study. However, having an initial estimation of antibiotic prescription rates may help LMICs implement effective policies and interventions to improve rational prescribing practices.

What The Study Did: How common asthma was among children with various developmental disabilities (including attention-deficit/hyperactivity disorder, autism spectrum disorder and vision, hearing or speech delay) was compared to children without disabilities in this survey study.

Authors: Sarah E. Messiah, Ph.D., M.P.H., of the Children's Health System of Texas in Dallas, is the corresponding author.

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

(doi:10.1001/jamanetworkopen.2020.7728)

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

A neuroscientist's neon pink arm cast led him and fellow researchers at Washington University School of Medicine in St. Louis to discover previously undetected neuronal pulses in the human brain that activate after an immobilizing illness or injury.

The pulses appeared on MRI scans used to measure brain activity of the neuroscientist and, later, two additional adults whose arms were in casts. The researchers compared those MRI images with scans of the scientists before and after their arms were put in casts.

The scans showed that the brain's main circuits responsible for movement in specific areas of the body disconnected within 48 hours of a person wearing a cast that encumbered movement in such an area. Also during this time, "disuse pulses" emerged to maintain neural activity and allow the main motor circuits to reactivate if and when mobility was restored through physical therapy.

The findings, published online June 16 in Neuron, offer clues to how the brain's billions of neurons -- cells that transmit nerve impulses -- can rewire and restore pathways after injury or illness. Understanding just what is behind this resiliency may lead to new therapies for people with broken limbs or recovering from strokes or other immobilizing conditions.

"Many scenarios exist in neurology in which a person doesn't use an arm or a leg and, consequently, related brain circuits for an extended period of time," said senior author Nico Dosenbach, MD, PhD, an assistant professor of neurology. "In offering the best care to patients, it's important to understand specifically what changes occur in brain function. Accurate understanding and mapping of these circuits may lead to advancements in treating patients who have lost use of their limbs."

In 2015, Dosenbach -- also an assistant professor of occupational therapy, of pediatrics, of radiology and of biomedical engineering -- wore the pink cast for two weeks despite the fact he had no injury requiring one. He aimed to collect high-quality data using brain-imaging techniques to evaluate neural networks that control movement.

Many of the patients Dosenbach treats at St. Louis Children's Hospital suffer from conditions that limit mobility and cause them to favor one side of the body. A common treatment is constraint-induced movement therapy, also known as forced-use therapy, which immobilizes the dominant arm with a cast, forcing the child to use the impaired arm.

"My goal was a better understanding of what my patients experience during therapy, although I acknowledge it's more difficult for them because of their disabilities," Dosenbach said.

He also wanted to pinpoint a timeline of when individual neural changes occur. Commonly, scientists gather MRI data from dozens of people and average it. "But I did not want to do that because everyone's brain is anatomically different, and when MRI data are averaged, it all blurs together," Dosenbach said.

So Dosenbach decided to wear a fiberglass cast on his dominant, right arm. It stretched from his fingertips to just below his shoulder. It was pink, the favorite color of his daughter, Maike, then age 2.

He wore it during the hot, humid summer. It itched. It was awkward. He had to learn how to change a diaper with one hand.

Every day, he arose predawn to lie stiffly for 30 minutes for a resting-state functional MRI. He did this for the two weeks his arm was in the cast, as well as for the two weeks before and after.

During the six weeks, Dosenbach also wore accelerometers on both wrists to track the motor strength of his arms while performing basic tasks such as writing and moving objects.

"It wasn't terrible, just unpleasant," Dosenbach recalled. "But immediately, I noticed my right arm got worse, and my left hand got stronger. It was much faster than any of us expected."

The MRI data showed that brain changes occurred within 48 hours. Additionally, the researchers measured a decrease in grip strength in his right arm -- from 124 pounds of force to 90 during the two weeks he wore the cast.

"Once my cast was removed, my right hand began to grow stronger," Dosenbach said. "My left returned to its former role, too."

Surprised by such resiliency, Dosenbach and the study's first author, Dillan Newbold, a MD, PhD student, conducted the same experiment on two "crazy-in-a-good-way" scientists -- one who wore a fluorescent yellow cast decorated in doodles, the other a forest green cast that recalled childhood memories of camping.

Using a resting-state functional MRI scan, the researchers identified and measured the precise regions in each individual's brain that controlled each casted arm, examining more than 20 hours of recordings for each person. These techniques allowed the researchers to discover and characterize the pulses.

Their MRI data nearly mirrored Dosenbach's. The findings indicated that disuse of each arm caused affected neurons to disconnect from the rest of the brain's motor system within two days. Newbold's analysis revealed that throughout the time the casts were worn, spontaneous pulses maintained activity in the disused circuits until the neurons began firing again when mobility was regained.

"Finding the spontaneous pulses was incredible," Newbold said. "People can be motionless, but their neurons seem to protect the brain from completely disengaging when it's not being used. More research is needed, but this was the most exciting part of the study because of the clinical implications."

A collaborative study by research groups from the VIB-UGent Center for Inflammation Research and Ghent University uncovered a new mechanism causing colorectal cancer. The researchers found that abnormal expression of the protein Zeb2 affects the integrity of the intestinal wall or 'epithelium'. This epithelium normally functions as a barrier to prevent infiltration by intestinal microbes. Zeb2 undermines this barrier and allows infiltrating bacteria to cause inflammation that drives cancer progression. Importantly, the scientists demonstrated that manipulating the immune system or removing the microbiota can prevent the development of cancer. These findings may lead to new treatments and are published in the leading journal Nature Cancer.

Colon cancer

Colorectal cancer is the third most common and fourth most deadly type of cancer. Unfortunately, anti-cancer therapies, including immunotherapy, have a relatively low effectiveness in colorectal cancer. In addition to genetic factors, environmental factors linked to a Western lifestyle (such as diet, obesity, and a sedentary lifestyle) also increase the risk for developing colorectal cancer.

The disease originates from the epithelial cells that line the intestines. These 'barrier' cells accumulate mutations and acquire malignant properties over time. A better understanding of the molecular mechanisms responsible for colorectal cancer development is essential to develop new therapies to effectively combat this deadly disease.

A new mechanism driving colon cancer

A collaboration between the research groups of prof. Geert van Loo, prof. Lars Vereecke, and prof. Geert Berx identified the protein Zeb2 as a possible cause of colorectal cancer. They showed that the abnormal expression of this protein in the epithelial cells of the gut in mice can induce colorectal cancer.

Zeb2 destabilizes the integrity of the intestinal barrier which allows bacteria to infiltrate the tissue and provoke inflammatory reactions. This causes an abnormal proliferation of epithelial cells which ultimately leads to the development of malignant intestinal tumors. Importantly, by treating mice with broad-spectrum antibiotics to kill intestinal bacteria, or by raising mice in complete sterile conditions, cancer development could be completely prevented.

Prof. Geert Berx (CRIG/UGent): "We study the molecular mechanisms that regulate tissue invasion and metastasis in various types of cancer. We knew Zeb2 regulates a molecular process which allows cancer cells to acquire tissue-invasive properties, resulting in malignant disease progression. By using transgenic mice expressing Zeb2, we can study this process in multiple tissues, including the intestine. This study demonstrates that Zeb2 reprograms the epithelial cells of the intestinal wall, which allows bacteria to pass and cause inflammation that can lead to tumor development."

Prof. Lars Vereecke (VIB-UGent Center for Inflammation Research/CRIG): "There is increasing evidence that the microbes in our gut play a central role in human health and disease. Many diseases are associated with distinct shifts in the microbiota-composition, including colorectal cancer. Proving that the microbiota contribute to disease requires functional studies in mice. Recently, we established the first Belgian germ-free mouse facility at Ghent University where we raise mice in completely sterile conditions. Using this new technology, we could prove that removing the intestinal microbes prevents colorectal cancer development in our model. Moreover, by modulating the activity of specific immune cells we could also suppress cancer development. Together, these findings demonstrate that complex immune-microbiota interactions contribute strongly to colorectal cancer development."

New therapies

The new Zeb2 mouse colorectal cancer model represents a unique tool to study tumor-immune-microbe interactions, which is very useful in the search for new therapies targeting colorectal cancer. Since cancer development in these mice is microbiota-dependent, germ-free Zeb2 mice represent a unique preclinical platform for microbiota research to identify cancer-promoting microbes, but also to test new microbiota-based therapies to prevent or treat colorectal cancer.

Prof. Geert van Loo (VIB-UGent Center for Inflammation Research/CRIG): "We identified a disease-causing mechanism using a new mouse model but also confirmed abnormal Zeb2 expression in human colorectal tumor cells, which proves the clinical significance of our model for human patients. Our results are important from a scientific point of view since they help us understand why and how colorectal cancer develops. But this knowledge also has therapeutic implications and suggests that altering the microbiota or targeting specific immune components may be effective strategies for developing new treatment options for colon cancer."

One in five adults in the United States report they have experienced change - mostly a decrease - in their sexual behavior during the early months of the COVID-19 pandemic, according to a new study by Indiana University researchers.

The study, co-authored by Devon Hensel, associate research professor of pediatrics at the IU School of Medicine, and Debby Herbenick, professor in sexual and reproductive health at the IU School of Public Health-Bloomington, examined changes in solo and partnered sexual behaviors from about mid-March to mid-April, when most of the country was subject to stay-at-home guidance, in an effort to learn more about Americans' sexual lives and relationships during the first month of social distancing. The study has been published via preprint in medRxiv.

Herbenick and Hensel will present preliminary findings of the study at a virtual conference of the American Association of Sexuality Educators, Counselors and Therapists on June 4.

"Understanding how sexual behavior changes during a pandemic, specifically COVID-19, is necessary to continue to adapt public health COVID-19 management in ways that are consistent with people's sexual health and well-being," said Hensel. "Our data illustrates the very personal ways in which different pandemic-associated factors may create or inhibit opportunities for solo and partnered sex."

The study used a U.S. nationally representative probability survey of adults to look at changes in 10 solo and partnered sexual behavior categories. Researchers looked at factors such as how knowledgeable individuals are about the virus; mitigation measures such as social distancing and recommended hygiene; if participants had children in the home and their ages, and mental health variables including depressive symptoms and loneliness.

Across all 10 behaviors studied, 50 percent of participants reported no change or stability in their sexual behaviors over the past month. Another third of participants reported that they had either increased or decreased in some behaviors.

The most common behaviors to increase and decrease were the same. Among the participants reporting an increase in sexual behavior, the most common increases were hugging, kissing, cuddling or holding hands with a partner. Similarly, those reporting decreases said the same sexual behaviors--hugging, kissing, cuddling, or holding hands--were the most common to decline.

"In the first month of social distancing and stay at home guidance, many people experienced substantial change in their relationships," said Herbenick. "While some people found themselves spending time constantly with their romantic or sexual partners, others found themselves separated from partners or unable to date or meet up with potential partners."

The study found that participants with any children at home under the age of five were three times more likely to report increased hugging, kissing, cuddling or holding hands with a partner in the past month, while having elementary-aged children was often linked to decreased reports of these behaviors.

Those findings could be attributed, Herbenick said, to parents of smaller children being able to better maintain pre-pandemic schedules and routines. Likewise, parents of small children could have reported an increase in hugging, kissing, cuddling or holding hands because it is part of group/family interactions such as family cuddles.

In terms of mental health factors, the study found that depressive symptoms and loneliness were associated with both reduced partnered bonding behaviors, such as hugging, cuddling, holding hands and kissing, as well as reduced partnered sexual behaviors. These mental health factors could be attributed to social distancing measures, the researchers said, that while necessary, can exacerbate feelings of depression and loneliness for some people.

Consistent with existing research, the study also found that people who perceived they were at greater odds for COVID-19 medical consequences (they or a loved one getting sick) or for COVID-19 social consequences (job loss or missing medical appointments) were more likely to report decreased partnered sexual behaviors.

Those with greater COVID-19 knowledge were more likely to report stability in partnered sexual behaviors. However, the study could not assess whether greater knowledge increased people's comfort to maintain existing habits, or how greater knowledge might lead some people (particularly single adults) to risk reduction behaviors that also affected their sexual behavior - for example, refraining from meeting up with new partners.

Individual circumstances, and access to resources such as health care and services, impact decisions about how and when to have sex, Hensel said. Pandemics cause interruptions in resources that can lead to adverse outcomes such as unintended pregnancies. Unwanted abstinence, Hensel said, could also result in mental and sexual health consequences.

"This study is a reminder that pandemics impact every aspect of the human experience, including sexuality," Hensel said. "Better understanding of how real-life pandemic management - such as childcare, mental health challenges, and worries about getting sick - impacts solo and partnered sex aids professionals in helping people tailor solutions to any sexual challenges they may have. "

ORLANDO, June 16, 2020 - When extreme climate conditions interact with stressors to social systems, such as the COVID-19 pandemic, the consequences could be severe unless experts from diverse backgrounds work together to develop comprehensive solutions to combat their negative impacts.

That's the recommendation of a new article in Nature Climate Change published Monday and co-authored by a University of Central Florida researcher.

Thomas Wahl, an assistant professor in UCF's Department of Civil, Environmental and Construction Engineering and a member of UCF's National Center for Integrated Coastal Research, is one of 14 experts with diverse backgrounds who authored the article.

"In the perspective article my input mainly focused on the impacts of connected extremes on the water sector," Wahl says. "With my research group at UCF, we have extensively worked on many different projects focused on compound flooding, when, for example, storm surges coincide with extreme rainfall or high river discharge."

The article brought together scientists and stakeholder representatives with different backgrounds, ranging from the natural sciences to social sciences, public health and engineering.

The authors focused on four main sectors - food, water, health and infrastructure - where connected extremes often lead to unforeseen impacts.

Examples of connected extremes include the impact of Hurricane Maria in 2017 on Puerto Rico's under-maintained infrastructure, limited budget and aging population, and the spring 2011 Mississippi River floods in which water was released to protect urban areas at the detriment of agricultural lands.

A present example could be the COVID-19 pandemic and the current hurricane season, Wahl says.

"The COVID-19 crisis will very likely increase the impacts associated with the climatic extreme events that will inevitably occur somewhere across the globe over the next weeks or months or already have occurred," Wahl says.

"For example, shelters cannot operate at full capacity, health care systems are already under pressure, and emergency funds are depleted."

The researcher says many of the most impactful natural hazards experienced over the past decade could be considered connected extremes, where either different factors in the physical climate system combined in unfortunate ways or the impacts were made worse by interactions between physical and societal systems.

"It's important to recognize and treat connected extremes as such, and for scientists from different fields to engage directly with stakeholders and decision makers to develop new, robust and flexible policies to better combat their negative impacts," Wahl says.

A new study conducted in Turku, Finland, reveals how symptoms indicating depression and anxiety are linked to brain function changes already in healthy individuals.

Researchers of the national Turku PET Centre have shown that the opioid system in the brain is connected to mood changes associated with depression and anxiety.

Depression and anxiety are typically associated with lowered mood and decreased experience of pleasure. Opioids regulate the feelings of pain and pleasure in the brain. The new study conducted in Turku shows that the symptoms associated with depression and anxiety are connected to changes in the brain's opioid system already in healthy individuals.

- We found that the more depressive and anxious symptoms the subjects had, the less opioid receptors there were in their brain. These receptors function like small "docks" that are influenced by both the brains own opioids as well as opiates. These type of opioid-mediated mood changes can be an important mechanism in the central nervous system, says Professor Lauri Nummenmaa from the University of Turku.

- These results show that the mood changes indicating depression can be detected in the brain already early on. Both the brain's own opioids and synthetic opiate-based drugs regulate mood. Based on the results, drugs that have an effect on the opioid system can help in the treatment of depression, adds Nummenmaa.

The study was conducted with Positron Emission Tomography (PET) and altogether 135 volunteers participated as subjects. A small dose of radioactive tracer binding to the brain's opioid receptors was injected in their circulation. The decay of the tracers was measured with a PET camera, whereas the depressive and anxious symptoms of the subjects were measured with questionnaires.

The study is based on the AIVO database hosted by Turku University Hospital and Turku PET Centre. The database contains different in vivo molecular brain scans for extensive analyses: https://aivo.utu.fi/

The smallest motor in the world - consisting of just 16 atoms: this was developed by a team of researchers from Empa and EPFL. "This brings us close to the ultimate size limit for molecular motors," explains Oliver Gröning, head of the Functional Surfaces Research Group at Empa. The motor measures less than one nanometer - in other words it is around 100,000 times smaller than the diameter of a human hair.

In principle, a molecular machine functions in a similar way to its counterpart in the macro world: it converts energy into a directed movement. Such molecular motors also exist in nature - for example in the form of myosins. Myosins are motor proteins that play an important role in living organisms in the contraction of muscles and the transport of other molecules between cells.

Energy harvesting on the nanoscale

Like a large-scale motor, the 16 atom motor consists of a stator and a rotor, i.e. a fixed and a moving part. The rotor rotates on the surface of the stator (see picture). It can take up six different positions. "For a motor to actually do useful work, it is essential that the stator allows the rotor to move in only one direction," explains Gröning.

Since the energy that drives the motor can come from a random direction, the motor itself must determine the direction of rotation using a ratcheting scheme. However, the atom motor operates opposite of what happens with a ratchet in the macroscopic world with its asymmetrically serrated gear wheel: While the pawl on a ratchet moves up the flat edge and locks in the direction of the steep edge, the atomic variant requires less energy to move up the steep edge of the gear wheel than it does at the flat edge. The movement in the usual 'blocking direction' is therefore preferred and the movement in 'running direction' much less likely. So the movement is virtually only possible in one direction.

The researchers have implemented this "reverse" ratchet principle in a minimal variant by using a stator with a basically triangular structure consisting of six palladium and six gallium atoms. The trick here is that this structure is rotationally symmetrical, but not mirror-symmetrical.

As a result, the rotor (a symmetrical acetylene molecule) consisting of only four atoms can rotate continuously, although the clockwise and counterclockwise rotation must be different. "The motor therefore has 99% directional stability, which distinguishes it from other similar molecular motors," says Gröning. In this way, the molecular motor opens up a way for energy harvesting at the atomic level.

Energy from two sources

The tiny motor can be powered by both thermal and electrical energy. The thermal energy provokes that the directional rotary motion of the motor changes into rotations in random directions - at room temperature, for example, the rotor rotates back and forth completely randomly at several million revolutions per second. In contrast, electrical energy generated by an electron scanning microscope, from the tip of which a small current flows into the motors, can cause directional rotations. The energy of a single electron is sufficient to make the rotors continue to rotate by just a sixth of a revolution. The higher the amount of energy supplied, the higher the frequency of movement - but at the same time, the more likely the rotor is to move in a random direction, since too much energy can overcome the pawl in the "wrong" direction.

According to the laws of classical physics, there is a minimum amount of energy required to set the rotor in motion against the resistance of the chute; if the supplied electrical or thermal energy is not sufficient, the rotor would have to stop. Surprisingly, the researchers were able to observe an independently constant rotation frequency in one direction even below this limit - at temperatures below 17 Kelvin (-256° Celsius) or an applied voltage of less than 30 millivolts.

From classical physics to the quantum world

At this point we are at the transition from classical physics to a more puzzling field: quantum physics. According to its rules, particles can "tunnel" - that is, the rotor can overcome the chute even if its kinetic energy is insufficient in the classical sense. This tunnel motion normally occurs without any loss of energy. Theoretically, therefore, both directions of rotation should be equally likely in this area. But surprisingly, the motor still turns in the same direction with 99% probability. "The second law of thermodynamics states that entropy in a closed system can never decrease. In other words: if no energy is lost in the tunneling event, the direction of the motor should be purely random. The fact that the motor still rotates almost exclusively in one direction therefore indicates that energy is also lost during tunnel movement," says Gröning.

Which way is time running?

If we open the scope a little more: When we watch a video, we can usually tell clearly whether time is running forward or backward in the video. If we watch a tennis ball, for example, which jumps a little higher after each impact on the ground, we intuitively know that the video runs backwards. This is because experience teaches us that the ball loses some energy with each impact and should therefore bounce back less high.

If we now think of an ideal system in which neither energy is added nor lost, it becomes impossible to determine in which direction time is running. Such a system could be an "ideal" tennis ball that bounces back at exactly the same height after each impact. So, it would be impossible to determine whether we are watching a video of this ideal ball forward or backward - both directions are equally plausible. If the energy remains in one system, we would no longer be able to determine the direction of time.

But this principle can also be reversed: If we observe a process in a system that makes it clear in which direction time is running, the system must lose energy or, more precisely, dissipate energy - for example through friction.

Back to our mini-motor: It is usually assumed that no friction is generated during tunneling. At the same time, however, no energy is supplied to the system. So how can it be that the rotor always turns in the same direction? The second law of thermodynamics does not allow any exceptions - the only explanation is that there is a loss of energy during tunneling, even if it is extremely small. Gröning and his team have therefore not only developed a toy for molecular craftsmen. "The motor could enable us to study the processes and reasons for energy dissipation in quantum tunneling processes," says the Empa researcher.

CHICAGO (June 16, 2020): Despite having the first confirmed case of coronavirus and the first major COVID-19 outbreak in the United States, the state of Washington implemented a response plan that kept its death rate the lowest among all states that have had major outbreaks. A multidisciplinary consensus panel of 26 experts analyzed western Washington's response and identified six key factors that contributed to "flattening the curve" in the state. They report on their findings in an "article in press" on the Journal of the American College of Surgeons website ahead of print.

The six pillars of the COVID-19 response identified by the consensus panel are early communication and coordination among stakeholders, regional coordination and situational awareness of the healthcare system, rapid development and access to testing, proactive management of long-term care facilities (LTCF) and vulnerable populations and effective physical distancing in the community.

As of June 5, Washington State had 22,729 confirmed cases of COVID-19 and 1,138 ensuing deaths, a rate of about 5 percent. The overall death rate in the United States is 5.7 percent, according to Centers for Disease Control and Prevention data. New York State, by comparison, has had more than 380,000 confirmed cases and 30,000 deaths, a death rate of 8 percent.

"Along with the governor's stay at home and physical distancing orders, preexisting relationships across the healthcare system were critical in facilitating this response," said corresponding author Eileen M. Bulger, MD, FACS, chief of trauma at Harborview Medical Center in Seattle and Chair of the American College of Surgeons (ACS) Committee on Trauma. The consensus panel noted that early communication and coordination among the various hospitals systems, emergency medical services, and LTCFs was pivotal in the response.

Days after the first case was identified on January 21, the Northwest Healthcare Response Network (NWHRN) coordinated with other entities--Public Health Seattle and King County (PHSKC), Harborview Medical Center Infection, Prevention and Control, the Washington Department of Health (DOH), and the Washington State Hospital Association, among others--to create communications channels across individual health systems. NWHRN is a non-profit coalition comprised of 3,000 health care organizations in 15 counties and 25 contiguous sovereign tribal nations in western Washington that collaborates on disaster preparedness and response.

"Normally we exist in a competitive landscape," said lead author Steven H. Mitchell, MD, medical director of the emergency department at Harborview Medical Center and medical director of the Western Washington Regional COVID Coordination Center (WRC), "but there was great willingness for each system and entity to do what they could to address the region's needs."

By the end of February, the first cluster of cases was identified at a Kirkland LTCF and the first COVID-19 death occurred in King County. Dr. Mitchell noted that as the outbreak unfolded, the stakeholders recognized the need for increased infrastructure to support a coordinated response and the WRC was established as a Regional Medical Operations Center (RMOC). The WRC realized LTCFs "were going to be significantly impacted," he said. However, there was no communication mechanism in place with those facilities. The NWHRN and WRC partnered with Microsoft (based in suburban Redmond), the state hospital association, and state DOH to build a communication platform to track critical hospital capacity data and leverage relationships between hospitals and LTCFs. This software platform will also support tracking of cases in LTCFs with mandatory reporting to the DOH.

Another key component of the response was the ability of the University of Washington virology laboratory to rapidly develop viral testing and make it widely available. Dr. Bulger called the virology lab staff "heroes in this response." She added, "They recognized very early that there would be a need for widespread testing that would likely exceed the capability of the state laboratory. They worked to develop their own testing platform and validate the test so that they could begin receiving samples from the initial outbreak." As of June 5, 383,587 people have been tested for SARS-CoV-2 in Washington.

To proactively engage LTCFs, health systems and PHSKC developed strike teams to provide them with on-site support. "Our geriatrics and post-acute care physicians have had longstanding relationships with many of the skilled nursing facilities, and each healthcare system has a group of LTCFs that they routinely work with for patient discharges, so they organized these strike teams to support these facilities," Dr. Bulger said. That on-site support includes COVID-19 testing for residents and staff and training for personal protective equipment and effective isolation and quarantine. "We were able to keep many of these patients in the nursing facilities and not overwhelm the hospitals by evacuating entire facilities," she said.

In addition to people in LTCFs, the response identified other vulnerable populations: minority and immigrant communities and non-English speakers; the homeless; and people in jails and prisons. PHSKC has convened nine task forces and community advisory groups to engage diverse populations. To service the homeless, King County added shelter space, hand-washing stations, and a call center along with locations where they can access isolation and quarantine services.

The WRC, Dr. Bulger noted, is built on the RMOC model first established in Texas and since promoted by the ACS Committee on Trauma to support disaster response. "The RMOC structure is a vital resource that I believe needs to be established in every community in the United States," Dr. Bulger said. The Department of Health and Human Services office of Assistant Secretary for Preparedness and Response (ASPR), which provides funding for regional coalitions, has promoted this approach as "Medical Operations Coordination Cells."

"Each region should begin to organize itself in this way because whether it's a pandemic or other type of large-scale disaster that occurs, it's critical for regions to prepare to develop communication structures that support situational awareness and patient distribution strategies," Dr. Mitchell said. "Otherwise, facilities get overwhelmed and patients suffer."

The authors proposed these "lessons learned" as a roadmap for preparation for future outbreaks, as well as establishing a lasting infrastructure which will strengthen the health systems response to all future mass casualty events and save lives.

OAK BROOK, Ill. (June 16, 2020) - A new multi-institutional study published in the journal Radiology identifies patterns in abnormal brain MRI findings in patients with COVID-19.

Current data on central nervous system (CNS) involvement in COVID-19 is uncommon but growing, demonstrating a high frequency of neurological symptoms. However, the delineation of a large cohort of confirmed brain MRI abnormalities (excluding ischemic infarcts) related to COVID-19 has never been performed, and the underlying pathophysiological mechanisms remain unknown.

The purpose of this current study was to describe the neuroimaging findings other than stroke in patients with severe COVID-19 and report the clinical and biological profile of these patients.

The retrospective observational national multicenter study was initiated by the French Society of Neuroradiology (SFNR) in collaboration with neurologists, intensivists and infectious disease specialists. Consecutive patients with COVID-19 infection and neurologic manifestations who underwent brain MRI from March 23 to April 27, 2020, in 16 French centers, including 11 university hospitals and five general hospitals were included in the study.

Thirty men (81%) and 7 women (19%) met inclusion criteria, with a mean age of 61 years. The most common neurologic manifestations were alteration of consciousness (27/37, 73%), pathological wakefulness when the sedation was stopped (15/37, 41%), confusion (12/37, 32%) and agitation (7/37, 19%).

Among the 37 patients included, 28/37 (76%) were associated with one neuroimaging pattern, 7/37 (19%) with two patterns, and 2/37 (5%) showed three patterns. The most frequent MRI findings were: signal abnormalities located in the medial temporal lobe in 16/37 (43%) patients, non-confluent multifocal white matter hyperintense lesions on FLAIR and diffusion sequences, with variable enhancement, with associated hemorrhagic lesions in 11/37 patients (30%), and extensive and isolated white matter microhemorrhages in 9/37 patients (24%).

A majority of patients (20/37, 54%) had intracerebral hemorrhagic lesions and a more severe clinical presentation.

"Three main neuroradiological patterns could be distinguished, and the presence of hemorrhage was associated with worse clinical status. SARS-CoV-2 RNA was detected in the cerebrospinal fluid in only one patient, and the underlying mechanisms of brain involvement remain unclear," the authors wrote. "Imaging and neurological follow up has to be undertaken in order to evaluate the prognosis of these patients."

SEATTLE -- June 16, 2020 -- Infectious disease experts from Fred Hutchinson Cancer Research Center and UW Medicine are advocating for earlier actions to reduce hospitalizations and deaths from COVID-19.

In a new review article published in Open Forum Infectious Diseases, the researchers outlined the strategy necessary to diagnose and treat the disease before it becomes uncontrollable. It includes:

The need for widely available home testing with nasal self-swabbing

Smaller, rapid studies using viral-shedding metrics and symptoms to measure risk of disease progression

The ability to safely deliver therapies to infected patients' homes

Including disproportionately affected minority and underserved communities

"Without a vaccine, the best way to keep people out of the hospital and potentially dying from COVID-19 is to diagnose and treat early," said lead author Dr. Joshua Schiffer, a physician and researcher in Fred Hutch's Vaccine and Infectious Disease Division. "We've seen similar strategies for other infectious diseases like HIV, Ebola and influenza significantly lower transmission rates and mortality and believe it would have the same types of benefits for COVID-19."

The authors note that most COVID-19-related clinical trials are evaluating therapies in patients who are already hospitalized. Given that the median time between development of symptoms and need for hospitalization is a week, they believe, "A golden opportunity to intervene early is being missed."

Fred Hutch researchers are playing a leading role in an international scientific response to the pandemic -- tracking the virus's spread, developing diagnostic tests, designing vaccine trials and working to prevent future outbreaks. For more information, visit Fred Hutch's Coronavirus Overview.

A top exercise researcher at the University of Virginia School of Medicine is urging clinical trials of exercise in patients with Friedreich's ataxia after finding that physical activity has a "profound" protective effect in mouse models of the debilitating genetic disease.

Friedreich's ataxia typically limits patients' ability to exercise. But the new findings from UVA's Zhen Yan, PhD, suggest that well-timed exercise programs early in life may slow the progression of the disease, which robs patients of their ability to walk.

The finding could prove particularly important because genetic testing is currently not mandatory, and there are no effective treatments for the condition.

"When dealing with a genetic disease, we often hope that gene therapy is advanced to a point with great precision and efficiency that we can replace the defect gene in the whole genome and in all the affected cells in the body, but the reality is that we are not there yet," said Yan, director of the Center for Skeletal Muscle Research at UVA's Robert M. Berne Cardiovascular Research Center. "This study points to a promising alternative approach of exercise intervention to promote the expression of an iron regulator to bypass the defect gene in maintaining normal mitochondrial function. This could fundamentally change for the good the life of Friedreich's ataxia patients."

About Friedreich's Ataxia

Friedreich's ataxia affects about 1 in 50,000 people. The disease is caused by a genetic mutation that impairs mitochondria, the powerhouses of cells. Symptoms typically appear between ages 5 and 15, though sometimes later; these symptoms include difficulty moving, poor balance, muscle weakness, type 2 diabetes and heart failure. Patients are often confined to a wheelchair within 10 to 20 years of symptom onset. Some patients with advanced disease become completely incapacitated, and the disease can lead to early death.

In a lab model of the disease, mice lose ability to run, develop blood sugar problems and show signs of moderate heart problems at 6 months of age, But Yan found that mice that started voluntary long-distance running at 2 months completely avoided those problems.

"We conclude that endurance exercise training prevents symptomatic onset of FRDA [Friedreich's ataxia] in mice associated with improved mitochondrial function and reduced oxidative stress," the researchers report in a scientific paper on the findings. "These preclinical findings may pave the way for clinical studies of the impact of endurance exercise in FRDA patients."

The Many Benefits of Exercise

The discovery is the latest in a series from Yan that speaks to the benefits of exercise. He recently made headlines around the world when he determined that exercise may help prevent a potentially deadly complication of COVID-19 known as acute respiratory distress syndrome.

"Unlike drug therapy, increased physical activity has very few side effects. In fact, regular exercise has positive effects to literally all vital organ systems in our body," he said. "You will benefit from just about any type of exercise as you age, as long as you're not at risk of injury."

Bloomington, Ind. and Chicago, Ill. -- Results from a new study show that risk factors for cardiovascular disease and diabetes were similar when participants consumed a healthy US-style eating pattern with and without an additional 5.3 ounces of lean beef. The added beef replaced carbohydrates, primarily refined starches. All participants were considered at risk for type 2 diabetes and followed a healthy diet as outlined by the 2015 U.S. Dietary Guidelines for Americans, and separately a similar diet modified to have a larger portion of calories from lean beef in random order.

"Most indicators of metabolic and cardiovascular health, such as insulin sensitivity and LDL cholesterol, did not differ between the two diets. The only significant difference observed was a shift toward a greater percentage of cholesterol carried in larger, more buoyant LDL particles during the higher beef condition. This difference is potentially important because larger, more buoyant LDL particles may be less likely to promote atherosclerosis," said Kevin C. Maki, Ph.D., who was the Study Director and is Adjunct Professor in Applied Health Science at the Indiana University School of Public Health-Bloomington.

"This study is important because it shows that red meat can be part of a healthy eating pattern," said Dr. Maki, "Our study compared US-style healthy eating patterns with red meat intake that was below-average for the United States (about 1.2 ounces per day), versus a similar diet that contained an additional 5.3 ounces per day of unprocessed, lean beef. All foods consumed by the subjects during each diet period were provided by the research team." The 33 study participants (26 women and 7 men) completed the crossover, controlled-feeding trial, where each subject was randomly assigned to follow one eating pattern for 4 weeks, followed by a washout of 2 weeks, then consumption of other diet for 4 weeks.

Beef is a nutrient-dense food with high quality protein, iron and zinc, but results from some observational studies have suggested that red meat consumption is associated with increased type 2 diabetes and cardiovascular disease incidence. "Our study showed that increasing intake of lean beef, as a replacement for refined starches in a healthy diet, did not worsen cardiometabolic risk factors. While this research is important for those who choose to include red meat in healthy diets, we are not encouraging people to increase red meat consumption or advocate that those who would otherwise consume a vegetarian-style eating pattern to begin eating red meat."

The results are published online at the Journal of Nutrition. The study was funded by the Beef Checkoff and was completed by Dr. Maki and his team at Midwest Biomedical Research.

Older men who have a weak or irregular circadian rhythm guiding their daily cycles of rest and activity are more likely to later develop Parkinson's disease, according to a new study by scientists at the UC San Francisco Weill Institute for Neurosciences who analyzed 11 years of data for nearly 3,000 independently living older men.

The scientists said their discovery of the link between circadian rhythms and Parkinson's -- a disease characterized by loss of control over movement, balance and other brain functions -- suggests these circadian disruptions may reflect neurodegenerative disease processes already affecting the brain's internal clock well before a Parkinson's diagnosis, and that they could be considered an early warning sign of the disease.

"The strength of the circadian rhythm activity seems to have a really important effect on health and disease, particularly in aging. In this latest study we found that even small changes in circadian rhythm in older men were associated with a greater likelihood of getting Parkinson's down the line," said study senior author Kristine Yaffe, MD, the Roy and Marie Scola Endowed Chair and vice chair of the Department of Psychiatry at UCSF, a professor of psychiatry, neurology, and epidemiology and biostatistics, and a member of the UCSF Memory and Aging Center.

The results -- published June 15, 2020 in JAMA Neurology -- merit follow-up, according to the study authors, to investigate whether physiological changes set off by disruptions in circadian rhythms might themselves be a trigger for neurodegeneration, and whether strengthening these rhythms could lower risk for developing Parkinson's.

Parkinson's is the second most common neurodegenerative disorder after Alzheimer's disease. 500,000 individuals in the United States have been diagnosed with Parkinson's disease, and many with the disease are undiagnosed, according to the National Institute of Neurological Disorders and Stroke. Most who have Parkinson's are diagnosed after age 60. There are no drugs known to prevent the disease, but there are a growing number of treatments to relieve symptoms.

Among older adults, weakened or irregular circadian rhythms of rest and activity are common, according to study lead author Yue Leng, MD, PhD, an assistant professor of psychiatry at UCSF. Other conditions -- constipation or deficits in the sense of smell -- have also been associated with increased likelihood of developing Parkinson's later on.

"Parkinson's is a disease that probably takes decades to develop, and apart from changes in movement, earlier signs might be critical in understanding the disease and its mechanisms," Leng said. "This is the first large, long-term study to find that disrupted circadian rhythms might be linked to Parkinson's that emerges years later."

The study, which enrolled 2,930 men with an average age of 76.3 when the research began, was part of the larger, population-based Osteoporotic Fractures in Men Study (MRoS), which began in 2000 and enrolled men at six medical centers nationwide. None of the participants in the subset of the MRoS cohort initially had Parkinson's, and all were living in community-based settings (i.e. not in nursing homes). Their status for many health-related factors was assessed at the start, and they were monitored through follow-up visits and questionnaires.

As part of the study, researchers monitored circadian rhythms of rest and activity over three separate 24-hour periods by having participants wear an actigraph -- a watch-like device that detects and records even slight wrist movements. The data collected from these devices were independently associated with the later development of Parkinson's.

In a previous study, Leng and Yaffe identified an association between daytime napping and the later development of Parkinson's. But the link between circadian rhythms and Parkinson's is not just a matter or disrupted sleep, according to the new study. The association held true even after accounting for indicators of sleep disturbances -- including loss of sleep; sleep inefficiency (time spent asleep after turning off the lights); leg movement during sleep; and the chronic, temporary cessation of breathing known as sleep apnea.

In drawing this conclusion, the researchers took into account numerous other variables collected as part of the MRoS study, including regional differences in study sites and participant demographics, education, baseline cognitive performance, chronic diseases, physical activity, symptoms of depression, body mass index, smoking, and use of benzodiazepines, alcohol, and caffeine.

Leng and Yaffe evaluated four parameters of participants' rest-activity rhythms as measured by actigraph: amplitude, the difference between the period of greatest to least activity; mesor, the average activity; robustness, how well the measured cyclical rest-activity matched a regular curve similar to a cosine wave; and acrophase, a measure of advance or delay in the 24-hour cycle relative to the population average.

During follow-up, 78 of the 2,930 study participants were diagnosed with Parkinson's. Those who scored lowest in actigraph amplitude, mesor or robustness had triple the risk of developing Parkinson's compared to those who scored highest. The researchers did not find an association between acrophase and Parkinson's risk.

Animal models of Parkinson's have shown that cells controlling the brain's circadian rhythm pacemaker often begin to degenerate even before cells in the part of the brain that are traditionally associated with Parkinson's symptoms, suggesting that weakening of circadian rhythm may in some cases represent an early stage of disease.

Leng also does not rule out the possibility that disruptions in circadian rhythm, already known to cause metabolic changes and inflammation, might themselves contribute to neurodegenerative disease. Leng hopes to investigate whether weakened circadian rhythms trigger inflammation or the abnormal accumulation of proteins seen in affected brain tissue in both Parkinson's and Alzheimer's.

"These neurodegenerative diseases are not reversible," she said. "But if research points to sleep or circadian problems being risk factors for neurodegeneration prior to traditional symptoms, then we may be able to use that information for early detection and diagnosis, or we might be able to intervene in ways that prevent development of neurodegenerative loss of function."