Body

More effective antiviral treatments could be on the way after research from The University of Texas at Austin sheds new light on the COVID-19 antiviral drug remdesivir, the only treatment of its kind currently approved in the U.S. for the coronavirus.

The study is published today in the journal Molecular Cell.

Remdesivir targets a part of the coronavirus that allows it to make copies of itself and spread through the body. For the first time, scientists identified a critical mechanism that the drug uses and unearthed information that drug companies can use to develop new and improved antivirals to take advantage of the same trick.

According to co-author Kenneth Johnson, the finding could also lead to more potent drugs, meaning a patient could take less of a dose, see fewer side effects and experience faster relief.

"Right now, it's a five-day regimen of taking quite a bit of remdesivir," said Johnson, professor of molecular biosciences at UT Austin. "That's inconvenient and comes with side effects. What if you could take just one pill and that was all you needed to do? That would make a huge difference in terms of the here and now."

Study co-author David Taylor likens the trick the team identified to a paper jam in the virus's photocopier. Remdesivir shuts down this photocopier -- called an RNA polymerase -- by preventing copying of the virus's genetic code and its ability to churn out duplicates and spread through the body. The team detected where the drug manages to gum up the gears, grinding the machine to a halt.

"We were able to identify the point where that paper jam happens," said Taylor, an assistant professor of molecular biosciences. "We know now exactly what's creating this block. So, if we want to make the blockage even worse, we could do so."

The search for more potent antivirals could soon become more urgent as new strains of SARS-CoV-2, the virus that causes COVID-19, regularly emerge.

"We might need other drugs that are like remdesivir, but different enough that they can then go after the mutated forms," Johnson said. "It's like having a backup system, like having an emergency parachute in case the main chute doesn't work."

The study's co-first authors are postdoctoral researcher Jack Bravo and graduate student Tyler Dangerfield.

The team re-created in a lab dish the process that plays out in a patient who is infected with SARS-CoV-2 and then receives remdesivir. In a scientific first, the scientists developed a method for producing fully functional RNA polymerases to copy the viral genetic material. Next, they added a form of remdesivir. As the drug did its work, the researchers paused the process just after the reaction with remdesivir was completed (15-20 seconds) and took a 3D snapshot of the molecules in exquisite detail using a cryo-electron microscope in UT Austin's Sauer Structural Biology Laboratory. The image allowed them to reconstruct exactly how remdesivir gums up the copying process.

Johnson said that SARS-CoV-2 is the third coronavirus to make the leap from animals to humans in less than 20 years. So even if this pandemic is brought under control soon, it still makes sense to continue developing weapons against coronaviruses.

"This is not the last unique coronavirus that's going to come after us," Johnson said. "Having better antivirals could buy us time to develop vaccines against potential future outbreaks."

BOSTON -- Routine screening of asymptomatic health care personnel (HCP) in the absence of confirmed exposures to COVID-19 is not a recommended strategy for preventing transmission of the coronavirus causing the current global pandemic, according to a new review co-authored by an infectious disease specialist at Massachusetts General Hospital (MGH). The review, published in Infection Control & Hospital Epidemiology, found that such testing is unlikely to affect the transmission of SARS-CoV-2 in health care settings and could even have unintended negative consequences.

Many universities, sports leagues and other institutions require individuals in their organization to undergo routine testing for COVID-19, whether or not they are experiencing symptoms. Current public health recommendations are to test individuals with symptoms consistent with COVID-19 and those with confirmed exposures. At MGH and across the Mass General Brigham health system, asymptomatic employees are provided access to testing when it is required (such as for travel), but routine surveillance of health care personnel has not been pursued. "People were constantly asking: If sports teams and local universities are doing routine asymptomatic surveillance, why aren't we doing this in health care? Wouldn't it make care for our patients safer?" says Erica S. Shenoy, MD, PhD, associate chief of the Infection Control Unit at MGH, who co-authored the review with David Weber, MD, MPH, professor of medicine in the division of Infectious Disease at the University of North Carolina.

Shenoy learned that her colleagues at other hospitals were being asked the same question, so she and Weber performed a focused review of health-care-associated transmission as well as what is known about the frequency of infection among asymptomatic health care providers, addressing the common questions they had received:

What portion of asymptomatic HCP have undiagnosed COVID-19 infections?

Do asymptomatic HCP with undiagnosed COVID-19 pose an infection risk to patients?

Do patients with undiagnosed COVID-19 pose an infection risk to HCP?

Shenoy and Weber compiled data from MGH's voluntary testing program as well as several other hospitals that had either screened or made COVID-19 testing available to asymptomatic health care personnel. Infection rates ranged from 0.2% to 0.4% (i.e., 1 in 250 to 1 in 500). "That's quite low," says Shenoy. MGH's asymptomatic on-demand testing program continues, and the frequency of positive COVID-19 tests in health care personnel prevalence has remained below 1%. "This low prevalence means that in a routine surveillance approach, you would have to test a lot of people in order to detect one asymptomatic case." Given the low frequency of positive tests, the possibility of false positive results is a concern, and Shenoy and Weber describe how facilities considering routine surveillance must consider whether confirmatory testing would be used to address the possibility of false-positive results. "This is the most comprehensive paper to review publicly available results for routine COVID-19 testing of asymptomatic health care providers," says Weber.

Meanwhile, a negative test result should have no impact on a HCP's day-to-day actions, says Shenoy, who is also an assistant professor of Medicine at Harvard Medical School. "Being negative today doesn't change anything that we do in the hospital," she says. "If I test negative today, I'm still wearing my surgical mask at work and my cloth mask when out and about outside of work. I'm still physically distancing and doing my symptom monitoring." Yet it's possible, she adds, that health care providers who test negative may change their behavior and relax their guard outside of the clinical setting, such as not wearing a face covering in hospital breakrooms or choosing to attend gatherings outside of work.

The literature suggests that the risk of health care personnel and patients transmitting the coronavirus to one another is very low when effective safety protocols such as wearing masks, testing when indicated, and screening symptomatic patients are followed. Reported instances of health care personnel acquiring infection through exposures to patients show overall low risk of transmission; similarly, risk to patients from asymptomatic infected health care providers has also been reported to be low, highlighting the efficacy of current protocols, Shenoy and Weber found.

Instead of considering routine screening of health care personnel for COVID-19, hospitals should continue to focus on interventions that are known to reduce spread of the disease, says Shenoy, which also include rapid identification and isolation of patients who are suspected of COVID-19, proper use of personal protective equipment when appropriate, and testing asymptomatic patients known to have been exposed to the coronavirus. "Health care is not a bubble," says Shenoy, "and routine surveillance won't make it one."

DALLAS - Jan. 28, 2021 - Simulation can be a viable way to quickly evaluate and refine new medical guidelines and educate hospital staff in new procedures, a recent study from UT Southwestern's Department of Pediatrics shows. The findings, published recently in the journal Pediatric Quality and Safety and originally shaped around new COVID-19-related pediatric resuscitation procedures at UTSW and Children's Health, could eventually be used to help implement other types of guidelines at medical centers nationwide.

For decades, U.S. hospitals have used the same standard procedures for CPR and intubation. But when the COVID-19 pandemic began early last year, some details of these procedures needed to change, explains Blake E. Nichols, M.D., assistant professor of pediatrics at UTSW and a critical care physician at Children's Health.

CPR and intubation are among procedures with the highest risk of spreading SARS-CoV-2, the virus that causes COVID-19, to health care workers. To help protect hospital staff, the American Heart Association (AHA) and the Society of Critical Care Medicine (SCCM) published recommendations in April 2020 for performing these procedures in the safest way possible on patients who are either positive for COVID-19 or suspected of having the virus.

Because children who are critically ill with COVID-19 make up just a fraction of the patient population, resuscitation is thankfully a rare event, says Nichols. But this rarity also makes it more difficult to create practical guidelines around these scenarios and educate hundreds of staff members who might be involved in these procedures at hospitals.

To evaluate best practices, Nichols and his colleagues performed a simulation using protocols that differ from the typical simulation events used for CPR or intubation training. The researchers started with new guidelines written by a UTSW/Children's Health committee based on AHA and SCCM recommendations. These guidelines had distinct differences from the usual resuscitation procedures, including involving a medical team with significantly fewer members, making sure each member is fully secured in personal protective equipment (PPE) before entering a patient's room, and ensuring the patient is enclosed in as much protective gear as possible to block the spray of infectious droplets.

Nichols pulled together a team of six individuals to participate in a resuscitation event. The team included pediatric intensive care physicians, nurses, respiratory therapists, and a writer from the guidelines committee.

The team tested the guidelines in two different scenarios: In one, a mock patient posed under a plastic equipment drape that had been repurposed as a protective shield, confirming its utility for protecting health care workers during intubation and CPR and determining how to secure the shield around the patient for best results. In another, the team performed simulated intubation and CPR on a mannequin in a negative pressure room, with some team members outside the room passing off equipment and medications and others actively treating the simulated patient.

During the four-hour event, the team used rapid cycle deliberate practice (RCDP), an established medical simulation technique that allows the exercise to be stopped at any time to refine guidelines or correct mistakes. But unlike typical RCDP - in which just one member acts as an expert and is in charge of stopping the simulation for corrections - in this case every member of the team was considered an expert, allowing each to give input, make quick changes, and hone the guidelines. The simulation was recorded to create an educational video for other hospital staff.

Nichols says the team identified several problems with the proposed guidelines written for UTSW/Children's Health. For example, the team found that two nurses were needed at the patient's bedside during resuscitation - rather than just one as proposed in the guidelines - to prevent task overload. Additionally, communication needed to be refined since the PPE prevented team members from clearly seeing facial expressions or hearing commands as they normally would.

The video was used to educate nearly 300 staff members at UTSW and Children's Health on the new guidelines within a few days, enabling a quick rollout, Nichols says. The entire procedure - from writing the guidelines to disseminating the video - took fewer than two weeks. He characterized that as an extremely fast turnaround necessitated by the pandemic.

"The COVID-19 pandemic required us to find new ways to provide the best care for our patients while protecting health care workers and educating these workers quickly on new procedures," Nichols says. "We've shown that simulation provides a great opportunity to accomplish this goal."

Peer-reviewed / Simulation or Modelling / People

A new modelling study has estimated that from 2000 to 2030 vaccination against 10 major pathogens - including measles, rotavirus, HPV and hepatitis B - will have prevented 69 million deaths in low-income and middle-income countries (LMICs).

The study estimated that, as a result of vaccination programmes, those born in 2019 will experience 72% lower mortality from the 10 diseases over their lifetime than if there was no immunisation.

The greatest impact of vaccination was estimated to occur in children under five - mortality from the 10 diseases in this age group would be 45% higher than currently observed in the absence of vaccination, according to the research.

This is the largest scale modelling study of the impact of vaccination in LMICs to date, assessing vaccination programmes against 10 pathogens within 98 countries. The findings indicate that if the progress in vaccination coverage is sustained, these public health gains will continue to increase in coming decades.

Vaccinations against 10 major pathogens have a substantial impact on public health in low-income and middle-income countries (LMICs), according to new modelling research published in The Lancet. The study estimated that from 2000 to 2019 vaccinations have prevented 37 million deaths, and that this figure will increase to 69 million deaths for the period 2000-2030. Most of this impact is estimated to be among children younger than five years, most notably from measles vaccinations.

Vaccines are cost-effective health interventions that substantially reduce death and illness from a range of diseases. International programmes have increased the coverage of routine childhood vaccines in LMICs and descriptions of impact are needed to inform future investment. Direct measurement of impact is difficult due to limitations in data and disease surveillance systems. Mathematical models can provide valuable estimates of impact based on data on disease burden and vaccine coverage.

The new study involved 16 independent research groups modelling the impact of childhood vaccination programmes in 98 LMICs. The study assessed impact of vaccination programmes against ten pathogens: hepatitis B (HepB), Haemophilus influenzae type b (Hib), human papillomavirus (HPV), Japanese encephalitis (JE), measles, Neisseria meningitidis serogroup A (MenA), Streptococcus pneumoniae, rotavirus, rubella virus and yellow fever virus (YF).

Dr Caroline Trotter from the University of Cambridge UK, and a co-author on the study, said: "There has been a much-needed investment in childhood vaccination programmes in low-income and middle-income countries (LMICs) and this has led to an increase in the number of children vaccinated. To inform future investment and ensure it continues we need to evaluate the impact of these programmes on public health. Our modelling has provided robust evidence on the effectiveness of vaccination programmes in LMICs and indicated what might be lost if current vaccination programmes are not sustained." [1]

Multiple models were applied for each pathogen (20 models in all) [2). Estimates of impact were based on past and future coverage of individual vaccines, vaccine effectiveness and data on deaths caused by the diseases, and on the years of healthy life lost due to premature death and disability from the diseases (DALYs) [3]. By comparing a scenario with no vaccination programmes in place to scenarios when vaccinations programmes had been implemented, the study estimated the impact on deaths and on DALYs.

The study used two methods to assess impact to provide both a cross-sectional (yearly) and longer-term (lifetime) view of impact. The first method assessed the difference in the number of deaths between the vaccination and no vaccination scenarios for each year and then totalled these annual results.

The second method assessed the long-term impact of vaccination by summarising impact over the lifetime for groups of people who were born in the same year between 2000 and 2030 and then calculated the difference between vaccination and no vaccination scenarios. This approach allowed for the inclusion of vaccination impact later in life, which is particularly relevant for diseases such as hepatitis B or HPV where there is a long delay between infection and severe outcomes. Most of the impact of hepatitis B vaccination will be seen after 2030 whilst for HPV impact will be seen after 2040.

Results demonstrated that between 2000 and 2019 there was an increase in the average number of vaccines received per child, both for existing vaccines such as measles, and for new vaccines such as rotavirus.

Considering impact per year, the study estimates that from 2000 to 2030, vaccination will have prevented 69 million deaths from the 10 diseases, 37 million of which were averted between 2000 and 2019. Vaccinations against measles had the biggest impact, preventing 56 million deaths between 2000 and 2030.

In terms of the impact of vaccination over the lifetime of people born between 2000 and 2030, the study estimated that vaccination will prevent 120 million deaths, of which 65 million are in children younger than five years. 58 million of deaths would be prevented by measles vaccines and 38 million by hepatitis B vaccines.

Considering those born in 2019 the study estimated that increases in vaccine coverage and introductions of additional vaccines resulted in a 72% reduction in lifetime mortality caused by the 10 pathogens. By taking this 2019 birth cohort and using UN World Population Prospects demographic estimates [4], the study estimated that mortality in children under five in the 98 countries would be 45% higher in the absence of vaccination against the 10 pathogens.

The study also examined the relative impact of each vaccine and demonstrated that measles, Hib and pneumococcal conjugate vaccines (PCVs) have the largest impact on deaths of children under five. Vaccines against HPV, hepatitis B and yellow fever have the largest impact per person vaccinated over lifetime.

Corresponding author, Professor Neil Ferguson from Imperial College London, UK said: "Our study signifies the huge public health benefits that can be achieved from vaccination programmes in low-income and middle-income countries. By projecting up until 2030 in these 98 countries we have provided insight on where investments in vaccine coverage should be directed to achieve further gains, for example increasing HPV coverage in girls and pneumococcal conjugate vaccines (PCV) coverage in children under five will have the most impact according to our modelling." [1]

Co-author Dr Katy Gaythorpe, also from Imperial College London, UK added: "By estimating how much higher mortality levels would be if there were no vaccination programmes in place, our study has highlighted how crucial it is to maintain high coverage levels. This will require continuing political commitment, funding, public engagement to promote the benefits and safety of vaccinations, and programmes to deliver education, training and supervision on immunisation." [1]

Researchers reported the level of uncertainty from data on disease burden and from the structural assumptions of the different models but they were unable to evaluate uncertainty in demographic estimates and estimates of past and future vaccine coverage. The study flagged a number of limitations, for example for those countries where certain vaccines were yet to be introduced the study assumed they will reach the same coverage as a reference vaccine, which may lead to an overestimation of impact. In addition, no models accounted for variation in vaccine coverage according to geographic region or clustering of hard-to-reach groups. Researchers highlighted the need for future models to stratify impact for different populations within countries to achieve more detailed estimates.

Researchers at the Beckman Institute for Advanced Science and Technology were part of a collaborative effort to investigate a new strategy to manage sodium levels in patients with kidney failure who were undergoing hemodialysis treatment.

"Thirst and chronic volume overload are some of the most perplexing and clinically significant problems in nephrology," said Kenneth Wilund, a professor of kinesiology and community health at the University of Illinois Urbana Champaign. However, the methods to treat these symptoms such as dietary and behavioral counseling are often ineffective. The study showed that four weeks of home-delivered, low sodium meals reduced weight gain associated with salt and water intake between hemodialysis sessions.

Along with this primary finding, this approach reduced dietary sodium, thirst, volume overload, and plasma phosphorus levels. The home-delivered meals also significantly reduced both sodium and phosphorous intake without reducing total protein and calorie intake.

The paper, "Pilot Study to reduce interdialytic weight gain by the provision of low-sodium, home-delivered meals in hemodialysis patients," was published in Hemodialysis International.

Magnetic resonance imaging technology was used to measure participants' muscle sodium concentrations. Beckman research scientist Ryan J. Larsen and Brad Sutton, a professor of bioengineering and the technical director of Beckman's Biomedical Imaging Center, lent their expertise for this part of the study.

The imaging was unique for Beckman experts in that it not only involved performing MRI scans of anatomical regions other than the brain, but it also involved using a Siemens Prisma 3T MRI scanner with both hydrogen and sodium coils to perform multinuclear imaging. Equipped with an additional amplifier to provide access to a wider range of frequencies for image acquisition, the machine could perform sodium nuclear imaging. This enabled the team to calculate sodium concentration in participants' calf muscle tissues.

Larsen said the study posed several unique challenges. Sodium imaging is inherently done at a different frequency than hydrogen, and the signal acquired using sodium nuclei is much weaker because of its lower abundance making the images acquired not nearly as crisp, he said. The team performed both hydrogen and sodium nuclear imaging in this study. The signal acquired using the sodium nucleus excitation relaxes more quickly than hydrogen, which results in a much noisier image.

The ability to measure sodium is critical to kidney research. Sodium is an essential nutrient that is important in various biological processes like maintaining action potentials. Action potentials can best be explained as an explosion of electrical activity that is created by a depolarizing current.

"We know this is impractical as a long-term solution, but we hypothesized that if we could provide the low-sodium meals for a short period, the patients' preference for salt would start to decline, and they would begin to see the benefits of reducing their salt intake," Wilund said. "The evidence from this pilot study suggests this strategy may work, but we need to test this in a larger trial, which is what we are working on now."

Plants and other organisms can adapt their phenotypes to fluctuating environmental conditions within certain limits. The leaves of the dandelion, for example, are much more small in sunny locations than in shady places. In the sun, less leaf area is adequate to drive sufficient photosynthesis. This makes sense and is part of the dandelion's genetic programming.

However, plants can deviate from their normal programming if they are under constant heat stress or other extreme factors that endanger their survival. They then develop, for example, a wide range of leaf shapes that are extremely rare under natural conditions. In this case, scientists speak of "hidden reaction norms".

Pitcher plants cultivated in growth chambers

The influences that cause these reactions have been largely unknown until now. But especially in view of climate change, researchers would like to find answers to this question.

An international research team now shows in the journal Proceedings of the Royal Society B what variety of malformed leaves the carnivorous Australian pitcher plant Cephalotus follicularis can form. To tease out these hidden reaction norms, they subjected the plants for twelve weeks to different conditions in growth chambers.

"The hidden reaction norms of this plant could be revealed when uncommon combinations of benign or neutral environmental stimuli prevail," says biologist Dr Kenji Fukushima from Julius-Maximilians-Universität (JMU) Würzburg in Bavaria, Germany. Then the plant deviates from its normal programming, according to which it either forms flat, photosynthetically active leaves or leaves transformed into insect traps.

Reaction to short days with high temperatures

If the plants grew in summer temperatures but with only a few hours of light, they increasingly formed misregulated leave phenotypes. These are exactly the conditions that are becoming more common in many regions of the world due to climate change: Short spring or autumn days which are too warm for the season.

The conclusion of Dr Fukushima and his co-authors from the National Institute for Basic Biology in Okazaki (Japan): "Climate change may challenge organismal responses through not only extreme cues but also through uncommon combinations of benign cues."

Contracting COVID-19 while pregnant can have deadly consequences for the mother, a new study published today in American Journal of Obstetrics and Gynecology shows.

The study, which followed 240 pregnant women between March and June 2020, found that the COVID-19 mortality rate in the pregnant women was significantly higher when compared to the COVID-19 mortality rate in similarly aged individuals within Washington state.

Specifically the study found:

Pregnant women with COVID-19 had 3.5 times higher COVID-19 associated hospitalization rate than the similarly aged general population in Washington state.

COVID-19 mortality rates were 13 times higher in pregnant mothers than in similarly aged individuals. This said, most of the pregnant patients with COVID-19 had asymptomatic or mild COVID-19 disease and healthy pregnancies.  

The three women who died of COVID-19 in Washington state were from minority ethnic groups and most of them had other conditions such as obesity and hypertension.

Of the 240 pregnant women with SARS-CoV-2 infections detected through June, three died from COVID-19, while 24 patients were hospitalized for COVID-19.  Dr. Kristina Adams Waldorf, an obstetrician-gynecologist with the University of Washington School of Medicine, and senior author of the study, noted that this shows a severe underreporting of mortality related to COVID among mothers in the United States. 

"The mortality rate was shockingly high," Adams Waldorf said. "We were very surprised by this."

The three maternal deaths from the study cohort in Washington state represent 6.7% of all maternal deaths associated with COVID-19 counted in the entire United  States through mid-October, although annual births at the collaborating sites make up only 1.4% of annual births nationally, she said.

"We are gravely concerned that COVID-19-associated maternal deaths have been massively undercounted nationally and that the impact on pregnant patients, particularly with underlying conditions is greater than currently underappreciated," she added. The date was compiled by aWashington state collaborative that  included 35 large hospitals and clinic systems.  They performed  61 percent of the 86,000 annual state deliveries. The Washington State COVID-19 in Pregnancy Collaborative was led by Dr. Adams Waldorf and Dr. Erica Lokken, an epidemiologist at the University of Washington.

The study made several comparisons between the clinical course of COVID-19 and Influenza A virus H1N1 2009.

Unlike the influenza A virus H1N1 2009 pandemic, when pregnant women were quickly identified in the United States as a high-risk and vulnerable group, pregnancy was not identified as a high-risk condition for COVID-19 disease or mortality for the first, critical eight months of the pandemic, the report noted.

Overall, the data in this study indicates that pregnant patients are at risk for severe or critical disease or mortality compared with non-pregnant adults, as well as for preterm birth, the report concludes.

"The idea that pregnant patients were protected from COVID-19 is a myth," said Adams Waldorf.

Use of this data in the report is important, Waldorf notes, because it can guide public health workers and physicians in their mitigation of COVID-19 among vulnerable populations. Pregnant health care workers are already receiving the COVID-19 vaccine. But as of Jan. 27, most pregnant individuals are not included in the groups that can receive vaccinations now.

"Our data indicates that pregnant people did not avoid the pandemic as we hoped that they would and communities of color bore the greatest burden," Waldorf said. She urges pregnant women to discuss the risks and benefits of COVID-19 vaccination with their prenatal care provider.

"These results suggest that the exclusion of pregnant patients from COVID-19 vaccine trials was a mistake," said  Adams Waldorf. "Here is an important group that is typically highly vulnerable to influenza infections and, yet they were excluded from COVID-19 vaccine trials. Pregnant patients should have been given the option to enroll in vaccine trials so that we would better understand vaccine risks and benefits to them."

Adams Waldorf added that although the community may be experiencing COVID-19 fatigue this is no time to let our collective guard down, especially with the new variants present within our communities.

"We still need to be really careful about how large our bubble is within our families, to be very careful about handwashing and mask use, and to do everything that we can until enough of the population is vaccinated that we have herd immunity in the U.S., " she said.

Dr. Richi Gill, MD, is back at work, able to enjoy time with his family in the evening and get a good night's sleep, thanks to research. Three years ago, Gill broke his neck in a boogie board accident while on vacation with his young family. Getting mobile again with the use of a wheelchair is the first thing, Gill says, most people notice. However, for those with a spinal cord injury (SCI), what is happening inside the body also severely affects their quality of life.

"What many people don't realize is that a spinal cord injury prevents some systems within the body from regulating automatically," says the 41-year-old. "My blood pressure would drop drastically, leaving me fatigued, dizzy, and unable to focus. The condition can be life threatening, requiring medication for life."

Dr. Aaron Phillips, PhD, at the University of Calgary's Cumming School of Medicine (CSM) and Grégoire Courtine, PhD, at Swiss Federal Institute of Technology (EPFL) , co-led an international study which has shown that spinal cord stimulators can bridge the body's autonomous regulation system, controlling blood pressure without medication. Findings are published in Nature.

For people with SCI, the discovery is life changing, "The spinal cord acts as a communication line allowing the brain to send signals to tell the body such as when and how to move, as well as how to control vital functions, including blood pressure," says Phillips, co-principal investigator and assistant professor at the CSM. "This communication line is broken after a spinal cord injury. We created the first platform to understand the mechanisms underlying blood pressure instability after spinal cord injury, which allowed us to develop a new cutting-edge solution."

Gill is the first study participant in a series of clinical trials planned for Calgary and Switzerland. "We are going to collaborate with a company called Onward to develop a neurostimulation system dedicated to the management of blood pressure in people with spinal cord injury," says Courtine, co-principal investigator and professor at the EPFL.

In the study, targeted epidural electrical stimulation (EES) of the spinal cord was used to stabilize hemodynamics (blood flow throughout the body) allowing for vital organs to maintain an appropriate supply of blood. The researchers discovered the exact placement on the spine for their stimulator, and the circuitry of the sympathetic nervous system underlying blood pressure control. This new knowledge allowed for the development of a neuroprosthetic closed-loop communication system, to replace lost hemodynamic control.

"We are really excited that people with spinal cord injury are able to stop their blood pressure medication and get back to enjoying a full daily routine with improved blood flow to their brain and organs," says Dr. Sean Dukelow, MD, PhD, clinician scientist at the CSM and author on the study. "People feel more alert, are able to be upright and in their wheelchair without losing consciousness, and over the long-term we think this will reduce the risk of heart disease and stroke."

"It's exciting to see the science help push things forward," says Gill. "I'm excited that Calgary will be one of the sites for a clinical trial. Research made a positive effect on my life and I'm glad others will benefit, too."

Gill continues to work as part of the Calgary Adult Bariatric Surgery Clinic and is now the Director of the Alberta Obesity Centre.

As surgeons balance the need to control their patients' post-surgery pain with the risk that a routine operation could become the gateway to long-term opioid use or addiction, a new study shows the power of an approach that takes a middle way.

In a new letter in JAMA Surgery, a team from Michigan Medicine at the University of Michigan reports on findings from a study of 620 patients who had surgery in hospitals across Michigan, had their painkiller use tracked, and took surveys within one to three months after their operations.

Half of the patients received pre-surgery counseling that emphasized non-opioid pain treatment as their first option. Some patients in this group received small, "just in case" prescriptions, but a third of them didn't receive any opioid prescription at all after surgery.

The other patients received standard care - meaning they got the usual amount of opioids given after these operations. Not only did every patient in that group get an opioid prescription, those prescriptions tended to be larger than those in the other group. And most patients didn't take them all - leaving extra pills that can pose a hazard to the patient or others in their household if taken inappropriately, or diverted to illicit use.

The patients in the two groups had the same operations - gallbladder removal, full or partial thyroid removal or hernia repair. But despite the difference in painkiller use, the patients in both groups were equally satisfied with their care and reported similar quality of life when contacted later. And those in the opioid-sparing group actually reported experiencing less pain overall.

First author Maia Anderson, M.D., a resident in the U-M Department of Surgery, says, "It's so exciting to think about the potential for opioid sparing postoperative pathways to not only reduce the risk of opioids for our patients, but also to substantially decrease the risk of opioid diversion into our communities."

Senior author and surgical resident Ryan Howard, M.D., adds, "We know that opioids pose serious risks to patients after surgery. We can protect patients from those risks by reducing or eliminating opioids after surgery. But that idea always raises the concern that patients will have uncontrolled pain and feel miserable. This study suggests that's not the case - patients who get small opioid prescriptions, or even no prescription, are just as satisfied with their recovery after surgery."

Anderson and Howard worked with the three U-M Medical School faculty who direct the Michigan Opioid Prescribing and Engagement Network -- Chad Brummett, M.D., Jennifer Waljee, M.D., M.P.H., M.S. and Michael Englesbe, M.D. -- and with Alex Hallway, B.S., a member of the program's staff who coordinates the effort to right-size surgery-related opioid prescribing in Michigan. Michigan-OPEN has published evidence-based prescribing guidelines for many procedures, as well as materials to support opioid-sparing patient education.

The study used data from the Michigan Surgical Quality Consortium that is working to improve surgical care in 70 hospitals across Michigan. Anderson and Howard are fellows of the U-M Center for Healthcare Outcomes and Policy.

People who are pregnant, breastfeeding or trying to conceive should be offered the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine based on ethical grounds, argue authors of a commentary in CMAJ (Canadian Medical Association Journal).

They discuss how health care providers and patients can use a shared decision-making approach to weigh the risks and benefits to decide on the right action for the individual.

"Core principles of medical ethics hold that medical decisions or interventions should respect individuals' autonomy, be just, be beneficial (beneficence), and not cause harm (nonmaleficence)," writes Dr. Jonathan Zipursky, Sunnybrook Health Sciences Centre and the University of Toronto, with coauthors. "Excluding individuals who are pregnant or breastfeeding from accessing the SARS-CoV-2 vaccine limits autonomy and lacks consideration of individual factors."

Although data do not indicate whether the vaccines are safe in this group, there is no evidence to show there are risks to getting vaccinated if pregnant, breastfeeding or trying to conceive. In the 23 participants in the Pfizer-BioNTech trial who conceived after vaccination, no adverse effects were observed. Animal trials also show no adverse effects.

Evidence exists, however, that pregnant individuals are at increased risk of severe COVID-19 and pregnancy complications, including preterm birth. As women are overrepresented in front-line health care and essential service jobs, the risk of contracting SARS-CoV-2 is elevated, and they should be offered protection from the virus.

"We argue that withholding the vaccine is ethically justified only if clear, substantial and imminent maternal or fetal harms are expected," the authors write.

The authors note that discussions between health care providers and patients about whether to be vaccinated will change as new evidence becomes available.

DALLAS, Jan. 27, 2021 -- Stroke survivors who completed a cardiac rehabilitation program focused on aerobic exercise, currently not prescribed to stroke survivors, significantly improved their ability to transition from sitting to standing, and how far they could walk during a six-minute walking test, according to new research published today in the Journal of the American Heart Association, an open access journal of the American Heart Association.

Cardiac rehabilitation is a structured exercise program prevalent in the U.S. for people with cardiovascular disease that has been shown to increase cardiovascular endurance and improve quality of life. Despite many similar cardiovascular risk factors, stroke is not among the covered diagnoses for cardiac rehab. Physical inactivity is common among stroke survivors, with more than 75% of all U.S. patients who survive a stroke not receiving the guideline-recommended amount of exercise (150 minutes of moderate-intensity or 75 minutes of vigorous-intensity physical activity per week). Currently, exercise-based cardiac rehab programs are not the standard of care provided to stroke survivors in the U.S.

"Through this study, we hoped to improve controllable risk factors for stroke survivors, and potentially prevent future stroke and cardiac events," said lead study author Elizabeth W. Regan, D.P.T., Ph.D., clinical assistant professor of exercise science in the physical therapy program at the University of South Carolina in Columbia, South Carolina. "Increasing physical activity is an important way to prevent stroke, and we wanted to see whether the rehab that patients receive after surviving a heart attack could have similar positive outcomes for patients who survive a stroke."

Researchers launched a pilot study at a North Carolina medical center to investigate the benefits of a cardiac rehab program for stroke survivors. In total, 24 participants, ages 33 to 81, who had a stroke from three months to 10 years earlier, were enrolled in a cardiac rehab program including 30-to-51-minute aerobic exercise sessions three times a week, for three months.

At the beginning of the program, participants were evaluated for physical function (cardiovascular endurance, functional strength and walking speed) and other health measures such as a mental health questionnaire and a balance test. In a post-program assessment, participants repeated these evaluations. At a six-month follow-up appointment, they completed the same tests a final time and answered life and exercise habit questionnaires. At the initial post-program assessment, researchers found that compared to the beginning of the study:

Participants saw an improvement in the distance they could walk during a six-minute walking test. On average, each participant improved their distance by 203 feet.

Participants improved their ability to quickly move from sitting to standing in the five-times-sit-stand test. Improvements on this test correspond to increased leg strength and can correspond to lower fall risk for people after stroke.

Study participants improved their metabolic equivalent of task (MET) level, or the maximum level of the amount of energy generated by the average person to perform a specific task, by about 3.6. For example, one metabolic equivalent of task is defined as the energy it takes to watch TV, and seven are required for jogging.

At the six-month follow-up visit, participants had maintained these gains, and 83.3% of participants reported that they were still exercising at least once a week.

"Our most important goal as health care professionals is to help stroke survivors reduce as many risk factors as possible to prevent future stroke or cardiovascular disease. Based on these preliminary findings, we hope prescribing cardiac rehab will be considered for all patients following a stroke, as it is for patients after a heart attack," Regan said. "We need to place value on exercise as medicine. Exercise is health, and it is important for every individual, regardless of physical limitations or age. Hopefully, increasing physical activity can be one of the first steps to improving overall health following a stroke."

This study included a small patient sample and was a pilot study at a single center in a multi-center health system; therefore, larger studies are needed to confirm these preliminary results.

Montreal, January 27, 2021 - Taking cannabidiol, a chemical in the cannabis sativa plant, isn't an effective way to reduce your dependence on cocaine, researchers at the CHUM Research Centre find.

In North America, close to 5.5 million people use cocaine regularly, and nearly one in five becomes addicted, developing cocaine use disorder, for which there is no clinical treatment. One solution has been touted, however: treatment with cannabidiol.

Better known as CBD, it's a chemical in the cannabis sativa plant known for its protective effects on the brain and liver. But there is very little scientific evidence to support its use as a treatment for addiction.

In fact, in a study published this month in the journal Addiction, a Canadian scientific team at the CHUM Research Centre (CRCHUM) shows that the therapeutic virtues of CBD are largely non-existent.

As a way to help coke addicts kick the habit, CBD simply doesn't work, according to the scientists, led by Université de Montréal psychiatry professor Didier Jutras-Aswad: it doesn't make addicts want cocaine less, nor does it reduce their risk of relapse into addiction.

78 addicts tested

In a clinical trial, Jutras-Aswad and his team recruited 78 coke addicts, average age 46, most of them with severe cocaine use disorder, and randomly divided the participants into two groups: one receiving cannabidiol (800 mg per day), the other a placebo.

Neither the participants nor the researchers knew which treatment was administered. Following 10 days in hospital to detox, the participants were sent home and for the next three months received weekly check-ups.

"In our study, the use of CBD was not more effective than a placebo in treating cocaine use disorder," said Violaine Mongeau-Pérusse, first author of the study and a PhD student in the Jutras-Aswad's lab.

"Although it is safe and produces only mild side effects, CBD reduces neither the craving to use cocaine nor the risk of a user's relapse after detoxification," she said.

More studies needed

Calling their results conclusive, the UdeM researchers hope their study will help orient medical guidelines on the therapeutic use of CBD, which has seen growing popularity in Canada and elsewhere in the world.

There are over 19 million cocaine users globally, according to recent estimates.

Other studies will be needed to continue to sort out the conditions under which CBD may be helpful or not, said Mongeau-Pérusse, but for now the evidence is in: if you want to beat your coke habit, cannabis isn't a good choice.

A compound that extends lifespan in a tiny nematode worm slows bone loss in aging mice. That surprising result comes from a longitudinal and functional study of 700 aging mice at the Buck Institute, a project that provides a treasure trove of data for researchers aiming to develop therapeutics to slow aging and age-related diseases. The study is currently online in the Journal of Bone and Mineral Research Plus.

The project, which involved five Buck labs and took several years to complete, involved serially profiling the individual mice as they aged while testing several therapeutics that extended lifespan in simple model organisms or reduced neurological disease in mice. Researchers established rates of change for clinically significant parameters in untreated mice including kyphosis, blood glucose, body composition, activity, metabolic measures and detailed parameters of skeletal aging in bone. The study involved collecting and analyzing terabytes of data over several years.

The online application is available at https://danielevanslab.shinyapps.io/buckMouseAging/

"This is a unique resource that comes from a study of multiple phenotypes of aging that had never been looked at before," said Buck professor Simon Melov, PhD, senior author of the paper. "Our hope is that our data will enable those working on pre-clinical studies to essentially model experiments virtually, in order to provide a starting point for testing other interventions in mice."

Benzoxazole, the compound that slowed bone aging by up to 31% over the course of a year's treatment in the mice, was first identified as one of five compounds that extended nematode lifespan in the Lithgow lab in a study that appeared in Nature in 2011. "If you have a therapeutic that extends lifespan in a simple animal that has no bone whatsoever, you certainly wouldn't predict that it would slow the rate of bone aging in a mammal," said Gordon Lithgow, PhD, Buck professor and Vice President. "It's obvious that aging-related pathways have been conserved during evolution. This new finding is a great example of the utility of screening compounds in simple animals as the starting point to look for unexpected and surprising benefits in mammals." In the Nature article, benzoxazole appeared to suppress age-related protein aggregation. The mechanism of action in mouse bone is still under study, although researchers say the compound appears to slow the reabsorption of osteoclasts, bone cells that are active during growth and healing.

Melov says the findings in the large study are relevant to humans, especially in regards to pre-clinical phenotypes. "The metrics we used are all directly applicable to aging in humans. They literally have direct clinical correlates to the types of things you would measure in humans." For example, for the first time researchers witnessed spontaneous fractures in aging mouse femurs. Melov says they occurred in 2.5% of the mouse population, not dissimilar to the 1 -2.7% incidence of hip fractures in people over the age of 65. He also notes that they developed a new unbiased method for evaluating kyphosis, an age-related curvature of the spine, and may pave the way for testing new interventions.

"We think using this new database could save substantial resources for those wanting to do pre-clinical studies of interventions," said Melov. "If someone wants to test a compound against a particular aging phenotype this database could provide information about how many mice are needed for the experiments and how long it would likely take to see results."

A research team from the CHUM Research Centre (CRCHUM) has shown that women who have had serious complications during pregnancy are twice as likely to die up to three decades later.

Serious conditions such as stroke, cardiac complications, acute kidney failure and pre-eclampsia affect just under 5 % of women during pregnancy and childbirth.

In a study published in Obstetrics & Gynecology, CRCHUM researcher Dr. Nathalie Auger and postdoctoral fellow Ugochinyere Vivian Ukah examined the long-term mortality risks of women with these types of pregnancy complications by analyzing more than 1.2 million records of women who gave birth in Quebec between 1989 and 2016.

Their findings? Compared to women who had no serious pregnancy complications, women in the study were twice as likely to die after childbirth, either in the postpartum period (42 days and less) or afterwards. Although there was a decline over time, the greater risk of death was still felt several years after delivery, with death occurring an average of 8.3 years earlier for women with severe pregnancy complications compared with no complications.

The research team was also able to identify the main causes of mortality after 42 days: serious cardiac complications during pregnancy (7 times more likely to die), acute renal failure (4 times more likely), and strokes (4 times more likely).

From a clinical point of view, closer follow-up and preventive interventions to reduce the risk of premature mortality could be justified for women with severe pregnancy complications.

In 2012, four-year-old Bertrand Might became the first-ever patient diagnosed with a rare genetic disorder called N-glycanase (NGLY1) deficiency. The discovery of this condition and Bertrand's diagnosis allowed doctors to look for other children with the same genetic defect. Since then, more than 60 additional patients have been found. The disease affects every system of the body and is characterized by low muscle tone, seizures, developmental delays, and an inability to produce tears.

Sadly, Bertrand passed away in October at the age of 12. Although his life was cut short, his legacy will benefit children around the world. Through their website, NGLY1.org, Bertrand's parents collect and share a wealth of research and family stories to help educate and inform the community. As more patients have been identified, it's become apparent that even though the same gene is deactivated in all of them, their symptoms and severity of disease vary widely.

Geneticist Clement Chow, Ph.D., assistant professor in the Department of Human Genetics at University of Utah Health, studies NGLY1 deficiency in the fruit fly, Drosophila melanogaster. To understand how the disease symptoms can vary so much, he and his colleagues are hunting for other genes that interact with NGLY1. In a paper published in eLife, Chow reports that his lab has found that one of these interacting genes moderates disease severity. The gene, called ncc69, has a human counterpart called NKCC1. Their experiments showed that NGLY1 chemically modifies NKCC1. Studying this interaction could help illuminate how NGLY1 deficiency affects the body.

Common diseases, such as heart disease or cancer, arise from a combination of many genetic and environmental causes, while rare diseases are more likely caused by a single gene. But every single-gene disease occurs against the individual patient's unique genetic backdrop, a patchwork of different genetic variants inherited from both parents. Children with NGLY1 deficiency start experiencing serious symptoms early in life, suggesting that environmental differences, such as diet, aren't a key factor. More likely, differences in their other genes are influencing the clinical course of the disease.

To search for genes that work together with NGLY1, the researchers needed to use flies with varied genetic backgrounds. Laboratory flies, however, are inbred to be genetically identical. To approximate the natural genetic diversity found in humans, Chow turned to a resource called the Drosophila Genetic Reference Panel. It's a collection of 200 different fruit fly lines, all bred from the same original population--but each one is just a bit different from the others.

"It's like if you sampled 200 Northern Europeans," Chow says. "They'd share lots of genetic variants, but lots of differences as well."

In each strain of flies, Chow and his research team swapped in a non-working copy of the NGLY1 gene, then looked for differences in survival. Strikingly, the flies' genetic background heavily influenced how long the young flies could survive without NGLY1.

"These flies all carry the same disease mutation that's supposed to cause the same disease," Chow says. "Yet here we're seeing that, in some genetic backgrounds, they can't live at all with NGLY1 deficiency. And in some genetic backgrounds, all the flies survived to adulthood."

The researchers analyzed the genes that varied among the flies that survived and those that died, coming up with a list of candidate genes that could be playing a role. They began studying one of these candidates, NKCC1, and soon switched from flies to mice.

"When we hit a wall in what we could do with flies, we decided to turn to the mouse model to try to fully characterize what NKCC1 and NGLY1 are doing to interact with each other," Chow says.

In cells from mice, the researchers discovered that the NKCC1 protein assumes its correct shape through glycosylation, a chemical process that tacks sugar molecules onto the protein. NGLY1 acts to remove these sugar molecules from specific targets.

In the absence of NGLY1, Chow found, NKCC1 was overloaded with extra sugars, reducing activity in the cell by 50%. Without NGLY1, NKCC1 can't do its job properly, which is to move fluids and ions out of the cell.

While application to human disease is still a long way off, the role of NKCC1 makes sense in terms of the symptoms seen in NGLY1 patients. One of the hallmark features of NGLY1 deficiency is the inability to make tears, sweat, and saliva. It turns out that patients who lack NKCC1 also have this symptom. NKCC1 is active in salivary glands, sweat glands, and tear ducts, which supports the idea that the molecule plays a role in causing the symptoms.

"This was all discovered through a genetic screen in Drosophila," Chow says. "This really speaks to the power of using simpler model organisms, especially for rare diseases, where you want to get results faster."